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The Leprosy, 2000 years later / Chapter I

La Lepra, 2.000 anos despues. / Capitulo I

The Leprosy 2000 year...Chapter II  Bibliographic refrences !!!

Data-Medicos
Dermagic/Express No. 2-(87)
26 Enero 2.000 26 January 2.000

~La Lepra, 2.000 años despues ~
~ The Leprosy, 2.000 years later ~


EDITORIAL ESPANOL
=================
Hola amigos de la red, DERMAGIC hoy con el tema de la ENFERMEDAD DE
HANSEN
(LEPRA)2.000 AÑOS DESPUES. Realmente esta enfermedad tiene mas de 2.000
años de evolucion en nuestro planeta pues las primeras descripciones de la
enfermedad
datan del siglo XVI antes de Cristo, encontrandose las primeras referencias
en el libro
sagrado de la antigua India.

Muchos años han pasado y muchas investigaciones se han hecho, enfermedad de
dificil
tratamiento, ancestral y de distribucion mundial que figura en la Biblia
lo cual le da ese
toque apocaliptico a esta temida enfermedad, causa de discriminacion social
aun en
nuestros dias.

Fue Armauer Hansen quien descubrio el bacilo que lleva su nombre en el año
de 1873, y
desde ese momento no han parado las investigaciones sobre esta enfermedad.

Desde el aceite de Chalmoogra introducido por el egipcio Tortoulis Bey en
1894 para
tratar la enfermedad hasta la fabricacion de diferentes vacunas que estan
siendo utilizadas
hoy dia, pasaron muchos años.

En estas 80 referencias bibliograficas se resumen muchos de los nuevos
avances en el
campo de la enfermedad, nuevas terapias, pero la enfermedad sigue "viva".

varios de los aspectos a resaltar son:

1.) La resistencia a la MTD con los nuevos ESQUEMAS ordenados por la
organizacion
mundial de la salud (OMS), la cual acorto el tiempo del tratamiento. gran
error.

2.) La comprobacion de que antibioticos como la OFLOXACINA, MINOCICLINA,
ACIDO CLAVULANICO mas AMOXACILINA) Y CLARITROMICINA son
altamente
bactericidas contra el Mycobacterium leprae.

3.) La comprobacion de la resistencia al tratamiento con
Diaminodifenilsulfona.

4.) El exito de la Talidomida para tratar el ERITEMA NODOSO LEPROSO, que
motivo su comercializacion OTRA VEZ EN LOS ESTADOS UNIDOS DE
NORTEMERICA
desde 1.998

5.) La aparicion de la inmunoquimioterapia como alternativa de tratamiento
tales como:
inmunoquimioterapia con interferon-gamma y terapia multiple (MTD),
ANTIBIOTICOS
y terapia multiple, vacunas y MTD.

6.) La utilizacion de Antileukotrienos como el ZAFIRLUKAST para tratar la
reaccion
leprosa.

7.) La aparicion de nuevas tecnicas diagnosticas (PCR) para observar el
comportamiento y pronostico de la enfermedad, que ayudan a las viejas tales
como
Mitsuda, Reaccion de Fernandez y CCB test.

8.) La comprobacion de una susceptibilidad genetica determinada por
losantigenos de
Histocompatibilidad (HLA) para adquirir o resistir la enfermedad.

9.) El exito en reproducir la enfermedad en animales.

10.) El comprobado efecto protectivo de bacilo de Calmette Guerin (BCG)
contra la
lepra.

11.) La aparicion de nuevas drogas con actividad antimicobacterial como las
RIMINOFENAZINAS.

12.) La nueva vacuna inmunoterapeutica para la lepra basada en el
Micobacterium w
(nombre codigo bajo el cual estas especies son investigadas) DESARROLLADA EN
LA INDIA.

13.) El talisman perdido: catastrofica declinacion en la utilizacion de
bacilos provenientes
de armadillos para la produccion de vacunas. (referencia 62)

14.) La Preservacion del Micobacterium leprae in vitro por 4 años por
liofilizacion.

15.) Todavia en nuestros dias el contacto con pacientes es el mayor
determinante en la
incidencia de lepra.

16.) La persistencia de la enfermedad en muchas areas de nuestro mundo.

17.) El bichito (bacilo) todavia no ha sido cultivado. Es un parasito
intracelular
obligatorio.

18.) La enfermedad no se trasmite con el embarazo, aun asi ha sido
descrita en niños
menores de 2 meses de edad. (ver attach y referencia 80)

Por ello y mucho mas, la lepra seguira siendo la lepra ...


Saludos a todos !!!

Dr. Jose Lapenta R.,,,

EDITORIAL ENGLISH
=================
Hello friends of the net, DERMAGIC today with the topic of the HANSEN'S
DISEASE
(LEPROSY) 2.000 YEARS LATER. This illness really has but of 2.000 years of
evolution in our planet the first descriptions of the illness date of the
XVI century before
Christ, being the first references in the sacred book of the old India.

Many years have passed and many investigations have been made, illness of
difficult
treatment,
ancestral and of world distribution that figures in the Bible that which
gives that
apocalyptic touch to this feared illness, cause of social discrimination
even in our days.

Armauer Hansen who discovered the bacillus that takes its name in the year
of 1873, was
and from that moment they have not stopped the investigations on this
illness.

From the oil of Chalmoogra introduced by the Egyptian Tortoulis Bey in 1894
to treat the
illness until the production of different VACCINES that are being used
nowadays, many
years passed.

In these 80 bibliographical references summary many of the new advances in
the field of
the illness, new therapies, but the illness continues "alive".
several of the aspects to stand out are:

1.) The resistance to the MTD with the new OUTLINES ordered by the world
organization of the health(WHO), which I shorten the time of the treatment,
great error.

2.) The confirmation that antibiotics as the OFLOXACIN, MINOCICLINE,
CLAVULANIC ACID plus AMOXICILIIN) AND CLARITHROMYCIN are highly
germicides against the Mycobacterium leprae.

3.) The confirmation of the resistance to the treatment with
Diaminodiphenylsulfone.

4.) The success of the Thalidomide to treat the ERYTHEMA NODOSUM LEPROSUM
(ENL) that I motivate their commercialization ANOTHER TIME IN U.S.A. since
1.998.

5.) The appearance of the Immunochemotherapy therapy like treatment
alternative,
example: interferon-gamma and multidrug therapy. (MTD), ANTIBIOTIC and
multidrug
THERAPY, vaccines and (MTD),


6.) The use of new drugs (Antileukotriene) like the ZAFIRLUKAST to treat
the leprous
reaction.

7.) The appearance of new diagnoses techniques (PCR) to observe the
behavior and I
predict of the illness, that help the old ones like mitsuda, Fernandez
Reaction, CCB test.

8.) The confirmation of a genetic susceptibility determined by the HLA
antigens to acquire
or to resist the illness.

9.) The success in reproducing the illness in animals.

10.) The proven Protective effect of Bacillus Calmette Guerin (BCG) against
leprosy.

11.) The appearance of new drugs with Antimycobacterial activities like the
RIMINOPHENAZINES.

12.) The new immunotherapeutic vaccine for the leprosy. based on
Mycobacterium w
(the code word under which this species hitherto unspecified was
investigated)
DEVELOPED IN THE INDIAN.

13.) A lost talisman: catastrophic decline in yields of leprosy bacilli
from armadillos used
for vaccine production. (reference 62)

14.) The Preservation of Mycobacterium leprae in vitro for four years by
lyophilization.

15.) Still in our days Patient contact is the major determinant in incident
leprosy.

16.) The persistence of the illness in many areas of our world.

17.) The bug (bacillus) it has not still been cultivated. Mycobacterium
leprae is an obligate
intracellular parasite.

18.) The illness is not transmitted with the pregnancy, even so it has been
described in
children less than 2 months of age. (See attach and reference 80)


For it and a lot but, the leprosy will continue being the leprosy...

Greetings to ALL, !!
Dr. Jose Lapenta R.,,,
===================================================================
REFERENCIAS BIBLIOGRAFICAS / BIBLIOGRAPHICAL REFERENCES
===================================================================
1.) A 21-kDa surface protein of Mycobacterium leprae binds peripheral nerve
laminin-2
and mediates Schwann cell invasion.
2.) Localization of Mycobacterium leprae to endothelial cells of epineurial
and perineurial
blood vessels and lymphatics.
3.) Delayed-type hypersensitivity to Mycobacterium leprae soluble antigens
as a test for
infection with the leprosy bacillus.
4.) Detection of M. leprae by gene amplification; combined ethidium-bromide
staining and
probe hybridization.
5.) In vitro and in vivo activity of K-130, a dihydrofolate reductase
inhibitor, against
Mycobacterium leprae.
6.) Secreted proteins of Mycobacterium leprae.
7.) In vitro studies on extracellular matrix production by M.leprae
infected murine
neurofibroblasts.
8.) Opposite effects of M. leprae or M. bovis BCG delipidation on cellular
accumulation
into mouse pleural cavity. Distinct accomplishment of mycobacterial lipids
in vivo.
9.) Role of alpha-dystroglycan as a Schwann cell receptor for Mycobacterium
leprae [see
comments]
10.) Human T cell recognition of the Mycobacterium leprae LSR antigen:
epitopes and
HLA restriction.
11.) A Mycobacterium leprae-specific human T cell epitope cross-reactive
with an
HLA-DR2 peptide.
12.) Association of HLA antigens with differential responsiveness to
Mycobacterium w
vaccine in multibacillary leprosy patients.
13.) HLA antigens and neural reversal reactions in Ethiopian borderline
tuberculoid
leprosy patients.
14.) Evidence for an HLA-DR4-associated immune-response gene for
Mycobacterium
tuberculosis. A clue to the pathogenesis of rheumatoid arthritis?
15.) Species-specific identification of Mycobacterium leprae by
PCR-restriction fragment
length polymorphism analysis of the hsp65 gene.
16.) Use of a whole blood assay to evaluate in vitro T cell responses to
new leprosy skin
test antigens in leprosy patients and healthy subjects.
17.) Relapse of leprosy after multidrug therapy.
18.) Leprosy resistant to multi-drug-therapy (MDT) successfully treated with
ampicillin-sulbactam combination--(a case report).
19.) Specificity and function of immunogenic peptides from the
35-kilodalton protein of
Mycobacterium leprae.
20.) [Morphological features to be considered as the growth of
Mycobacterium leprae
Thai-53 strain on a silicon coated slide in a cell-free liquid medium]
21.) Leprosy patients with lepromatous disease recognize cross-reactive T
cell epitopes
in the Mycobacterium leprae 10-kD antigen.
22.) Diaminodiphenylsulfone resistance of Mycobacterium leprae due to
mutations in the
dihydropteroate synthase gene.
23.) In vitro activity of epiroprim, a dihydrofolate reductase inhibitor,
singly and in
combination with brodimoprim and dapsone, against Mycobacterium leprae.
24.) Lymphoproliferative responses of leprosy patients and healthy controls
to
nitrocellulose-bound M. leprae antigens.
25.) Dominant recognition of a cross-reactive B-cell epitope in
Mycobacterium leprae 10
K antigen by immunoglobulin G1 antibodies across the disease spectrum in
leprosy.
26.) Immune responses to recombinant proteins of Mycobacterium leprae.
27.) Causative organism and host response. International Leprosy Congress,
28.) Immunohistological analysis of in situ expression of mycobacterial
antigensin skin
lesions of leprosy patients across the histopathological spectrum.
Association of
Mycobacterial lipoarabinomannan (LAM) and Mycobacterium leprae phenolic
glycolipid-I (PGL-I) with leprosy reactions.
29.) IL-18 promotes type 1 cytokine production from NK cells and T cells in
human
intracellular infection.
30.) Identification of M.leprae in conjunctiva of leprosy patients using
the superior tarsal
conjunctiva scrape technique.
31.) [Present situation of leprosy in highly endemic area of tropical Asia--a
seroepidemiological study of Mycobacterium leprae infection in general
inhabitants]
32.) Anti M. leprae IgM antibody determination by ultramicroimmunoenzymatic
(UMELISA HANSEN) for the diagnosis and monitoring leprosy.
33.) Opposite cellular accumulation and nitric oxide production in vivo
after pleural
immunization with M. leprae or M. bovis BCG.
34.) Use of a whole blood assay to monitor the immune response to
mycobacterial
antigens in leprosy patients: a predictor for type 1 reaction onset?
35.) A clinical and bacteriological examination of Mycobacterium leprae in
the epidermis
and cutaneous appendages of patients with multibacillary leprosy.
36.) Quality control tests for vaccines in leprosy vaccine trial, Avadi.
37.) Comparative leprosy vaccine trial in south India.
38.) Evolutionary bottlenecks in the agents of tuberculosis, leprosy, and
paratuberculosis.
39.) Role of S-100 staining in differentiating leprosy from other
granulomatous diseases of
the skin.
40.) Assessment of anti-PGL-I as a prognostic marker of leprosy reaction.
41.) Conjunctival biopsy in patients with leprosy.
42.) Experimental leprosy in rhesus monkeys: transmission, susceptibility,
clinical and
immunological findings.
43.) Lepromatous uveitis diagnosed by iris biopsy.
44.) Preservation of Mycobacterium leprae in vitro for four years by
lyophilization.
45.) Minocycline in lepromatous leprosy.
46.) Efficacy of minocycline in single dose and at 100 mg twice daily for
lepromatous
leprosy.
47.) Field trial on efficacy of supervised monthly dose of 600 mg rifampin,
400 mg ofloxacin and 100 mg minocycline for the treatment of leprosy; first
results.
48.) Bactericidal activity of a single-dose combination of ofloxacin plus
minocycline, with
or without rifampin, against Mycobacterium leprae in mice and in
lepromatous patients.
49.) Efficacy of single dose multidrug therapy for the treatment of
single-lesion
paucibacillary leprosy. Single-lesion Multicentre Trial Group.
50.) Bactericidal activity of single dose of clarithromycin plus
minocycline, with or without
ofloxacin, against Mycobacterium leprae in patients.
51.) WHO Expert Committee on Leprosy.
52.) Experimental evaluation of possible new short-term drug regimens for
treatment of
multibacillary leprosy.
53.) Powerful bactericidal activities of clarithromycin and minocycline
against
Mycobacterium leprae in lepromatous leprosy.
54.) Differential protective effect of bacillus calmette-guerin vaccine
against multibacillary
and paucibacillary leprosy in nagpur, india.
55.) An immunotherapeutic vaccine for multibacillary leprosy.
56.) Protective effect of Bacillus Calmette Guerin (BCG) against leprosy: a
population-based case-control study in Nagpur, India.
57.) The antigen 85 complex vaccine against experimental Mycobacterium leprae
infection in mice.
58.) Induction of lepromin positivity following immuno-chemotherapy with
Mycobacterium w vaccine and multidrug therapy and its impact on
bacteriological
clearance in multibacillary leprosy: report on a hospital-based clinical
trial with the
candidate antileprosy vaccine.
59.) Disabilities in multibacillary leprosy following multidrug therapy
with and without
immunotherapy with Mycobacterium w antileprosy vaccine.
60.) SIMLEP: a simulation model for leprosy transmission and control.
61.) Antigenic definition of plasma membrane proteins of Bacillus
Calmette-Guerin:
predominant activation of human T cells by low-molecular-mass integral
proteins.
62.) A lost talisman: catastrophic decline in yields of leprosy bacilli
from armadillos used
for vaccine production.
63.) HLA-DRB1 leprogenic motifs in nigerian population groups.
64.) Testing candidate genes that may affect susceptibility to leprosy.
65.) [Leprosy, an "exemplary" humanitarian disease]?
66.) Prediction of elimination of leprosy in leprosy endemic areas of China.
67.)[Global leprosy, current status and a future outlook].
68.) Lot quality assurance sampling (LQAS) for monitoring a leprosy
elimination
program.
69.) Patient contact is the major determinant in incident leprosy:
implications for future
control.
70.) A continuing focus of Hansen's disease in Texas.
71.) An epidemiological study on Mycobacterium leprae infection and
prevalence of
leprosy in endemic villages by molecular biological technique.
72.) Antimycobacterial activities of riminophenazines.
73.) Nasal mucosa and skin of smear-positive leprosy patients after 24
months of fixed
duration MDT: histopathological and microbiological study.
74.) Resolution of lepromatous leprosy after a short course of
amoxicillin/clavulanic acid,
followed by ofloxacin and clofazimine.
75.) Effect of zafirlukast on leprosy reactions.
76.) Immunochemotherapy with interferon-gamma and multidrug therapy for
multibacillary
leprosy.
77.) Thalidomide's effectiveness in erythema nodosum leprosum is associated
with a
decrease in CD4+ cells in the peripheral blood.
78.) La lepra, Evolucion Historia, epidemiologica y medidas de control.
79.) Leprosy in infants.
80.) Leprosy in a child of less than two months of age.
============================================================
============================================================
1.) A 21-kDa surface protein of Mycobacterium leprae binds peripheral nerve
laminin-2 and mediates Schwann cell invasion.
============================================================
Author
Shimoji Y; Ng V; Matsumura K; Fischetti VA; Rambukkana A
Address
Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller
University, New York, NY 10021, USA.
Source
Proc Natl Acad Sci U S A, 96(17):9857-62 1999 Aug 17
Abstract
Nerve damage is the hallmark of Mycobacterium leprae infection, which
results from M. leprae invasion of the Schwann cell of the peripheral
nervous system. We have recently shown that the laminin-2 isoform,
specially the G domain of laminin alpha2 chain, on the Schwann cell-axon
unit serves as an initial neural target for M. leprae. However, M. leprae
surface molecules that mediate bacterial invasion of peripheral nerves are
entirely unknown. By using human alpha2 laminins as a probe, a major 28-kDa
protein in the M. leprae cell wall fraction that binds alpha2 laminins was
identified. After N-terminal amino acid sequence analysis, PCR-based
strategy was used to clone the gene that encodes this protein. Deduced
amino acid sequence of this M. leprae laminin-binding protein predicts a
21-kDa molecule (ML-LBP21), which is smaller than the observed molecular
size in SDS/PAGE. Immunofluorescence and immunoelectron microscopy on
intact M. leprae with mAbs against recombinant (r) ML-LBP21 revealed that
the protein is surface exposed. rML-LBP21 avidly bound to alpha2 laminins,
the rG domain of the laminin-alpha2 chain, and the native peripheral nerve
laminin-2. The role of ML-LBP21 in Schwann cell adhesion and invasion was
investigated by using fluorescent polystyrene beads coated with rML-LBP21.
Although beads coated with rML-LBP21 alone specifically adhered to and were
ingested by primary Schwann cells, these functions were significantly
enhanced when beads were preincubated with exogenous alpha2 laminins. Taken
together, the present data suggest that ML-LBP21 may function as a critical
surface adhesin that facilitates the entry of M. leprae into Schwann cells.

