In vitro evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington's disease

A unifying feature of the CAG expansion diseases is the formation of intracellular aggregates composed of the mutant polyglutamine-expanded protein. Despite the presence of aggregates in affected patients, the precise relationship between aggregates and disease pathogenesis is unresolved. Results from in vivo and in vitro studies of mutant huntingtin have lead to the hypothesis that nuclear localization of aggregates is critical for the pathology of Huntington's disease (HD). We tested this hypothesis using a 293T cell culture model system that compared the frequency and toxicity of cytoplasmic and nuclear huntingtin aggregates. We first assessed the mode of nuclear transport of N-terminal fragments of huntingtin, and show that the predicted endogenous NLS is not functional, providing data in support of passive nuclear transport. This result suggests that proteolysis is a necessary step for nuclear entry of huntingtin. Additionally, insertion of nuclear import or export sequences into huntingtin fragments containing 548 or 151 amino acids was used to reverse the normal localization of these proteins. Changing the subcellular localization of the fragments did not influence their total aggregate frequency. There were also no significant differences in toxicity associated with the presence of nuclear compared with cytoplasmic aggregates. The findings of nuclear and cytoplasmic aggregates in affected brains, together with these in vitro data, support the nucleus and cytosol as subcellular sites for pathogenesis in HD.      

Is there a relationship between vitamin D with insulin resistance and diabetes mellitus?

Available data suggest a possible link between abnormal vitamin D level and abnormal glucose homeostasis, two of the most common chronic medical conditions. Both conditions are associated with inflammation, and the exact mechanism for role of either on the other is not well clear. Literature investigating the link between vitamin D and either pre-diabetic states or diabetes is reviewed. Vitamin D deficiency is detrimental to insulin synthesis and secretion in animal and human studies. In humans, it has been shown by majority of observational studies, that vitamin D is positively correlated with insulin sensitivity and its role is mediated both by direct mechanism through the availability of vitamin D receptors in several tissues and indirectly through the changes in calcium levels. Large number of, but not all, variable samples cross sectional human trials have demonstrated an inverse relation between vitamin D status and impaired glucose tolerance, insulin resistance or diabetes. To compliment this conclusively, evidence from intervention studies is critically warranted before we can frankly state that vitamin D plays a role in diabetes prevention or treatment. Absence of both sizable prospective observational trials utilizing 25(OH)D as the main variable and the non-availability of randomized studies specifically designed to assess the effects of vitamin D on pre-diabetes and diabetes states, are the main obstacles to draw solid and conclusive relationships.     

EARLY DIAGNOSIS IN POST RENAL TRANSPLANT OPPORTUNISTIC INFECTIONS: A FRESH LOOK

A total of 86 renal transplant patients who were transplanted with live related donor (LRD) and live unrelated donor (LURD) kidneys were studied for opportunistic infections. Immune diagnosis of Toxoplasma, Cytomegalovirus (CMV), Herpes-simplex virus type II (HSV-2), Aspergillosis and Tuberculosis was carried out in these patients along with sputum examination, CSF studies and biopsy of lymphnode and other tissues in few cases. A high degree of Toxoplasma, CMV & HSV-2 positivity was seen in transplanted patients. However sensitivity of serological diagnosis of tuberculos was found to be low with standard criteria, which increased significantly when modified criteria were used. It is concluded that regular immunological monitoring should be carried out in transplanted patients so as to reach an early diagnosis and management of opportunistic infections.KEY WORDS: Immune diagnosis, Opportunistic infections, Transplantation     

An intense 18F-FDG pulmonary microfocus on PET without detectable abnormality on CT: A manifestation of an iatrogenic FDG pulmonary embolus

An incidental finding of an intense focus of ¹⁸F-Fluorodeoxyglucose (FDG) pulmonary uptake on positron emission tomography (PET) without detectable lesions on computed tomography (CT) is highly suggestive of FDG microembolus. Its microscopic nature means it is undetectable on CT. It is an artefact attributable to ¹⁸F-FDG-tracer contamination at the injection site. This paper reports a case of a 61 year-old lady with a past history of breast carcinoma, in whom follow-up PET/CT images demonstrated an incidental intense FDG pulmonary abnormality. A follow-up PET/CT seven months later demonstrated complete resolution of the abnormality.     

Effects of collagen membranes enriched with in vitro-differentiated N1E-115 cells on rat sciatic nerve regeneration after end-to-end repair

Preventing falls and fall-related fractures in the elderly is an objective yet to be reached. There is increasing evidence that a supplementation of vitamin D and/or of calcium may reduce the fall and fracture rates. A vitamin D-calcium supplement appears to have a high potential due to its simple application and its low cost. However, published studies have shown conflicting results as some studies failed to show any effect, while others reported a significant decrease of falls and fractures. Through a 15-year literature overview, and after a brief reminder on mechanism of falls in older adults, we reported evidences for a vitamin D action on postural adaptations - i.e., muscles and central nervous system - which may explain the decreased fall and bone fracture rates and we underlined the reasons for differences and controversies between published data. Vitamin D supplementation should thus be integrated into primary and secondary fall prevention strategies in older adults.     

