Novel antidiabetic and hypolipidemic agents. 5. Hydroxyl versus benzyloxy containing chroman derivatives.

Several thiazolidinediones having chroman moieties were synthesized and evaluated for their euglycemic and hypolipidemic activities. Some of the analogues having an aminoalkyl group as a linker between the chroman ring and 4-[5-(2,4-dioxo-1, 3-thiazolidinyl)methyl]phenoxy moiety seem to be better than troglitazone. In vitro transactivation assays of PPARgamma have been carried out with these glitazones to understand their molecular mechanism. For the first time we have found that some of the unsaturated thiazolidinediones are superior to their saturated counterpart in the in vivo assay. A more potent thiazolidinedione analogue than troglitazone is reported. Pharmacokinetic studies have shown that protection of the OH group in the chroman moiety leads to a decrease in metabolism, thereby resulting in a superior pharmacological profile.     

A topical dosage form of liposomal clofazimine: research and clinical implications

A novel topical clofazimine (CLO) gel formulation containing liposomally encapsulated CLO, was prepared and investigated in vitro followed by a clinical evaluation. CLO liposomes were prepared by the lipid film hydration technique. Comparative in vitro diffusion studies were conducted with plain and liposomal CLO in HPMC K4M gel base (2% and 5%) using human cadaver skin (HCS). A double blind clinical study was conducted on eight leprosy patients. The results of these studies show that the new liposomal topical gel formulation not only prolongs the drug release but also promotes drug retention by the skin. Studies further support formation of a reservoir of drug on the skin modifying therapeutic efficacy of the formulation. The new liposomal gel formulation of CLO considerably reduces the healing time of external lesions due to a significantly prolonged skin residence time compared to plain CLO gel and hence is expected to reduce the time needed for leprosy treatment.     

Inheritance of Biomass Yield and Tropane Alkaloid Content in Hyoscyamus muticus

The nature of gene action for biomass yield and tropane alkaloid content was ascertained through diallel analysis in Egyptian henbane, HYOSCYAMUS MUTICUS L. Dominance variation was preponderant over additive genetic variance, dominance being in the overdominance range for both traits. On an overall basis, recessive alleles had a positive (i.e. increasing) effect on both the characters. However, the positive or negative effects of recessive or dominant alleles were genotype-specific. Hence, transgressive breeding was suggested for isolating segregants with dominant alleles for herb yield and with recessives for alkaloid content so as to achieve overall high yields of tropane alkaloid per unit area.     

Cytoprotective influence of ZVAD-fmk and glycine on gel-entrapped rat hepatocytes in a bioartificial liver

BACKGROUND: This study was designed to determine if an anti-necrotic compound, glycine, and/or an anti-apoptotic agent, ZVAD-fmk, improved the viability and function of hepatocytes in a bioartificial liver. METHODS: Isolated rat hepatocytes were entrapped in collagen gel (1.0-10.0 x 10(6) cells/mL) and cultured in serum-free medium (1:10 ratio of gel:media) supplemented with glycine alone, ZVAD-fmk alone, or glycine and ZVAD-fmk. The cytoprotective effects of glycine and ZVAD-fmk on gel-entrapped rat hepatocytes (GERH) were determined after anoxic exposure (0-20 hours). Cell functionality (measured by urea production), cell viability (quantitated by vital staining with fluorescein diacetate:ethidium bromide [FDA:EB]), and the mechanism of cell death (verified by electron microscopy and DNA fragmentation studies) were determined for each condition. RESULTS: The viability of GERH declined gradually and then stabilized 12 hours after hepatocyte isolation. The rate of urea production by GERH was directly proportional to the number of viable hepatocytes. Apoptotic death predominated at low cell density, and necrotic cell death became significant at high cell density. Hepatocyte necrosis became more significant after exposure to longer periods of anoxia (4, 8, 12, and 20 hours). ZVAD-fmk provided dose-dependent cytoprotection to GERH with an optimum benefit at a concentration of 60 mumol/L. After anoxic exposure or under high cell density culture, glycine demonstrated a maximum benefit of inhibiting necrosis at a concentration of 3 mmol/L. The beneficial effects of glycine and ZVAD-fmk were additive. CONCLUSIONS: The metabolic activity of a hepatocyte bioartificial liver may benefit from the use of cytoprotective agents such as ZVAD-fmk and glycine.     

Central motor conduction time in malnourished children

The functional status of the descending motor pathways was assessed in malnourished children using transcranial electromagnetic stimulation of the cortex. Twenty children with different severities of malnutrition and 20 control subjects were studied electrophysiologically. The circular coil of a Dentac MAG 2 magnetic stimulator was applied tangentially over the vertex to stimulate the cortex. The muscle evoked potential in the children's arms was recorded from the abductor pollicis brevis muscle and in their legs from the extensor digitorum brevis muscle on both sides of the body using surface electrodes. The muscle evoked potential of the abductor pollicis brevis and extensor digitorum brevis muscles was further obtained using root stimulation by applying the coil at the cervical and lumbar spine, respectively. The indices of cortical threshold, cortical latency, and central motor conduction time (ms) were evaluated in both arm and leg muscles on both sides. The results showed an increased cortical threshold (mean (SD) 1232.5 (134.06) in the study group v 1147.5 (99.31) in the control group) for the abductor pollicis brevis muscle and for the extensor digitorum brevis muscle (1325.00 (115.70) in the study group v 1190.0 (125.24) in the control group). Similarly, significant prolongation of the central motor conduction time (ms) (study group 6.67 (0.91) v control group 5.71 (0.74)) in the abductor pollicis brevis muscle was seen in malnourished children.     

