Leprosy Associated with Atypical Cutaneous Leishmaniasis in Nicaragua and Honduras.

In Central America, few cases of leprosy have been reported, but the disease may be unrecognized. Diagnosis is based on clinical criteria and histology. Preliminary field work in Nicaragua and Honduras found patients, including many children, with skin lesions clinically suggestive of atypical cutaneous leishmaniasis or indeterminate leprosy. Histology could not distinguish these diseases although acid-fast organisms were visible in a few biopsies. Lesions healed after standard antimicrobial therapy for leprosy. In the present study, patients, family members, and other community members were skin-tested and provided nasal swabs and blood samples. Biopsies were taken from a subgroup of patients with clinical signs of infection. Two laboratories analyzed samples, using local in-house techniques. Mycobacterium leprae, Leishmania spp. and Leishmania infantum were detected using polymerase chain reactions. Mycobacterium leprae DNA was detected in blood samples and nasal swabs, including some cases where leprosy was not clinically suspected. Leishmania spp. were also detected in blood and nasal swabs. Most biopsies contained Leishmania DNA and coinfection of Leishmania spp. with M. leprae occurred in 33% of cases. Mycobacterium leprae DNA was also detected and sequenced from Nicaraguan and Honduran environmental samples. In conclusion, leprosy and leishmaniasis are present in both regions, and leprosy appears to be widespread. The nature of any relationship between these two pathogens and the epidemiology of these infections need to be elucidated.

Therapeutic vaccines for tuberculosis--a systematic review.

For eradication of tuberculosis (TB) by 2050, the declared aim of the Stop TB Partnership, novel treatment strategies are indispensable. The emerging epidemic of multi-drug resistant (MDR) TB has fuelled the debate about TB vaccines, as increasing numbers of patients can no longer be cured by pharmacotherapy. Of several proposed modalities, TB vaccines administered in therapeutic manner represents a promising alternative, despite the controversial history due to the occurrence of exacerbated immune response. A modified concept of immunotherapy is required in order to justify further exploration. In this paper we systematically reviewed the most advanced therapeutic vaccines for TB. We address the rationale of immunotherapeutic vaccination combined with optimized pharmacotherapy in active TB. We summarize preclinical and patient data regarding the five most advanced therapeutic vaccines currently in the pipeline. Of the five products that have been tested in animal models and in humans during active or latent TB, the quality of the published clinical reports of two of these products justify further studies in patients with active TB. This systematic review fuels further clinical evaluation eventually including head-to-head comparative studies.

Interview: Investigating immunomodulators among the Actinomycetales. Interview by Hannah Wilson.

John L Stanford speaks to Hannah Wilson, Assistant Commissioning Editor John L Stanford is Chief Scientific Officer at BioEos Ltd (Kent, UK). Dr Stanford began his career as a senior lecturer and then reader in microbiology at Middlesex Hospital Medical School (London, UK), then University College London Medical School, where he became Professor in Medical Microbiology and Head of Department in 1997. He retired and became Professor Emeritus in 2004. Dr Stanford's career has been devoted to research into mycobacteria, the diseases that they cause and the practical uses of this research. His special interest in recent years has been the development of bacterial immunotherapeutics for a range of diseases including tuberculosis and cancer. Dr Stanford was one of the founding directors of Stanford Rook Ltd (London) and of BioEos Ltd, where he remains a director. He also played a part in the founding of Immodulon Therapeutics Ltd (London) and of a new company, ActinoPharma Ltd (London), and has published more than 200 peer-reviewed scientific papers.

Targeting multidrug-resistant tuberculosis (MDR-TB) by therapeutic vaccines.