============================================================
2.) Localization of Mycobacterium leprae to endothelial cells of epineurial
and perineurial blood vessels and lymphatics.
============================================================
Author
Scollard DM; McCormick G; Allen JL
Address
Department of Research Pathology, G. W. L. Hansen's Disease Center at
Louisiana State University, Baton Rouge, LA, USA. [email protected]
Source
Am J Pathol, 154(5):1611-20 1999 May
Abstract
Infection of peripheral nerve by Mycobacterium leprae, the
histopathological hallmark of leprosy, is a major factor in this disease,
but the route and mechanisms by which bacilli localize to peripheral nerve
are unknown. Experimentally infected armadillos have recently been
recognized as a model of lepromatous neuritis; the major site of early
accumulation of M. leprae is epineurial. To determine the epineurial cells
involved, 1-cm segments of 44 nerves from armadillos were screened for
acid-fast bacilli and thin sections were examined ultrastructurally. Of 596
blocks containing nerve, 36% contained acid-fast bacilli. Overall, M.
leprae were found in endothelial cells in 40% of epineurial blood vessels
and 75% of lymphatics, and in 25% of vessels intraneurally. Comparison of
epineurial and endoneurial findings suggested that colonization of
epineurial vessels preceded endoneurial infection. Such colonization of
epineurial nutrient vessels may greatly increase the risk of endoneurial M.
leprae bacteremia, and also enhance the risk of ischemia following even
mild increases in inflammation or mechanical stress. These findings also
raise the possibility that early, specific mechanisms in the localization
of M. leprae to peripheral nerve may involve adhesion events between M.
leprae (or M. leprae-parasitized macrophages) and the endothelial cells of
the vasa nervorum.

============================================================
3.) Delayed-type hypersensitivity to Mycobacterium leprae soluble antigens
as a test for infection with the leprosy bacillus.
============================================================
Author
Sterne JA; Fine PE; P¨onnighaus JM; Rees RJ; Chavula D
Address
Department of Public Health Medicine, United Medical and Dental Schools of
Guy's and St Thomas's Hospitals, London, UK.
Source
Int J Epidemiol, 27(4):713-21 1998 Aug
Abstract
BACKGROUND: Mycobacterium leprae (M. leprae) soluble antigen (MLSA)
reagents have been developed with the aim of finding a reagent, comparable
to tuberculin, which could identify individuals infected with the leprosy
bacillus. They have yet to be evaluated fully in human populations.
METHODS: More than 15000 individuals living in a leprosy endemic area of
northern Malawi were skin tested with one of five batches of MLSA prepared
using two different protocols. The main difference in preparation was the
introduction of a high G centrifugation step in the preparation of the last
three ('second-generation') batches. RESULTS: The prevalence of skin-test
positivity (delayed-type hypersensitivity (DTH)) and association with the
presence of a BCG scar were greater for first (batches A6, A22) than second
(batches AB53, CD5, CD19) generation reagents. The association of
positivity with M. leprae infection was investigated by comparing results
among known (household) contacts of leprosy cases, and among newly
diagnosed leprosy patients with those in the general population. While
positivity to 'first-generation' antigens appeared to be associated with M.
leprae infection, positivity to later antigens was unrelated either to
exposure to leprosy cases or presence of leprosy disease. There were
geographical differences in the prevalence of DTH to the various batches,
probably reflecting exposure to various mycobacteria in the environment.
CONCLUSIONS: Our results suggest that the 'second-generation' batches have
lost antigens that can detect M. leprae infections, but that they retain
one or more antigens which are shared between M. leprae and environmental
mycobacteria. Natural exposure to these both sensitizes individuals and
provides natural protection against M. leprae infection or disease.
Identification of antigens present in these groups of skin test reagents
may assist in production of improved skin test reagents.

============================================================
4.) Detection of M. leprae by gene amplification; combined ethidium-bromide
staining and probe hybridization.
============================================================
Sharma RK; Katoch K; Shivannavar CT; Sharma VD; Natrajan M; Bhatia AS;
Saxena N;
Katoch VM
Central JALMA Institute for Leprosy (ICMR), Taj Ganj, Agra, India.
Int J Lepr Other Mycobact Dis (UNITED STATES) Dec 1996 64 (4) p409-16
ISSN:
0148-916X
Language: ENGLISH
Document Type: JOURNAL ARTICLE
Journal Announcement: 9705
Subfile: INDEX MEDICUS
Biopsy and skin-scraping specimens from 130 leprosy cases across the
disease spectrum (56 TT/BT/I, 73 BB/BL/LL, and 1 neuritic case) and 50
healthy contacts were studied to assess the application of gene
amplification. The nucleic acids from these clinical specimens were
extracted by an integrated freeze-thawing-optimized lysozyme-/proteinase-k
treatment-purification and fractionation procedure. The nucleic acids from
cultured organisms were isolated by the stepwise procedure earlier
standardized at this laboratory. Gene amplification for a 360-bp fragment
of the 18-kDa protein gene was carried out using primer and the procedure
described by its developers, and a 360-bp fragment on Southern blot was
taken as the yardstick of positivity. The polymerase chain reaction
product was analyzed by electrophoresis, ethidium-bromide (EB) staining,
and blot (B) hybridization. Overall sensitivity ranged from 71% in
specimens with undetectable acid-fast organisms to 100% in specimens with
demonstrable acid-fast bacilli. A positivity of 73% in TT/BT/I specimens
and 93% in BB/BL/LL specimens was observed. Four combinations were
discerned: EB+, B+ (71%); EB-suspicious, B+ (14%); EB-, B+ (3%) and EB-, B-
(12%). By combining the blot hybridization with EB staining, the
sensitivity could be
significantly improved as compared to EB staining alone. The test was
found to be absolutely specific by the absence of any false positivity in
control specimens as well as with purified DNAs from mycobacterial as well
as non-mycobacterial organisms, grown from these specimens. It is
recommended that for optimum sensitivity and specificity both EB staining
and blot hybridization should be done.

============================================================
5.) In vitro and in vivo activity of K-130, a dihydrofolate reductase
inhibitor, against Mycobacterium leprae.
============================================================
Author
Dhople AM
Address
Florida Institute of Technology, Department of Biological Sciences,
Melbourne, USA.
Source
Arzneimittelforschung, 49(3):267-71 1999 Mar
Abstract
The antimicrobial effects of a new dihydrofolate reductase inhibitor, K-130
(2,4-diaminodiphenyl sulfone substituted 2,4-diamino-5-benzylpyrimidine),
alone and in combination with dapsone (CAS 80-08-0) against both
dapsone-sensitive and dapsone-resistant strains of Mycobacterium leprae
were evaluated in vitro, in cell-free culture system, and in vivo, in mouse
foot pads. The minimal inhibitory concentration of K-130 against
dapsone-sensitive as well as dapsone resistant strains of M, leprae was
0.03 microgram/ml, and the activity was bactericidal in both cases.
However, when combined with dapsone, K-130 exhibited synergism in case of
dapsone-sensitive M. leprae, while in case of dapsone-resistant M. leprae,
the effect was merely additive. Similar synergistic effects were also
observed in the mouse foot pad system for both types of M. leprae strains.

============================================================
6.) Secreted proteins of Mycobacterium leprae.
============================================================
Author
Harboe M; Wiker HG
Address
Institute of Immunology and Rheumatology, University of Oslo, Norway.
Source
Scand J Immunol, 48(6):577-84 1998 Dec
Abstract
In mycobacteria, secreted proteins represent a distinct group, probably of
particular importance for development of immune responses following
infection. Quantification of individual proteins in culture fluid and
corresponding disrupted bacilli permits determination of a localization
index for identification of secreted proteins. This procedure cannot be
applied to Mycobacterium leprae because secreted proteins are lost during
isolation of bacilli from tissues. The DNA sequences of secreted proteins
of Mycobacterium tuberculosis were compared with sequences of M. leprae.
Genes for homologues of the 85a, 85b, 85c, mpt32 (apa), mpt51, erp, mtc28,
Rv2376c, Rv3354 and Rv0526 genes were identified. All of these contain
signal sequences typical for secretion in M. leprae. In several instances
the local distance between marker genes and occurrence on the same or the
complementary DNA strand was similar in these two species. The genomic
organisation of genes for secreted proteins is thus very similar in M.
leprae and M. tuberculosis, the homology being higher for the mature
polypeptide chains than for the corresponding signal peptides.

============================================================
7.) In vitro studies on extracellular matrix production by M.leprae
infected murine neurofibroblasts.
============================================================
Author
Singh N; Birdi TJ; Chandrashekar S; Antia NH
Address
Foundation for Medical Research, R.G. Thadani Marg, Bombay, India.
Source
Lepr Rev, 69(3):246-56 1998 Sep
Abstract
Fibroblasts and a host of macrophage secretory products have been
implicated in a number of diseases where excess extracellular matrix (ECM)
deposition is the main pathological feature. Fibrosis characterized by
excessive deposition of collagen also contributes to the irreversible nerve
damage observed in leprosy. Since M. leprae are seen within
neurofibroblasts (Nf) in the advanced stages of the disease and macrophages
form a common infiltrating cellular constituent of leprous nerves at all
stages, secretion of ECM proteins by Nf was studied, in vitro following
infection with M. leprae and in the presence of macrophage secretory
products. These studies were compared in cells derived from two strains of
mice, Swiss White (SW) and C57BL/6, as they differ in their response to M.
leprae infection and parallel those observed in lepromatous and tuberculoid
patients, respectively. On infection with M. leprae, Nfs showed a decrease
in secretion of collagen type IV in SW and type I in C57Bl/6 strain.
Macrophages caused a further decrease in the secretion of collagen types
affected by M. leprae infection per se, while the other collagen types,
viz. I and III in SW strain and III and IV in C57Bl/s strain, were
unaffected. This study indicates that neural collagenization in nerves in
advanced leprosy may be of Nf origin. However, unlike other diseases with
excess collagen deposition, ECM proteins produced by Nfs in response to
nerve damage may not be of prime importance in the progression of leprous
neuropathy and occur as a general response to loss of cellular content in
leprous nerves.

============================================================
8.) Opposite effects of M. leprae or M. bovis BCG delipidation on cellular
accumulation into mouse pleural cavity. Distinct accomplishment of
mycobacterial lipids in vivo.
============================================================
Author
Moura AC; Leonardo PS; Henriques MG; Cordeiro RS
Address
Departmento de Biologia Celular e Gen´etica, Instituto de Biologia,
Universidade do Rio de Janeiro, Brazil. [email protected]
Source
Inflamm Res, 48(6):308-13 1999 Jun
Abstract
OBJECTIVES AND DESIGN: The effect of mycobacterial lipids on the onset of
the early acute inflammatory response in BALB/c mice pleurisy was
investigated. MATERIALS AND METHODS: Intact Mycobacterium leprae and
Mycobacterium bovis BCG (BCG), their lipids, and delipidated mycobacteria
were used to evaluate total leukocytes and cell types migrated to the
pleural cavity (8 animals/experimental group). RESULTS: BCG Moreau
(x10(-6)/cavity), delipidated BCG and its lipids gradually recruited cells
leading to arrival, respectively, of neutrophils (7.8+/-1.9, 4.7+/-0.9,
1.8+/-0.25) followed by mononuclear cells (4.8+/-0.8, 3.7+/-0.7,
2.45+/-0.22) and eosinophils (0.39+/-0.08, 0.32+/-0.11, 0.41+/-0.65). BCG
delipidation decreased the number of migrated total leukocytes (ANOVA, and
Newman-Keuls-Student-test), whereas M. leprae delipidation accumulated
neutrophils (0.85+/-0.01) and eosinophils (1.65+/-0.18). CONCLUSIONS:
Intact M. leprae and its lipids did not incite any cell recruitment. Apolar
external cell wall lipids from M. leprae and BCG induce different cellular
responses. They seem to have a crucial importance at the first contact of
mycobacteria with the host cell, modulating the influx of
neutrophils/macrophages in the early (4/24 h) onset of the inflammatory
reaction.

============================================================
9.) Role of alpha-dystroglycan as a Schwann cell receptor for Mycobacterium
leprae [see comments]
============================================================
Author
Rambukkana A; Yamada H; Zanazzi G; Mathus T; Salzer JL; Yurchenco PD;
Campbell KP; Fischetti VA
Address
Laboratory of Bacterial Pathogenesis and Immunology, Rockefeller
University, New York, NY 10021, USA. [email protected]
Source
Science, 282(5396):2076-9 1998 Dec 11
Abstract
alpha-Dystroglycan (alpha-DG) is a component of the dystroglycan complex,
which is involved in early development and morphogenesis and in the
pathogenesis of muscular dystrophies. Here, alpha-DG was shown to serve as
a Schwann cell receptor for Mycobacterium leprae, the causative organism of
leprosy. Mycobacterium leprae specifically bound to alpha-DG only in the
presence of the G domain of the alpha2 chain of laminin-2. Native alpha-DG
competitively inhibited the laminin-2-mediated M. leprae binding to primary
Schwann cells. Thus, M. leprae may use linkage between the extracellular
matrix and cytoskeleton through laminin-2 and alpha-DG for its interaction
with Schwann cells.

============================================================
10.) Human T cell recognition of the Mycobacterium leprae LSR antigen:
epitopes and HLA restriction.
============================================================
Author
Oftung F; Lundin KE; Meloen R; Mustafa AS
Address
Department of Vaccinology, National Institute of Public Health, Oslo,
Norway. [email protected]
Source
FEMS Immunol Med Microbiol, 24(2):151-9 1999 Jun
Abstract
We have in this work mapped epitopes and HLA molecules used in human T cell
recognition of the Mycobacterium leprae LSR protein antigen. HLA typed
healthy subjects immunized with heat killed M. leprae were used as donors
to establish antigen reactive CD4+ T cell lines which were screened for
proliferative responses against overlapping synthetic peptides covering the
C-terminal part of the antigen sequence. By using this approach we were
able to identify two epitope regions represented by peptide 2 (aa 29-40)
and peptide 6 (aa 49-60), of which the former was mapped in detail by
defining the N- and C-terminal amino acid positions necessary for T cell
recognition of the core epitope. MHC restriction analysis showed that
peptide 2 was presented to T cells by allogeneic cells coexpressing HLA-DR4
and DRw53 or DR7 and DRw53. In contrast, peptide 6 was presented to T cells
only in the context of HLA-DR5 molecules. In conclusion, the M. leprae LSR
protein antigen can be recognized by human T cells in the context of
multiple HLA-DR molecules, of which none are reported to be associated with
the susceptibility to develop leprosy. The results obtained are in support
of using the LSR antigen in subunit vaccine design.

