Amplification of engrafted hepatocytes by preparative manipulation of the host liver

Scarcity of donor livers is a major obstacle to the general application of hepatocytes for the development of bioartificial liver assist devices as well as intracorporeal engraftment of hepatocytes for the treatment of inherited metabolic diseases. The number of hepatocytes that can be transplanted into the liver safely in a single sitting also limits the utility of this procedure. These limitations could be addressed by providing preferential proliferative advantage to the transplanted cells. Studies using transgenic mouse recipients or donors have indicated that massive repopulation of the host liver by engrafted hepatocytes requires that the transplanted cells are subjected to a proliferative stimulus to which the host hepatocytes cannot respond. Prevention of host hepatocyte proliferation has been achieved by treatment with a plant alkaloid, retrorsine. Because retrorsine is carcinogenic, we have evaluated preparative irradiation for this purpose. The proliferative stimulus may consist of the loss of hepatic mass (e.g., partial hepatectomy, reperfusion injury or induction of Fas-mediated apoptosis by gene transfer) or administration of stimulants of hepatocellular mitosis (e.g., growth factors or thyroid hormone). Potential applications of these preparative manipulations of the host liver include the treatment of inherited metabolic disorders by transplantation of allogeneic hepatocytes, hepatocyte-mediated ex vivo gene therapy, rescuing liver cancer patients from radiation-induced liver damage, and expansion of human hepatocytes in animal livers.     

The Montgomery T-tube: anaesthetic problems and solutions

The Montgomery T-tube is a device used as a combined trachealstent and an airway after laryngotracheal surgery. The deviceis used mostly in specialist centres for head and neck surgery,and therefore, many anaesthetists may be unfamiliar with itsuse. The Montgomery T-tube presents the anaesthetist with challengesboth during its surgical insertion when acute loss of the airwaymight occur and also during induction of anaesthesia in patientswho have such a tube in situ. Anaesthetists who are unfamiliarwith the tube may have to resort to ingenious ways of copingwith the problems of a shared airway with a T-tube, which doesnot have a suitable adaptor for a standard catheter mount, aswell as controlling and maintaining ventilation through thedevice. Safe management of such patients requires careful planning.We describe the anaesthetic management of two cases to illustratethe problems associated with Montgomery tubes. Br J Anaesth 2001; 87: 787–90     

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

While 25% of human cancers harbor oncogenic Ras mutations, such mutations are not found in astrocytomas. We have previously demonstrated that the activation of receptor tyrosine kinases expressed by malignant human astrocytoma cells and specimens results in functional upregulation of the Ras signalling pathway and increased levels of activated Ras*GTP. Farnesyl transferase inhibitors (FTIs) are promising anti-cancer agents in early clinical trials, which may exert their effect through pharmacological inhibition of the Ras signalling pathway. In this study we establish the anti-tumorigenic properties of the FTI L-744,832 against a panel of malignant human astrocytoma cell lines. Furthermore, we demonstrate the multiple mechanisms by which L-744,832 exerts its effect. L-744,832 demonstrates both cytostatic and cytotoxic effects on astrocytoma cells, and cells expressing a truncated constitutively phosphorylated Epidermal Growth Factor Receptor common in high-grade astrocytomas (EGFRvIII/p140EGF-R) demonstrate increased sensitivity to the agent. L-744,832 is capable of inducing apoptosis in astrocytoma cells under anchorage-dependent conditions; this process occurs in a p53-independent manner and is associated with increased expression of Bax and Bak. L-744,832 also induces cell cycle arrest at both the G1/M and G2/S checkpoints; this process is also independent of p53 mutational status. Cell cycle arrest in drug-treated cells can be accompanied by induction of p21WAF1/CIP1, but this induction is not necessary for the cell cycle inhibitory effects, nor is it dependent on functional p53. Finally, angiogenesis in astrocytomas has been shown to be dependent on secretion of Vascular Endothelial Growth Factor (VEGF) by tumour cells, particularly under hypoxic conditions. L-744,832 potently inhibits the secretion of VEGF under hypoxic conditions. These combinations of mechanisms suggest that these tumours, despite the absence of oncogenic Ras mutations, will be amenable to growth inhibition by FTIs, through a combination of anti-proliferative, pro-apoptotic, and anti-angiogenic effects.     