Tuberculosis (TB) has scourged humankind for millennia, and latent infection affects nearly one-third of today's world population. The emergence of multidrug-resistant (MDR)-TB is a major global threat and reflects treatment failure of drug-sensitive disease. MDR-TB management is a burden for patients and society; success rates are unacceptably low with prolonged treatment duration. Mycobacterium tuberculosis (Mtb) possesses the ability to transform into a dormant state in which it can persist in the face of antimicrobial treatment and host defense. This sub-population of persisters is largely responsible for lengthy and difficult treatment. Targeting persistent bacilli could eventually improve the treatment success rate (currently 50-65 %) and shorten duration of treatment. A subset of therapies in the pipeline, termed therapeutic vaccines, use the host immune response to attack Mtb. The historical occurrence of an exacerbated host response has resulted in a negative perception of therapeutic vaccines. Thus, a renewed concept of immunotherapy is needed. We review current perspectives of immunotherapy in MDR-TB based on the knowledge of TB immunology and briefly discuss the profiles of several therapeutic vaccine products.

Successful immunotherapy of canine flea allergy with injected Actinomycetales preparations.

AIMS: Can heat-killed, borate-buffered suspensions of Gordonia bronchialis, Rhodococcus coprophilus or Tsukamurella inchonensis be used to treat canine flea allergy? MATERIALS & METHODS: Organisms cultured on Sauton's medium into stationary phase were autoclaved in borate-buffered saline and stored at 10 mg wet weight/ml. Intradermal injections of 0.1 ml containing 1 mg of bacilli were administered on the first and 20th days of the study. G. bronchialis and R. coprophilus were most effective in a pilot study of a small number of dogs with flea allergy. A larger number of affected dogs were then randomized to receive placebo or either of the two selected reagents. The extent and severity of allergic signs and symptoms were scored and blood samples were collected just before the first injection and 28 days after the second. RESULTS: Both selected reagents reduced the extent and severity of lesions (p < 0.001) and reduced scratching. Eosinophil numbers were reduced (p < 0.0001) between the first and second assessment. CONCLUSIONS: Injections of G. bronchialis or R. coprophilus effectively reduce the signs and symptoms of flea allergy in dogs.

Immunotherapy for malignant melanoma--tracing Ariadne's thread through the labyrinth.

A working group (FEBIM) within the European Organisation for Research and Treatment of Cancer undertook extensive studies on the possible association of infectious diseases and the risk of malignant melanoma. These studies provided evidence that several infectious diseases and also some vaccines including the anti-tuberculosis vaccine, BCG, derived from Mycobacterium bovis, confer a significant level of protection against this form of cancer. In recent years, the importance of immunoregulatory networks in the establishment of tolerance to tumour antigens and the key role of the innate immune system in the development of such networks have been recognised. The molecular patterns of micro-organisms activate pattern recognition receptors on antigen presenting cells and determine the qualitative nature of the ensuing immune response. Bacteria in the actinomycetales family, notably members of the genus Mycobacterium, exhibit particularly powerful adjuvant activity and profoundly affect underlying patterns of immune reactivity. In particular, there is growing evidence that a heat-killed preparation of a strain of Mycobacterium vaccae is able to down-regulate patterns of immune reactivity that favour the tumour and to induce those that lead to anti-cancer immune responses. The results of preliminary clinical observations with melanoma patients, and published studies on other cancers, point to the need for more formal clinical trials.

Pathogen-associated molecular pattern in cancer immunotherapy.

Observations from different research frontiers--epidemiological data, case studies on spontaneous regressions from cancer, clinical studies, tumor immunology--indicate that exposure by vaccination or infection to pathogen-associated molecular patterns (PAMP) can have beneficial effects on neoplastic diseases, both prophylactically and therapeutically. These effects have not yet been harnessed to their full extent for the prophylaxis and therapy of cancer. Here, we summarize clinical, epidemiological, and experimental data and discuss the role of PAMP in cancer therapy.

Interfacial interactions in polymer-layered silicate nanocomposites.

