Clofazimine therapy for lepromatous leprosy: a historical perspective.
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Adult↗
Biomedical subjects
G P Walsh
Publications and source records attributed to G P Walsh.
Protective immunization of monkeys with BCG or BCG plus heat-killed Mycobacterium leprae: clinical results.
Rhesus and sooty mangabey monkeys (RM and SMM) were vaccinated and boosted with BCG or BCG + low dose (LD) or high dose (HD) heat-killed Mycobacterium leprae (HKML). One group was not vaccinated. Except for a group of controls, all monkeys were challenged with live M. leprae. All animals were studied longitudinally to determine antileprosy protective efficacy. BCG reduced the numbers of RM with histopathologically-diagnosed leprosy by 70% and slowed and ameliorated the appearance of symptoms. BCG + LDHKML reduced the number of RM with leprosy by 89% and BCG + HDHKML by 78%. BCG did not protect SMM from developing leprosy, but disease progress was slowed; disease in SMM was exacerbated by the addition of HKML to the vaccine. RM, as a species, are prone to paucibacillary (PB) forms of leprosy, whereas SMM are prone to multibacillary (MB) forms. Thus, BCG vaccination offers significant protection from clinical disease and slows/ameliorates the rate of progression/degree of disease at the PB end and appears to at least ameliorate symptoms at the MB end of the leprosy spectrum. BCG + HKML protects at the PB end and exacerbates disease progress at the MB end of the leprosy spectrum.
Animals↗
Experimental leprosy in rhesus monkeys: transmission, susceptibility, clinical and immunological findings.
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.
Animals↗
Comparison of pentoxifylline, thalidomide and prednisone in the treatment of ENL.
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Adolescent↗
Multiple lesions of sporotrichoid leishmaniasis in a Filipino expatriate.
Sporotrichoid cutaneous leishmaniasis (CL) was diagnosed in a Filipino man who had worked in Saudi Arabia for 2 years. Two primary lesions-one on the forearm and one on the abdomen-were characterized by "satellite" papules and subcutaneous nodules extending proximally in a sporotrichoid pattern. Leishmania organisms were found in both primary lesions and a subcutaneous nodule. There was no evidence of systemic involvement. Recognition that Old World CL may disseminate through lymphatic channels has diagnostic and therapeutic importance.
Adult↗
Recombinant interleukin-2 in lepromatous leprosy lesions: immunological and microbiological consequences.
Seven patients with lepromatous leprosy (LL) were inoculated with recombinant interleukin-2 (rIL-2) at 5 lesional sites on the back, four sites receiving one dose of 10 micrograms and biopsy specimens being obtained on 4 consecutive days after the injection. At the 5th site, rIL-2 was instead administered over several days, three patients receiving a total dose of 40 micrograms and 4 patients 150 micrograms, while biopsy specimens from this site were obtained 7, 14 and 21 days after the first injection. Most injection sites developed features of a delayed-type hypersensitivity reaction, namely erythema and induration at the injection site, infiltrates rich in T helper cells, monocytes, and Langerhans cells, and at sites receiving higher doses, multinucleated Langhans giant cells and epithelioid granulomas. In some patients, there were favourable shifts in histological classification or small changes in bacterial load. Low doses of rIL-2 injected into LL lesions rapidly enhance cellular immunity and may alter the histological classification or bacterial load at the injection site.
Adolescent↗
Vitamin E and coronary heart disease.
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Animals↗
The Philippine cynomolgus monkey (Macaca fasicularis) provides a new nonhuman primate model of tuberculosis that resembles human disease.
A nonhuman primate model of tuberculosis that closely resembles human disease is urgently needed. We have evaluated the Philippine cynomolgus monkey, Macaca fasicularis, as a model of TB. Cynomolgus monkeys challenged intratracheally with extremely high doses of Mycobacterium tuberculosis (10(5) or 10(4) CFU) developed an acute, rapidly progressive, highly fatal multilobar pneumonia. However, monkeys challenged with moderate or low doses of M. tuberculosis (</=10(3) CFU) developed a chronic, slowly progressive, localized form of pulmonary TB, akin to the disease in humans, that was frequently accompanied by such clinical syndromes as ocular tuberculosis, meningitis and tuberculous spondylitis. A significant proportion of monkeys challenged with 10(2) or 10(1) CFU contained the infection in a subclinical state. The Philippine cynomolgus monkey model is an excellent model of chronic TB and provides an opportunity to study subclinical and potentially latent disease in an animal model.