============================================================
11.) A Mycobacterium leprae-specific human T cell epitope cross-reactive
with an HLA-DR2 peptide.
============================================================
ARTICLE SOURCE: Science (United States), Oct 14 1988, 242(4876) p259-61
AUTHOR(S): Anderson DC; van Schooten WC; Barry ME; Janson AA; Buchanan
TM;
de Vries RR
PUBLICATION TYPE: JOURNAL ARTICLE
ABSTRACT: Mycobacterium leprae induces T cell reactivity and protective
immunity in the majority of exposed individuals, but the minority that
develop leprosy exhibit various types of immunopathology. Thus, the
definition of epitopes on M. leprae antigens that are recognized by T cells
from different individuals might result in the development of an effective
vaccine against leprosy. A sequence from the 65-kD protein of this organism
was recognized by two HLA-DR2-restricted, M. leprae-specific helper T cell
clones that were derived from a tuberculoid leprosy patient. Synthetic
peptides were used to define this epitope as
Leu-Gln-Ala-Ala-Pro-Ala-Leu-Asp-Lys-Leu. A similar peptide that was derived
from the third hypervariable region of the HLA-DR2 chain,
Glu-Gln-Ala-Arg-Ala-Ala-Val-Asp-Thr-Tyr, also activated the same clones.
The unexpected cross-reactivity of this M. leprae-specific DR2-restricted T
cell epitope with a DR2 peptide may have to be considered in the design of
subunit

============================================================
12.) Association of HLA antigens with differential responsiveness to
Mycobacterium w vaccine in multibacillary leprosy patients.
============================================================
ARTICLE SOURCE: J Clin Immunol (United States), Jan 1992, 12(1) p50-5
AUTHOR(S): Rani R; Zaheer SA; Suresh NR; Walia R; Parida SK; Mukherjee A;
Mukherjee R; Talwar GP
PUBLICATION TYPE: JOURNAL ARTICLE
ABSTRACT: Leprosy patients undergoing phase II trials in two hospitals of
New Delhi, India, were HLA typed to see the association of HLA with
differential responsiveness to Mycobacterium w vaccine. The vaccine
comprises an atypical, nonpathogenic mycobacterium, Mycobacterium w, which
has cross-reactive antigens with M. leprae. Multibacillary patients who are
lepromin negative are vaccinated at an interval of 3 months. Considerable
improvement is evident in the patients in terms of a decline in bacterial
indices and histopathological and immunological upgrading. But all the
patients do not respond to the vaccine in the same manner; some are slow
responders, while others are good responders. HLA-A28 and DQw3 (DQw8 + 9)
were found to be associated with slow responsiveness, while DQw1 and DQw7
were found to be associated with a more rapid responsiveness to the M. w
vaccine. However, these associations were not significant after P
correction for the number of antigens tested for each locus except for
HLA-DQw3 (DQw8 and DQw9) and DQw7. DQw7, a new defined split of
HLA-DQw3,
seems to be associated with the responsiveness to M. w vaccine.

============================================================
13.) HLA antigens and neural reversal reactions in Ethiopian borderline
tuberculoid leprosy patients.
============================================================
ARTICLE SOURCE: Int J Lepr Other Mycobact Dis (United States), Jun 1987,
55(2) p261-6
AUTHOR(S): Ottenhoff TH; Converse PJ; Bjune G; de Vries RR
PUBLICATION TYPE: JOURNAL ARTICLE
ABSTRACT: Reversal reactions (RR) or acute neuritis episodes are
frequently observed in borderline tuberculoid (BT) leprosy patients during
the first year of treatment, and are associated with a rapid increase in
cell-mediated immunity. Because HLA-linked genes have been shown to be an
important factor in determining the type of leprosy that develops in
susceptible individuals and because HLA molecules regulate cellular
interactions in the immune system, we have investigated whether RR are
associated with HLA antigens in Ethiopian patients. The data reported here
indicate that this is not the case: no significant differences in the
distribution of HLA class I and class II antigens were observed among three
groups: 28 BT patients with a history of RR, 27 BT patients with no history
of RR, and 33 healthy individuals. In contrast to these negative results,
we observed that HLA-DR3 was associated with high skin-test responsiveness
against Mycobacterium leprae antigens among RR patients. Since DR3 was not
associated with RR per se, the observed DR3-associated high responsiveness
to M. leprae may not be primarily

============================================================
14.) Evidence for an HLA-DR4-associated immune-response gene for
Mycobacterium
tuberculosis. A clue to the pathogenesis of rheumatoid arthritis?
============================================================
ARTICLE SOURCE: Lancet (England), Aug 9 1986, 2(8502) p310-3
AUTHOR(S): Ottenhoff TH; Torres P; de las Aguas JT; Fernandez R; van Eden
W; de Vries RR; Stanford JL
PUBLICATION TYPE: JOURNAL ARTICLE
ABSTRACT: Antigens of Mycobacterium tuberculosis, M leprae, M
scrofulaceum, and M vaccae were injected intradermally in 86 caucasoid
leprosy patients, and skin responses (measured in mm of induration at 72 h)
were analysed in relation to HLA class II phenotypes. HLA-DR4 was
associated with high responsiveness to antigens specific to M tuberculosis
but not to antigens shared with other mycobacteria (p = 0.0005). Because
DR4 is associated with rheumatoid arthritis (RA) and because a role for M
tuberculosis antigens has been suggested both in experimentally induced
autoimmune arthritis in rats and in RA, the DR4 associated regulation of
the immune response to M tuberculosis may be relevant to the pathogenesis
of RA.

============================================================
15.) Species-specific identification of Mycobacterium leprae by
PCR-restriction
fragment length polymorphism analysis of the hsp65 gene.
============================================================
Author
Rastogi N; Goh KS; Berchel M
Address
Unit´e de la Tuberculose et des Mycobact´eries, Institut Pasteur, 97165
Pointe `a Pitre Cedex, Guadeloupe. [email protected]
Source
J Clin Microbiol, 37(6):2016-9 1999 Jun
Abstract
PCR-restriction fragment length polymorphism analysis (PRA) of the hsp65
gene present in all mycobacteria was used in the present investigation to
characterize Mycobacterium leprae. Bacilli were extracted and purified from
different organs from experimentally infected armadillos and nude mice
(Swiss mice of nu/nu origin). A total of 15 samples were assayed in
duplicate, and the results were compared with those obtained for a total of
147 cultivable mycobacteria representing 34 species. Irrespective of its
origin or viability, M. leprae strains from all the samples were uniformly
characterized by two fragments of 315 and 135 bp upon BstEII digestion and
two fragments of 265 and 130 bp upon HaeIII digestion. PRA is a relatively
simple method and permits the conclusive identification of M. leprae to the
species level.

============================================================
16.) Use of a whole blood assay to evaluate in vitro T cell responses to
new leprosy skin test antigens in leprosy patients and healthy subjects.
============================================================
Author
Weir RE; Brennan PJ; Butlin CR; Dockrell HM
Address
Department of Infectious and Tropical Diseases, London School of Hygiene &
Tropical Medicine, London, UK. [email protected]
Source
Clin Exp Immunol, 116(2):263-9 1999 May
Abstract
Development of an immunological tool to detect infection with Mycobacterium
leprae would greatly benefit leprosy control programmes, as demonstrated by
the contribution of the tuberculin test to tuberculosis control. In a new
approach to develop a 'tuberculin-like' reagent for use in leprosy, two new
fractions of M. leprae depleted of cross-reactive and immunomodulatory
lipids- MLSA-LAM (cytosol-derived) and MLCwA (cell wall-derived)-have been
produced in a form suitable for use as skin test reagents. T cell responses
(interferon-gamma (IFN-gamma) and lymphoproliferation) to these two new
fractions were evaluated in a leprosy-endemic area of Nepal using a simple
in vitro whole blood test. The two fractions were shown to be highly potent
T cell antigens in subjects exposed to M. leprae-paucibacillary leprosy
patients and household contacts. Responses to the fractions decreased
towards the lepromatous pole of leprosy. Endemic control subjects also
showed high responses to the fractions, indicating high exposure to M.
leprae, or cross-reactive mycobacterial antigens, in this Nepali
population. The new fractions, depleted of lipids and lipoarabinomannan
(LAM) gave enhanced responses compared with a standard M. leprae sonicate.
The cell wall fraction appeared a more potent antigen than the cytosol
fraction, which may be due to the predominance of the 65-kD GroEL antigen
in the cell wall. The whole blood assay proved a robust field tool and a
useful way of evaluating such reagents prior to clinical trials.

============================================================
17.) Relapse of leprosy after multidrug therapy.
============================================================
Dasananjali K
Department of Communicable Disease Control, Ministry of Public Health,
Nonthaburi,
Thailand.
J Med Assoc Thai (THAILAND) Oct 1996 79 (10) p635-9 ISSN: 0125-2208
Language: ENGLISH
Document Type: JOURNAL ARTICLE
Journal Announcement: 9704
Subfile: INDEX MEDICUS
Relapse of leprosy after multidrug therapy among leprosy patients treated
at Mahasarakarm, Kalasin and Roi-et from 1984 to 1994 were analyzed.
Twenty PB relapses (45.45%) and twenty four MB relapses (54.55%) were found
among 5,298 originally classified PB patients and 5 MB relapses occurred in
2,624 originally classified MB patients. Mean relapse interval was between
3-4 years. The relapse rate within 10 years after stopping MDT was 0.83
per cent in PB and 0.19 per cent in MB. The estimated relapse rate per
1,000 patient-years was 1.55 for PB and 0.41 for MB respectively.

============================================================
18.) Leprosy resistant to multi-drug-therapy (MDT) successfully treated
with ampicillin-sulbactam combination--(a case report).
============================================================
Mehta VR
L.T.M.M. College, Bombay.
Indian J Med Sci (INDIA) Nov 1996 50 (11) p305-7 ISSN: 0019-5359
Language: ENGLISH
Document Type: JOURNAL ARTICLE
Journal Announcement: 9707
Subfile: INDEX MEDICUS
A 50 year male developed a discoid lesion of leprosy on the face.
Inspite of Dapsone 100 mg/day and Rifampicin 600 mgm per day the disease
spread to both sides of the face and forehead. It became worse with
Prednisolone and Clofazimine. It cleared completely when Sultamicillin was
added to the latter. This seems to be the first patient of leprosy to be
treated with this combination and reported.

============================================================
19.) Specificity and function of immunogenic peptides from the
35-kilodalton protein of Mycobacterium leprae.
============================================================
Author
Wilkinson RJ; Wilkinson KA; Jurcevic S; Hills A; Sinha S; Sengupta U;
Lockwood DN; Katoch K; Altman D; Ivanyi J
Address
MRC Clinical Sciences Center, Imperial College School of Medicine,
Hammersmith Hospital, London W12 0NN, United Kingdom.
Source
Infect Immun, 67(3):1501-4 1999 Mar
Abstract
We identified a T-cell determinant of the 35-kDa antigen of Mycobacterium
leprae which is discriminatory against cross-sensitization by its closely
related homologue in Mycobacterium avium. From synthetic peptides covering
the entire sequence, those with the highest affinity and permissive binding
to purified HLA-DR molecules were evaluated for the stimulation of
proliferation of peripheral blood mononuclear cells (PBMCs) from leprosy
patients and healthy sensitized controls. Responses to the peptide pair
206-224, differing by four residues between M. leprae and M. avium,
involved both species-specific and cross-reactive T cells. Lymph node cell
proliferation in HLA-DRB1*01 transgenic mice was reciprocally species
specific, but only the response to the M. leprae peptide in the context of
DR1 was immunodominant. Of the cytokines in human PBMC cultures, gamma
interferon production was negligible, while interleukin 10 (IL-10)
responses in both patients and controls were more pronounced. IL-10 was
most frequently induced by the shared 241-255 peptide, indicating that
environmental cross-sensitization may skew the response toward a
potentially pathogenic cytokine phenotype.

============================================================
20.) [Morphological features to be considered as the growth of
Mycobacterium leprae Thai-53 strain on a silicon coated slide in a
cell-free liquid medium]
============================================================
Author
Nakamura M; Matsuoka M
Address
Koga Hospital Medical Research Institute, Kurume, Japan.
Source
Nihon Hansenbyo Gakkai Zasshi, 67(2):287-91 1998 Jul
Abstract
Morphological findings of the cells of Mycobacterium leprae Thai-53 strain
smeared on a silicon-coated slide cultured in Kirchner liquid medium pH
7.0, enriched with adenosine, egg yolk, folinic acid, vitamin K3, lecithin,
and N-acetylglucosamine at 30 degrees C were demonstrated. On the basis of
the results with exquisite morphological growth patterns and the increase
in the amount of tempelate DNA prepared from the cultured cells, it is
evident that the cells of M.leprae are capable of multiplication under
cell-free in vitro conditions. The reason why the ATP content did not
increase in parallel with morphological features and the increase in the
DNA is presumably that the multiplication of M.leprae in this culture
system was supported only by consuming the energy derived from the infected
host cells.

============================================================
21.) Leprosy patients with lepromatous disease recognize cross-reactive T
cell epitopes in the Mycobacterium leprae 10-kD antigen.
============================================================
Author
Hussain R; Dockrell HM; Shahid F; Zafar S; Chiang TJ
Address
Department of Microbiology, The Aga Khan University, Karachi, Pakistan.
Source
Clin Exp Immunol, 114(2):204-9 1998 Nov
Abstract
T cell responses play a critical role in determining protective responses
to leprosy. Patients with self-limiting tuberculoid leprosy show high T
cell reactivity, while patients with disseminated lepromatous form of the
disease show absent to low levels of T cell reactivity. Since the T cell
reactivity of lepromatous patients to purified protein derivative (PPD), a
highly cross-reactive antigen, is similar to that of tuberculoid patients,
we queried if lepromatous patients could recognize cross-reactive epitopes
in Mycobacterium leprae antigens as well. T cell responses were analysed to
a recombinant antigen 10-kD (a heat shock cognate protein) which is
available from both M. tuberculosis (MT) and M. leprae (ML) and displays
90% identity in its amino acid sequence. Lymphoproliferative responses were
assessed to ML and MT 10 kD in newly diagnosed leprosy patients
(lepromatous, n = 23; tuberculoid, n = 65). Lepromatous patients showed
similar, but low, lymphoproliferative responses to ML and MT 10 kD, while
tuberculoid patients showed much higher responses to ML 10 kD. This
suggests that the tuberculoid patients may be recognizing both
species-specific and cross-reactive epitopes in ML 10 kD, while lepromatous
patients may be recognizing only cross-reactive epitopes. This was further
supported by linear regression analysis. Lepromatous patients showed a high
concordance in T cell responses between ML and MT 10 kD (r=0.658; P<0.0006)
not observed in tuberculoid patients (r=0.203; P>0.1). Identification of
cross-reactive T cell epitopes in M. leprae which could induce protective
responses should prove valuable in designing second generation
peptide-based vaccines.

============================================================
22.) Diaminodiphenylsulfone resistance of Mycobacterium leprae due to
mutations in the dihydropteroate synthase gene.
============================================================
Author
Kai M; Matsuoka M; Nakata N; Maeda S; Gidoh M; Maeda Y; Hashimoto K;
Kobayashi K; Kashiwabara Y
Address
Leprosy Research Center, National Institute of Infectious Diseases, Tokyo,
Japan. [email protected]
Source
FEMS Microbiol Lett, 177(2):231-5 1999 Aug 15
Abstract
The nucleotide sequence analysis of the dihydropteroate synthase (DHPS)
gene of six diaminodiphenylsulfone-resistant Mycobacterium leprae strains
revealed that the mutation was limited at highly conserved amino acid
residues 53 or 55. Though the mutation at amino acid residue 55 or its
homologous site has been reported in other bacteria, the mutation at
residue 53 is the first case in bacteria. This is the first paper which
links the mutations in DHPS and sulfonamide resistance in M. leprae. This
finding is medically and socially relevant, since leprosy is still a big
problem in certain regions.

