SARS-CoV-2 (COVID-19) structural and evolutionary dynamicome: Insights into functional evolution and human genomics.

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has challenged the speed at which laboratories can discover the viral composition and study health outcomes. The small ∼30-kb ssRNA genome of coronaviruses makes them adept at cross-species spread while enabling a robust understanding of all of the proteins the viral genome encodes. We have employed protein modeling, molecular dynamics simulations, evolutionary mapping, and 3D printing to gain a full proteome- and dynamicome-level understanding of SARS-CoV-2. We established the Viral Integrated Structural Evolution Dynamic Database (VIStEDD at RRID:SCR_018793) to facilitate future discoveries and educational use. Here, we highlight the use of VIStEDD for nsp6, nucleocapsid (N), and spike (S) surface glycoprotein. For both nsp6 and N, we found highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we developed a quantitative dynamics cross-correlation matrix to gain insights into its interactions with the angiotensin I-converting enzyme 2 (ACE2)-solute carrier family 6 member 19 (SLC6A19) dimer. Using this quantitative matrix, we elucidated 47 potential functional missense variants from genomic databases within ACE2/SLC6A19/transmembrane serine protease 2 (TMPRSS2), warranting genomic enrichment analyses in SARS-CoV-2 patients. These variants had ultralow frequency but existed in males hemizygous for ACE2. Two ACE2 noncoding variants (rs4646118 and rs143185769) present in ∼9% of individuals of African descent may regulate ACE2 expression and may be associated with increased susceptibility of African Americans to SARS-CoV-2. We propose that this SARS-CoV-2 database may aid research into the ongoing pandemic.

SARS-CoV-2 infection: molecular mechanisms of severe outcomes to suggest therapeutics.

Introduction:The year 2020 was defined by the 29,903 base pairs of RNA that codes for the SARS-CoV-2 genome. SARS-CoV-2 infects humans to cause COVID-19, spreading from patient-to-patient yet impacts patients very divergently.Areas covered: Within this review, we address the known molecular mechanisms and supporting data for COVID-19 clinical course and pathology, clinical risk factors and molecular signatures, therapeutics of severe COVID-19, and reinfection/vaccination. Literature and published datasets were reviewed using PubMed, Google Scholar, and NCBI SRA tools. The combination of exaggerated cytokine signaling, pneumonia, NETosis, pyroptosis, thrombocytopathy, endotheliopathy, multiple organ dysfunction syndrome (MODS), and acute respiratory distress syndrome (ARDS) create a positive feedback loop of severe damage in patients with COVID-19 that impacts the entire body and may persist for months following infection. Understanding the molecular pathways of severe COVID-19 opens the door for novel therapeutic design. We summarize the current insights into pathology, risk factors, secondary infections, genetics, omics, and drugs being tested to treat severe COVID-19.Expert opinion: A growing level of support suggests the need for stronger integration of biomarkers and precision medicine to guide treatment strategies of severe COVID-19, where each patient has unique outcomes and thus require guided treatment.

Diagnostic Accuracy of Clinical and Microbiological Signs in Patients With Skin Lesions Resembling Buruli Ulcer in an Endemic Region.

Background: The diagnosis of the neglected tropical skin and soft tissue disease Buruli ulcer (BU) is made on clinical and epidemiological grounds, after which treatment with BU-specific antibiotics is initiated empirically. Given the current decline in BU incidence, clinical expertise in the recognition of BU is likely to wane and laboratory confirmation of BU becomes increasingly important. We therefore aimed to determine the diagnostic accuracy of clinical signs and microbiological tests in patients presenting with lesions clinically compatible with BU. Methods: A total of 227 consecutive patients were recruited in southern Benin and evaluated by clinical diagnosis, direct smear examination (DSE), polymerase chain reaction (PCR), culture, and histopathology. In the absence of a gold standard, the final diagnosis in each patient was made using an expert panel approach. We estimated the accuracy of each test in comparison to the final diagnosis and evaluated the performance of 3 diagnostic algorithms. Results: Among the 205 patients with complete data, the attending clinicians recognized BU with a sensitivity of 92% (95% confidence interval [CI], 85%-96%), which was higher than the sensitivity of any of the laboratory tests. However, 14% (95% CI, 7%-24%) of patients not suspected to have BU at diagnosis were classified as BU by the expert panel. The specificities of all diagnostics were high (≥91%). All diagnostic algorithms had similar performances. Conclusions: A broader clinical suspicion should be recommended to reduce missed BU diagnoses. Taking into consideration diagnostic accuracy, time to results, cost-effectiveness, and clinical generalizability, a stepwise diagnostic approach reserving PCR to DSE-negative patients performed best.

