Discovery of 4 exonic and 1 intergenic novel susceptibility loci for leprosy.

Seven new risk coding variants have been identified through an exome-wide association study (EWAS), which studied the contributions of protein-coding variants to leprosy susceptibility. But some potential susceptibility loci were not studied in the previous EWAS study because of the project consideration. Seventeen unstudied potential susceptibility loci of the previous EWAS were validated in 3169 cases and 9814 controls in this study. Four disease-associated exonic loci were identified: rs671 in ALDH2 (P = 2.0 × 10-20 , odds ratio [OR] = 1.35), rs13259978 in SLC7A2 (P = 1.74 × 10-8 , OR = 1.28), rs925368 in GIT2 (P = 9.18 × 10-17 , OR = 1.44), and rs75680863 in TCN2 (P = 8.37 × 10-21 , OR = 0.74). Potentially implicating ZFP36L1 as a new susceptibility gene, 1 intergenic single nucleotide polymorphism (SNP), rs1465788 (P = 7.81 × 10-6 , OR = 0.88), was also suggested to be associated with leprosy. A luciferase reporter assay showed that the rs1465788 risk allele notably decreased the transcription activity of the flanking sequence. These findings suggest the possible involvement of lipid metabolism, NF-κB homeostasis and macrophage antimicrobial pathways in leprosy pathogenesis.

[Anterior dislocation of the fibula resulting from surgical malreduction: a case report].

Ankle joint fracture is one of the most common types of fracture. There are many researches on the injury mechanism, treatment principles and surgical techniques. A type of injury which combines posterior dislocation of fibula, known as the Bosworth injury, is relatively rare. In 1947, Bosworth first described this type of injury as an unusual ankle fracture dislocation with fixed posterior fracture dislocation of the distal part of the fibula. In this type of fracture, the proximal fibular shaft fragment locks behind the tibialis posterior tubercle. This rare ankle fracture variant is often not recognized in initial radiographs and requires a computed tomographic (CT) scan for verification. But there are already many reports, discussing the injury mechanism, treatment principles and surgical techniques. However, there are few reports of anterior dislocation of the fibula, caused by either injury or surgery. The mechanism of the injury is still not clear. This article reports a case of anterior dislocation of the fibula. We report a patient with left ankle open fracture (Lauge-Hansen pronation-external rotation stage III, Gustilo IIIA). Open reduction and internal fixation was done in the initial surgery, but ended up with poor reduction, resulting in fibula anterior dislocation, anterior dislocation of talus and tibia fibular dislocation. The fibula was dislocated anteriorly of the tibia, which rarely happened. The patient suffered severe ankle joint dysfunction. The second operation took out the original internal fixation, reduced the fracture, and reset the internal fixation. The function of ankle joint was improved obviously after operation. But because of the initial injury and the two operations, the soft tissue around the fracture was greatly damaged. 6 months after the second operation, and the fracture still not healed, so the bone graft was carried out in the third surgery. Two months after the third surgery, the function of the ankle was significantly better than before, but the fracture healing was poor, which needed further review. Through this case, we understand the rare type of ankle fracture with anterior dislocation of the fibula, and recognize that the timing and quality of initial surgery has a great impact on the patient's prognosis and rehabilitation period.

HLA-B*13:01 and the dapsone hypersensitivity syndrome.

BACKGROUND: Dapsone is used in the treatment of infections and inflammatory diseases. The dapsone hypersensitivity syndrome, which is associated with a reported mortality of 9.9%, develops in about 0.5 to 3.6% of persons treated with the drug. Currently, no tests are available to predict the risk of the dapsone hypersensitivity syndrome. METHODS: We performed a genomewide association study involving 872 participants who had received dapsone as part of multidrug therapy for leprosy (39 participants with the dapsone hypersensitivity syndrome and 833 controls), using log-additive tests of single-nucleotide polymorphisms (SNPs) and imputed HLA molecules. For a replication analysis, we genotyped 24 SNPs in an additional 31 participants with the dapsone hypersensitivity syndrome and 1089 controls and performed next-generation sequencing for HLA-B and HLA-C typing at four-digit resolution in an independent series of 37 participants with the dapsone hypersensitivity syndrome and 201 controls. RESULTS: Genomewide association analysis showed that SNP rs2844573, located between the HLA-B and MICA loci, was significantly associated with the dapsone hypersensitivity syndrome among patients with leprosy (odds ratio, 6.18; P=3.84×10(-13)). HLA-B*13:01 was confirmed to be a risk factor for the dapsone hypersensitivity syndrome (odds ratio, 20.53; P=6.84×10(-25)). The presence of HLA-B*13:01 had a sensitivity of 85.5% and a specificity of 85.7% as a predictor of the dapsone hypersensitivity syndrome, and its absence was associated with a reduction in risk by a factor of 7 (from 1.4% to 0.2%). HLA-B*13:01 is present in about 2 to 20% of Chinese persons, 1.5% of Japanese persons, 1 to 12% of Indians, and 2 to 4% of Southeast Asians but is largely absent in Europeans and Africans. CONCLUSIONS: HLA-B*13:01 was associated with the development of the dapsone hypersensitivity syndrome among patients with leprosy. (Funded by the National Natural Science Foundation of China and others.).

Composition and antimicrobial activity of the essential oil of Actinidia macrosperma from China.

