Controlled Clinical Trial of Clofazimine in Untreated Lepromatous Leprosy

A comparison of clofazimine and dapsone in the management of untreated lepromatous leprosy showed no significant differences between the two drugs in terms of morphological and bacterial indices. The incidence of erythema nodosum leprosum was similar in the two groups. Since dapsone is cheaper than clofazimine it remains the drug of choice for the routine management of untreated lepromatous leprosy.     

Osteological and Biomolecular Evidence of a 7000-Year-Old Case of Hypertrophic Pulmonary Osteopathy Secondary to Tuberculosis from Neolithic Hungary

Seventy-one individuals from the late Neolithic population of the 7000-year-old site of Hódmezővásárhely-Gorzsa were examined for their skeletal palaeopathology. This revealed numerous cases of infections and non-specific stress indicators in juveniles and adults, metabolic diseases in juveniles, and evidence of trauma and mechanical changes in adults. Several cases showed potential signs of tuberculosis, particularly the remains of the individual HGO-53. This is an important finding that has significant implications for our understanding of this community. The aim of the present study was to seek biomolecular evidence to confirm this diagnosis. HGO-53 was a young male with a striking case of hypertrophic pulmonary osteopathy (HPO), revealing rib changes and cavitations in the vertebral bodies. The initial macroscopic diagnosis of HPO secondary to tuberculosis was confirmed by analysis of Mycobacterium tuberculosis complex specific cell wall lipid biomarkers and corroborated by ancient DNA (aDNA) analysis. This case is the earliest known classical case of HPO on an adult human skeleton and is one of the oldest palaeopathological and palaeomicrobiological tuberculosis cases to date.     

Differential Dermal Expression of CCL17 and CCL18 in Tuberculoid and Lepromatous Leprosy

Background

Leprosy is characterized by polar clinical, histologic and immunological presentations. Previous immunologic studies of leprosy polarity were limited by the repertoire of cytokines known at the time.

Methodology

We used a candidate gene approach to measure mRNA levels in skin biopsies from leprosy lesions. mRNA from 24 chemokines and cytokines, and 6 immune cell type markers were measured from 85 Nepalese leprosy subjects. Selected findings were confirmed with immunohistochemistry.

Principal Results

Expression of three soluble mediators (CCL18, CCL17 and IL-10) and one macrophage cell type marker (CD14) was significantly elevated in lepromatous (CCL18, IL-10 and CD14) or tuberculoid (CCL17) lesions. Higher CCL18 protein expression by immunohistochemistry and a trend in increased serum CCL18 in lepromatous lesions was observed. No cytokines were associated with erythema nodosum leprosum or Type I reversal reaction following multiple comparison correction. Hierarchical clustering suggested that CCL18 was correlated with cell markers CD209 and CD14, while neither CCL17 nor CCL18 were highly correlated with classical TH1 and TH2 cytokines.

Conclusions

Our findings suggest that CCL17 and CCL18 dermal expression is associated with leprosy polarity.     

Mycobacterium leprae-Infected Macrophages Preferentially Primed Regulatory T Cell Responses and Was Associated with Lepromatous Leprosy

Background

The persistence of Mycobacterium leprae (M. leprae) infection is largely dependent on the types of host immune responses being induced. Macrophage, a crucial modulator of innate and adaptive immune responses, could be directly infected by M. leprae. We therefore postulated that M. leprae-infected macrophages might have altered immune functions.

Methodology/Principal Findings

Here, we treated monocyte-derived macrophages with live or killed M. leprae, and examined their activation status and antigen presentation. We found that macrophages treated with live M. leprae showed committed M2-like function, with decreased interleukin 1 beta (IL-1beta), IL-6, tumor necrosis factor alpha (TNF-alpha) and MHC class II molecule expression and elevated IL-10 and CD163 expression. When incubating with naive T cells, macrophages treated with live M. leprae preferentially primed regulatory T (Treg) cell responses with elevated FoxP3 and IL-10 expression, while interferon gamma (IFN-gamma) expression and CD8⁺ T cell cytotoxicity were reduced. Chromium release assay also found that live M. leprae-treated macrophages were more resistant to CD8⁺ T cell-mediated cytotoxicity than sonicated M. leprae-treated monocytes. Ex vivo studies showed that the phenotype and function of monocytes and macrophages had clear differences between L-lep and T-lep patients, consistent with the in vitro findings.

Conclusions/Significance

Together, our data demonstrate that M. leprae could utilize infected macrophages by two mechanisms: firstly, M. leprae-infected macrophages preferentially primed Treg but not Th1 or cytotoxic T cell responses; secondly, M. leprae-infected macrophages were more effective at evading CD8⁺ T cell-mediated cytotoxicity.     

Forensic Osteological Analysis: A Book of Case Studies

Forensic Osteological Analysis:. Book of Case Studies. Scott I. Fairgrieve. Springfield, IL: Charles C. Thomas Publisher, 1999. 340 pp.     

Osteological development of the lophiid anglerfish,lophius gastrophysus

The osteological development of the head skeleton and dorsal, pectoral, and anal fin supports, are described from cleared and stained specimens ofLophius gastrophysus larvae, ranging from 4.6 to 21.8 mm NL; the results are compared with those of juvenile (79.8 mm SL) and adult (398 mm SL) specimens. Tiny conical teeth are present on the premaxillary, dentary, palatine and vomer since early stage. The first three dorsal fin spines are initially positioned on the midline of body posterior to the supraoccipital, but they migrate forward with growth and become cephalic in juveniles. The forward movement of the dorsal spines is produced by the forward extension of the cartilaginous basal inside the subepidermal space. During the planktonic larval stage the pectoral fins are on the sides of body as in ordinary fishes, but they move ventrad and become leg-like in bottom living juveniles and adults. Ossification of the caudal complex ofL. gastrophysus larvae proceeds very slowly and only the 21.8 mm NL larva has an almost completely ossified caudal complex. Eight principal caudal rays are loosely attached on the posterior edge of the hypurals and no procurrent rays are present. Larvae have well developed parhypurapophysis at the mid-portion of the urostyle which transforms into keel-like structure in juveniles and adults.     