Buruli ulcer in traveler from Suriname, South America, to the Netherlands.

We report Buruli ulcer in a man in the Netherlands. Phenotyping of samples indicate the Buruli pathogen was acquired in Suriname and activated by trauma on return to the Netherlands. Awareness of this disease by clinicians in non-Buruli ulcer-endemic areas is critical for identification.

Patient access innovations: integrating patients within the system of care.

Clinically integrated networks seeking to ensure in-network access and strengthen patient engagement should adopt five strategic areas of focus: Extend access beyond traditional models. Manage out-migration. Make it easy for patients to stay in the network. Build patient engagement into clinical care models. Explore innovative methods to engage patients.

Origin and spread of leprosy in Suriname. A historical and biomedical study.

The new world was considered free of leprosy before the arrival of Europeans. In Suriname, historical migration routes suggest that leprosy could have been introduced from West Africa by the slave trade, from Asia by indentured workers, from Europe by the colonizers, and more recently by Brazilian gold miners. Previous molecular studies on environmental and ancient samples suggested a high variability of the strains circulating in the country, possibly resulting from the various migration waves. However, a current overview of such diversity in humans still needs to be explored. The origin and spread of leprosy in Suriname are investigated from a historical point of view and by strain genotyping of Mycobacterium leprae from skin biopsies of 26 patients with multibacillary leprosy using PCR-genotyping and whole-genome sequencing. Moreover, molecular signs of resistance to the commonly used anti-leprosy drugs i.e. dapsone, rifampicin and ofloxacin, were investigated. Molecular detection was positive for M. leprae in 25 out of 26 patient samples, while M. lepromatosis was not found in any of the samples. The predominant M. leprae strain in our sample set is genotype 4P (n=8) followed by genotype 1D-2 (n=3), 4N (n=2), and 4O/P (n=1). Genotypes 4P, 4N, 4O/P are predominant in West Africa and Brazil, and could have been introduced in Suriname by the slave trade from West Africa, and more recently by gold miners from Brazil. The presence of the Asian strains 1D-2 probably reflects an introduction by contract workers from India, China and Indonesia during the late 19th and early 20th century after the abolition of slavery. There is currently no definite evidence for the occurrence of the European strain 3 in the 26 patients. Geoplotting reflects internal migration, and also shows that most patients live in and around Paramaribo. A biopsy of one patient harbored two M. leprae genotypes, 1D-2 and 4P, suggesting co-infection. A mutation in the dapsone resistance determining region of folP1 was detected in two out of 13 strains for which molecular drug susceptibility was obtained, suggesting the circulation of dapsone resistant strains.

Lepra Bubalorum, a Potential Reservoir of Mycobacterium leprae.

In 1926, a mycobacterial skin disease was observed in water buffaloes by researchers in Indonesia. The disease was designated as skin tuberculosis, though it was hypothesized that it might be a form of leprosy or a leprosy-like disease. In a follow-up study (Ph.D. thesis Lobel, 1934, Utrecht University, Netherlands) a similar nodular skin disease was described in Indonesian water buffaloes and named "lepra bubalorum" or "nodular leprosy." Two decades later Kraneveld and Roza (1954) reported that, so far, the diagnosis lepra bubalorum had been made in 146 cases in Indonesia. After a final series of research reports by Indonesian veterinarians in 1961, no subsequent cases were published. Based on information from these reports, it can be concluded that, even though evidence of nerve involvement in buffaloes was not reported, similarities exist between lepra bubalorum and Hansen's disease (leprosy), i.e., nodular skin lesions with a chronic course and microscopically granulomatous reactions with AFB in globi in vacuoles. This raises the question as to whether these historical cases might indeed have been caused by Mycobacterium leprae, Mycobacterium lepromatosis or another representative of the M. leprae complex. The future use of state-of-the-art molecular techniques may answer this question and may also help to answer the question whether water buffaloes should be considered as a potential natural reservoir of the causative pathogen of Hansen's disease.

