M-line titin homozygous truncations cause the first congenital and purely recessive titinopathy, and the first to involve both cardiac and skeletal muscle. These results expand the spectrum of early-onset myopathies and suggest that titin segments downstream of the kinase domain are dispensable for skeletal and cardiac muscle development, but are crucial for maintaining sarcomere integrity.

Three diagnostic tests for visceral leishmaniasis (VL), the freeze-dried direct agglutination test (FD-DAT), the rK39 dipstick and a urine latex antigen test (KAtex), were evaluated for use in primary care in East Africa and the Indian subcontinent. Clinical suspects were prospectively recruited and tissue, blood and urine samples were taken. Direct microscopic examination of tissue smear, and FD-DAT, rK39 and KAtex were performed. Sensitivity and specificity with 95% credible intervals were estimated using Bayesian latent class analysis. On the Indian subcontinent both the FD-DAT and the rK39 strip test exceeded the 95% sensitivity and 90% specificity target, but not so in East Africa. Sensitivity of the FD-DAT was high in Ethiopia and Kenya but lower in Sudan, while its specificity was below 90% in Kenya. Sensitivity of the rK39 was below 80% in the three countries, and its specificity was only 70% in Ethiopia. KAtex showed moderate to very low sensitivity in all countries. FD-DAT and rK39 can be recommended for clinical practice on the Indian subcontinent. In East Africa, their clinical use should be carefully monitored. More work is needed to improve existing formats, and to develop better VL diagnostics.

Accuracy of rapid diagnostic tests was high in the Indian subcontinent; however, in Brazilian and East African samples, reduced sensitivity suggests that several cannot be used alone to exclude visceral leishmaniasis. Data on ease of use and performance using whole blood and in human immunodeficiency virus coinfections is needed.

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BackgroundVisceral leishmaniasis (VL) is diagnosed by microscopic confirmation of the parasite in bone marrow, spleen or lymph node aspirates. These procedures are unsuitable for rapid diagnosis of VL in field settings. The development of rK39-based rapid diagnostic tests (RDT) revolutionized diagnosis of VL by offering high sensitivity and specificity in detecting disease in the Indian subcontinent; however, these tests have been less reliable in the African subcontinent (sensitivity range of 75–85%, specificity of 70–92%). We have addressed limitations of the rK39 with a new synthetic polyprotein, rK28, followed by development and evaluation of two new rK28-based RDT prototype platforms.Methodology/Principal FindingsEvaluation of 62 VL-confirmed sera from Sudan provided sensitivities of 96.8% and 93.6% (95% CI = K28: 88.83–99.61%; K39: 84.30–98.21%) and specificities of 96.2% and 92.4% (95% CI = K28: 90.53–98.95%; K39: 85.54–96.65%) for rK28 and rK39, respectively. Of greater interest was the observation that individual VL sera with low rK39 reactivity often had much higher rK28 reactivity. This characteristic of the fusion protein was exploited in the development of rK28 rapid tests, which may prove to be crucial in detecting VL among patients with low rK39 antibody levels. Evaluation of two prototype lateral flow-based rK28 rapid tests on 53 VL patients in Sudan and 73 VL patients in Bangladesh provided promisingly high sensitivities (95.9% [95% CI = 88.46–99.1 in Sudan and 98.1% [95% CI = 89.93–99.95%] in Bangladesh) compared to the rK39 RDT (sensitivities of 86.3% [95% CI = 76.25–93.23%] in Sudan and 88.7% [95% CI = 76.97–95.73%] in Bangladesh).Conclusions/SignificanceOur study compares the diagnostic accuracy of rK39 and rK28 in detecting active VL cases and our findings indicate that rK28 polyprotein has great potential as a serodiagnostic tool. A new rK28-based RDT will prove to be a valuable asset in simplifying VL disease confirmation at the point-of-care.

In an exploration of the natural history of post-kala-azar dermal leishmaniasis (PKDL), 134 residents of Sudan who had recently been diagnosed as cases of the disease were investigated. In each case, diagnosis had been based on clinical criteria, the temporal relationship between the rash and the treatment of visceral leishmaniasis (VL), positive results in direct agglutination tests (DAT) and/or leishmanin skin tests (LST), and the exclusion of other skin conditions. The mean (S.D.) age of the subjects was 6.4 (3.0) years. Although PKDL appeared commonest among those aged 4-8 years (P < 0.05), it was most severe in children aged

Both rhesus and cynomolgus macaques have been used as animal models for measles vaccination and immunopathogenesis studies. A number of studies have suggested that experimental measles virus (MV) infection induces more-characteristic clinical features in rhesus than in cynomolgus monkeys. In the present study, both macaque species were infected with two different wild-type MV strains and clinical, virological and immunological parameters were compared. The viruses used were a genotype C2 virus isolated in The Netherlands in 1991 (MV-Bil) and a genotype B3 virus isolated from a severe measles case in Sudan in 1997 (MV-Sudan). Following infection, all rhesus monkeys developed a skin rash and conjunctivitis, which were less obvious in cynomolgus monkeys. Fever was either mild or absent in both species. Virus reisolation profiles from peripheral blood mononuclear cells and broncho-alveolar lavage cells and the kinetics of MV-specific IgM and IgG responses were largely identical in the two animal species. However, in animals infected with MV-Sudan, viraemia appeared earlier and lasted longer than in animals infected with MV-Bil. This was also reflected by the earlier appearance of MV-specific serum IgM antibodies after infection with MV-Sudan. Collectively, these data show that cynomolgus and rhesus macaques are equally susceptible to wild-type MV infection, although infection in the skin seems to follow a different course in rhesus macaques. MV-Sudan proved more pathogenic for non-human primates than MV-Bil, which may render it more suitable for use in future pathogenesis studies.