============================================================
23.) In vitro activity of epiroprim, a dihydrofolate reductase inhibitor,
singly and in combination with brodimoprim and dapsone, against
Mycobacterium leprae.
============================================================
Author
Dhople AM
Address
Department of Biological Sciences, Florida Institute of Technology,
Melbourne 32901, USA. [email protected]
Source
Int J Antimicrob Agents, 12(4):319-23 1999 Aug
Abstract
The antimicrobial effects of a new dihydrofolate reductase inhibitor,
epiroprim, alone and in combination with dapsone and brodimoprim against
Mycobacterium leprae were evaluated in vitro in cell-free culture system.
Two biochemical parameters were used to measure metabolic activity (and
growth) of the organism. The minimal inhibitory activity of epiroprim
against M. leprae was 10 mg/l and the action was bactericidal. When
combined with dapsone, epiroprim exhibited a strong synergism; on the other
hand, combination of epiroprim and brodimoprim provided only additive
effects. The results suggest that epiroprim can be a component in multidrug
therapy regimen in leprosy.

============================================================
24.) Lymphoproliferative responses of leprosy patients and healthy controls
to nitrocellulose-bound M. leprae antigens.
============================================================
Author
Sachdeva G; Kaur G; Bhutani LK; Bamezai RN
Address
Human Genetics Laboratory, School of Life Sciences, Jawaharlal Nehru
University, New Delhi, India.
Source
Int J Lepr Other Mycobact Dis, 67(2):133-42 1999 Jun
Abstract
The lymphoproliferative responses of 51 leprosy patients and 11 healthy
contacts were analyzed using the nitrocellulose-bound specific antigen
fractions from the cell-free extract of Mycobacterium leprae. The main
proliferation-inducing fraction for peripheral blood mononuclear cells of
the healthy contacts was found to be the Fraction II, bearing antigens in
the range of 66-45 kDa. However, this fraction failed to induce
lymphoproliferation in the leprosy patients, unlike healthy contacts (p <
0.032). The number of responders as well as the strength of the responses
to 66-45 kDa proteins were found to be low in the leprosy patients compared
to the healthy contacts. Further, preliminary analysis with the
subfractions of Fraction II produced a similar pattern, suggesting that the
immune response to the antigens in the range of 66-45 kDa M. leprae
proteins remains suppressed in subjects with clinical signs and symptoms of
the disease.

============================================================
25.) Dominant recognition of a cross-reactive B-cell epitope in
Mycobacterium leprae 10 K antigen by immunoglobulin G1 antibodies across
the disease spectrum in leprosy.
============================================================
Author
Hussain R; Dockrell HM; Chiang TJ
Address
Department of Microbiology, The Aga Khan University. PO Box 3500, Karachi,
Pakistan.
Source
Immunology, 96(4):620-7 1999 Apr
Abstract
Mycobacterium leprae-specific immunoglobulin G1 (IgG1) antibodies in
patients with leprosy show a direct correlation with bacterial load
(rho=0.748; P<0002) suggesting that IgG1 B-cell responses may be surrogate
markers of disease progression. To investigate if this upregulation was a
general feature of IgG1 responses to all M. leprae (ML) antigens, we
analysed responses to several recombinant purified ML heat-shock proteins
(HSP). Three recombinant HSPs (ML10 K, ML 18 K and ML 65 K) were tested for
their ability to induce various IgG subclasses in patients with either the
lepromatous (LL/BL, n=26) or tuberculoid form (BT/TT, n=39) of the disease
as well as in healthy households (HC, n=14) and endemic controls (EC=19).
Our major findings were: (1) selective augmentation of IgG1 antibody
responses to ML10 K; (2) recognition of a restricted number of epitopes
across the disease spectrum and healthy controls by IgG1 antibodies; (3)
dominant recognition of cross-reactive epitopes which were common to both
ML and MT 10 K. This response was not related to contamination with
endotoxin. Epitope mapping using 15-mer overlapping peptides spanning the
ML 10 000 MW revealed an immunodominant IgG1 binding peptide (aa41-55) in
patients as well as healthy controls. This peptide is a shared epitope with
M. tuberculosis 10 K suggesting that postswitched IgG1 B cells recognizing
this epitope rather than naive B cells are being expanded.

============================================================
26.) Immune responses to recombinant proteins of Mycobacterium leprae.
============================================================
Author
Wilkinson KA; Katoch K; Sengupta U; Singh M; Sarin KK; Ivanyi J; Wilkinson RJ
Address
Medical Research Council Clinical Sciences Center, Imperial College of
Science, Technology, and Medicine, Hammersmith Hospital, London, W12 ONN,
United Kingdom. [email protected]
Source
J Infect Dis, 179(4):1034-7 1999 Apr
Abstract
Identification of antigenic determinants of the polar immune response in
leprosy may illuminate both protection and pathogenesis. Thirty subjects
were studied (22 with polar disease and 8 healthy controls who were heavily
exposed but disease-free) by assaying the proliferative, interferon
(IFN)-gamma, and antibody responses to recombinant antigens of
Mycobacterium leprae (10, 28, 36, and 65 kDa). The 10-kDa antigen elicited
IFN-gamma production from all tuberculoid (TT) and borderline tuberculoid
(BT) patients but little from controls, lepromatous (LL), or borderline
lepromatous (BL) patients (P<.05). Production of 65-kDa-specific IFN-gamma
was higher in TT/BT than in controls or LL/BL patients (P<.006). All
subjects produced 65-kDa-specific antibody, but it was higher in LL/BL
patients than in healthy controls, whose responses were higher than in
TT/BT subjects (P=.035). The 36-kDa antibody responses were selectively
increased in LL/BL subjects (P<.02). The intermediate phenotype of the
controls suggests that M. leprae-specific production of IFN-gamma may
contribute to pathology and to protection in leprosy.

============================================================
27.) Causative organism and host response. International Leprosy Congress,
============================================================
Beijing, 7-12 September 1998. Workshop report.
Author
Krahenbuhl JL
Source
Lepr Rev, 70(1):95-102 1999 Mar
Abstract
Whether or not the leprosy elimination target is met in all endemic
countries by the year 2000, the MDT programme will have greatly reduced
worldwide prevalence. However, our workshop chairmen were asked to ignore
the prevalence-based leprosy 'elimination' programme and focus on
recommendations for a long term, incidence-based eradication target where
transmission is blocked. They were asked to be concerned with basic leprosy
research goals in the post 2000 era. The members of our workshops are
actively productive workers, committed to their special interests. They are
fully cognizant of the obstacles faced daily in working with leprosy and M.
leprae, the requirement for clever experimental design even with the
availability of the powerful tools of molecular biology which can now be
brought to bear on some of the research obstacles. They are also aware of
our lack of understanding about leprosy and M. leprae. How do you block
transmission if you don't know how infection is transmitted? Can infection
be detected, diagnosis made earlier? Is there a non-human reservoir host, a
carrier state, an environmental source? What is the basis of M. leprae's
predilection for nerves, the mechanisms underlying reactions? What needs to
be targeted to treat reactions? Can a vaccine play a role? There is nothing
startling in the workshops' recommendations. Other individuals and groups
of experts have made the same suggestions, with slightly varying
priorities. What one can read between the lines of these reports, is a
sense of urgency to get as much done as soon as possible. Worldwide
interest in leprosy will soon be diminished, not by design but as a
consequence of the laudable success of the MDT programme. The experiment is
still underway, but chemotherapy alone, killing bacilli in the detectable
human host, does not appear to be the answer to blocking transmission. A
number of goals must be addressed while there are still intact national and
international leprosy programmes, while there are still leprosy treatment
and research centres that can co-ordinate and facilitate the necessary
trials for early diagnosis, early detection of reactions, evaluation of
immunosuppressive regimens for reactions. A key recommendation is concerned
with the means of measuring progress. A clear and explicit means of
reporting incidence, prevalence and 'case detection' should be implemented
to avoid a distorted picture of worldwide leprosy. These recommendations
are non-controversial. What should be done is clear. The uncertainty is in
determining who will do the work. Who will fund the laboratories engaged in
this work? Look around you. There are fewer scientists attending this
Congress but browsing the abstracts and attending our sessions and posters
clearly revealed to me that fewer of us are doing far better work than in
the past. Alternative sources of funding will help. Tuberculosis research
is enticing researchers away from leprosy in the developed countries but is
visibly sustaining leprosy research in many centres in developing
countries. Formation of alliances was a key goal of this Congress. I asked
my colleagues from Carville to identify in their own discipline, dedicated
people, committed laboratories that will sustain their leprosy research
efforts over the next 5, 10 or more years. These are the people with whom
we wish to collaborate, form alliances, share resources and expertise,
address the future of worldwide leprosy.

============================================================
28.) Immunohistological analysis of in situ expression of mycobacterial
antigensin skin lesions of leprosy patients across the histopathological
spectrum. Association of Mycobacterial lipoarabinomannan (LAM) and
Mycobacterium leprae phenolic glycolipid-I (PGL-I) with leprosy reactions.
============================================================
Author
Verhagen C; Faber W; Klatser P; Buffing A; Naafs B; Das P
Address
Departments of Dermatology, Academic Medical Center, University of
Amsterdam, The Netherlands.
Source
Am J Pathol, 154(6):1793-804 1999 Jun
Abstract
The presence of mycobacterial antigens in leprosy skin lesions was studied
by immunohistological methods using monoclonal antibodies (MAbs) to
Mycobacterium leprae-specific phenolic glycolipid I (PGL-I) and to
cross-reactive mycobacterial antigens of 36 kd, 65 kd, and
lipoarabinomannan (LAM). The staining patterns with MAb to 36 kd and 65 kd
were heterogeneous and were also seen in the lesions of other skin
diseases. The in situ staining of PGL-I and LAM was seen only in leprosy.
Both antigens were abundantly present in infiltrating macrophages in the
lesions of untreated multibacillary (MB) patients, whereas only PGL-I was
occasionally seen in scattered macrophages in untreated paucibacillary
lesions. During treatment, clearance of PGL-I from granulomas in MB lesions
occurred before that of LAM, although the former persisted in scattered
macrophages in some treated patients. This persistence of PGL-I in the
lesions paralleled high serum anti-PGL-I antibody titers but was not
indicative for the presence of viable bacilli in the lesions.
Interestingly, we also observed a differential expression pattern of PGL-I
and LAM in the lesions of MB patients with reactions during the course of
the disease as compared with those without reactions. In conclusion, the in
situ expression pattern of PGL-I and LAM in MB patients may assist in early
diagnosis of reactions versus relapse.

============================================================
29.) IL-18 promotes type 1 cytokine production from NK cells and T cells in
human intracellular infection.
============================================================
Author
Garc´ia VE; Uyemura K; Sieling PA; Ochoa MT; Morita CT; Okamura H; Kurimoto
M; Rea TH; Modlin RL
Address
Division of Dermatology and Department of Microbiology and Immunology,
University of California, Los Angeles, CA 90095, USA.
Source
J Immunol, 162(10):6114-21 1999 May 15
Abstract
We investigated the role of IL-18 in leprosy, a disease characterized by
polar cytokine responses that correlate with clinical disease. In vivo,
IL-18 mRNA expression was higher in lesions from resistant tuberculoid as
compared with susceptible lepromatous patients, and, in vitro, monocytes
produced IL-18 in response to Mycobacterium leprae. rIL-18 augmented M.
leprae-induced IFN-gamma in tuberculoid patients, but not lepromatous
patients, while IL-4 production was not induced by IL-18. Anti-IL-12
partially inhibited M. leprae-induced release of IFN-gamma in the presence
of IL-18, suggesting a combined effect of IL-12 and IL-18 in promoting M.
leprae-specific type 1 responses. IL-18 enhanced M. leprae-induced
IFN-gamma production rapidly (24 h) by NK cells and in a more sustained
manner (5 days) by T cells. Finally, IL-18 directly induced IFN-gamma
production from mycobacteria-reactive T cell clones. These results suggest
that IL-18 induces type 1 cytokine responses in the host defense against
intracellular infection.

============================================================
30.) Identification of M.leprae in conjunctiva of leprosy patients using
the superior tarsal conjunctiva scrape technique.
============================================================
Author
Campos WR; Rodrigues CA; Or´efice F; Monteiro LG
Address
S~ao Geraldo Hospital, Medical School, Federal University of Minas Gerais,
Belo Horizonte, Brazil.
Source
Indian J Lepr, 70(4):397-403 1998 Oct-Dec
Abstract
The technique of superior tarsal conjunctiva scrape was used for
identifying M.leprae in the conjunctiva in 56 leprosy patients (all of them
multibacillary, some untreated and others treated with multidrug therapy).
The technique of tarsal conjunctiva scrape was shown to be more suitable
than conjunctival biopsy for identifying lepra bacilli. This technique is
also easier to perform and has shown a statistical relation between
bacilloscopical index of skin (BIsk) and bacilloscopical index of tarsal
conjunctiva (BIconj) values. Thus, if the bacilli can be identified at
tarsal conjunctiva we can assume greater systemic bacillary load in the
patients.

============================================================
31.) [Present situation of leprosy in highly endemic area of tropical
Asia--a seroepidemiological study of Mycobacterium leprae infection in
general
inhabitants]
============================================================
Author
Izumi S; Budiawan T; Matsuoka M; Saeki K; Kawatsu K
Address
National Leprosarium Oshima Seisho-En, Kagawa, Japan.
Source
Nihon Hansenbyo Gakkai Zasshi, 67(3):401-8 1998 Nov
Abstract
One of the most important unsolved problems in epidemiology of leprosy is
the heterogeneous geographic distribution of the disease. There are highly
endemic area called "Pocket" in the endemic countries. Little is known why
leprosy is so endemic in the area. We conducted, therefore, an
epidemiological study on M. leprae infection and distribution of leprosy
bacilli in the environment by using serological and molecular biological
techniques. It was found that considerable number of general inhabitants in
the pocket are infected with leprosy bacilli and more than 20% of the
villagers are carrying M. leprae on the surface of the nasal cavity;
suggesting that leprosy bacilli in the residential environment play an
important role in high prevalence of leprosy in the endemic area. New
preventive measures such as chemoprophylaxis, in addition to MDT, will be
needed for global elimination of the disease.

============================================================
32.) Anti M. leprae IgM antibody determination by ultramicroimmunoenzymatic
(UMELISA HANSEN) for the diagnosis and monitoring leprosy.
============================================================
Author
Torrella A; Solis RL; Perez E; Medina Y; Kerguelen C; Olaya P
Address
Immunoassay Center, C. Habana, Cuba.
Source
Rev Inst Med Trop Sao Paulo, 40(3):177-81 1998 May-Jun
Abstract
The relationship between the IgM antibody response, antigenic load as well
as the clinical improvement after chemotherapy was studied in order to
obtain useful data for the early diagnosis and monitoring leprosy. A level
of 82% (94/115) agreement was obtained between IgM UMELISA HANSEN and
slit-skin smear examination. Discrepant results were observed in 16
patients who showed positive IgM response despite negative by the skin
smear examination. In these patients, the IgM response was seen to be
associated to the early signal for bacilli recurrence in the skin. In one
of these patients the presence of bacilli was demonstrated in the skin, two
months after IgM antibodies being detected by UMELISA HANSEN. Also in one
of the treated patients positive by both diagnostic techniques, a
remarkable decrease in the IgM antibody levels was seen, correlating with a
significant clinical improvement. Moreover it was found a direct
relationship between the IgM antibody response and bacterial antigenic
load, regardless the time elapsed in the disease's evolution.