High-Density Blood Transcriptomics Reveals Precision Immune Signatures of SARS-CoV-2 Infection in Hospitalized Individuals.

The immune response to COVID-19 infection is variable. How COVID-19 influences clinical outcomes in hospitalized patients needs to be understood through readily obtainable biological materials, such as blood. We hypothesized that a high-density analysis of host (and pathogen) blood RNA in hospitalized patients with SARS-CoV-2 would provide mechanistic insights into the heterogeneity of response amongst COVID-19 patients when combined with advanced multidimensional bioinformatics for RNA. We enrolled 36 hospitalized COVID-19 patients (11 died) and 15 controls, collecting 74 blood PAXgene RNA tubes at multiple timepoints, one early and in 23 patients after treatment with various therapies. Total RNAseq was performed at high-density, with >160 million paired-end, 150 base pair reads per sample, representing the most sequenced bases per sample for any publicly deposited blood PAXgene tube study. There are 770 genes significantly altered in the blood of COVID-19 patients associated with antiviral defense, mitotic cell cycle, type I interferon signaling, and severe viral infections. Immune genes activated include those associated with neutrophil mechanisms, secretory granules, and neutrophil extracellular traps (NETs), along with decreased gene expression in lymphocytes and clonal expansion of the acquired immune response. Therapies such as convalescent serum and dexamethasone reduced many of the blood expression signatures of COVID-19. Severely ill or deceased patients are marked by various secondary infections, unique gene patterns, dysregulated innate response, and peripheral organ damage not otherwise found in the cohort. High-density transcriptomic data offers shared gene expression signatures, providing unique insights into the immune system and individualized signatures of patients that could be used to understand the patient's clinical condition. Whole blood transcriptomics provides patient-level insights for immune activation, immune repertoire, and secondary infections that can further guide precision treatment.

Reservoirs and transmission routes of leprosy; A systematic review.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae (M. leprae) and the more recently discovered Mycobacterium lepromatosis (M. lepromatosis). The two leprosy bacilli cause similar pathologic conditions. They primarily target the skin and the peripheral nervous system. Currently it is considered a Neglected Tropical Disease, being endemic in specific locations within countries of the Americas, Asia, and Africa, while in Europe it is only rarely reported. The reason for a spatial inequality in the prevalence of leprosy in so-called endemic pockets within a country is still largely unexplained. A systematic review was conducted targeting leprosy transmission research data, using PubMed and Scopus as sources. Publications between January 1, 1945 and July 1, 2019 were included. The transmission pathways of M. leprae are not fully understood. Solid evidence exists of an increased risk for individuals living in close contact with leprosy patients, most likely through infectious aerosols, created by coughing and sneezing, but possibly also through direct contact. However, this systematic review underscores that human-to-human transmission is not the only way leprosy can be acquired. The transmission of this disease is probably much more complicated than was thought before. In the Americas, the nine-banded armadillo (Dasypus novemcinctus) has been established as another natural host and reservoir of M. leprae. Anthroponotic and zoonotic transmission have both been proposed as modes of contracting the disease, based on data showing identical M. leprae strains shared between humans and armadillos. More recently, in red squirrels (Sciurus vulgaris) with leprosy-like lesions in the British Isles M. leprae and M. lepromatosis DNA was detected. This finding was unexpected, because leprosy is considered a disease of humans (with the exception of the armadillo), and because it was thought that leprosy (and M. leprae) had disappeared from the United Kingdom. Furthermore, animals can be affected by other leprosy-like diseases, caused by pathogens phylogenetically closely related to M. leprae. These mycobacteria have been proposed to be grouped as a M. leprae-complex. We argue that insights from the transmission and reservoirs of members of the M. leprae-complex might be relevant for leprosy research. A better understanding of possible animal or environmental reservoirs is needed, because transmission from such reservoirs may partly explain the steady global incidence of leprosy despite effective and widespread multidrug therapy. A reduction in transmission cannot be expected to be accomplished by actions or interventions from the human healthcare domain alone, as the mechanisms involved are complex. Therefore, to increase our understanding of the intricate picture of leprosy transmission, we propose a One Health transdisciplinary research approach.