The distinctive profile of risk factors of nasopharyngeal carcinoma in comparison with other head and neck cancer types

Background

Nasopharyngeal carcinoma (NPC) and other head and neck cancer (HNCA) types show a great epidemiological variation in different regions of the world. NPC has multifactorial etiology and many interacting risk factors are involved in NPC development mainly Epstein Barr virus (EBV). There is a need to scrutinize the complicated network of risk factors affecting NPC and how far they are different from that of other HNCA types.

Methods

122 HNCA patients and 100 control subjects were studied in the region of the Middle East. Three types of HNCA were involved in our study, NPC, carcinoma of larynx (CL), and hypopharyngeal carcinoma (HPC). The risk factors studied were the level of EBV serum IgG and IgA antibodies measured by ELISA, age, sex, smoking, alcohol intake, histology, and family history of the disease.

Results

EBV serum level of IgG and IgA antibodies was higher in NPC than CL, HPC, and control groups (p < 0.01). NPC was associated with lymphoepithelioma (LE) tumors, males, regular alcohol intake, and regular smoking while CL and HPC were not (p < 0.05). CL and HPC were associated with SCC tumors (p < 0.05). Furthermore, NPC, unlike CL and HPC groups, was not affected by the positive family history of HNCA (p > 0.05). The serum levels of EBV IgG and IgA antibodies were higher in LE tumors, regular smokers, younger patients, and negative family history groups of NPC patients than SCC tumors, non-regular smokers, older patients and positive family history groups respectively (p < 0.05) while this was not found in the regular alcoholics (p > 0.05).

Conclusion

It was concluded that risk factors of NPC deviate much from that of other HNCA. EBV, smoking, alcohol intake, LE tumors, male patient, and age > 54 years were hot risk factors of NPC while SCC and positive family history of the disease were not. Earlier incidence, smoking, LE tumors, and negative family history of the disease in NPC patients were associated much clearly with EBV. It is proposed that determining the correct risk factors of NPC is vital in assigning the correct risk groups of NPC which helps the early detection and screening of NPC.     

Familial eosinophilic cellulitis, dysmorphic habitus, and mental retardation

Background: Eosinophilic cellulitis is a polymorphous, chronic disease characterized by eosinophil infiltration and granulomatous inflammation. Objective: Our purpose was to describe the clinical, histologic, and immunohistologic findings in three family members who have had eosinophilic cellulitis since childhood associated with mental retardation and abnormal body habitus. Methods: Family members were evaluated. Multiple skin biopsy specimens were obtained and examined after hematoxylin-and-eosin staining, by immunofluorescence and by electron microscopy. Blood specimens were analyzed by immunoassays for eosinophil granule proteins and eosinophil active cytokines. Results: Three short-statured, mentally retarded family members with abnormal body habitus in at least two generations had recurrent eosinophilic cellulitis. Peripheral blood and bone marrow eosinophilia was present. Plasma eosinophil granule major basic protein and eosinophil-derived neurotoxin levels were elevated with normal plasma eosinophil cationic protein levels. Eosinophil survival in culture was increased by patients’ plasma and was blocked with monoclonal interleukin-5 antibody. The level of plasma interleukin-5 was elevated. Lesional skin biopsy specimens showed massive staining for three eosinophil granule proteins. Electron microscopy showed eosinophil disruption. Conclusion: Eosinophilic cellulitis, mental retardation, and abnormal body habitus were likely inherited as a dominant syndrome in this family in which eosinophil involvement was striking. (J Am Acad Dermatol 1998;38:919-28.)     

Stress fractures—a prospective study amongst recruits

Background

Stress fracture (SF) is the single most common cause for the lost number of manpower days during training of recruits in the Armed Forces. This prospective study was undertaken with a view to develop baseline data on incidence of SF and to identify related variables.

Methods

A prospective study over a period of five years during 2004–2009 in which a total of 8,570 recruits were enrolled at the start of their training to find out the incidence and pattern of SFs.

Results

A total of 604 (7.04%, 95% CI 6.40–7.40%) out of a total of 8,570 recruits sustained SF during the study period. The majority of fractures occurred during basic training. The factors like urban residence, vegetarianism and those without prior history of physical activity were found to be associated with SF. Tibia was the commonest bone involved.

Conclusion

Prevention is undoubtedly the best approach in SF and other sports injuries. Priority should be given to individuals with good sports and physical activity background during recruitment. Intensity of training should be gradually increased during first three months (12 weeks) of training.Key Words: recruits, stress fracture