Osteological development of Cope's Gray Treefrog,Hyla chrysoscelis

Hyla chrysoscelis, Cope's Gray Treefrog, is a generalized treefrog found throughout much of east‐central North America. Although it is a model for many behavioural and ecological studies, little is known of its skeletal morphology or development. Herein, we describe the postembryonic skeletal development and adult osteology of H. chrysoscelis. The adult skull is well ossified with slight dermal ornamentation, the postcranial and tadpole skeletons are fairly non‐distinct with no obvious novel morphologies, and the Gosner stage by which bony elements first appear varies. We compare the rank order sequence of ossification to that of its sibling species Hyla versicolor and use examples from this study to demonstrate current complications with conducting ossification sequence meta‐analyses.     

Lepromatous leprosy presenting with polyarthritis,myositis, and immune-complex glomerulonephritis.

A Pakistani man aged 19 years was admitted to a rheumatological unit in the United Kingdom with acute widespread polyarthritis accompanied by night sweats and fever. Preliminary examination suggested Reiter''s disease, but further investigation showed acute glomerulonephritis with uraemia. The possibility of periarteritis nodosa, and the prominence of muscle tenderness in the legs, led to biopsies of striated muscle and skin, in both of which were changes typical of lepromatous leprosy, with many Mycobacterium leprae on Ziehl-Neelsen staining. Serum showed IgG-IgM cryoglobulinaemia without antiglobulin activity, and in the recovery phase renal biopsy showed a resolving proliferative glomerulonephritis with linear IgG and IgM immunofluorescence and granular deposits of C3. Clinical signs subsided rapidly under steroid treatment and subsequent progress on anti-leprosy drugs was uneventful. The term erythema nodosum leprosum is inadequate and misleading as a title for a common and important immune-complex reaction of lepromatous leprosy, in which numerous body systems may be involved.     

Osteological and molecular identification of Brucellosis in ancient Butrint, Albania

Ancient skeletal remains can harbor unique information about past civilizations at both the morphological and molecular levels. For instance, a number of diseases manifest in bone, some of which have been confirmed through DNA analysis, verifying their presence in ancient populations. In this study, anthropological analysis of skeletal remains from the ancient Albanian city of Butrint identified individuals with severe circular lytic lesions on their thoracic and lumbar vertebrae. Differential diagnosis suggested that the lesions resulted from pathologies known to affect these skeletal regions, such as tuberculosis (TB) or brucellosis. Relevant bones of two adolescent males from the 10th to 13th century AD that displayed the lesions, along with unaffected individuals, were collected in the field. Genetic screening of the skeletal samples for TB was repeatedly negative, thus additional testing for Brucella spp.-bacteria of livestock and the causative agent of brucellosis in humans-was conducted. Two Brucella DNA markers, the IS6501 insertion element and Bcsp31 gene, amplified from the affected vertebrae and/or ribs, whereas all unaffected individuals and control samples were negative. Subsequent DNA sequencing confirmed the presence of the brucellar IS6501 insertion element. On the basis of the skeletal lesions, negative tests for TB, and positive Brucella findings, we report a confirmed occurrence of brucellosis in archaeologically recovered human bone. These findings suggest that brucellosis has been endemic to the area since at least the Middle Ages.     

Cost-Effectiveness Analysis of Three Leprosy Case Detection Methods in Northern Nigeria

Background

Despite several leprosy control measures in Nigeria, child proportion and disability grade 2 cases remain high while new cases have not significantly reduced, suggesting continuous spread of the disease. Hence, there is the need to review detection methods to enhance identification of early cases for effective control and prevention of permanent disability. This study evaluated the cost-effectiveness of three leprosy case detection methods in Northern Nigeria to identify the most cost-effective approach for detection of leprosy.

Methods

A cross-sectional study was carried out to evaluate the additional benefits of using several case detection methods in addition to routine practice in two north-eastern states of Nigeria. Primary and secondary data were collected from routine practice records and the Nigerian Tuberculosis and Leprosy Control Programme of 2009. The methods evaluated were Rapid Village Survey (RVS), Household Contact Examination (HCE) and Traditional Healers incentive method (TH). Effectiveness was measured as number of new leprosy cases detected and cost-effectiveness was expressed as cost per case detected. Costs were measured from both providers'' and patients'' perspectives. Additional costs and effects of each method were estimated by comparing each method against routine practise and expressed as incremental cost-effectiveness ratio (ICER). All costs were converted to the U.S. dollar at the 2010 exchange rate. Univariate sensitivity analysis was used to evaluate uncertainties around the ICER.

Results

The ICER for HCE was $142 per additional case detected at all contact levels and it was the most cost-effective method. At ICER of $194 per additional case detected, THs method detected more cases at a lower cost than the RVS, which was not cost-effective at $313 per additional case detected. Sensitivity analysis showed that varying the proportion of shared costs and subsistent wage for valuing unpaid time did not significantly change the results.

Conclusion

Complementing routine practice with household contact examination is the most cost-effective approach to identify new leprosy cases and we recommend that, depending on acceptability and feasibility, this intervention is introduced for improved case detection in Northern Nigeria.