Role of clinical, radiological, and neurophysiological changes in predicting the outcome of tuberculous meningitis: a multivariable analysis

OBJECTIVES: The role of EEG and evoked potentials has not been evaluated in predicting the prognosis of tuberculous (TB) meningitis. The present study was aimed at evaluating the prognostic significance of clinical, radiological, and neurophysiological variables using multi-variable analysis. METHODS: Patients with TB meningitis diagnosed on the basis of clinical, radiological, and CSF criteria have been prospectively evaluated. All the patients were subjected to a detailed neurological evaluation. The outcome was defined 6 months after starting treatment on the basis of the Barthel index (BI) score into poor (BI <12) and good recovery (BI> or =12). Death was included in the poor recovery group for statistical analysis. Thirteen clinical (age, sex, seizure, focal weakness, stage of meningitis, Glasgow coma scale score, methyl prednisolone therapy), CT (infarction, hydrocephalus, tuberculoma) and neurophysiological (EEG, motor and somatosensory evoked potentials) variables were evaluated employing single variable logistic regression followed by multivariable logistic regression analysis. The best set of predictors were obtained by stepdown logistic regression analysis. RESULTS: Fifty four patients were included in the present study. Their age ranged between 5 and 62 years, 11 were children younger than 12 years and 14 were female. Nine patients were in stage I meningitis, 12 in stage II, and 33 in stage III. On single variable logistic regression analysis the significant predictors of 6 months outcome of TB meningitis included focal weakness, Glasgow coma scale (GCS), motor evoked potential (MEP) and somatosensory evoked potential (SEP). On multivariable analysis the best set of predictors comprised focal weakness, GCS, and SEP. CONCLUSIONS: In patients with TB meningitis focal weakness, GCS, and SEP are the best predictors of 6 month outcome.     

Trends in compliance with the national colposcopy guidelines.

This study aims to assess trends in compliance with current colposcopy guidelines in 10 gynaecological units in four English counties since 1996; to identify constraints on compliance and suggest change in practice. All 10 gynaecology units in Oxfordshire, Buckinghamshire, Northamptonshire and Berkshire participated. Data were collected prospectively by colposcopists from 23,500 new referrals across a 55-month period from September 1996 to March 2001. The Oxford Cancer Intelligence Unit performed collation, quality assurance and retrieval of data for incomplete records. Audit results were disseminated annually to colposcopists via the Regional Colposcopy Group. Colposcopy waiting times exceeded the standards, but waiting times for high-grade referrals showed statistically significant improvement. Six standards were achieved; relating to accuracy, appropriateness of management and outcomes. The seven unmet standards relate to waiting times, colposcopist's caseload, follow-up policy and the proportion of cervical epithelial neoplasia (CIN) on histology. Changes in practice are suggested, constraints on compliance are identified and the appropriateness of some guidelines is questioned.     

Levonorgestrel-releasing intrauterine system vs. transcervical endometrial resection for dysfunctional uterine bleeding.

OBJECTIVE: To compare the acceptability, efficacy, adverse effects, and user satisfaction of a levonorgestrel intrauterine system (LNG-IUS) and transcervical resection of the endometrium (TCRE) for the treatment of dysfunctional uterine bleeding. METHOD: Of 50 women with a pictoral blood loss assessment chart (PBAC) score of 100 or greater, 25 had a LNG-IUS inserted (Mirena; Schering, Berlin, Germany) and 25 underwent TCRE. Procedure-related complications, PBAC score, hemoglobin levels, adverse effects, and rates of acceptability and satisfaction were recorded at 3-month intervals for a period of 12 months. RESULTS: At the end of 1 year there were a 97% and a 94% reduction in menstrual blood loss in the LNG-IUS and TCRE groups, respectively, and hemoglobin concentration had increased by 5.5% in the LNG-IUS group and 5.2% in the TCRE group. Adverse effects were similar in both groups except for systemic effects, which were seen only in the LNG-IUS group. Satisfaction rates were about 80% in the 2 groups. CONCLUSION: Both treatments were found to be equally effective but LNG-IUS placement requires less operator skill and entails no operative hazards, and the device provides effective contraception.     

Electroconvulsive therapy and the alpha-2 noradrenergic receptor: implications of treatment schedule effects

Six factorially designed studies evaluated the effects of different schedules of electroconvulsive shocks (ECSs) on alpha-2 adrenoceptor function in the rat brain. Attenuation of the hypomotility response to a clonidine challenge was taken to indicate alpha-2 adrenoceptor downregulation, a putative mediator of antidepressant action. Six daily and six alternate-day ECSs were shown separately to produce this receptor change. Three alternate-day ECSs produced comparable downregulation for a comparable period as six daily ECSs; this suggests that ECS produces time-dependent effects. No changes were elicited with a single ECS, which indicates that a single ECS may not influence alpha-2 receptor function. Three daily ECSs produced brief downregulation, which has implications for receptor dynamics as a function of the ECS schedule. Finally, maintenance ECSs sustained alpha-2 adrenoceptor downregulation over 6 weeks, which suggests a possible neurochemical basis for maintenance electroconvulsive therapy. The clinical relevance and scope for further research are discussed.     

Nonalcoholic Fatty Liver Disease after Liver Transplant

Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease in the world. The rising prevalence of nonalcoholic steatohepatitis (NASH) has led to a 170% increase in NASH cirrhosis as the listing indication for liver transplantation from 2004 to 2013. As of 2018, NASH has overtaken hepatitis C as an indication for liver transplantation in the USA. After liver transplantation, the allograft often develops recurrent NAFLD among patients with known NASH cirrhosis. In addition to recurrent disease, de novo NAFLD has been reported in patients with other indications for liver transplantation. In this review, we will discuss the risk factors associated with recurrent and de novo NAFLD, natural course of the disease, and management strategies after liver transplantation.