Acute Disease↗
Ultrastructure of normal armadillo epidermis.
In view of the importance of the nine-banded armadillo (Dasypus novemcinctus) in leprosy research, we studied the ultrastructure of the normal epidermis of this species. The three basic cell types of human epidermis were identified in armadillo skin: keratinocytes, melanocytes, and Langerhans' cells. The role of Langerhans' cells in the human cell-mediated immune system and the description of changes in the number and structure of Langerhans' cells in human leprosy make detailed observations of these cells in the armadillo highly relevant. Clear cells with ultrastructural features typical of Langerhans' cells were observed in normal armadillo epidermis in all areas of skin sampled (abdomen, chin, ear, and thigh), but are fewer than in human skin. These baseline findings are valuable for further studies on Langerhans' cells and the cell-mediated immune function in armadillos with naturally acquired or experimental leprosy.
Animals↗
Primary dapsone resistance in Cebu, The Philippines; cause for concern.
At a time when primary dapsone resistance was prevalent in many leprosy endemic areas, Cebu in The Philippines reported only 3.6% in the period 1975-1978 and later 8.1% in the period 1979-1982. In our current study of patients in the period 1988-1992, the number increased dramatically to 52.7%. In addition, 7.9% of the isolates are highly resistant to dapsone, a level of resistance not seen in earlier studies. This finding could have severe ramifications to the World Health Organization's multidrug therapy (WHO-MDT) mode of treatment, where dapsone is one of the principal drugs. Moreover, the increase in primary dapsone resistance may be a contributing factor in the recent finding that there has been no decline in the number of new cases found in Cebu, even after the implementation of WHO-MDT in 1985. There is a need for new drugs that could be included in the multidrug treatment for multibacillary and paucibacillary leprosy.
Animals↗
Use of NASBA RNA amplification for detection of Mycobacterium leprae in skin biopsies from untreated and treated leprosy patients.
This study was performed to assess the value of NASBA RNA amplification of a 16S rRNA target for the detection of presumably viable Mycobacterium leprae in sections of skin biopsies from leprosy patients. The NASBA positivity rate was 90.4% (84/93) for untreated multibacillary (MB) patients [bacterial index (BI) > or = 2] and 16.7% (8/48) for the untreated paucibacillary (PB) patients (BI < 2). NASBA positivity showed a good concordance with the presence of solidly stained M. leprae [morphological index (MI)] in skin biopsies from leprosy patients, but no relationship could be demonstrated between the strength of the NASBA signals and the BI. Furthermore, the usefulness of the detection of 16S rRNA by NASBA to monitor the efficacy of leprosy treatment was investigated using an additional 154 biopsy specimens analyzed from 80 MB patients during the course of treatment. The NASBA positivity rate declined during treatment. A significant decrease was observed after only 1-3 months. These results favor the view that detection of RNA by NASBA may reflect the viability of M. leprae.
Biopsy↗
Does diet or alcohol explain the French paradox.
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Adult↗
Minocycline in lepromatous leprosy.
Twelve patients were treated with three dose levels of minocycline for 30 days, primarily to detect the dose-related effects on Mycobacterium leprae viability, followed by another 5 months of daily minocycline for overall efficacy and persistence of clinical and antibacterial effects. Subsequently, the patients were given standard WHO/MDT chemotherapy for multibacillary leprosy. Clinical improvement was recognizable during the first month, occurring much earlier among those on minocycline 200 mg daily than those who received minocycline 100 mg daily. A similar change also was observed in one patient 11 days after three daily doses of 100 mg of minocycline. At the end of 6 months, all patients were clinically improved with a slight reduction in the average bacterial index (BI) and logarithmic index of bacilli in biopsy (LIB). The effects of minocycline on viability by mouse foot pad inoculation and palmitic acid oxidation assays were noted beginning at 10 to 14 days of daily dosing and becoming more definite after 30 days of treatment. Both tests correlated fairly well. Doses of 200 mg daily did not appear to be more efficient than minocycline 100 daily. Phenolic glycolipid-I (PGL-I) antigen determinations done on some patients during the first month remained positive and did not correlate with changes in viability results. At the end of 6 months, after 5 months of 100 mg of minocycline monotherapy, no viable organisms could be demonstrated by mouse foot pad inoculation and palmitic acid oxidation assays; assays for PGL-I antigen were all negative.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
T cells bearing V beta 6 T cell receptors in the cell-mediated immune response to Mycobacterium leprae.