Interactions between sodium montmorillonite (Na-MMT) and a variety of probes, some of which are intended to model components of a polyurethane system, have been studied. Particular attention was given to the effect of preadsorbed water on the adsorption behavior of the probes. Flow microcalorimetry (FMC), diffuse reflectance Fourier transform infrared spectroscopy (DRIFTS), and wide-angle X-ray scattering (WAXS) were used to monitor the adsorption process. The probe set included alcohols, amines, ethers, poly(propylene glycol) monobutyl ethers (PPG), and 4-ethylphenyl isocyanate (4-EPI). FMC revealed that the preadsorbed water molecules on undried Na-MMT hindered the adsorption of alcohol and ether probes, but had little effect on the adsorption of amines. Drying of Na-MMT to less than 0.3% w/w H2O led to an increase in heat of adsorption and generally greater retention of the probes. PPG showed strong interaction with Na-MMT due to multipoint adsorption. With dried Na-MMT, WAXS revealed that PPG of molecular weight (MW) 1000 was partly intercalated into the gallery while lower molecular weight PPG (MW 340) did not intercalate the Na-MMT. DRIFTS spectra of 4-EPI adsorbed on undried Na-MMT revealed urea linkages, indicating formation of N,N'-bis(4-ethylphenyl) urea. In contrast, with dried Na-MMT the 4-EPI formed a urethane linkage with hydroxyl groups present at the edges of the silicate platelets.

Application of Polymerase Chain Reaction for the Detection of Mycobacterium leprae DNA in Specimens from Treated Leprosy Patients

Resumo: In this study of leprosy patients apparently cured by dapsone monotherapy, the polymerase chain reaction (PCR), one of the most reliable and sensitive DNA-based assays, was used for the specific detection of Mycobacterium leprae DNA. Sputum and slit-skin samples from 44 such patients at Baba Baghi Leprosy Sanatorium in Iran were examined. Primers for a 530-base-pair fragment of the gene encoding the 36-kDa antigen of M. leprae were used for the study. The PCR results were compared with microscopy for acid-fast bacilli. Of the 44 sputum samples, 2 were positive by PCR (4.5%) and of the 44 slit-skin swabs taken from the same patients, 10 were PCR positive (22.7%). Only one patient was PCR positive for both sputum and slit-skin specimens (2.3%). No positive results were found by acid-fast microscopy. In total, 11 of 44 (25%) patients in this study were found to be PCR positive for M. leprae, and it was thought probable that this indicated the presence of live organisms. Particularly interesting was the statistically significant association of positive results from slit-skin swabs with paucibacillary rather than multibacillary leprosy. It is suggested that whereas relapse or immunological reaction in paucibacillary disease may result from surviving organisms, in multibacillary leprosy this may be due to re-infection

Skin test studies on close contacts of leprosy patients in India

Skin-test studies with a series of tuberculins have been carried out in close contacts of multibacillary (MB) leprosy patients around three leprosy centers in India, and casual contacts of the disease around two centers. The results show that the rate of acquisition of leprosin A positivity is associated with age and the closeness of contact with MB leprosy. At the age of 15 years, the differences between the two types of contact were highly significant (p less than 0.00001). Many responses to leprosin A are directed toward the group iv species-specific, antigens of the leprosy bacillus, and the significance of positivity is discussed in relation to protective immunity from leprosy. The differences from Iran show that positivity to leprosin A is not solely the effect of the degree of contact with the disease, but must also have a genetic or environmental element, the latter being favored. The results from Miraj show that the high levels of tuberculin, scrofulin, and vaccin positivity seen in Fathimanagar, and to a lesser extent in Karigiri, are not a consequence of contact with leprosy. BCG vaccination made little difference to the leprosin A positivity of close contacts of leprosy patients, although it significantly enhanced positivity among casual contacts around Miraj (p less than 0.002). BCG vaccination significantly increased tuberculin positivity in Miraj and Karigri, and in those under 11 years of age in Fathimanagar. It made no difference to the already high level of positivity found in older persons around Fathimanagar