============================================================
33.) Opposite cellular accumulation and nitric oxide production in vivo
after pleural immunization with M. leprae or M. bovis BCG.
============================================================
Author
Moura AC; Werneck-Barroso E; Rosas EC; Henriques MG; Cordeiro RS
Address
Department of Cell Biology and Genetics, Universidade do Rio de Janeiro
(UERJ), Rio de Janeiro, Brazil.
Source
Int J Mol Med, 3(1):69-74 1999 Jan
Abstract
Mycobacteria as intracellular pathogens have evolved mechanisms to survive
within macrophages. Our previous data showed that M. leprae (ML), unlike M.
bovis BCG, did not induce an inflammatory response in the mice subcutaneous
tissue. Further, ML inhibited BCG-induced foot pad oedema and seemed to
transform macrophages in epithelioid cells. Since these mycobacteria share
common antigens, here we seeked to compare the acute and chronic cellular
response evoked by ML and BCG in pleurisy of a mycobacteria-susceptible
mice (BALB/c). The total leukocytes, the cell type that migrated to the
pleural cavity and macrophage activation assayed by nitric oxide release
were determined. Live or dead BCG Moreau recruited the same extent of
cells, essentially monocytes and neutrophils, dose-dependently, in both
acute and chronic pleurisy. BCG-induced eosinophilia was observed only in
the acute response (after 24 h of injection). A significant nitric oxide
release by pleural macrophages was triggered by BCG Moreau without previous
activation. Nevertheless, ML failed to recruit leukocytes to the pleural
space or to lead to nitric oxide production despite the number of bacilli
used and the time studied (1, 7 or 14 days after injection). Although these
mycobacteria have common antigens that cross-react, these data show a
distinct ability of ML or BCG to recruit cells to the pleural space and to
activate pleural macrophage for nitric oxide production in vivo.

============================================================
34.) Use of a whole blood assay to monitor the immune response to
mycobacterial antigens in leprosy patients: a predictor for type 1 reaction
onset?
============================================================
Author
Weir RE; Butlin CR; Neupane KD; Failbus SS; Dockrell HM
Address
Department of Infectious and Tropical Diseases, London School of Hygiene &
Tropical Medicine, UK.
Source
Lepr Rev, 69(3):279-93 1998 Sep
Abstract
Longitudinal studies are more appropriate than cross-sectional studies for
investigating changes in the immune response to Mycobacterium leprae during
leprosy, such as occur in type 1 (reversal) reactions. A test for
predicting the onset of reactions in leprosy would greatly reduce
disability associated with leprosy. Whole blood assays are appropriate for
longitudinal studies of the in vitro T-cell response, as they are robust
and reproducible, and require only a small volume of blood. Whole blood
assays were used to assess the natural variation in the 'normal' T-cell
response to mycobacterial antigens in healthy UK donors, and healthy Nepali
donors, tested over 6 months. This was compared with variation in T-cell
responses measured over 6 months in 22 leprosy patients in Nepal, including
eight who developed type 1 reactions during this time. The in vitro T-cell
response to M. leprae sonicate, M. tuberculosis PPD, the mitogen PHA, and
(in the UK study) recombinant mycobacterial antigens (70 kD and 30/31 kD
proteins) was measured by lymphoproliferation and interferon-gamma (IFN
gamma) responses, and variation in responses over time in each subject
calculated as a coefficient of variation (CV). The baseline high, low or
non-responder status of the healthy UK donors remained stable. The
magnitude of IFN gamma responses varied by mean CV ranging from 26% (to
PPD) to 63% (to Mtb 70 kD); proliferation responses showed less variation,
ranging from mean CV of 18% (to PHA) to 47% (to Mtb 70 kD). Response
variation was independent of lymphocyte number in culture. Similar
variation in lymphoproliferation responses to MLS, PPD and PHA was observed
in the group of healthy Nepali subjects, and in Nepali leprosy patients who
did not experience reactions during the study. Of the eight leprosy
patients who developed type 1 reactions, four (two BT, one BB, one BL)
showed significantly increased proliferation to MLS at the time of reaction
(74-300% above baseline); four (one BB, two BL, one LL) remained low or
non-responders to MLS throughout. An alternative marker of immune
response--anti-phenolic glycolipid-1 (PGL-1) antibody titre--was not
predictive of reaction onset in these patients. This study demonstrated
that whole blood assays provide reproducible in vitro measurements that can
be used to monitor changes in T-cell responses to M. leprae antigens; their
practical use as a diagnostic marker of type 1 reaction onset is discussed.

============================================================
35.) A clinical and bacteriological examination of Mycobacterium leprae in
the epidermis and cutaneous appendages of patients with multibacillary
leprosy.
============================================================
Author
Hosokawa A
Address
Department of Dermatology, Ryukyu University School of Medicine, Okinawa,
Japan.
Source
J Dermatol, 26(8):479-88 1999 Aug
Abstract
In the specimens examined at Ryukyu University Hospital, acid-fast bacilli
(AFB) were observed in the epidermis, cutaneous appendages and endothelial
cells of capillaries. These specimens were taken from non-ulcerating skin
lesions of patients with multibacillary leprosies such as LL and borderline
lepromatous leprosy (BL). Of the 211 specimens examined, 23 (10.9%) were
AFB-positive [AFB (+)] in the above mentioned skin regions. These AFB (+)
samples were taken from nine leprosy patients; six cases (17 samples) of
LL, two cases (5 samples) of BL, and one case (one sample) of BB. The AFB
positive rate [AFB (+)-rate] in the above mentioned skin regions was high
in the unmedicated LL sample (50.0%, 7/14) and low in the medicated
mid-borderline leprosy (BB) samples (0.0%, 0/10). Particularly in the
intraepidermal eccrine sweat duct (acrosyringium), a relatively high number
of AFB were observed. The AFB (+)-rate appears likely to be higher in
non-ulcering skin lesions with minor inflammation or in lesions with
leprosy reaction than typical skin lesions such as papules, nodules, and
infiltrated punched out skin lesions. Although the possibility that viable
bacilli could be excreted from non-ulcerating skin lesions appeared to be
small, these lesions were suspected of being a possible source of infection.

============================================================
36.) Quality control tests for vaccines in leprosy vaccine trial, Avadi.
============================================================
Author
Sreevatsa; Hari M; Gupte MD
Address
BCG Vaccine Laboratory, Guindy, Chennai.
Source
Indian J Lepr, 70(4):389-95 1998 Oct-Dec
Abstract
All the vaccines supplied for the large scale comparative leprosy vaccine
trial of ICRC bacilli, M.w, BCG plus killed M. leprae (candidate vaccines),
BCG and normal saline (control arms) at CJIL Field Unit, Chennai were
tested for quality control by the suppliers following the procedures laid
down in the WHO protocol for killed M. leprae. Quality control for BCG was
carried out at BCG vaccine laboratory as per protocol. Toxicity and
sterility tests were done on all the vaccine batches/lots received. As part
of the quality control, bacterial count, and protein estimation were also
done. Studies showed that the bacterial content and protein concentration
were comparable with the original preparations. Vaccines were free from
micro-organisms, toxic materials and safe for human use. Thus the quality
of all vaccine preparations was satisfactory.

============================================================
37.) Comparative leprosy vaccine trial in south India.
============================================================
Author
Gupte MD; Vallishayee RS; Anantharaman DS; Nagaraju B; Sreevatsa;
Balasubramanyam S; de Britto RL; Elango N; Uthayakumaran N; Mahalingam VN;
Lourdusamy G; Ramalingam A; Kannan S; Arokiasamy J
Source
Indian J Lepr, 70(4):369-88 1998 Oct-Dec
Abstract
This report provides results from a controlled, double blind, randomized,
prophylactic leprosy vaccine trial conducted in South India. Four vaccines,
viz BCG, BCG+ killed M. leprae, M.w and ICRC were studied in this trial in
comparison with normal saline placebo. From about 3,00,000 people, 2,16,000
were found eligible for vaccination and among them, 1,71,400 volunteered to
participate in the study. Intake for the study was completed in two and a
half years from January 1991. There was no instance of serious toxicity or
side effects subsequent to vaccination for which premature decoding was
required. All the vaccine candidates were safe for human use. Decoding was
done after the completion of the second resurvey in December 1998. Results
for vaccine efficacy are based on examination of more than 70% of the
original "vaccinated" cohort population, in both the first and the second
resurveys. It was possible to assess the overall protective efficacy of the
candidate vaccines against leprosy as such. Observed incidence rates were
not sufficiently high to ascertain the protective efficacy of the candidate
vaccines against progressive and serious forms of leprosy. BCG+ killed M.
leprae provided 64% protection (CI 50.4-73.9), ICRC provided 65.5%
protection (CI 48.0-77.0), M.w gave 25.7% protection (CI 1.9-43.8) and BCG
gave 34.1% protection (CI 13.5-49.8). Protection observed with the ICRC
vaccine and the combination vaccine (BCG+ killed M. leprae) meets the
requirement of public health utility and these vaccines deserve further
consideration for their ultimate applicability in leprosy prevention.

============================================================
38.) Evolutionary bottlenecks in the agents of tuberculosis, leprosy, and
paratuberculosis.
============================================================
Author
Frothingham R
Address
Infectious Disease Section, Durham Veterans Affairs Medical Center, Durham,
North Carolina 27705, USA. [email protected]
Source
Med Hypotheses, 52(2):95-9 1999 Feb
Abstract
Parasitic mycobacteria cause important human and animal diseases including
tuberculosis, leprosy, and paratuberculosis. Several methods demonstrate a
high degree of sequence conservation in three parasitic mycobacterial
species (Mycobacterium tuberculosis, M. leprae, and M. avium subspecies
paratuberculosis). Each of these species has completely conserved
deoxyribonucleic acid (DNA) sequence in an internal transcribed spacer. In
contrast, several species of environmental mycobacteria (M. intracellulare,
M. kansasii, M. gordonae, and M. scrofulaceum) have substantial
strain-to-strain variation in this region. These data suggest that each of
the parasitic species has gone through a recent evolutionary bottleneck.
Comparisons of tandem-repeat DNA from ancient and modern mycobacterial
strains may allow this hypothesis to be tested directly.

============================================================
39.) Role of S-100 staining in differentiating leprosy from other
granulomatous diseases of the skin.
============================================================
Author
Thomas MM; Jacob M; Chandi SM; George S; Pulimood S; Jeyaseelan L; Job CK
Address
Department of Dermatology, Christian Medical College and Hospital, Vellore,
Tamil Nadu, India.
Source
Int J Lepr Other Mycobact Dis, 67(1):1-5 1999 Mar
Abstract
Since Mycobacterium leprae are rarely demonstrable in the tuberculoid
spectrum of leprosy, a confirmatory diagnosis of leprosy can be made on the
basis of finding active destruction of cutaneous nerves by granulomatous
inflammation in a skin biopsy. Immunoperoxidase staining for S-100 protein,
which is a marker for Schwann cells, was used to delineate nerves in
lesional skin biopsies of 25 patients with tuberculoid and borderline
tuberculoid leprosy as well as 15 controls with nonleprous granulomatous
inflammation. Four different patterns of nerve damage were observed:
infiltrated, fragmented, absent, and intact. All of the nonleprous
granulomatous dermatoses showed only intact nerves, either inside or
outside the granuloma, and so S-100 staining can be used to rule out leprosy.

============================================================
40.) Assessment of anti-PGL-I as a prognostic marker of leprosy reaction.
============================================================
Author
Stefani MM; Martelli CM; Morais-Neto OL; Martelli P; Costa MB; de Andrade AL
Address
Department of Immunology, University Hospital, Federal University of Goias,
Goiania, Brazil. [email protected]
Source
Int J Lepr Other Mycobact Dis, 66(3):356-64 1998 Sep
Abstract
The anti-phenolic glycolipid-I (PGL-I) assay as currently applied for
leprosy is conceived as an early marker of asymptomatic infection, early
disease diagnosis and cure monitoring. Its use as a prognostic marker of
reaction is still a matter of controversy. We conducted a case-control
study to investigate whether IgM and IgG anti-PGL-I antibodies could
discriminate patients at increased risk of developing reactions. Eligible
cases were untreated leprosy patients at the onset of type 1 and type 2
reactions recruited from among 600 concurrent, newly detected, untreated
leprosy patients attending an outpatient clinic in central Brazil. For the
patients with reaction, approximately the same number of leprosy cases
without reaction matched as to bacterial index (BI), age and gender were
randomly selected. Individuals without clinical leprosy were evaluated as
healthy controls. Sera from type 1 reaction (N = 43) and type 2 reaction (N
= 26) patients were tested by an ELISA using PGL-I synthetic
disaccharide-BSA antigen and 1:300 sera dilution (cut-off point > or = 0.2
OD). Antibody profiles were evaluated by exploratory data analysis and
reverse cumulative distribution curves. The IgG anti-PGL-I response did not
have a defined pattern, being detected only at low levels. Our results
indicate that leprosy patients, independently of their reactional status,
produce high levels of IgM anti-PGL-I, demonstrating a strong correlation
between the magnitude of antibody response and the BI. Patients with a
higher BI were at least 3.4 times more prone to produce an antibody
response compared to healthy controls.

============================================================
41.) Conjunctival biopsy in patients with leprosy.
============================================================
Author
Campos WB; Or´efice F; Sucena MA; Rodrigues CA
Address
S~ao Geraldo Hospital, Medical School of the Federal University of Minas
Gerais, Brazil.
Source
Indian J Lepr, 70(3):291-4 1998 Jul-Sep
Abstract
The authors examined the eyes of 120 leprosy patients comprising of 30
cases each of tuberculoid, indeterminate, borderline and lepromatous
leprosy. The investigation included biopsy of the bulbar conjunctiva on the
upper temporal quadrant of the right eye. The study patients included both
who were untreated, those that were being treated and those who were in
observation after the end of treatment. The aim of the study was to
identify the presence of M. leprae in the conjunctiva. Four such cases were
found: one borderline patient with no treatment and three lepromatous
patients who were being treated with MDT.

============================================================
42.) Experimental leprosy in rhesus monkeys: transmission, susceptibility,
clinical and immunological findings.
============================================================
Author
Gormus BJ; Xu K; Baskin GB; Martin LN; Bohm RP Jr; Blanchard JL; Mack PA;
Ratterree MS; Meyers WM; Walsh GP
Address
Department of Microbiology, Pathology, Tulane Regional Primate Research
Center, Covington, LA 70433, USA.
Source
Lepr Rev, 69(3):235-45 1998 Sep
Abstract
A total of 46 Rhesus monkeys (RM) was inoculated with Mycobacterium leprae
(ML) and followed clinically and immunologically for extended periods.
Twenty-one (45.7%) of the RM developed leprosy spanning the known leprosy
spectrum, with six of 21 (28.6%) having disease in the borderline
lepromatous to lepromatous area of the spectrum. RM with paucibacillary
forms of leprosy produced predominantly IgG anti-phenolic glycolipid
(PGL-I) antibodies and positive lepromin skin test and/or in vitro
blastogenesis responses; IgM anti-PGL-I predominated in animals with BB-LL
leprosy and correlated with negative immune responses to lepromin. IgG
anti-PGL-I antibodies persisted in a number of RM for several years without
histopathological evidence of leprosy, suggesting possible persisting
subclinical infection. The data show that RM are a valuable model for the
study of leprosy. Eleven of the 46 RM were inoculated with ML from sources
infected with simian immunodeficiency virus (SIV), the monkey counterpart
to the human immunodeficiency virus (HIV). The possible effect of SIV on
the clinical outcome of ML infection could not be determined due to
insufficient numbers of animals to yield statistically significant results.

============================================================
43.) Lepromatous uveitis diagnosed by iris biopsy.
============================================================
Author
Messmer EM; Raizman MB; Foster CS
Address
University Eye Hospital, Munich, Germany.
Source
Graefes Arch Clin Exp Ophthalmol, 236(9):717-9 1998 Sep
Abstract
Ocular leprosy is rarely seen in developed countries. We report the
long-term follow-up of a patient with bilateral uveitis, glaucoma, and
keratitis. Skin, iris and aqueous humor biopsies disclosed abundant
Wade-Fite-positive organisms consistent with Mycobacterium leprae. Leprosy
must be considered in the differential diagnosis of keratitis and uveitis.