The skin lesions of leprosy provide a window into the immunoregulatory events involved in the human immune response to infection. T cells are thought to play a vital role in the pathogenesis of different forms of the disease. To identify predominant specific T cell subpopulations in leprosy lesions, the TCR-beta chain repertoire was simultaneously studied in skin biopsy specimens and PBMC from both immunologically resistant tuberculoid leprosy and susceptible lepromatous leprosy patients. This was accomplished by obtaining RNA from lesions and PBMC, synthesizing cDNA, and performing the polymerase chain reaction. We found that TCR gene subfamilies V beta 6.1 through V beta 6.4 (V beta 6.1-4) were strikingly overrepresented in lesions vs PBMC of seven of nine tuberculoid patients but only one of nine lepromatous patients. Similarly, V beta 6.5/6.8/6.9 subfamilies were predominant in four of nine tuberculoid patients, but none of the nine lepromatous patients. To explore the influence of the complementarity-determining region 3 (CDR3) in selection of T cells expressing V beta 6 TCR, we sequenced the V beta 6.1-4-C beta polymerase chain reaction products derived from the lesions and PBMC of two tuberculoid patients. From the analysis of deduced amino acid sequences, we found conserved amino acid residues and amino acid motifs in the CDR3 region of the lesion-derived sequences from each patient. Our data suggest that the nominal Ag select T cells bearing V beta 6 TCR in the cell-mediated immune response to Mycobacterium leprae.
Amino Acid Sequence↗
Evaluation of polymerase chain reaction amplification of Mycobacterium leprae-specific repetitive sequence in biopsy specimens from leprosy patients.
Biopsy specimens were obtained from 102 leprosy patients before chemotherapy and examined by polymerase chain reaction (PCR) using the primers amplifying the 372-bp DNA of a repetitive sequence of Mycobacterium leprae. The PCR results were then compared with bacterial indices (BI) of slit-skin smears and biopsy specimens. The intensities of DNA bands were in general correlated with the numbers of acid-fast bacilli, and even a sample with only one organism gave a PCR positive result. Ten 5-micron sections from each frozen tissue sample were pooled and processed for DNA preparation. PCR was positive for 11 (73.3%) of 15 biopsy specimens with BI of 0 determined for the paraffin sections from the same biopsy samples. PCR also gave positive results for 84 (96.6%) of 87 BI positive biopsy samples. Although the difference in overall results between the two methods was not statistically significant, PCR seemed to have an advantage over microscopic examination in detecting M. leprae in biopsy specimens negative for acid-fast bacilli. Further evaluation of PCR using more specimens from leprosy patients who are bacteriologically negative is warranted to ensure PCR's advantage over the conventional microscopic examination for the diagnosis of leprosy.
Base Sequence↗
Cross-sectional assessment of ELISA reactivity in leprosy patients, contacts, and normal population using the semisynthetic antigen natural disaccharide octyl bovine serum albumin (ND-O-BSA) in Cebu, The Philippines.
An indirect enzyme-linked immunosorbent assay (ELISA) using natural disaccharide octyl bovine serum albumin (ND-O-BSA) as antigen was used in testing leprosy patients, contacts and a normal population in Cebu, The Philippines, from 1985 to 1989. A total of 1413 persons were studied. The results suggested that ELISA reactivity and the bacterial index (BI) correlate in a general way. In multibacillary (MB) leprosy, positivity ranges from 54.2% to 92.3% among patients with a BI of < 2+ to > 4+ on the Ridley scale, with an overall average of 84.5%. Paucibacillary (PB) leprosy patients have a low degree of reactivity, with only 15.0% ELISA positive. The test is more efficient in detecting MB than PB leprosy. The contacts of MB leprosy showed 6.5% positivity; contacts of PB leprosy, 7.0% positivity. The normal population showed 1.7% positive ELISA or 17 per thousand population, which is very much less than that of the household contacts. However, because the normal population is a much larger population than the household contact population in a community, more new leprosy cases would emanate from it. Leprosy workers are concerned about the transmission of the disease to household contacts. However, for the reason stated above, we should be more concerned with the silent spread of the disease to the normal population in the community.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