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.

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.

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.

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.

Pattern of bacillary clearance in multibacillary leprosy patients with multidrug therapy.

The bacteriological index (BI) of the skin smears is traditionally one of the important parameters of assessment of severity and of progress of leprosy under multidrug therapy. The present study reports on BI clearance among 578 multibacillary treated leprosy patients and the factors that influence this clearance. The patients were treated till smear negativity or for 2 years fixed duration and their skin smears periodically examined every 6 to 12 months till negativity (and even afterwards). We confirm that bacterial clearance is a slow process. The time taken for each log-unit decline in BI is between 13.6 to 24 months probably depending on initial BI level. The rate of smear negativity appears to be dependent on immune competence of the patients as reflected by a rapid BI decline in borderline BT-BB patients vis-à-vis BL-LL lepromatous patients both in the low and high BI group. Patients who had several episodes of ENL, took significantly longer time (63.7 months versus 53.5 months, p<0.0001) to become smear negative than those without ENL.

Design guidelines for accommodating amputees in the workplace.

Rehabilitation experts have been addressing the problem of accommodating disabled workers in the workplace for many years. When these disabled workers return to work, accomplishing the tasks they performed prior to their disability can present a serious challenge. Meeting this challenge successfully requires that employers provide accommodations at the workplace so that the disabled workers can continue to contribute efficiently to the operation of the enterprise. Disabilities that are caused by amputations are quite critical. The severity of the injury in terms of loss of a limb and the costs associated with accommodations make this type of disability extremely significant. This paper deals with accommodating "permanent partial" and "permanent total disabilities" due to amputations. The paper is divided into two main parts. The first part focuses on the causes of amputations, types, and difficulties that an amputee faces in the work environment. In this part, an understanding of the amputee physiology has been developed. The second part of the paper addresses the various measures that employers may take in accommodating the amputees at the workplace. Design guidelines are provided to make the workplace suitable for the amputees.

Immunological profile of treated lepromatous leprosy patients.

The immune responses of 19 treated lepromatous patients who had remained smear negative for a long period were assessed for specific cell-mediated immunity (CMI), anti-Mycobacterium leprae antibodies and cytokine release in response to challenge with M. leprae soluble antigen (MLSA). All of these patients remained anergic to Mitsuda lepromin. Lymphoproliferation in response to M. leprae antigen was noted in only two patients. Significant reduction in the phenolic glycolipid I (PGL-I) antibody response in treated patients with no difference in the M. leprae 35-kDa antibody response was observed when these responses were compared with those of active lepromatous patients. More treated patients produced interleukin-2 (IL-2) and interferon gamma (IFN-gamma) than did active patients. On the other hand, fewer treated patients produced IL-10 than did active patients. These limited findings suggest that the host immune response makes an attempt toward upregulation of CMI in some treated LL/BL patients.

Some epidemiological observations on leprosy in India.

This population sample survey conducted in rural and urban areas of the Agra District in India showed an active leprosy caseload of 60.1/10,000 in the rural and 39.1/10,000 in the urban areas against a targeted prevalence of < 1/10,000. The disease appeared to be widespread since almost 65% of the villages or urban pockets surveyed had at least one prevalent case of leprosy. Significantly larger numbers of leprosy patients were found among males, agricultural/manual workers, persons with no formal schooling, individuals living in unkept households with dirty surroundings, and among those living in dark and poorly ventilated houses. The epidemiological significance of this study reveals the endemic nature of leprosy in Agra and suggests the need to intensify and widen case-detection activities to achieve leprosy control.

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.

Protective sensibility--its monofilament nylon threshold equivalents in leprosy patients.

An attempt has been made to definite the levels of "protective sensibility" in terms of perception thresholds to monofilament nylon induced touch/pressure stimuli. Certain problems were observed while interpreting the observations. There appears to be a range of threshold values instead of a clear cut-off point. We suggest that a monofilament nylon stimulus two times the normal threshold value for that patient be taken as cut-off point. This will make the observations of Birke and Sims (1986) and Hammond and Klenerman (1987) reasonable without having any need to exclude the cases who defy the boundaries laid by them. Since the genesis of plantar ulcer is multifactorial, it appears logical to include all patients who have a certain degree of hypoaesthesia, for special ulcer care program. The likely problems while using monofilament nylons in the field and their possible solutions have also been outlined.

Calcification of peripheral nerves in leprosy.

A study conducted in 74 TT/TB patients, with gross thickening of nerves together with nerve abscess, showed calcification in 8 patients. Calcification was most common in the ulnar nerve followed by the lateral popliteal nerve. All eight patients were males with significantly longer duration of illness before start of treatment. Patients with late onset of nerve abscess were found to be more prone to calcium deposition in the nerves. Caseous pus of the abscess had high lipid content with raised cholesterol and cholesterol ester ratio to total lipids suggesting a dystrophic nature of calcification.

Neuritic leprosy: further progression and significance.

Sixteen neuritic cases have been seen developing cutaneous lesions. These cutaneous lesions by and large appear within 4 months after the diagnosis of neuritic leprosy. Leprosy pathology in cutaneous lesions has been found ranging between indeterminate and borderline lepromatous group. Development of cutaneous lesions does not seem to be influenced by age, sex or number of nerves or lepromin status. Neither lesions seem to appear in any particular part of the body. Therapy, duration and type i.e. monodrug or multidrug, also does not seem to influence the development of cutaneous lesions in either way. It appears that neuritic cases with either very early (indeterminate) or with advanced multibacillary neural pathology may develop skin lesions. Skin lesion possibly appear following reversal reaction in skin. Cases with newly developed skin lesions well respond to standard therapy. Development of cutaneous lesions by neuritic cases possibly indicates towards the natural history of the disease, conforming to the hypothesis that leprosy is basically neural in inception and that all other forms emerge from it.

Sensory functions in limbs of normal persons and leprosy patients with peripheral trunk damage.

The threshold to touch was tested in hands and feet of normal persons using Semmes-Weinstein graded monofilament nylons. The minimum stimulus to which response could be elicited was nylon number 3.61 in palms and 4.31 in soles. These numbers relate to the logarithm of the force applied, 3.61 corresponding to 0.217 gm force and 4.31 to 2.35 gm force respectively. The area of pain insensitivity complained by the patient more or less corresponds to that revealed by objective testing. It was interesting to observe that loss of pain sensitivity was confined to a smaller area compared to touch and thermal insensibility in the part innervated by the same nerve trunk.

Trigeminal neuralgia--a presenting feature of facial leprosy.

Trigeminal neuralgia is a well recognized clinical entity. However, it has not been reported to mimic leprosy or vice versa. Of the 3 cases reported here, 2 initially presented with neuralgic symptoms similar to that seen in trigeminal neuralgia and later developed borderline lesions on the face. The 3rd case demonstrated a tingling sensation along with firm and palpable supraorbital nerve (a branch of trigeminal nerve), and a very early skin lesion on the face pointed to the need to consider neuritic type leprosy before concluding the final diagnosis of a disease like trigeminal neuralgia which calls for a different therapeutic approach.

Evolution of early lesions in leprosy.

We observed 29 patients presenting with vague peripheral neurological symptoms for 6 months or more. During this period, 16 developed clinical leprosy, 3 developed borderline tuberculoid leprosy and the other 13 developed neuritic leprosy. Of these 13 cases 11 subsequently developed skin lesions similar to those seen in indeterminate and in borderline tuberculoid leprosy. Based on the above observations, an attempt has been made to explain the evolution of early lesions of leprosy.