============================================================
44.) Preservation of Mycobacterium leprae in vitro for four years by
lyophilization.
============================================================
ARTICLE SOURCE: Int J Lepr Other Mycobact Dis (United States), Sep 1993,
61(3) p415-20
AUTHOR(S): Kohsaka K; Matsuoka M; Hirata T; Nakamura M
PUBLICATION TYPE: JOURNAL ARTICLE
ABSTRACT: Although the viability of Mycobacterium leprae suspended in
distilled water with or without 10% fetal calf serum was reduced
approximately 10(-2) to 10(-4) from that of the starting material during
the process of lyophilization, bacilli capable of multiplication in nude
mouse foot pads were found in the lyophilized samples stored for 4 years at
4 degrees C. The multiplication rate of the lyophilized bacilli which were
suspended in 10% serum-water was much higher than that of the bacilli
suspended in water only. On the other hand, no reduction of the viability
of M. leprae suspended in 10% skim milk-water was demonstrated during the
process of lyophilization as well as storage for 2 years at 4 degrees C.
From the results obtained here, it could be suggested that M. leprae might
be preserved in vitro by means of lyophilized M. leprae was extremely
stable during cryopreservation when the bacilli were suspended in 10% skim
milk-water. Therefore, the composition of the solution for suspending the
bacilli is definitely critical for the maintenance of M. leprae viability
by means of lyophilization.

=========================================================================
45.) Minocycline in lepromatous leprosy.
=========================================================================
Author
Fajardo TT Jr; Villahermosa LG; dela Cruz EC; Abalos RM; Franzblau SG;
Walsh GP
Address
Clinical Research Branch, Leonard Wood Memorial Center, Cebu City, The
Philippines.
Source
Int J Lepr Other Mycobact Dis, 63(1):8-17 1995 Mar
Abstract
Twelve patients were treated with three dose levels of minocycline for 30
days, primarily to detect the dose-related effects on Mycobacterium leprae
viability, followed by another 5 months of daily minocycline for overall
efficacy and persistence of clinical and antibacterial effects.
Subsequently, the patients were given standard WHO/MDT chemotherapy for
multibacillary leprosy. Clinical improvement was recognizable during the
first month, occurring much earlier among those on minocycline 200 mg daily
than those who received minocycline 100 mg daily. A similar change also was
observed in one patient 11 days after three daily doses of 100 mg of
minocycline. At the end of 6 months, all patients were clinically improved
with a slight reduction in the average bacterial index (BI) and logarithmic
index of bacilli in biopsy (LIB). The effects of minocycline on viability
by mouse foot pad inoculation and palmitic acid oxidation assays were noted
beginning at 10 to 14 days of daily dosing and becoming more definite after
30 days of treatment. Both tests correlated fairly well. Doses of 200 mg
daily did not appear to be more efficient than minocycline 100 daily.
Phenolic glycolipid-I (PGL-I) antigen determinations done on some patients
during the first month remained positive and did not correlate with changes
in viability results. At the end of 6 months, after 5 months of 100 mg of
minocycline monotherapy, no viable organisms could be demonstrated by mouse
foot pad inoculation and palmitic acid oxidation assays; assays for PGL-I
antigen were all negative.(ABSTRACT TRUNCATED AT 250 WORDS)

=========================================================================
46.) Efficacy of minocycline in single dose and at 100 mg twice daily for
lepromatous leprosy.
=========================================================================
Int J Lepr Other Mycobact Dis (United States), Dec 1994, 62(4) p568-73
AUTHOR(S): Gelber RH; Murray LP; Siu P; Tsang M; Rea TH
AUTHOR'S ADDRESS: San Francisco Regional Hansen's Disease Program, CA
94115.
PUBLICATION TYPE: CLINICAL TRIAL; JOURNAL ARTICLE
ABSTRACT: A clinical trial of minocycline in a total of 10 patients with
previously untreated lepromatous leprosy was conducted in order to evaluate
the efficacy of a single, initial, 200-mg dose and 100 mg twice daily of
minocycline for a total duration of up to 3 months. Patients improved
remarkably quickly. Although single-dose therapy did not result in a
significant killing of Mycobacterium leprae, viable M. leprae were cleared
from the dermis regularly by 3 months of twice-daily therapy, a rate
similar to that achieved by minocycline 100 mg once daily. Because more
side effects were noted herein than previously with 100 mg daily, we
recommend that minocycline, when applied, be administered at 100 mg daily
to leprosy patients.

=========================================================================
47.) Field trial on efficacy of supervised monthly dose of 600 mg rifampin,
400 mg ofloxacin and 100 mg minocycline for the treatment of leprosy; first
results.
=========================================================================
Author
Mane I; Cartel JL; Grosset JH
Address
Institut de Leprologie Appliquee, Dakar CD Annexe, Senegal.
Source
Int J Lepr Other Mycobact Dis, 65(2):224-9 1997 Jun
Abstract
In 1995, a field trial was implemented in Senegal in order to evaluate the
efficacy of a regimen based on the monthly supervised intake of rifampin
600 mg, ofloxacin 400 mg and minocycline 100 mg to treat leprosy. During
the first year of the trial, 220 patients with active leprosy (newly
detected or relapsing after dapsone monotherapy) were recruited: 102
paucibacillary (PB) (60 males and 42 females) and 118 multibacillary (MB)
(71 males and 47 females). All of them accepted the new treatment (none
requested to be preferably put under standard WHO/MDT), no clinical sign
which could be considered as a toxic effect of the drug was noted, and none
of the patients refused to continue treatment because of any clinical
trouble. The compliance was excellent: the 113 patients (PB and MB)
detected during the first 6 months of the trial have taken six monthly
doses in 6 months, as planned. The rate of clearance and the progressive
decrease of cutaneous lesions was satisfactory. Although it is too soon to
give comprehensive results, it should be noted that no treatment failure
was observed in the 56 PB patients who have completed treatment and have
been followed up for 6 months. The long-term efficacy of the new regimen is
to be evaluated on the rate of relapse during the years following the
cessation of treatment. If that relapse rate is acceptable (similar to that
observed in patients after treatment with current standard WHO/ MDT), the
new regimen could be a solution to treat, for instance, patients very
irregular and/or living in remote or inaccessible areas since no selection
of rifampin-resistant Mycobacterium leprae should be possible (a monthly
dose of ofloxacin and minocycline being as effective as a dose of dapsone
and clofazimine taken daily for 1 month). Nevertheless, until longer term
results of this and other trials become available, there is no
justification for any change in the treatment strategy, and all leprosy
patients should be put under standard WHO/MDT.

=========================================================================
48.) Bactericidal activity of a single-dose combination of ofloxacin plus
minocycline, with or without rifampin, against Mycobacterium leprae in mice
and in lepromatous patients.
=========================================================================
Author
Ji B; Sow S; Perani E; Lienhardt C; Diderot V; Grosset J
Address
Facult´e de M´edecine Piti´e-Salp^etri`ere, Paris, France.
[email protected]
Source
Antimicrob Agents Chemother, 42(5):1115-20 1998 May
Abstract
To develop a fully supervisable, monthly administered regimen for treatment
of leprosy, the bactericidal effect of a single-dose combination of
ofloxacin (OFLO) and minocycline (MINO), with or without rifampin (RMP),
against Mycobacterium leprae was studied in the mouse footpad system and in
previously untreated lepromatous leprosy patients. Bactericidal activity
was measured by the proportional bactericidal method. In mouse experiments,
the activity of a single dose of the combination OFLO-MINO was dosage
related; the higher dosage of the combination displayed bactericidal
activity which was significantly inferior to that of a single dose of RMP,
whereas the lower dosage did not exhibit a bactericidal effect. In the
clinical trial, 20 patients with previously untreated lepromatous leprosy
were treated with a single dose consisting of either 600 mg of RMP plus 400
mg of OFLO and 100 mg of MINO or 400 mg of OFLO plus 100 mg of MINO. The
OFLO-MINO combination exhibited definite bactericidal activity in 7 of 10
patients but was less bactericidal than the RMP-OFLO-MINO combination. Both
combinations were well tolerated. Because of these promising results, a
test of the efficacy of multiple doses of ROM in a larger clinical trial
appears justified.

=========================================================================
49.) Efficacy of single dose multidrug therapy for the treatment of
single-lesion paucibacillary leprosy. Single-lesion Multicentre Trial Group.
=========================================================================
Source
Indian J Lepr, 69(2):121-9 1997 Apr-Jun
Abstract
A multicentre double-blind controlled clinical trial was carried out to
compare the efficacy of a combination of rifampicin 600 mg plus ofloxacin
400 mg plus minocycline 100 mg (ROM) administered as single dose with that
of the standard six-month WHO/MDT/PB regimen. The subjects included 1483
cases with one skin lesion who were previously untreated, were
smear-negative, and had no evidence of peripheral nerve trunk involvement,
and they were randomly divided into study and control groups. The total
duration of the study from the day of intake was 18 months, and 1381
patients completed study. Only 12 patients were categorized as treatment
failure and no difference was observed between the two regimens. Occurrence
of mild side-effects and leprosy reactions were minimal (less than 1%) in
both groups. This study showed that ROM is almost as effective as the
standard WHO/MDT/PB in the treatment of single lesion PB leprosy.

=========================================================================
50.) Bactericidal activity of single dose of clarithromycin plus
minocycline, with or without ofloxacin, against Mycobacterium leprae in
patients.
=========================================================================
Author
Ji B; Jamet P; Perani EG; Sow S; Lienhardt C; Petinon C; Grosset JH
Address
Facult´e de M´edecine Piti´e-Salp^etri`ere, Paris, France.
Source
Antimicrob Agents Chemother, 40(9):2137-41 1996 Sep
Abstract
Fifty patients with newly diagnosed lepromatous leprosy were allocated
randomly to one of five groups and treated with either a month-long
standard regimen of multidrug therapy (MDT) for multibacillary leprosy, a
single dose of 600 mg of rifampin, a month-long regimen with the dapsone
(DDS) and clofazimine (CLO) components of the standard MDT, or a single
dose of 2,000 mg of clarithromycin (CLARI) plus 200 mg of minocycline
(MINO), with or without the addition of 800 mg of ofloxacin (OFLO). At the
end of 1 month, clinical improvement accompanied by significant decreases
of morphological indexes in skin smears was observed in about half of the
patients of each group. A significant bactericidal effect was demonstrated
in the great majority of patients in all five groups by inoculating the
footpads of mice with organisms recovered from biopsy samples obtained
before and after treatment. Rifampin proved to be a bactericidal drug
against Mycobacterium leprae more potent than any combination of the other
drugs. A single dose of CLARI-MINO, with or without OFLO, displayed a
degree of bactericidal activity similar to that of a regimen daily of doses
of DDS-CLO for 1 month, suggesting that it may be possible to replace the
DDS and CLO components of the MDT with a monthly dose of CLARI-MINO, with
or without OFLO. However, gastrointestinal adverse events were quite
frequent among patients treated with CLARI-MINO, with or without OFLO, and
may be attributed to the higher dosage of CLARI or MINO or to the
combination of CLARI-MINO plus OFLO. In future trials, therefore, we
propose to reduce the dosages of the drugs to 1,000 mg of CLARI, 100 mg of
MINO, and 400 mg of OFLO.

=========================================================================
51.) WHO Expert Committee on Leprosy.
=========================================================================
Source: World Health Organ Tech Rep Ser, 874():1-43 1998
Abstract
Considerable progress has been made in the fight against leprosy during the
past 10-15 years, following the introduction of multidrug therapy (MDT)
regimens and the establishment of the goal of eliminating leprosy as a
public health problem by the year 2000. Current estimates indicate that
there are about 1.15 million cases of leprosy in the world, compared with
10-12 million cases in the mid-1980s. This report presents the conclusions
of a WHO Expert Committee convened to review the global leprosy situation
and the technology available for eliminating the disease, to identify the
remaining obstacles to reaching the goal of eliminating leprosy as a public
health problem, and to make appropriate recommendations for the future on
technical and operational matters. The current status of leprosy
elimination is discussed, and the various antileprosy drugs are reviewed,
including the most recently available drugs. On the basis of field trials
and clinical studies, the Committee concludes that a single dose of a
combination of rifampicin, ofloxacin and minocycline is an acceptable and
cost-effective alternative regimen for the treatment of single-lesion
paucibacillary leprosy, and that the duration of the current MDT regimen
for multibacillary leprosy could possibly be shortened to 12 months. The
Committee points out the need for improved management of reactions and
neuritis and prevention of leprosy-related disabilities and impairments,
and recommends that antileprosy activities should become an integral part
of general health services and should involve communities to the fullest
extent possible.

=========================================================================
52.) Experimental evaluation of possible new short-term drug regimens for
treatment of multibacillary leprosy.
=========================================================================
Author
Banerjee DK; McDermott-Lancaster RD; McKenzie S
Address
Department of Medical Microbiology, St George's Hospital Medical School,
London, United Kingdom. [email protected].
Source
Antimicrob Agents Chemother, 41(2):326-30 1997 Feb
Abstract
Groups of nude mice, with both hind footpads infected with 10(8)
Mycobacterium leprae organisms, were treated with 4-week courses of
different drug combinations. The effect treatment on each group was
evaluated by subinoculating footpad homogenates from the treated mice into
groups of normal and nude mice for subsequent regrowth, assessed 1 year
later. A combination of rifampin (RMP) with clarithromycin (CLARI),
minocycline (MINO), and ofloxacin (OFLO) resulted in the complete killing
of M. leprae after 3 weeks of treatment. A combination of sparfloxacin
(SPAR) and RMP also resulted in a similar bactericidal effect after 3 weeks
of treatment. Other drug combinations showed variable effects. Very little
or no effect was observed with any regimen if the treatment was given for
less than 2 weeks. World Health Organization (WHO) multidrug therapy (MDT)
given for 8 weeks was as effective as the two combinations described above.
The results suggest that multidrug combinations consisting of RMP-OFLO (or
SPAR)-CLARI (and/or MINO) are as effective as the WHO MDT for the treatment
of experimental leprosy. Moreover, they imply that these combinations,
which were found to be active in a 4-week experimental treatment protocol,
could be administered as treatment to patients for a period of time shorter
than the present 2-year regimen without a loss of effectiveness.

=========================================================================
53.) Powerful bactericidal activities of clarithromycin and minocycline
against Mycobacterium leprae in lepromatous leprosy.
=========================================================================
ARTICLE SOURCE: J Infect Dis (United States), Jul 1993, 168(1) p188-90
AUTHOR(S): Ji B; Jamet P; Perani EG; Bobin P; Grosset JH
AUTHOR'S ADDRESS: Faculte de Medecine Pitie-Salpetriere, Paris, France.
PUBLICATION TYPE: CLINICAL TRIAL; JOURNAL ARTICLE; RANDOMIZED
CONTROLLED
TRIAL
ABSTRACT: Thirty-six patients with newly diagnosed lepromatous leprosy
were allocated randomly to three groups and treated for 56 days with
minocycline (100 mg daily), clarithromycin (500 mg daily), or
clarithromycin (500 mg) plus minocycline (100 mg daily). All groups had
rapid and remarkable clinical improvement and significant decline of the
bacterial and morphologic indices in skin smears during treatment. More
than 99% and 99.9% of the viable Mycobacterium leprae had been killed by 28
and 56 days of treatment, respectively, as measured by inoculation of
organisms recovered from skin samples, taken before and during treatment,
into the footpads of immunocompetent and nude mice. Clinical improvement
and bactericidal activity did not differ significantly among the three
groups. Adverse reactions were rare and mild, and no laboratory abnormality
was detected during the trial. Both clarithromycin and minocycline
displayed powerful bactericidal activities against M. leprae in leprosy
patients and may be considered important components of new multidrug
regimens for the treatment of multibacillary leprosy.

=========================================================================
54.) Differential protective effect of bacillus calmette-guerin vaccine
against multibacillary and paucibacillary leprosy in nagpur, india.
=========================================================================
Public Health 1999 Nov;113(6):311-3

Kulkarni HR, Zodpey SP
Department of Preventive and Social Medicine and Clinical Epidemiology
Unit, Government Medical College, Nagpur, India.

For this paper we conducted a secondary data analysis to test the
hypothesis that a linear trend exists in the protective effect of bacillus
Calmette-Guerin (BCG) vaccine against types of leprosy. We used data from
two previous case-control studies to perform an unmatched test for linear
trend. We observed that both the studies revealed a significant linear
trend (P<0.00001). One study that estimated an insignificant protective
effect of BCG against paucibacillary leprosy showed a significant departure
from linearity. We conclude that, the protective effect of BCG vaccination
is differential across severity of leprosy as it brings about a shift in
the immune response to a higher level of cell mediated immunity. We
recommend that future studies dealing with the protective effect of BCG
against leprosy should also conduct an analysis for trend.

=========================================================================
55.) An immunotherapeutic vaccine for multibacillary leprosy.
=========================================================================
Int Rev Immunol 1999;18(3):229-49

Talwar GP
International Centre for Genetic Engineering & Biotechnology, New Delhi,
India.

