Perturbations of endogenous levels of orotic acid and carcinogenesis: effect of an arginine-deficient diet and carbamyl aspartate on hepatocarcinogenesis in the rat and the mouse

Feeding excess orotic acid (OA) In the diet promotes the carcinogenicprocess in different organs Including the liver. A number ofmetabolic and genetic disorders are associated with Increasedsynthesis of endogenous OA and some of these disorders appearto pose an Increased risk of liver cancer development. Thisstudy therefore examines whether excess OA of endogenous originalso exerts a promoting effect on hepatocarcinogenesis in themouse and the rat. Increased endogenous synthesis of OA wasachieved by (i) feeding a diet deficient in arginine (AD) and(ii) feedIng excess dietary carbamylaspartate (CA), a precursorfor the synthesis of OA. A single dose of diethylnitrosamine(DENA) was given i.p. to male Fischer 344 rats (200 mg/kg) orto male DBA/2 mice (90 mg/kg). One week later they were placedon either AD diet or the same diet supplemented with 1.3% arginine(AS) for a total of weeks. Two-thirds partial hepatectomy (PH)was performed at the end of the second week. All animals werethen transferred to a control semisynthetic basal diet for atotal of 20 weeks before they were killed. The results indicatedthat AD diet increased the incidence of hepatic nodules in bothrats (percentage area occupied by nodules was 4.7 ± 0.4in the AD group compared to a control value of 0.7 ±0.5) and mice (4/10 mice had nodules >5 mm diameter in theAD group while none in the AS group had such large nodules).In another experiment male Fischer 344 rats similarly initiatedwIth DENA were exposed to either basal diet or basal diet containing2% CA for 4 weeks coupled with PH performed at the end of thesecond week. This regimen was followed by 20 weeks of feedingbasal diet to both groups. Rats given CA developed larger hepatlcfoci and nodules (0.84 ± 0.56 mm³) compared to the controlgroup, which was fed basal diet throughout the experiment (0.07± 0.03 mm³) Further, both AD diet and dietary CA, likedietary OA, induced an increase In hepatic uridine nucleotides.Taken together, these results suggest that Increased levelsof endogenously synthesized OA, like exo genously supplied excessOA, can induce an Imbalance in hepatic nucleotide pools andcan exert a promoting effect on hepatocarcinogenesis.     

Altered immune response to liposomal allergens of Aspergillus fumigatus in mice

Aspergillus fumigatus has been implicated as the major pathogenic fungus causing Aspergillus-mediated disorders. It secretes complex glycoprotein antigens and allergens, which induce type I and type III mediated hypersensitivity reactions. The immune response to these allergens/antigens in allergic disorders is characterized by elevated levels of specific IgE, Th2 cytokines and eosinophilia. In the current study, the ability of negatively charged liposomes entrapped with glycoprotein antigens and allergens of A. fumigatus to modulate the immune response was studied. Immune response in mice was evaluated with both free and liposomal formulations. Liposome entrapped glycoprotein antigens/allergens of A. fumigatus elicited a Th1 type response with increased levels of TNF-alpha (5.5-folds), IFN-gamma (four-folds), specific IgG (three-folds) and IgG2a (2.4-folds), low titers of specific IgG1 (2.2-folds decrease) and IgE (three-folds decrease), and decreased peripheral eosinophilia by four-folds in comparison to mice receiving free glycoprotein allergens/antigens of A. fumigatus. Histopathological examination of lung tissue sections clearly indicated reduced eosinophil infiltration in mice immunized with liposomal formulations. These results suggest potential of liposomal formulations for A. fumigatus allergens/antigens for exploration in immunotherapy.     

Post-cardiorespiratory arrest beta-alpha coma: an unusual electroencephalographic phenomenon

The presence of frontally-dominant alpha pattern in the EEG is common in patients with coma due to trauma, toxic-metabolic causes and following cardiorespiratory arrest. Diffuse beta activity following resuscitation after a cardiac arrest is not well recognized. We report a case of coma in a 3-year-old girl who had a cardiac arrest from which she was revived. Initial EEG showed diffuse beta activity, which later evolved to predominantly alpha activity. The possible mechanisms involved in the generation of such rhythms are discussed. Transition of EEG activity from faster to slower frequencies is suggested as an adverse prognostic factor in post-cardiorespiratory arrest coma.     

