Impact of peripheral immune status on central molecular responses to facial nerve axotomy.

When facial nerve axotomy (FNA) is performed on immunodeficient recombinase activating gene-2 knockout (RAG-2-/-) mice, there is greater facial motoneuron (FMN) death relative to wild type (WT) mice. Reconstituting RAG-2-/- mice with whole splenocytes rescues FMN survival after FNA, and CD4+ T cells specifically drive immune-mediated neuroprotection. Evidence suggests that immunodysregulation may contribute to motoneuron death in amyotrophic lateral sclerosis (ALS). Immunoreconstitution of RAG-2-/- mice with lymphocytes from the mutant superoxide dismutase (mSOD1) mouse model of ALS revealed that the mSOD1 whole splenocyte environment suppresses mSOD1 CD4+ T cell-mediated neuroprotection after FNA. The objective of the current study was to characterize the effect of CD4+ T cells on the central molecular response to FNA and then identify if mSOD1 whole splenocytes blocked these regulatory pathways. Gene expression profiles of the axotomized facial motor nucleus were assessed from RAG-2-/- mice immunoreconstituted with either CD4+ T cells or whole splenocytes from WT or mSOD1 donors. The findings indicate that immunodeficient mice have suppressed glial activation after axotomy, and cell transfer of WT CD4+ T cells rescues microenvironment responses. Additionally, mSOD1 whole splenocyte recipients exhibit an increased astrocyte activation response to FNA. In RAG-2-/- + mSOD1 whole splenocyte mice, an elevation of motoneuron-specific Fas cell death pathways is also observed. Altogether, these findings suggest that mSOD1 whole splenocytes do not suppress mSOD1 CD4+ T cell regulation of the microenvironment, and instead, mSOD1 whole splenocytes may promote motoneuron death by either promoting a neurotoxic astrocyte phenotype or inducing Fas-mediated cell death pathways. This study demonstrates that peripheral immune status significantly affects central responses to nerve injury. Future studies will elucidate the mechanisms by which mSOD1 whole splenocytes promote cell death and if inhibiting this mechanism can preserve motoneuron survival in injury and disease.

A Randomized Controlled Trial of Intravenous versus Oral Cyclophosphamide in Steroid-resistant Nephrotic Syndrome in Children.

This is a randomized, parallel group, active-controlled trial to compare the efficacy of intravenous cyclophosphamide (IVCP) with oral cyclophosphamide (OCP) in patients with steroid-resistant nephrotic syndrome (SRNS) in children. Fifty consecutive children with idiopathic SRNS were biopsied and then randomized to receive either OCP at a dose of 2 mg/kg/day for 12 weeks or IVCP at a dose of 500 mg/m2/month for 6 months. Both groups received tapering doses of oral steroids. The response was evaluated in terms of induction of complete remission (CR) or partial remission (PR), time to remit, and side effects. The groups were followed up to determine the duration of remission, percentage of patients who remain in sustained remission for more than 1 year after completion of therapy, change in steroid response status, progression to chronic kidney disease stage 3 or more. Of the fifty patients, OCP was given to 25 children and IVCP to 25 children. The demographic data, histopathology, biochemical profile, and duration of follow-up in the two groups were comparable. The rates of induction of CR were 52% versus 44% and of PR were 8% versus 8% in the intravenous (IV) and oral group, respectively. Time to remit was shorter with OCP than IVCP (53 days vs. 84.4 days). Incidence of side effects (both major and minor) was 36% in IVCP versus 20% in OCP group. The actuarial cumulative sustained remission in our study was 12% in IVCP compared with 16% in OCP at 1 year after completion of therapy. Twelve percent children in both the groups exhibited restoration of steroid sensitivity. Thus, in our study, overall, more than half of SRNS patients showed initial response to cyclophosphamide, but only one-fourth patients had sustained remission on follow-up. OCP and IVCP were equally efficacious and safe in idiopathic SRNS in children.

Upper extremity impairments, pain and disability in patients with diabetes mellitus.