On January 30, 1998, a vaccine for leprosy based on Mycobacterium w (the
code word under which this species hitherto unspecified was investigated)
was launched for public use for therapeutic purposes. The vaccine has
completed phase III immunotherapeutic trials as an adjunct to chemotherapy
in urban and rural leprosy control centres and has received the
authorization from the Drugs Controller of India for industrial
manufacture. It will be made available by M/s Cadila Pharmaceuticals,
Ahmedabad. As an adjunct to chemotherapy, the vaccine expediates bacterial
clearance and accelerates clinical regression of lesions. It shortens
significantly the period for release from treatment (RFT) of patients. It
is effective in inducing a fall of bacterial index (BI) in multibacillary
patients who are either nonresponders or slow responders to the standard
multidrug therapy and who have persistent BI over long periods. An
additional benefit of immunization with this vaccine is the conversion of
>60% of LL, 71% of BL and 100% of BB patients from lepromin negativity to
lepromin positivity status. A significant number of vaccinated patients
showed histopathological upgrading and eventually attainment of a state of
nonspecific infiltration without dermal granulomas. The vaccine was well
tolerated and the incidence of Type 2 reactions and their severity was less
in combined immuno cum chemotherapy group than in the group receiving only
chemotherapy. This review describes the nature of the vaccine and the way
it was developed.

=========================================================================
56.) Protective effect of Bacillus Calmette Guerin (BCG) against leprosy: a
population-based case-control study in Nagpur, India.
=========================================================================
Lepr Rev 1999 Sep;70(3):287-94

Zodpey SP, Bansod BS, Shrikhande SN, Maldhure BR, Kulkarni SW
Clinical Epidemiology Unit, Govt Medical College, Nagpur, MS, India.

A population-based pair-matched case-control study was carried out in an
urban community, Nagpur, India, to estimate the effectiveness of BCG
vaccination in the prevention of leprosy. The study included 212 cases of
leprosy (diagnosed by WHO criteria), below the age of 35 years, detected
during a leprosy survey conducted by the Government of Maharashtra over a
population of 20,03,325. Each case was pair-matched with one neighbourhood
control for age, sex and socioeconomic status. A significant protective
association between BCG and leprosy was observed (OR = 0.40, 95% CI =
0.23-0.68). The overall vaccine effectiveness (VE) was estimated to be 60%
(95% CI = 32-77). The BCG effectiveness against multi-bacillary and
paucibacillary leprosy was 72% (95% CI = 35-88) and 45% (95% CI = 3-73),
respectively. Vaccine was more effective during the first decade of life,
among females and in lower socioeconomic strata. The overall prevented
fraction was 39% (95% CI = 16-58). In conclusion, this first ever
population-based case control study performed in Central India, identified
a beneficial role of BCG vaccination in prevention of leprosy in study
population.

=========================================================================
57.) The antigen 85 complex vaccine against experimental Mycobacterium
leprae infection in mice.
=========================================================================
Vaccine 1999 Dec 10;18(9-10):795-8

Naito M, Matsuoka M, Ohara N, Nomaguchi H, Yamada T
Department of Oral Bacteriology, Nagasaki University School of Dentistry,
Sakamoto 1-7-1, Nagasaki, Japan.

The proteins in culture filtrate derived from Bacillus Calmette-Guerin
(BCG) were examined for protection against infection by Mycobacterium
leprae. Immunization with the major secreted proteins, antigen 85 complex
(Ag 85) A, B and C, induced effective protective immunity against
multiplication of M. leprae in the foot pads of mice. The most effective
protection was observed when mice were immunized with Ag 85A. A single
immunization with Ag 85 could induce antigen-specific interferon gamma
(IFNgamma) synthesis and more effective protection than live BCG vaccine.
This study demonstrates that Ag 85 is an important immunoprotective
molecule against leprosy infection.

=========================================================================
58.) Induction of lepromin positivity following immuno-chemotherapy with
Mycobacterium w vaccine and multidrug therapy and its impact on
bacteriological clearance in multibacillary leprosy: report on a
hospital-based clinical trial with the candidate antileprosy vaccine.
=========================================================================
Int J Lepr Other Mycobact Dis 1999 Sep;67(3):259-69

Sharma P, Kar HK, Misra RS, Mukherjee A, Kaur H, Mukherjee R, Rani R
National Institute of Immunology, New Delhi, India.

A vaccine based on autoclaved Mycobacterium w was administered, in addition
to standard multidrug therapy (MDT), to 157 bacteriologically positive,
lepromin-negative, multibacillary (LL, BL and BB) leprosy patients. The
vaccinees were supported by a well-matched control group of 147 patients
with similar type of disease who received a placebo injection in addition
to MDT. The MDT was given for a minimum period of 2 years and continued
until skin-smear negativity, while the vaccine was given at 3-month
intervals up to a maximum of 8 doses. The lepromin response evaluated in
terms of percentage of subjects converting to positivity status,
measurement in millimeters, and duration of lepromin positivity sustained,
reflected a statistically significant better outcome in the vaccine group
patients (especially LL and BL leprosy) in comparison to those in the
placebo group. The data indicate that lepromin-positivity status seems to
have an impact on accelerating the bacteriological clearance, as is evident
by the statistically significant accelerated decline in the BI of those
patients who converted to lepromin positivity as compared to those
remaining lepromin negative throughout therapy and post-therapy follow up.
To conclude, the addition of the Mycobacterium w vaccine to standard MDT
induces a lepromin response of a statistically significant higher magnitude
than that observed with MDT alone.

=========================================================================
59.) Disabilities in multibacillary leprosy following multidrug therapy
with and without immunotherapy with Mycobacterium w antileprosy vaccine.
=========================================================================
Int J Lepr Other Mycobact Dis 1999 Sep;67(3):250-8

Sharma P, Kar HK, Misra RS, Mukherjee A, Kaur H, Mukherjee R, Rani R
National Institute of Immunology, New Delhi, India. [email protected]

A vaccine based on autoclaved Mycobacterium w was administered, in addition
to standard multidrug therapy (MDT), to 157 bacteriologically positive,
lepromin-negative, multibacillary leprosy patients supported by a
well-matched control group of 147 patients with similar type of disease who
received a placebo injection in addition to MDT. The MDT was given for a
minimum period of 2 years and continued until skin-smear negativity, while
the vaccine/placebo was given at 3-month intervals up to a maximum of 8
doses in the initial 2 years. The overall incidence of type 1 and type 2
reactions and neuritis during treatment and follow up was nearly equal in
the patients in the vaccine and placebo groups; the differences were not
statistically significant. The occurrence of disabilities, such as
anesthesia, trophic ulcers, claw hand and grade 3 deformities, were not
different statistically in the vaccine and placebo groups, an observation
valid both for deformities present at induction and for those which
developed during the course of therapy and surveillance. A statistically
significant difference was observed in the recovery of newly developed
trophic ulcers; recovery was quicker in the vaccine group. The recovery
rate for motor deformities was marginally higher in the vaccine group,
although not significant (p = 0.068) statistically. There was a
statistically significant reduction in the incidence of grade 3 deformities
following MDT with and without immunotherapy. To conclude, the addition of
vaccine to MDT did not precipitate neuritis or deformities over and above
that encountered with MDT alone, although it did accelerate bacteriological
clearance, histopathological upgrading, conversion to lepromin positivity,
and clinical improvement.

=========================================================================
60.) SIMLEP: a simulation model for leprosy transmission and control.
=========================================================================
Int J Lepr Other Mycobact Dis 1999 Sep;67(3):215-36

Meima A, Gupte MD, van Oortmarssen GJ, Habbema JD
Department of Public Health, Faculty of Medicine, Erasmus University
Rotterdam, The Netherlands. [email protected]

SIMLEP is a computer program for modeling the transmission and control of
leprosy which can be used to project epidemiologic trends over time,
producing output on indicators such as prevalence, incidence and
case-detection rates of leprosy. In SIMLEP, health states have been defined
that represent immunologic conditions and stages of leprosy infection and
disease. Three types of interventions are incorporated: vaccination, case
detection and chemotherapy treatment. Uncertainties about leprosy have led
to a flexible design in which the user chooses which of many aspects should
be included in the model. These aspects include natural immunity,
asymptomatic infection, type distribution of new cases, delay between onset
of disease and start of chemotherapy, and mechanisms for leprosy
transmission. An example run illustrates input and output of the program.
The output produced by SIMLEP can be readily compared with observed data,
which allows for validation studies. The support that SIMLEP can give to
health policy research and actual decision making will depend upon the
extent of validation that has been achieved. SIMLEP can be used to improve
the understanding of observed leprosy trends, for example, in relation to
early detection campaigns and the use of multidrug therapy, by exploring
which combinations of assumptions can explain these trends. In addition,
SIMLEP allows for scenario analysis in which the effects of control
strategies combining different interventions can be simulated and evaluated.

=========================================================================
61.) Antigenic definition of plasma membrane proteins of Bacillus
Calmette-Guerin: predominant activation of human T cells by
low-molecular-mass integral proteins.
=========================================================================
Scand J Immunol 1999 Oct;50(4):411-9

Mehrotra J, Mittal A, Rastogi AK, Jaiswal AK, Bhandari NK, Sinha S
Division of Membrane Biology, Central Drug Research Institute, Lucknow,
India.

Mycobacterial plasma membrane proteins, in particular the detergent-soluble
or 'integral' ones, comprise a class of mostly unexplored antigens capable
of inducing potent activation of human T cells. Plasma membrane isolated
from culture-grown Bacillus Calmette-Guerin (BCG; Indian vaccine; Danish
strain) was subjected to a Triton X-114-based biphasic extraction procedure
for isolation of peripheral (water-soluble) and integral proteins (PMP and
IMP). A distinction between the two protein pools was evident from results
of SDS-PAGE and immunoblotting using antisera raised in rabbits. An
enzyme-linked immunosorbant assay with a panel of WHO-IMMYC monoclonal
antibodies against various mycobacterial antigens revealed that three
well-known antigens, 19 kDa, 33/36 kDa (proline rich) and 38 kDa (PstS
homologue), were part of the IMP pool; and another such antigen, 14/16 kDa
alpha-crystallin homologue, partly constituted the PMP pool. Apparently,
antigenically distinct species of the immunomodulatory moiety
lipoarabinomannan partitioned in aqueous and detergent phases. Human T-cell
proliferation assays in donors comprising tuberculoid leprosy and pulmonary
tuberculosis patients and healthy BCG vaccinees showed significantly
greater potency of IMP over PMP and this immunodominance appeared to be
directed towards CD4+ cells. IMP of < 56 kDa were resolved by 'continuous
elution SDS-PAGE' into 15 fractions which, after extraction of SDS, were
used in T-cell proliferation assays for the identification of
immunodominant constituents. Proteins falling within three
low-molecular-mass zones (all < 35 kDa) performed better than the rest,
particularly a approximately 22 kDa fraction, which strongly stimulated T
cells from all five donors. Partial overlap between IMP and secreted
proteins, as noticed in this study, could provide clues to immunodominance
of the latter. The apparent uniqueness and a high T-cell activating potency
make mycobacterial IMP attractive candidates for designing future vaccines
or immunotherapeutic agents.

=========================================================================
62.) A lost talisman: catastrophic decline in yields of leprosy bacilli
from armadillos used for vaccine production.
=========================================================================
Int J Lepr Other Mycobact Dis 1999 Mar;67(1):67-70

Storrs EE
Publication Types:
Letter
=========================================================================

=========================================================================
63.) HLA-DRB1 leprogenic motifs in nigerian population groups.
=========================================================================
Clin Exp Immunol 1999 Oct;118(1):56-62

Uko GP, Lu LY, Asuquo MA, Fici D, Mahan S, Awdeh Z, Udim ER, Ding W, Umana
U, Adewole T, Fraser PA
The Nigerian Institute of Medical Research, Yaba, Lagos, Nigeria.

Amino acid residues involved in the peptide binding groove of HLA-DRB1
alleles were examined in three Nigerian ethnic groups with leprosy (n =
287) and 170 controls to determine the role of DRB1 alleles in disease
outcome with Mycobacterium leprae. Nine positively charged motifs and two
others with neutral charge to the binding groove were detected. These
motifs occurred more frequently in leprosy (leprogenic) than was expected
by chance (P < 0.0001). In contrast, five motifs with net negative or
'modified' neutral charges to the pocket were negatively associated with
leprosy. We conclude that clinical outcome of infection with M. leprae is
largely determined by a shared epitope in DRB1 alleles marked by several
motifs. These motifs occur in otherwise normal DRB1 alleles, characterized
by net positive or neutral charges in the binding groove. We hypothesize
that these polarities cause poor binding of DRB1 to M. leprae. On
presentation, the signal via the T cell receptor results in muted
cell-mediated immunity. The resulting response translates to various forms
of leprosy depending on degree of charge consonance between M. leprae and
host DRB1 allele. Other factors within or without the HLA complex, such as
the T cell receptor repertoire, may also influence the resulting disease.

=========================================================================
64.) Testing candidate genes that may affect susceptibility to leprosy.
=========================================================================
Tissue Antigens 1998 Aug;52(2):147-52

Cervino AC, Curnow RN
Department of Applied Statistics, University of Reading, U.K.

Several statistical methods have been used to search familial data sets for
marker alleles associated with the occurrence of a disease. In the present
paper, a recently developed method is used to re-analyze published data on
leprosy and candidate genes at the HLA loci. This new method of analysis,
the randomization transmission disequilibrium test (TDT), confirmed
previous conclusions that there was no significant evidence against random
transmission at the HLA-A locus but significant positive association with
the HLA-DR2 allele. The randomization TDT detected significant protective
associations, that had not previously been found, with alleles HLA-B8 in
Egyptian families and HLA-B21 (current nomenclature B x 4901, 5001-5002) in
South Indian families, highlighting a major advantage of permutation tests
in analyzing candidate gene loci with rare alleles. These findings provide
evidence that HLA class I restricted T lymphocytes may be of protective
importance in leprosy.

=========================================================================
65.) [Leprosy, an "exemplary" humanitarian disease]?
=========================================================================
Ann Chir Plast Esthet 1999 Feb;44(1):46-55

Mole B
Leprosy still remains a dreaded disease despite the possibilities of
permanent cure, the efficacy of surgical corrections, and its forthcoming
disappearance. The authors conducted several surgical missions in
Benin-Africa--over 4 years and report an interesting rate of control in the
survey of patients as the results of their procedures were reviewed in 84%
of them. Leprosy represents the perfect example of the difficulties of any
humanitarian involvement with apparent contradictions between the aims of
the medical wishes and the presence of a dreaded symbol that--fortunately
or not--allow the existence of the many associations involved in the fight
against leprosy.

=========================================================================
66.) Prediction of elimination of leprosy in leprosy endemic areas of China.
=========================================================================
Indian J Lepr 1999 Apr-Jun;71(2):189-201

Chen XS, Li WZ, Jiang C, Ye GY
Institute of Dermatology, CAMS&PUMC National Centre for STD and Leprosy
Control, Nanjing, China.

A study was carried out based upon the data from the National System for
Leprosy Surveillance and using appropriate mathematical models. The results
showed that of 337 counties where the national goal of basic eradication of
leprosy had not been reached and in 40 counties where the WHO goal of
leprosy elimination had not been achieved in 1996, the detection rates in
calendar years followed exponential models with significant
goodness-of-fit. In the 67 counties with downward trends of detection
rates, the national goal can be met in terms of detection rate in 6% of
counties before the year 2000 or 34.4% before the year 2010, or, in terms
of prevalence rate in 31.3% before the year 2010. In the 11 counties with
downward trends of the detection rates, the WHO target can be met in eight
to ten counties within this century when the duration of disease was
determined with the WHO definition. If the MB proportion among new cases
increased by 10%, the target would be met one year later. However, at the
same MB proportion, the change of fixed treatment schedules from PB six
months and MB two years to PB nine months and MB three years will cause
achievement of the goal to be postponed by two to ten years.

=========================================================================
67.)[Global leprosy, current status and a future outlook].
=========================================================================
Nihon Hansenbyo Gakkai Zasshi 1999 Jul;68(2):87-90

Yuasa Y
Sasakawa Memorial Health Foundation.

Successful "Leprosy Elimination Programme" since 1991 managed to reduce
global case load to nearly 1/10 in 10 years. However, this rapid fall of
case detection/incident rate. This means that even after year 2,000,
control effort of leprosy as an infectious disease must be sustained, while
adequate control/care of leprosy as a deformity/disability causing disease
need more attention.