A comparative study of balloon mitral valvuloplasty and closed mitral commissurotomy in patients with rheumatic mitral stenosis

Rheumatic mitral stenosis is frequently encountered in our country. It affects younger population and is a major cause of morbidity Mitral valvotomy is the definitive therapy for this disease and can be achieved by closed mitral commissurotomy (CMC), open mitral commissurotomy (OMC) or by percutaneous transluminal mitral valvuloplasty (PTMV). Compared to CMC, PTMV is less invasive but more expensive at this moment. With the reduction of cost, PTMV may become the procedure of choice for the treatment of rheumatic mitral stenosis in future.     

Arsenicosis and Dietary Nutrient Intake Among Men and Women

To determine the dietary intake of nutrients and its correlation with manifestations of arsenicosis and gender a cross-sectional study was conducted in India among two groups of participants, Group 1 (108 cases having skin lesions) and Group 2 (exposed controls, 100 cases not having skin lesions) with exposure to arsenic drawn from geographical areas known to have high level of arsenic in ground water (above permissible limit, i.e. >50 μg/L). For diet survey, combinations of two methods of diet study i.e. weighment of cooked food and the 24-h diet recall were followed. The nutrients in each food items and calorie consumption were calculated. The mean calorie intake of males was significantly less than that of females in both cases and controls. In both the sexes, mean protein consumption was significantly less than that of the controls. In females, intake of most of the nutrients like thiamin, riboflavin, niacin, magnesium, copper and zinc were less in comparison to controls. In both the sexes mean choline intake was lower significantly in comparison to exposed controls. Riboflavin, copper, zinc and vitamin B₆ consumption were below the RDAs in nearly 90 % of the study population. The strongest trend in ORs was for protein (4.28). The present study revealed that low socio-economic status along with dietary intake of calorie, protein and micronutrients like thiamine, riboflavin, niacin, zinc and choline may have a definite role in increasing the risk of development of arsenicosis.     

Concanavalin A-induced agglutination of Ehrlich ascites carcinoma cells during growth of the tumor in mice

ConA-induced agglutination of Ehrlich ascites carcinoma (EAC) cells during development of the tumor in mice has been studied in vitro. EAC cells were incubated with different concentrations of ConA at 37 degrees C for various intervals of time and the cell aggregates of different sizes were scored under microscope. The older EAC cells (20-day-old) showed a decrease in cytoagglutination with respect to large aggregates formation compared to the younger (10-day-old) ones. The small aggregates formed by the 5-day-old EAC cells are dissociated by competition with alpha-methyl-D-mannoside but the large aggregates are not affected by the sugar treatment. The observed differences in the agglutination patterns are discussed in view of the influence of the lipid content of EAC cells and the ascites fluid on ConA-induced cytoagglutination.     

Correlation Analyses Reveal a Substantial Influence of Allelic Gaps on the Investigation of Genetic Diversity of Modern Human Populations with Microsatellites

High intra-population genetic diversity and multiple measures of genetic variability at STR loci are useful in inferring past evolutionary history. However, STRs, categorized by their repeat motif size, differ in a number of aspects, requiring separate analyses. We analyzed 783 STRs in 36 worldwide populations to examine marker suitability as well as correlations between various measurements, to evaluate the extent of genomic diversity present in modern human populations. The loci were grouped by type and analyzed separately for each population group. Genetic variation defined by gene diversity and allele size variance, shows different trends of variation across four types of STRs. Additionally, there is little variation of genetic diversity, but there is decreased allelic size variance with increasing repeat motifs. A poor correlation between genetic diversity and allelic size variance across loci in all groups for Di-STRs is probably caused by the presence of allelic size gaps. In contrast, allelic size variance, genetic diversity, and number of alleles are strongly correlated with both tri- and tetra-STRs. The positive correlation of allelic size variance and presence of gaps within the range of allelic sizes in Di-STRs alone explains these observations. An unexpected high imbalance index (β) at Di-STRs due to high allelic size variance also supports this assertion.