Biologics in Leprosy: A Systematic Review and Case Report.

Tumor necrosis factor (TNF)-α inhibitors increase susceptibility to tuberculosis, but the effect of biologics on susceptibility to leprosy has not been described. Moreover, biologics may play a role in treating erythema nodosum leprosum (ENL). The objectives of this systematic review were to determine whether the development of clinical leprosy is increased in patients being treated with biologics and to assess the use of biologics in treating leprosy reactions. A systematic literature review was completed of patients with leprosy who received treatment with biologics either before or after a diagnosis of leprosy was confirmed. All studies and case reports were included for qualitative evaluation. The search yielded 10 cases (including one duplicate publication) of leprosy diagnosed after initiation of TNF-α inhibitors and four case reports of refractory ENL successfully treated with infliximab or etanercept. An unpublished case of persistent ENL responsive to infliximab is also presented. These data demonstrate that the use of TNF-α inhibitors may be a risk factor for developing leprosy or reactivating subclinical infections. Leprosy can present with skin lesions and arthritis, so leprosy should be considered in patients presenting with these signs before starting treatment with these agents. Leprosy should be considered in patients who develop worsening eruptions and neurologic symptoms during treatment with TNF-α inhibitors. Finally, TNF-α inhibitors appear effective in some cases of refractory ENL.

SARS-CoV2 (COVID-19) Structural/Evolution Dynamicome: Insights into functional evolution and human genomics.

The SARS-CoV-2 pandemic, starting in 2019, has challenged the speed at which labs perform science, ranging from discoveries of the viral composition to handling health outcomes in humans. The small ~30kb single-stranded RNA genome of Coronaviruses makes them adept at cross species spread and drift, increasing their probability to cause pandemics. However, this small genome also allows for a robust understanding of all proteins coded by the virus. We employed protein modeling, molecular dynamic simulations, evolutionary mapping, and 3D printing to gain a full proteome and dynamicome understanding of SARS-CoV-2. The Viral Integrated Structural Evolution Dynamic Database (VIStEDD) has been established (prokoplab.com/vistedd), opening future discoveries and educational usage. In this paper, we highlight VIStEDD usage for nsp6, Nucleocapsid (N), and Spike (S) surface glycoprotein. For both nsp6 and N we reveal highly conserved surface amino acids that likely drive protein-protein interactions. In characterizing viral S protein, we have developed a quantitative dynamics cross correlation matrix insight into interaction with the ACE2/SLC6A19 dimer complex. From this quantitative matrix, we elucidated 47 potential functional missense variants from population genomic databases within ACE2/SLC6A19/TMPRSS2, warranting genomic enrichment analyses in SARS-CoV-2 patients. Moreover, these variants have ultralow frequency, but can exist as hemizygous in males for ACE2, which falls on the X-chromosome. Two noncoding variants (rs4646118 and rs143185769) found in ~9% of African descent individuals for ACE2 may regulate expression and be related to increased susceptibility of African Americans to SARS-CoV-2. This powerful database of SARS-CoV-2 can aid in research progress in the ongoing pandemic.

Increased chitotriosidase activity in serum of leprosy patients: association with bacillary leprosy.