OBJECTIVES: To determine the severity of, and relationships between, upper extremity impairments, pain and disability in patients with diabetes mellitus, and to compare upper extremity impairments in patients with diabetes with non-diabetic controls. DESIGN: Case-control, cross-sectional design. SETTING: University-based, outpatient diabetes centre and physical therapy research clinic. PARTICIPANTS: Two hundred and thirty-six patients with diabetes attending an outpatient diabetes clinic completed the Shoulder Pain and Disability Index (SPADI) questionnaire. A detailed shoulder and hand examination was conducted on a subgroup of 29 volunteers with type 2 diabetes, and 27 controls matched for age, sex and body mass index. INTERVENTIONS: None. MAIN OUTCOME MEASURES: SPADI score, passive shoulder range of motion (ROM) and strength, grip strength, hand sensation, dexterity and limited joint mobility of the hand. RESULTS: Sixty-three percent (149/236) of patients with diabetes reported shoulder pain and/or disability [median SPADI score 10.0 (interquartile range 0.0 to 39.6)]. Compared with the control group, the subgroup of patients with diabetes had substantial reductions in shoulder ROM, shoulder muscle strength, grip and key pinch strength (P<0.05). Patients with diabetes had a greater prevalence of decreased sensation (26/27 vs 14/27) and limited joint mobility of the hand (17/27 vs 4/27) compared with the control group. Total SPADI score was negatively correlated (P<0.05) with shoulder ROM (r=-0.42 to -0.74) and strength measures (r=-0.44 to -0.63) in patients with diabetes. CONCLUSIONS: Upper extremity impairments in this sample of patients with diabetes were common, severe and related to complaints of pain and disability. Additional research is needed to understand the unique reasons for upper extremity problems in patients with diabetes, and to identify preventative treatments.

Epstein-Barr virus and carcinogenesis: beyond Burkitt's lymphoma.

Subsequent to its discovery over 45 years ago, Epstein-Barr virus (EBV) has been associated with numerous human carcinomas. Approximately 95% of the world's population sustain an asymptomatic life-long EBV infection. EBV persists in the memory B cell pool of normal healthy individuals and any disruption of this interaction results in virus-associated B cell tumours. The association of EBV with epithelial cell tumours, specifically nasopharyngeal carcinoma and EBV-positive gastric carcinoma, is less clear and is currently considered to be a consequence of the aberrant establishment of virus latency in epithelial cells displaying pre-malignant genetic changes. Although the precise role of EBV in the carcinogenic process is currently poorly understood, the presence of the virus in all tumour cells provides opportunities for the development of novel therapeutic and diagnostic approaches. The study of EBV and its role in carcinomas continues to provide insights into the carcinogenic process that are relevant to a broader understanding of tumour pathogenesis and to the development of targeted cancer therapies.

The EBV-encoded latent membrane proteins, LMP2A and LMP2B, limit the actions of interferon by targeting interferon receptors for degradation.

Although frequently expressed in Epstein-Barr virus (EBV)-positive malignancies, the role that latent membrane protein 2A and 2B (LMP2A and LMP2B) have in the oncogenic process remains obscure. Here we show a novel function for these proteins in epithelial cells, namely, their ability to modulate signalling from type I/II interferon receptors (IFNRs). We show that LMP2A- and LMP2B-expressing epithelial cells show decreased responsiveness to interferon (IFN)alpha and IFNgamma, as assessed by STAT1 phosphorylation, ISGF3 and GAF-mediated binding to IFN-stimulated response element and IFNgamma-activated factor sequence elements and luciferase reporter activation. Transcriptional profiling highlighted the extent of this modulation, with both viral proteins impacting 'globally' on IFN-stimulated gene expression. Although not affecting the levels of cell-surface IFNRs, LMP2A and LMP2B accelerated the turnover of IFNRs through processes requiring endosome acidification. This function may form part of EBV's strategy to limit anti-viral responses and define a novel function for LMP2A and LMP2B in modulating signalling from receptors that participate in innate immune responses.

Autoimmune thyroiditis perdating the presentation of systemic lupus erythematosus: two cases and a review of literature.

Autoimmune diseases are commonly encountered in dermatology practice. While the association of two autoimmune diseases in the same individual is not unknown, it is relatively rare for the second disease to be suspected based on cutaneous manifestations. We present two such cases wherein cutaneous manifestations were the first clue to the development of lupus erythematosus in a setting of autoimmune thyroiditis. Further, we have reviewed literature on this uncommon occurrence and discuss various aspects of this association.

THERAPEUTIC HYPERBARIC OXYGENATION AS AN ADJUNCT TO MULTIDRUG THERAPY IN HANSEN'S DISEASE.

Hansen's disease is a chronic infection caused by Mycobacterium leprae. Current therapy for this disease is with the WHO recommended Multi Drug Therapy (MDT) with DDS, rifampicin and clofazimine. Hyper Baric Oxygen Therapy (HBOT) has been used to treat many medical conditions including infections with a great deal of success. It's efficacy on various species of mycobacteria and other bacteria have been studied in vitro and in vivo and it is found to be an effective antimicrobial agent under specified conditions. HBOT has been used to treat Hansen's disease, including drug resistant lepromatous leprosy cases with good results. However there is a paucity of literature on this form of therapy. We have treated twenty cases of Hansen's disease with HBOT prior to exhibiting MDT as per the WHO schedule. There has been a marked regression in skin signs especially decrease in erythema and flattening of raised lesions. This correlated well with the histopathological picture which showed a reduction in the inflammatory exudate.