Actinidia macrosperma is a medicinal plant in China and has been well known for its attraction to cats and activities against leprosy and cancers. The compositions and the antimicrobial activity of its leaf oil were reported for the first time. The oil obtained by hydrodistillation and analyzed by GC and GC-MS, was characterized by the high content of monoterpenes. Linalool (48.14%) is the major component identified, followed by 1,2-dimethyl-lindoline (7.94%), linolenic acid methylester (6.57%) and (E)-phytol (5.29%). The antimicrobial activity of the oil was evaluated against four bacterial and three fungal species. The results showed that it exhibited a mild antibacterial activity against two Gram-positive bacteria (Staphylococcus aureus and Bacillus subtilis), a significant activity against Gram-negative bacteria (Escherichia coli), and no activity on Pseudomonas aeruginosa. The test fungi were more sensitive to the oil, with a MIC range of 0.78-1.56 microL mL(-1) than bacteria in the range which were significantly higher from 0.78 to 25.50 microL mL(-1).

Experiences from a collaborative project on the prevention of disability in leprosy patients in Shandong Province, the People's Republic of China.

Shandong Province (present population 89 million) in the People's Republic of China established a leprosy control programme in 1955. Between that year and the end of 1999, allowing for death and migration, the cumulative number of cases registered was 53,618, including 120 cases on multiple drug therapy (MDT) and 18,248 who had completed satisfactory courses of dapsone monotherapy and/or MDT. Of this latter group, 9500 cases (52%) suffered from visible disabilities (grade 2 of the WHO classification). Prevalence and incidence rates of leprosy have decreased dramatically since 1955 and, on average, only 50-70 new cases are now being detected annually in the entire province. Leprosy is thus no longer a public health problem, but the existence of such a large number of patients with grade 2 disabilities is clearly a matter of serious concern. This paper describes a pilot project to investigate the potential of health personnel in the leprosy programme and the dermatology and sexually transmitted diseases services to (a) prevent deterioration of existing disabilities in ex-patients through self-care and (b) prevent new neuritis in patients on MDT through early detection and the use of steroids.

Techniques for covering soft tissue defects resulting from plantar ulcers in leprosy: Part I--General considerations and summary of results.

Recurrent plantar ulceration is a common and serious complication occurring consequent to impairment of the tibial nerve in leprosy patients. In spite of many therapies and long therapeutic course, it is extremely difficult to abolish this complication in many cases because of extensive skin and soft tissue cushion loss due to repeated infection. Since the early 70's we have been using microscopic surgical techniques to reconstruct the ulcerated area using eight types of the flaps. In this series of papers we review our experience (76 patients). Post-operatively, the flaps survived in all cases, the long-term results have proved satisfactory, and recurrent ulceration occurred in only three patients.

Pilot study to determine acceptability and ability of heat-killed Mycobacterium leprae plus BCG (HKML+BCG) vaccine to induce skin test conversion.

Although local reactions, including erythema, induration and ulcers, appeared in every patient after the injection of the combined HKML+BCG vaccine, they were accepted by the patients. There was no tendency for the local reaction to become aggravated after repeated vaccination. However, systemic reactions, mainly iridocyclitis and complaint of numbness of the fingers and toes, became quite common after the 5th vaccination and therefore significantly reduced the acceptability of vaccine by injection. It seems that repeated vaccination might activate the iridocyclitis, but the relationship between the complaint of numbness and vaccination has not been well established. Neither typical ENL nor reversal reaction had been observed throughout the trial. A significant proportion of patients converted to SMLA positivity after repeated vaccination. However, it seems the positive status was not stable as many of them reverted to negative after the following vaccination. After the 7th vaccination, the positive conversion rate to SMLA-I was 45% and to SMLA-II was 35%. After the 8th vaccination, 66.7% of patients converted to Mitsuda reaction positive, which has been confirmed by histopathological examination. Nevertheless, further follow-up is required in order to determine whether or not such conversion will be of a long duration. The reactions to SMLA-I and SMLA-II were associated but only correlated at a moderate level. Overall, the positive conversion rate to SMLA-I was significantly higher than that to SMLA-II after repeated vaccination. Neither the early reaction nor the late (Mitsuda) reaction of the lepromin test were correlated to either SMLA reaction. The repeated vaccination of HKML+BCG vaccine did not affect the weakly-positive anti-PGL-1 Mycobacterium leprae antibody level seen in the skin-smear negative lepromatous patients participating in this study.

Diagnostic exploration of enlarged peripheral nerves in suspected cases of leprosy. An analysis of 55 cases.

In 55 cases presenting with enlarged peripheral nerves without any skin lesions, a rice grain-sized biopsy of the nerve lesion was taken for histopathological examination. As a result definitive diagnoses could be established: leprosy was diagnosed in 32 cases. In 23 cases the cause of nerve enlargement was not leprosy: post-traumatic neuritis 9, cysts 5, hypertrophic neuritis 3, nonspecific 4, neurofibroma 1, and amyloidosis 1. In all of these cases there was a deficit of the nerve function and postoperatively there were no complications. The authors, as a result of this experience, believe that surgical exploration and biopsy is a harmless diagnostic tool for establishing a definitive diagnosis of leprosy in cases presenting with enlarged peripheral nerves without any skin lesions. In 23 out of 55 such cases the nerve enlargement was proved to be other causes than leprosy.