Human phagocyte-specific chitotriosidase is associated with several diseases involving macrophage activation. Since macrophage activation plays an important role in the control of Mycobacterium leprae infection, we studied the association of chitotriosidase with leprosy both in serum and in situ in lesional skin biopsies from patients. Serum samples from 78 Indonesian leprosy patients (39 non-reactional and 39 reactional leprosy patients) and 36 healthy controls (HC) from the same endemic region were investigated. The patients were classified as multibacillary (MB, n=69) or paucibacillary (PB, n=9) based on the bacterial index in slit-skin smears. Thirty-six of the reactional patients had erythema nodosum leprosum (ENL), while only 3 had reversal reaction (RR). Follow-up serum samples after corticosteroid treatment were also obtained from 17 patients with ENL and one with RR. Multibacillary (MB) patients showed increased chitotriosidase activity in serum as compared to paucibacillary (PB) patients and healthy controls. Although no significant difference was observed between reactional and the corresponding non-reactional groups, ENL showed significantly higher chitotriosidase activity as compared to HC. Furthermore, corticosteroid treatment resulted in significant decline of enzyme activity in ENL sera. Chitotriosidase activity correlated with levels of neopterin, another macrophage activation marker, but not with IL-6, IFN-gamma, TNF-alpha and IL-10. Immunohistochemical staining of 6 MB (LL=5, BL=1) lesional skin sections from stored material showed positive staining for chitotriosidase within lipid-laden macrophages suggesting that macrophages are the source of the enzyme detected in serum. Thus, serum chitotriosidase activity is potentially useful in distinguishing MB from PB leprosy and in monitoring response to therapy in ENL.

The role of radiology in nerve function impairment and its musculoskeletal complications in leprosy.

Conventional techniques, such as plain radiography and bone-scintigraphy, were used in the past to evaluate skeletal changes in patients with leprosy. More recent publications focus on radiological imaging of affected nerves, and involve advanced modalities such as Computed Tomography (CT-scan), Ultrasonography (US), and Magnetic Resonance Imaging (MRI). US and MRI can play an especially important role in the evaluation of nerve involvement in newly diagnosed patients, and also during leprosy reactions. This is important, because when nerve involvement is diagnosed in time, it may be reversible with adequate treatment. Radiological modalities can also play an important role during the followup of patients with leprosy with nerve function impairment. Skeletal and soft-tissue abnormalities occur, even after treatment. The so-called neuropathic foot is a well known consequence. Because of nerve function impairment, there is a constant risk of developing ulcers and subsequent osteomyelitis, or neuro-osteoarthropathy (Charcot foot or tarsal disintegration), which can lead to the amputation of the affected limb. Different radiological modalities can be used during the evaluation and follow-up of patients with leprosy with a neuropathic foot. With this up-to-date review, we highlight the importance and potential role of radiological imaging techniques in leprosy.

The potential role of magnetic resonance imaging in patients with Hansen's neuropathy of the feet: a preliminary communication.

A magnetic resonance imaging (MRI) protocol was performed in leprosy patients with a neuropathic foot and superficial ulcers and/or localized cellulitis but no clinical suspicion of osteomyelitis. The aim of the study was to determine if unsuspected osteomyelitis was present in this defined group of leprosy patients. A total of 15 neuropathic feet from 9 patients were included. Clinically and on MRI, the forefoot was predominantly affected. MRI findings of osteomyelitis were found in 4 feet. In feet with osteomyelitis, 3 had a superficial ulcer and 3 had clinical signs of localized cellulitis. A clinical diagnosis of cellulitis was confirmed on MRI in 2 feet.A striking discrepancy between clinical and MRI findings was found.This study shows that, compared with clinical evaluation, MRI is a sensitive method for the detection of unsuspected osteomyelitis in neuropathic feet with superficial ulcers and/or cellulitis. MRI findings in this group of patients may influence clinical decision making and may prevent further complications, because osteomyelitis requires more aggressive medical treatment. This preliminary communication should pave the wave for designed controlled studies so that patients with Hansen's neuropathy may get the best medical care.

Detection of Mycobacterium leprae DNA in soil: multiple needles in the haystack.