=========================================================================
68.) Lot quality assurance sampling (LQAS) for monitoring a leprosy
elimination program.
=========================================================================
Int J Lepr Other Mycobact Dis 1999 Jun;67(2):143-9

Gupte MD, Narasimhamurthy B
Institute for Research in Medical Statistics, Tamil Nadu, India.

In a statistical sense, prevalences of leprosy in different geographical
areas can be called very low or rare. Conventional survey methods to
monitor leprosy control programs, therefore, need large sample sizes, are
expensive, and are time-consuming. Further, with the lowering of prevalence
to the near-desired target level, 1 case per 10,000 population at national
or subnational levels, the program administrator's concern will be shifted
to smaller areas, e.g., districts, for assessment and, if needed, for
necessary interventions. In this paper, Lot Quality Assurance Sampling
(LQAS), a quality control tool in industry, is proposed to identify
districts/regions having a prevalence of leprosy at or above a certain
target level, e.g., 1 in 10,000. This technique can also be considered for
identifying districts/regions at or below the target level of 1 per 10,000,
i.e., areas where the elimination level is attained. For simulating various
situations and strategies, a hypothetical computerized population of 10
million persons was created. This population mimics the actual population
in terms of the empirical information on rural/urban distributions and the
distribution of households by size for the state of Tamil Nadu, India.
Various levels with respect to leprosy prevalence are created using this
population. The distribution of the number of cases in the population was
expected to follow the Poisson process, and this was also confirmed by
examination. Sample sizes and corresponding critical values were computed
using Poisson approximation. Initially, villages/towns are selected from
the population and from each selected village/town households are selected
using systematic sampling. Households instead of individuals are used as
sampling units. This sampling procedure was simulated 1000 times in the
computer from the base population. The results in four different prevalence
situations meet the required limits of Type I error of 5% and 90% Power. It
is concluded that after validation under field conditions, this method can
be considered for a rapid assessment of the leprosy situation.

=========================================================================
69.) Patient contact is the major determinant in incident leprosy:
implications for future control.
=========================================================================
Int J Lepr Other Mycobact Dis 1999 Jun;67(2):119-28

van Beers SM, Hatta M, Klatser PR
Department of Biomedical Research, Royal Tropical Institute, Amsterdam, The
Netherlands.

Notwithstanding the elimination efforts, leprosy control programs face the
problem of many leprosy patients remaining undetected. Leprosy control
focuses on early diagnosis through screening of household contacts,
although this high-risk group generates only a small proportion of all
incident cases. For the remaining incident cases, leprosy control programs
have to rely on self-reporting of patients. We explored the extent to which
other contact groups contribute to incident leprosy. We examined
retrospectively incident leprosy over 25 years in a high-endemic village of
2283 inhabitants in Sulawesi, Indonesia, by systematically reviewing data
obtained from the local program and actively gathering data through
interviews and a house-to-house survey. We investigated the contact status
in the past of every incident case. In addition to household contact, we
distinguished neighbor and social contacts. Of the 101 incident cases over
a 25-year period, 79 (78%) could be associated to contact with another
leprosy patient. Twenty-eight (28%) of these 101 cases were identified as
household contacts, 36 (36%) as neighbors, and the remaining 15 (15%) as
social contacts. Three patients had not had a traceable previous contact
with another leprosy patient, and no information could be gathered from 19
patients. The median span of time from the registration of the primary case
to that of the secondary case was 3 years; 95% of the secondary cases were
detected within 6 years after the primary case. The estimated risk for
leprosy was about nine times higher in households of patients and four
times higher in direct neighboring houses of patients compared to
households that had had no such contact with patients. The highest risk of
leprosy was associated with households of multibacillary patients. The risk
of leprosy for households of paucibacillary patients was similar to the
risk of leprosy for direct neighboring houses of multibacillary patients,
indicating that both the type of leprosy of the primary case and the
distance to the primary case are important contributing factors for the
risk of leprosy. Contact with a leprosy patient is the major determinant in
incident leprosy; the type of contact is not limited to household
relationships but also includes neighbor and social relationships. This
finding can be translated into a valuable and sustainable tool for leprosy
control programs and elimination campaigns by focusing case detection and
health promotion activities not only on household contacts but also on at
least the neighbors of leprosy cases.

=========================================================================
70.) A continuing focus of Hansen's disease in Texas.
=========================================================================
Am J Trop Med Hyg 1999 Mar;60(3):449-52

Taylor JP, Vitek I, Enriquez V, Smedley JW
Tuberculosis Elimination Division and Hansen's Disease Program, Texas
Department of Health, Austin 78756, USA.

To describe epidemiologic and clinical characteristics of Hansen's disease
cases in Texas, information was abstracted from records of 810 patients
reported from 1973 through 1997. Annually, from 18 to 54 patients were
reported. Average annual incidence rates ranged from 1.9 to 2.4 cases per
million population. A majority of the patients were male (63%) and white
(77%). More than half (53%) of the patients were born in the United States;
a majority (83%) of the patients born in the United States were born in
Texas. Most (76%) patients were diagnosed with multi-bacillary leprosy.
Foreign-born patients were more likely to be younger at onset and have
multi-bacillary disease compared with patients born in the United States.
Within Texas, an endemic focus of Hansen's disease exists along the Gulf of
Mexico coast.

=========================================================================
71.) An epidemiological study on Mycobacterium leprae infection and
prevalence of leprosy in endemic villages by molecular biological technique.
=========================================================================
Indian J Lepr 1999 Jan-Mar;71(1):37-43

Izumi S, Budiawan T, Saeki K, Matsuoka M, Kawatsu K
Ternate Leprosy Hospital, Maluku, Indonesia.

One of the most important unsolved questions in epidemiology of leprosy is
the highly uneven geographic distribution of the disease. There are many
hyperendemic "pockets" in endemic countries. Little is known about the
reasons why leprosy is hyperendemic in these areas. We conducted,
therefore, a series of epidemiological studies on Mycobacterium leprae
infection and prevalence of leprosy in North Maluku district, Maluku
Province, Indonesia where leprosy is highly endemic. It was found that
considerable number of general inhabitants are seropositive to various
mycobacterial antigens and 27% of the villagers were carrying leprosy
bacilli on their surface of nasal cavity. These results suggested the
importance of M. leprae in the residential environment in infection of the
leprosy bacillus and the resulting transmission of the disease. Based on
these observations, we conclude that new preventive measures are essential
for global elimination of leprosy in addition to early diagnosis and
multidrug therapy (MDT).

=========================================================================
72.) Antimycobacterial activities of riminophenazines.
=========================================================================
J Antimicrob Chemother 1999 May;43(5):615-23

Reddy VM, O'Sullivan JF, Gangadharam PR
Department of Biomedical Sciences, UIC College of Medicine at Rockford, IL
61107, USA.

Riminophenazines were specifically developed as drugs active against
Mycobacterium tuberculosis but extensive research over several decades has
shown that these compounds are also active against many other mycobacterial
infections, particularly those caused by Mycobacterium leprae and the
Mycobacterium avium complex (MAC). Clofazimine, the lead compound in this
series, is included in the regimens that are approved by the WHO for the
treatment of leprosy and has contributed significantly to the control of
that disease, particularly that caused by dapsone-resistant bacteria.
Despite early problems, clofazimine has shown clinical efficacy in
tuberculosis, in particular that caused by multiple drug resistant strains.
Clofazimine does not induce resistance and also inhibits emergence of
resistance to isoniazid in M. tuberculosis. The efficacy of clofazimine
against MAC is more varied and the availability of better drugs has limited
its use. Newer riminophenazines, such as B746 and B4157, not only showed
increased anti-mycobacterial activity but also produced less skin
pigmentation, which is the main drawback of this group of compounds. The
most important virtues of riminophenazines, such as intracellular
accumulation in mononuclear phagocytic cells, anti-inflammatory activity, a
low incidence of drug resistance and slow metabolic elimination, make them
attractive candidates for the treatment of mycobacterial infections. It is
essential, however, to investigate the newer analogues clinically, while
continuing the pursuit of alternate candidates that demonstrate higher
anti-mycobacterial activity and lower rates of skin pigmentation.

=========================================================================
73.) Nasal mucosa and skin of smear-positive leprosy patients after 24
months of fixed duration MDT: histopathological and microbiological study.
=========================================================================
Int J Lepr Other Mycobact Dis 1999 Sep;67(3):292-7

Ebenezer GJ, Job A, Abraham S, Arunthathi S, Rao PS, Job CK
Department of Histopathology and Experimental Pathology, Schieffelin
Leprosy Research and Training Center, Tamil Nadu, India.

The skin and nasal mucosa of 10 lepromatous leprosy patients who had
completed 24 doses of fixed duration multidrug therapy (MDT) but who
continued to be skin-smear positive for acid-fast bacilli (AFB) were
examined histopathologically. The nasal mucosa showed granuloma fractions
that exceeded those seen in the skin specimens, signifying that activity in
this region subsides much more gradually than the activity in the skin.
Mouse foot pad studies done using T900r mice with an inoculum from the
nasal mucosa biopsy specimens of these patients did not demonstrate any
growth of Mycobacterium leprae, indicating that these bacilli were not
viable. A skin specimen from one patient grew significant amounts of
bacteria in the T900r mouse foot pad. These results show that 2 years of
treatment with MDT would prevent dissemination of M. leprae from the nasal
mucosa and, therefore, should preclude further transmission of the disease.
It also indicates that viable bacteria might persist in the skin of
patients, especially those with an initial bacterial index of > or = 4+ who
have completed 24 doses of regular MDT. Therefore, a more cautious approach
to administering only 12 doses of MDT to highly positive multibacillary
patients is suggested.

=========================================================================
74.) Resolution of lepromatous leprosy after a short course of
amoxicillin/clavulanic acid, followed by ofloxacin and clofazimine.
=========================================================================
Int J Dermatol 1999 Jul;38(7):558-60

Villahermosa LG, Walsh DS, Fajardo TT Jr, Abalos RM, dela Cruz EC,
Veerasubramanian P, Walsh GP
Publication Types:

letter
=========================================================================
=========================================================================
75.) Effect of zafirlukast on leprosy reactions.
=========================================================================
Int J Lepr Other Mycobact Dis 1999 Mar;67(1):71-5

Vides EA, Cabrera A, Ahern KP, Levis WR
Publication Types:


Clinical trial
Clinical trial, phase ii
Letter
=========================================================================
=========================================================================
76.) Immunochemotherapy with interferon-gamma and multidrug therapy for
multibacillary leprosy.
=========================================================================
Acta Trop 1999 Mar 15;72(2):185-201

Barral-Netto M, Santos S, Santos I, von Sohsten R, Bittencourt AL, Carvalho
EM, Barral A, Waters M
Servico de Immunologia HUPES, Universidade Federal da Bahia, Brazil.
[email protected]

Treatment for multibacillary leprosy is presently performed with a
multidrug therapy (MDT) scheme maintained for 2 years. Leprosy treatment
however can benefit from the reduction of length. The lack of
interferon-gamma (IFN-gamma) production by lepromatous leprosy (LL)
patients' lymphocytes lead us to use this cytokine in the treatment of
multibacillary leprosy associated with MDT in the treatment of
multibacillary leprosy, and monitor several clinical and immunological
parameters during the course of treatment. A total of 20 multibacillary
leprosy patients were evaluated, 10 treated with MDT alone, and 10 treated
with MDT + 10 daily doses of 2 x 10(6) international units (IU) of
recombinant human IFN-gamma/m2 followed by 10 daily doses of 10(7) IU
IFN-gamma/m2, intramuscularly, during the first 20 days of MDT. IFN-gamma
was well tolerated and did not cause any increase in the rate of leprosy
reactions development during treatment. Decrease of bacillary load, fall of
anti-Mycobacterium leprae IgG serum antibodies, changes of histological
pattern, as well as changes in lymphocyte proliferation assay in response
to mitogens (PHA or PWM), M. leprae antigen or PPD was similar in both
groups of patients. Among several soluble immunological markers measured
before and 30 days after beginning of treatment, levels of soluble IL-2R
receptor increased in patients treated with MDT plus IFN-gamma whereas
decreased in patients treated with MDT alone. Soluble ICAM-1 levels
decreased in the MDT group but did not change in the MDT + IFN-gamma
treated patients. Soluble CD4 and soluble CD8 markers did not change
significantly in either group of patients. Neopterin, a marker of
macrophage activation, increased in all but one patient treated with MDT +
IFN-gamma but in none treated with MDT alone, indicating that IFN-gamma was
active in vivo. Our findings indicate that despite being able to promote
macrophage activation in multibacillary leprosy patients a short course of
systemically administered IFN-gamma is not able to change the clinical
course of a long standing disease such as leprosy.

===================================================================
77.) Thalidomide's effectiveness in erythema nodosum leprosum is
associated with a decrease in CD4+ cells in the peripheral blood.
===================================================================

SO - Lepr Rev 1992 Mar;63(1):5-11
AU - Shannon EJ; Ejigu M; Haile-Mariam HS; Berhan TY; Tasesse G
AD - Pharmacology Research Department, G.W. Long Hansen's Disease Center,
Carville, La 70721.
MJ - CD4-CD8 Ratio; Erythema Nodosum [drug therapy]; Leprosy, Lepromatous
[drug therapy]; Thalidomide [therapeutic use]
MN - Adult; Erythema Nodosum [immunology]; Leprosy, Lepromatous [immunology]
MT - Human; Male; Support, Non-U.S. Gov't
PT - JOURNAL ARTICLE
AB - Thalidomide is well documented as being an effective drug in the
treatment of erythema nodosum leprosum (ENL). The mechanism of action of
thalidomide in ENL as well as the pathogenesis of ENL are yet to be fully
determined. Lepromatous leprosy patients experiencing ENL have been
reported to have an increase in the ratio of CD4+ to CD8+ cells in their
blood and ENL skin lesions. Thalidomide has been shown to cause a decrease
in the ratio of CD4+ to CD8+ lymphocytes in the blood of healthy males.
This decrease was due to a significant reduction in the numbers of Cd4+
lymphocytes and an apparent increase in the numbers of CD8+ lymphocytes. In
this study, thalidomide's effectiveness in halting chronic ENL and
arresting a relapse into ENL was consistently associated with a decrease in
the numbers of CD4+ lymphocytes in the blood of 2 male lepromatous leprosy
patients.

===================================================================
78.) La lepra, Evolucion Historia, epidemiologica y medidas de control.
Autor: Zulueta R, Ana M
Dermatologia Venezolana, Vol. 2 No. 4, 1.992
===================================================================
79.) Leprosy in infants.
===================================================================
Baker B. et al.
In J leprosy 53:517-23
===================================================================
===================================================================
80.) Leprosy in a child of less than two months of age.
===================================================================
Benerjee, K, Meyers W.M.,
Clinical Dermatology, The CMD Case collection, World Congress Of Dermatology
Berlin (West),
May 24-29-1.987,: 149.

History. Patient was a less than 2 months oid male baby belonging to one of
the trained
nurses of our Institute. The chud had close, intimate contact with a
relative who suffered
from dimorphous
leprosy and who had taken treatment for only 6 months before discontinuing
it on his
own.
Examination. A round, elevated, red-dish lesion was detected on the face
(see attach).
Investigations. KOH mount of scrap-ings showed no fungus. A slit smear for
acid fast
bacilli was negative.
Histopathology. Skin biopsy material was sent to 4 different centres. Ah of
them
confirmed it to be Hansen's disease of a tuberculoid nature.
Treatment. The lesion resolved com-pletely within three months' treatment
with D.D.S.
2.5 mg for 5 days each week.
Conclusion. To my knowledge leprosy at less than 2 months of age has not
yet been
reported and may be disputed. Two cases of leprosy at 6 months of age were
reported
by Bruce Baker et al. The precise mode of natural transmission, the
incuba-tion period
and clinical manifestation have not yet been established. Early signs and
diagnosis may be
missed in the mistaken belief that leprosy is non-existent in the very young.
==================================================================
DATA-MEDICOS/DERMAGIC-EXPRESS No 2-(87) 26/01/2.000 DR. JOSE
LAPENTA R.
===================================================================

Produced by Dr. Jose Lapenta R. Dermatologist
              Maracay Estado Aragua Venezuela 2.000
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