Anti-complement strategies in experimental sepsis

Using the cecal ligation/puncture (CLP) model of sepsis in rodents, evidence was obtained for excessive activation of the complement system, which leads to nearly total loss of innate immune protective functions of blood neutrophils. These defects are associated with profound defects in chemotaxis, respiratory burst (H2O2 production) and phagocytosis. The molecular mechanisms of these defects are linked to the complement activation product C5a. In CLP rats and mice, the C5a receptor (C5aR) is widely up-regulated in organs, in part owing to the production of interleukin-6 (IL-6). The up-regulation of C5aR in the thymus is linked to C5a-dependent induction of apoptosis in thymocytes, as revealed by caspase activation, increased binding of C5a and DNA laddering. Such events in thymocytes are prevented if rats first are treated with anti-C5a or with anti-C5aR at the time of CLP. Treatment of CLP rats and mice with anti-C5a, anti-IL-6 or anti-C5aR dramatically improves survival rates after CLP, indicating a linkage between C5a and C5aR in the harmful outcomes of sepsis in rodents. Studies are underway in humans with sepsis to determine whether similar mechanisms are in play.     

Quantifying sodium in the human wrist in vivo by using MR imaging

The authors quantified sodium content in the wrist joints of six healthy volunteers with no known history of arthritis or pain. Average sodium concentrations ranged from 115 to 150 mmol/L in noncartilaginous regions and from 200 to 210 mmol/L in cartilaginous regions. The feasibility of quantifying sodium in vivo was demonstrated. This method has potential applications in monitoring the integrity of cartilaginous tissue in vivo.     

Preparation and evaluation of 90 Y skin patches for therapy of superficial tumours in mice

90Y, a beta emitting radionuclide, was immobilized in a bandage patch for possible application for the therapy of superficial maladies such as tumours and skin cancers. The aim was to prepare a radiation source that could deliver uniform dose within a short duration and avoid the inconveniences faced with the gamma sources used in teletherapy and brachytherapy. 90Y-ferric hydroxide macroaggregates were prepared, filtered and immobilized between two layers of gauze. When placed in saline, no radioactivity leached for 3 days, proving its safety for external application. Fibrosarcoma was induced in mice for checking the efficacy of 90Y patches. 90Y patches of various activities were prepared and applied on the tumours. The effect of time gap between inception and treatment of tumour, dose delivered and multiple application in fractionated doses was studied. In all the cases, tumour growth in the treated animals was considerably reduced in comparison with controls. It was concluded from the experiments that treatment should be started at the earliest stage possible, i.e. when the tumour is palpable. Delivery of dose from radioactive patches of approximately 90-100 MBq each, thrice at weekly intervals proved to be more effective for regression of tumour growth.     

Epilepsy care in six Indian cities: a multicenter study on management and service

BACKGROUND: Epilepsy care in developing countries is lagging behind than in the developed countries. Precise data on delivery of neurological services for epilepsy is essential to optimize the medical services for epilepsy care with limited resources. OBJECTIVE: This study was carried out in order to examine the management practices and utilization of various medical services for epilepsy in different parts of India. METHODOLOGY: University centers with epilepsy clinics, one each from six states of India, had participated in this study. Demographic data, clinical details, and data on epilepsy care were collected simultaneously on standard proforma. RESULTS: Data on 285 patients with epilepsy (generalized epilepsy: 49.1%, localization-related epilepsy: 49.9%, others: 1%) were included. Mean age of onset of epilepsy was 14.8+11.1 years. Mean delay in diagnosis was 1.5+/-4 years. Mean distance from place of residence to the consulting neurologist was 70+/-82 km. Medical consultations before referral to epilepsy center included general practitioners (54.1%) and specialists (43.3%). Very few patients received services from clinical psychologist or social worker. Investigations included, EEG (63.2%), CT Scan (36.2%). MRI brain (8.5%) and video EEG (2.1%) were limited to a few. Nearly 75.5% were on monotherapy. Newer Anti-Epileptic Drugs (AEDs) were used only in less than 5% patients. CONCLUSION: The services for epilepsy are urban-based and there is underutilization of services, general practitioners and specialists. Newer AEDs (although expensive) are gradually emerging in Indian market. Facilities for epilepsy surgery, therapeutic drug monitoring and services of clinical psychologist or medical social workers are limited.