Leprosy is an infectious disease caused by Mycobacterium leprae affecting the skin and nerves. Despite decades of availability of adequate treatment, transmission is unabated and transmission routes are not completely understood. Despite the general assumption that untreated M. leprae infected humans represent the major source of transmission, scarce reports indicate that environmental sources could also play a role as a reservoir. We investigated whether M. leprae DNA is present in soil of regions where leprosy is endemic or areas with possible animal reservoirs (armadillos and red squirrels). Soil samples (n = 73) were collected in Bangladesh, Suriname and the British Isles. Presence of M. leprae DNA was determined by RLEP PCR and genotypes were further identified by Sanger sequencing. M. leprae DNA was identified in 16.0% of soil from houses of leprosy patients (Bangladesh), in 10.7% from armadillos' holes (Suriname) and in 5% from the habitat of lepromatous red squirrels (British Isles). Genotype 1 was found in Bangladesh whilst in Suriname the genotype was 1 or 2. M. leprae DNA can be detected in soil near human and animal sources, suggesting that environmental sources represent (temporary) reservoirs for M. leprae.

Comparison between quantitative nucleic acid sequence-based amplification, real-time reverse transcriptase PCR, and real-time PCR for quantification of Leishmania parasites.

DNA or RNA amplification methods for detection of Leishmania parasites have advantages regarding sensitivity and potential quantitative characteristics in comparison with conventional diagnostic methods but are often still not routinely applied. However, the use and application of molecular assays are increasing, but comparative studies on the performance of these different assays are lacking. The aim of this study was to compare three molecular assays for detection and quantification of Leishmania parasites in serial dilutions of parasites and in skin biopsies collected from cutaneous leishmaniasis (CL) patients in Manaus, Brazil. A serial dilution of promastigotes spiked in blood was tested in triplicate in three different runs by quantitative nucleic acid sequence-based amplification (QT-NASBA), quantitative real-time reverse transcriptase PCR (qRT-PCR), and quantitative real-time PCR (qPCR). In addition, the costs, durations, and numbers of handling steps were compared, and 84 skin biopsies from patients with suspected CL were tested. Both QT-NASBA and qRT-PCR had a detection limit of 100 parasites/ml of blood, while qPCR detected 1,000 parasites/ml. QT-NASBA had the lowest range of intra-assay variation (coefficients of variation [CV], 0.5% to 3.3%), while qPCR had the lowest range of interassay variation (CV, 0.4% to 5.3%). Furthermore, qRT-PCR had higher r2 values and amplification efficiencies than qPCR, and qPCR and qRT-PCR had faster procedures than QT-NASBA. All assays performed equally well with patient samples, with significant correlations between parasite counts. Overall, qRT-PCR is preferred over QT-NASBA and qPCR as the most optimal diagnostic assay for quantification of Leishmania parasites, since it was highly sensitive and reproducible and the procedure was relatively fast.

Imported tropical infectious ulcers in travelers.

Skin ulcers are a commonly encountered problem at departments of tropical dermatology in the Western world. Furthermore, the general dermatologist is likely to be consulted more often for imported chronic skin ulcers because of the ever-increasing travel to and from tropical countries. The most common cause of chronic ulceration throughout the world is probably pyoderma. However, in some parts of the world, cutaneous leishmaniasis is one of the most prevalent causes. Mycobacterium ulcerans is an important cause of chronic ulcers in West Africa. Bacterial infections include pyoderma, mycobacterial infections, diphtheria, and anthrax. Pyoderma is caused by Staphylococcus aureus and/or beta-hemolytic streptococci group A. This condition is a common cause of ulcerative skin lesions in tropical countries and is often encountered as a secondary infection in travelers. The diagnosis is often made on clinical grounds. Antibacterial treatment for pyoderma should preferably be based on culture outcome. Floxacillin is generally active against S. aureus and beta-hemolytic streptococci. Infection with Mycobacterium ulcerans, M. marinum, and M. tuberculosis may cause ulcers. Buruli ulcers, which are caused by M. ulcerans, are endemic in foci in West Africa and have been reported as an imported disease in the Western world. Treatment is generally surgical, although a combination of rifampin (rifampicin) and streptomycin may be effective in the early stage. M. marinum causes occasional ulcerating lesions in humans. Treatment regimens consist of combinations containing clarithromycin, rifampin, or ethambutol. Cutaneous tuberculosis is rare in travelers but may be encountered in immigrants from developing countries. Treatment is with multiple drug regimens consisting of isoniazid, ethambutol, pyrazinamide, and rifampin. Cutaneous diphtheria is still endemic in many tropical countries. Cutaneous diphtheria ulcers are nonspecific and erythromycin and penicillin are both effective antibacterials. Antitoxin should be administered intramuscularly in suspected cases. Anthrax is caused by spore-forming Bacillus anthracis. This infection is still endemic in many tropical countries. Eschar formation, which sloughs and leaves behind a shallow ulcer at the site of inoculation, characterizes cutaneous anthrax. Penicillin and doxycycline are effective antibacterials. Cutaneous leishmaniasis is caused by different species belonging to the genus Leishmania. The disorder is one of the ten most frequent causes of skin diseases in travelers returning from (sub)tropical countries. The clinical picture is diverse, ranging from a painless papule or nodule to an ulcer with or without a scab. Treatment depends on the clinical manifestations and the species involved.Sporotrichosis, chromo(blasto)mycosis, and mycetoma are the most common mycoses that may be accompanied by ulceration. Infections are restricted to certain regions and often result from direct penetration of the fungus into the skin. Anti-mycotic treatment depends on the microorganism involved. The most common causes of infectious skin ulceration encountered in patients from tropical countries who present at a department of tropical dermatology are reviewed in this article.