A pilot study of three potential vaccines for leprosy in Bombay

Three vaccines, BCG Glaxo alone (vaccine A), BCG Glaxo plus 10(7) killed Mycobacterium vaccae (vaccine B), and BCG Glaxo plus 10(7) killed M. leprae (vaccine C), were given to groups of selected children. The effects of these vaccines on subsequent quadruple skin testing 1-3 years after vaccination were compared. All three vaccines equally and significantly (p less than 0.00001) increased positivity to tuberculin, but only vaccine B was found to significantly enhance development of skin-test positivity to leprosin A (p less than 0.002). The data support the evidence previously obtained in rural Iran that the combination of BCG with killed M. vaccae is likely to be a better vaccine for leprosy than is BCG alone

Vaccination and skin test studies on the children of leprosy patients

The purpose of this study carried out in Iranian Azerbaijan was to determine the pattern of skin-test positivity to mycobacterial antigens in children living in the valley, and to assess the effect on this of a series of vaccines against mycobacterial disease. Set up in 1978, 1707 tuberculin-negative children without scars of previous BCG vaccination were vaccinated with BCG Glaxo alone (vaccine A) or with the addition of a suspension of killed Mycobacterium vaccae (vaccine B). One hundred children were vaccinated with BCG Glaxo plus a suspension of M. leprae (vaccine C). Eight to 10 years later about half of the children were found for follow up. At this time further children were skin tested, and the results obtained were related to whether or not they had scars of vaccination with BCG Pasteur (Teheran) given by the local health authorities. Between setting up the study and the first follow up, cases of leprosy or tuberculosis had occurred in some of the villages, although not among those we had vaccinated. Differences between the effects of the vaccines were only found in villages with cases of leprosy. In these villages positivity to leprosin A was significantly greater after vaccine B (49%) than after vaccine A (36%; p less than 0.04). The results for scrofulin and vaccine were the same after both vaccines, and significantly lower than in the villages without cases of leprosy. The general reduction in skin-test positivity in the villages with leprosy cases was mainly due to a loss of category 1 responders to group i, common mycobacterial, antigens. It was concluded that where casual contact with cases of leprosy occurs the combination of BCG with killed M. vaccae is likely to be a better vaccine for leprosy than is BCG alone. Although few children received the combination with M. leprae, the results obtained were not particularly promising

Vaccination and skin test studies on children living in villages with differing endemicity for leprosy and tuberculosis

The purpose of this study carried out in Iranian Azerbaijan was to determine the pattern of skin-test positivity to mycobacterial antigens in children living in the valley, and to assess the effect on this of a series of vaccines against mycobacterial disease. Set up in 1978, 1707 tuberculin-negative children without scars of previous BCG vaccination were vaccinated with BCG Glaxo alone (vaccine A) or with the addition of a suspension of killed Mycobacterium vaccae (vaccine B). One hundred children were vaccinated with BCG Glaxo plus a suspension of M. leprae (vaccine C). Eight to 10 years later about half of the children were found for follow up. At this time further children were skin tested, and the results obtained were related to whether or not they had scars of vaccination with BCG Pasteur (Teheran) given by the local health authorities. Between setting up the study and the first follow up, cases of leprosy or tuberculosis had occurred in some of the villages, although not among those we had vaccinated. Differences between the effects of the vaccines were only found in villages with cases of leprosy. In these villages positivity to leprosin A was significantly greater after vaccine B (49%) than after vaccine A (36%; p less than 0.04). The results for scrofulin and vaccine were the same after both vaccines, and significantly lower than in the villages without cases of leprosy. The general reduction in skin-test positivity in the villages with leprosy cases was mainly due to a loss of category 1 responders to group i, common mycobacterial, antigens. It was concluded that where casual contact with cases of leprosy occurs the combination of BCG with killed M. vaccae is likely to be a better vaccine for leprosy than is BCG alone. Although few children received the combination with M. leprae, the results obtained were not particularly promising