HIV INFECTION IN HERPES ZOSTER.

The interaction of Herpes zoster and Human Immunodeficiency Virus (HIV) was evaluated in 120 cases of herpes zoster admitted to our hospital and in 157 HIV positive cases detected in the hospital during the same period. The incidence of HIV seropositivity was 22.5 per cent in cases of herpes zoster without AIDS defining disease conditions. Whereas the incidence of Herpes zoster in cases detected to be HIV positive in the same period was 17.2 per cent. A large number of herpes zoster cases found to be HIV positive were in the sexually active age group viz. 21-30 years. Thoracic dermatomal segments were most frequently involved. None of the cases had severe complications or showed evidence of progression to symptomatic HIV disease.

Fracture stiffness measurement in tibial shaft fractures: a non-invasive method.

This paper presents a non-invasive method of assessing healing by measurement of fracture stiffness. The method works on the principle that if the load (F) applied at a certain known distance (Y) from the fracture is measured, then the moment (M = FY) at the fracture site can be calculated. By measuring the angle/deflection (straight theta) occurring at the fracture site using a suitable instrument (electrogoniometer), the necessary data to calculate fracture stiffness (FY/straight theta) would be available. The method was employed to assess the stiffness in a series of tibial shaft fractures treated conservatively, all of which healed uneventfully. This paper concentrates on a group of tibial shaft fractures in which the radiological criteria for fracture union were not satisfied even after a mean duration of 20 weeks treatment. The non-invasive method of measuring fracture stiffness supported the clinical impression of union in most cases at the first test, but was repeated on two more occasions to confirm the trend of progressive healing. The objective evaluation of fracture healing led to avoidance of surgical intervention in these patients, who went on to sound union.

Biomechanical study on femoral neck fracture fixation in relation to bone mineral density.

Twenty pairs of fresh-frozen cadaveric femurs were used in the study. The left femurs were used as control for the mechanical testings and bone mineral content scans, the right femurs were divided into two experimental groups, i.e. 'fractured' group and 'healed' group. In the 'fractured' group, twelve right femurs were osteotomized at the plane perpendicular to the femoral neck shaft axis, through the mid-cervical area of the femoral neck. The artificially created fractures were fixed with the AO dynamic hip screw system using a 4-hole plate and a compression screw. In the 'healed' group, the dynamic hip screws were applied to eight intact right femurs to simulate healed fractures. Bone mineral density scans and mechanical testings were performed on all the femurs. Good correlation was observed between bone mineral density and femoral neck strength in the control group. There was a decrease of 43.5% in strength in the 'fractured' group when compared to the control group. However, in the 'healed' group the failure load was found to be 15.2% lower than the control group. The femoral fixation strength in the 'fractured' and 'healed' groups had good correlation with the bone mineral density. RELEVANCE--:Results from this study indicated that bone mineral density is an important predictive factor in fracture fixation failure. Therefore it may be appropriate to consider the bone mineral density of a patient with proximal femoral fracture treated with fixation devices, as a criterion in prescribing a more protective postoperative management, with respect to weight bearing protocol.

Effect of decalcification on bone mineral content and bending strength of feline femur.

The relationships between bone mineral content (BMC), bone calcium, and bone strength were studied in fractionally demineralized feline femurs. In 44 pairs of cat femurs, the right bones were decalcified in ethylene diaminetetra acetic acid (EDTA) to 20%, 40%, 60%, 80%, and 100% of the mineral content of the intact left bone (= control). The bones were then loaded to failure, and maximum strength values were recorded. The data were then used to calculate the percentage strength of the right relative to the left femurs. A correlation coefficient (r) of 0.970 was found between the percentage decalcification and percentage bending strength. A direct relationship (r = 0.876) was also observed between the total calcium extracted and total loss in BMC. The EDTA solutions were spot checked for protein content to determine if the organic matrices had been altered by demineralization. Protein was never detected. Nor did the demineralized tissues display histologic evidence of gross microscopic damage. This study has shown that in cat femurs, 20% decalcification led to about 35% loss in bending strength, and 60% decalcification caused 75% loss in strength. These values are significant as they highlight the importance of calcium to the strength of osteopenic bone.