Leprosy-specific B-cells within cellular infiltrates in active leprosy lesions.

Leprosy is a spectral disease with polar lepromatous and tuberculoid forms correlating with enhanced humoral and cell-mediated immunity, respectively, against Mycobacterium leprae and the borderline forms, borderline lepromatous, midborderline, and borderline tuberculoid showing in-between clinical and immunological characteristics. Histopathologically, the cellular infiltrates of leprosy lesions show predominantly the presence of interacting T-cells and antigen presenting cells like macrophages, whereas the presence of B-cells has only been sporadically reported. The present study demonstrates by immunohistochemical techniques the presence of B-cells, including plasma cells, in active lesions from lepromatous leprosy, skin smear negative borderline lepromatous, and paucibacillary borderline tuberculoid leprosy. Furthermore, the study demonstrates the in situ production of M leprae-specific antibodies from BT lesions using an organotypic skin explant culture model. Finally, analysis of the cytokine release profile in supernatants of lesional organotypic skin cultures showed a microenvironment conducive to the differentiation and maturation of B-cells. The results demonstrate the presence of different functionally active B-cell stages within lesions of patients with leprosy, including borderline tuberculoid patients, which could secrete anti-M leprae-specific antibodies. However, their role in leprosy pathology remains to be elucidated.

Risk factors for developing leprosy--a population-based cohort study in Indonesia.

We identified risk factors associated with increased yearly incidence rates of leprosy in five island populations. Age, sex, household size and Mycobacterium leprae-specific antibodies as well as contact factors were studied. Of 94 index patients (patients diagnosed in 2000), 43 (46%) were classified as multibacillary (MB), 17 (19%) were seropositive for PGL-1 [corrected] antibodies and 6 (7%) had M. leprae DNA in nasal swabs as determined by polymerase chain reaction (PCR) testing. All PCR positive patients were also seropositive. Forty-four of 4903 initially symptom free persons developed leprosy within 4 years, giving an incidence rate of 298 per 1000 person-years. Men had a 22 times higher risk [95% confidence interval (CI): 1.2-4.1] of developing leprosy than women. People living in households with more than 7 members had a 3.1 times higher risk (95% CI: 1.3-7.3) than households of 1-4 members. Persons who were seropositive in 2000 had a 3.8 times higher risk (95% CI: 1.1-12.6) than seronegative persons. Household contacts of MB patients had an adjusted hazard ratio (aHR) of 4.6 (95% CI: 1.6-12.9) and household contacts of PCR positive patients an aHR of 9.36 (95% CI: 2.5-34.9) compared with non-contacts. Patients with PCR positive nasal swabs, suggesting nasal excretion of M. leprae, are probably the patients with the highest transmission potential. Since all index patients who were PCR positive were also seropositive, serology seems an adequate tool to identify these patients. Preventing seropositive persons from becoming seropositive and infectious patients might break the chain of transmission.