|
The Leprosy, 2000 years
later
La Lepra, 2.000 años después.
Data-Médicos
Dermagic/Express No.
2-(87)
26 Enero 2.000 26 January 2.000
EDITORIAL ESPAÑOL
=================
Hola
amigos de la red, DERMAGIC hoy con el tema de la ENFERMEDAD DE
HANSEN (LEPRA)2.000 AÑOS DESPUÉS.
Realmente esta enfermedad
tiene mas de 2.000 años de evolución en nuestro planeta pues las
primeras descripciones de la enfermedad datan del siglo XVI
antes de Cristo, encontrándose las primeras referencias en el
libro sagrado de la antigua India.
Muchos años han
pasado y muchas investigaciones se han hecho, enfermedad de
difícil tratamiento, ancestral y de distribución mundial que
figura en la Biblia lo cual le da ese toque apocaliptico a
esta temida enfermedad, causa de discriminación social aun en
nuestros días.
Fue Armauer Hansen quien descubrió 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 fabricación de
diferentes vacunas que están siendo utilizadas hoy dia,
pasaron muchos años.
En estas 80 referencias bibliográficas
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
organización mundial de la salud (OMS), la cual acorto el tiempo
del tratamiento. gran error.
2.) La comprobación de que
antibióticos como la OFLOXACINA, MINOCICLINA, ACIDO CLAVULANICO
mas AMOXACILINA) Y CLARITROMICINA son altamente bactericidas
contra el Mycobacterium leprae.
3.) La
comprobación de la
resistencia al tratamiento con Diaminodifenilsulfona.
4.)
El éxito de la Talidomida para tratar el ERITEMA NODOSO LEPROSO, que
motivo su comercialización OTRA VEZ EN LOS ESTADOS UNIDOS DE
NORTEAMÉRICA desde 1.998
5.) La aparición de la
inmuno-quimioterapia como alternativa de tratamiento tales como:
inmuno-quimioterapia con interferón-gamma y terapia múltiple
(MTD), ANTIBIÓTICOS y terapia múltiple, vacunas y MTD.
6.) La utilización de Anti leukotrienos como el ZAFIRLUKAST para
tratar la reacción leprosa.
7.) La aparición de
nuevas técnicas diagnosticas (PCR) para observar el
comportamiento y pronostico de la enfermedad, que ayudan a las
viejas tales como Mitsuda, Reacción de Fernández y CCB test.
8.) La comprobación de una susceptibilidad genética
determinada por los antígenos de Histocompatibilidad (HLA)
para adquirir o resistir la enfermedad.
9.) El éxito en
reproducir la enfermedad en animales.
10.) El comprobado
efecto protectivo de bacilo de Calmette Guerin (BCG) contra la
lepra.
11.) La aparición de nuevas drogas con actividad
anti-micobacteriana como las RIMINOFENAZINAS.
12.) La
nueva vacuna inmuno-terapéutica para la lepra basada en el Micobacterium w
(nombre código bajo el cual estas especies son
investigadas) DESARROLLADA EN LA INDIA.
13.) El talismán
perdido: catastrófica declinación en la utilización de bacilos
provenientes de armadillos para la producción de vacunas.
(referencia 62)
14.) La Preservación del Micobacterium
leprae in vitro por 4 años por liofilización.
15.)
Todavía en nuestros dias el contacto con pacientes es el mayor
determinante en la incidencia de lepra.
16.) La
persistencia de la enfermedad en muchas áreas de nuestro mundo.
17.) El bichito (bacilo) todavía 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 seguirá siendo la lepra ...
Saludos a todos !!!
Dr. José 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 inocycline, 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 BacillusCalmette-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
inkage 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). T
he
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.
Not with standing 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-MÉDICOS/DERMAGIC-EXPRESS No 2-(87) 26/01/2.000 DR. JOSÉ
LAPENTA R.
===================================================================
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