The nuclear import receptor Kapß2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD.

Expanded intronic G4C2 repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These intronic repeats are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and neurotoxic. Here, we report that Kapß2 and GR interact, co-aggregating, in cultured neurons in-vitro and CNS tissue in-vivo. Importantly, this interaction significantly decreased the risk of death of cultured GR-expressing neurons. Downregulation of Kapß2 is detrimental to their survival, whereas increased Kapß2 levels mitigated GR-mediated neurotoxicity. As expected, GR-expressing neurons displayed TDP-43 nuclear loss. Raising Kapß2 levels did not restore TDP-43 into the nucleus, nor did alter the dynamic properties of GR aggregates. Overall, our findings support the design of therapeutic strategies aimed at up-regulating Kapß2 expression levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.

Two microbiological relapses in a patient with lepromatous leprosy.

A lepromatous patient treated with dapsone in the pre-MDT era to the point of smear negativity (> 6 years), relapsed 5 years after stopping treatment. He was then put on WHO-MDT for multibacillary (MB) leprosy, and was treated again; he had negative slit skin smears (3 years). He again presented with a relapse of leprosy 17 years after stopping treatment, and this time he presented with borderline leprosy in reaction.

Increased level of urinary nitric oxide metabolites in leprosy patients during type 2 reactions and decreased after antireactional therapy.

OBJECTIVES: To assess the urinary nitric oxide metabolites in lepromatous patients in ENL (type 2 reactions) and to compare these metabolites after subsidence of reactions following antireactional therapy. Further to compare the levels in a group of lepromatous leprosy patients without reactions. DESIGN: The initial urine samples were collected from lepromatous leprosy patients when they came with ENL before commencing antireactional therapy and repeat samples were taken after resolution of ENL. Morning urine samples were collected from LL patients without reactions. Nitrites and nitrates in urine were measured using commercially available kit. Mean levels of nitric oxide metabolites of LL patients with ENL and without ENL were compared by student's 't' test. The level during ENL and after resolution was compared by paired 't' test. RESULTS: The nitric oxide metabolites were analyzed in 14 LL patients with ENL and after resolution of ENL and in 5 LL patients without reaction. The level of urinary nitric oxide metabolite is higher in LL patients in ENL reaction compared to LL patients without reaction (P < 0.04). These levels were reduced significantly with resolution of reaction following antireactional therapy (P < 0.004). CONCLUSION: The findings of this study suggested that the NO/NOM excretion is increased in leprosy patients during ENL episodes. With antireactional therapy (steroids) and clinical improvement the levels are reduced.

Advances in the treatment of reactions in leprosy.

Morbidity in leprosy is almost always due to reactions. Similarly, to a great extent, deformities in leprosy are the consequence of reactions occurring both in borderline patients (type 1 or reversal reactions) and in lepromatous patients (type 2 or ENL reactions). Over the last three decades, work has centred around finding who are prone to getting the reactions, identifying the risk factors and improving the management of reactions in order to alleviate quickly the suffering and prevent and reverse nerve damage consequent to reactions. Though several new drugs have been tried and found somewhat useful, corticosteroids and thalidomide continue to be the mainstay in the management of leprosy reactions. A brief review of the current understanding is presented.

Leprosy situation in the slums of Agra City--epidemiological findings.

The present article is the result of a study of the leprosy caseload in Agra City and is based on a house-to-house survey conducted during April-July 2003 in 5 areas. During the survey 198,150 persons were examined, and 287 cases were detected, giving a prevalence rate of 14.5/10,000. A majority of them (92%) were new cases, detected and diagnosed for the first time. The patient load was found to be unevenly distributed with comparatively more number of patients in areas such as Jamuna Kinara, Shah Ganj and Lohamandi. Among the 264 newly detected cases, 14.8% were of MB type. Overall deformity of grade > or = 2 was seen in 2.8% of patients--0.4% in PB and significantly high at 18% in MB leprosy. The observations reveal that leprosy is endemic in slum areas of Agra City.

Relapses in multibacillary leprosy patients: effect of length of therapy.

Two groups of MB leprosy patients, one treated to the point of smear negativity (TSN) and the other given therapy for fixed duration (24 doses of WHO MB regimen) (FDT), were compared for relapse rates during treatment and in the post-treatment period. During the follow-up of 980.2 person years in 260 patients treated with FDT, 20 relapses (2.04/100 patient years) were observed. In the other group of 301 patients, who received therapy till smear negativity, 12 relapses in 1085.46 person years (1.10/100 patient years) occurred. Comparison of survival rates (without relapse) has shown that although there is no difference up to 4 years, the risk of relapse was significantly higher on longer follow-up in the FDT group. In addition, when patients were compared on the basis of initial bacterial load, it was found that the relapse rates in patients with BI > or = 4 was significantly higher (P < 0.01) in the FDT group as compared to those receiving treatment till the point of smear negativity (4.29 versus 1.27/100 patient years). All the relapsed patients responded to retreatment with the same drug combination, indicating that the exacerbation in their condition was because of insufficient treatment. It is suggested that to prevent or reduce relapses, treatment where feasible would be continued till smear negativity, at least in patients with high BI.

Excretion of clofazimine in human milk in leprosy patients.

Clofazimine is an important and effective constituent of multi drug therapy for leprosy. A study has been conducted to determine the distribution of clofazimine in maternal milk so that the safety of breast-feeding during maternal ingestion of the drug can be ascertained. Eight female leprosy patients (LL/BL) on clofazimine, 50 mg daily or 100 mg on alternate days for 1-18 months, (mean 5.0 +/- 1.81 months; median 3.25 months) and in the early lactating phase were studied. Blood samples and milk specimens were collected 4-6 hr after the last daily dose. Clofazimine was assayed in the milk and plasma samples by HPTLC. Mean plasma and milk clofazimine levels were 0.9 +/- 0.03 micrograms/ml and 1.33 +/- 0.09 micrograms/ml respectively. The ratio of milk to plasma drug concentration ranged from 1.0 to 1.7 with a mean of 1.48 +/- 0.08. The amount of drug ingested by the infants was 0.199 +/- 0.013 mg/kg/day which represented 22.1 +/- 1.9% of the maternal dose.

Histoid lesion in nerve of a lepromatous patient.

This report pertains to a patient who had untreated diffuse lepromatous disease of 8- to 10-years' duration. Two peripheral nerves were beaded, which on biopsy showed histoid features. Because of its rarity, the case is reported.

Nasal myiasis in leprosy.

Infestation of the nose with larvae of certain files can occur in leprosy patients. This results in severe distress and agony and can cause extensive tissue damage. The predisposing factors, clinical presentation and treatment is described.