Effect of insulin-sensitizing agents in combination with ezetimibe, and valsartan in rats with non-alcoholic fatty liver disease

AIM: To assess whether treatment with insulin-sensitizing agents (ISAs) in combination with ezetimibe and valsartan have greater effect on hepatic fat content and lipid peroxidation compared to monotherapy in the methionine choline-deficient diet (MCDD) rat model of non-alcoholic fatty liver disease (NAFLD). METHODS: Rats (n = 6 per group) were treated with different drugs, including MCDD only, MCDD diet with either metformin (200 mg/kg), rosiglitazone (3 mg/kg), metformin plus rosiglitazone (M R), ezetimibe (2 mg/ kg), valsartan (2 mg/kg), or combination of all drugs for a total of 15 wk. Liver histology, lipids, parameters of oxidative stress and TNF-alpha were measured. RESULTS: Fatty liver (FL) rats demonstrated severe hepatic fatty infiltration (> 91% fat), with an increase in hepatic TG ( 1263%, P < 0.001), hepatic cholesterol ( 245%, P < 0.03), hepatic MDA levels ( 225%, P < 0.001), serum TNF-alpha (17.8±10 vs 7.8±0.0, P < 0.001), but a decrease in hepatic alpha tocopherol (-74%, P < 0.001) as compared to the control rats. Combination therapy with all drugs produced a significant decrease in liver steatosis (-54%), hepatic TG (-64%), hepatic cholesterol (-31%) and hepatic MDA (-70%), but increased hepatic alpha tocopherol ( 443%) as compared to FL rats. Combination therapy with ISA alone produced a smaller decrease in liver steatosis (-32% vs -54%, P < 0.001) and in hepatic MDA levels (-55% vs -70%, P < 0.01), but a similar decrease in hepatic lipids when compared with the all drugs combination. TNF-alpha levels decreased significantly in all treatment groups except in ISA group. CONCLUSION: Combination therapies have a greater effect on liver fat content as compared to monotherapy. Rosiglitazone appears to improve hepatic steatosis to a greater extent than metformin.     

Parent–Adolescent Cross-Informant Agreement in Clinically Referred Samples: Findings From Seven Societies

To conduct international comparisons of parent–adolescent cross-informant agreement in clinical samples, we analyzed ratings on the Child Behavior Checklist (CBCL) and Youth Self-Report (YSR) for 6,762 clinically referred adolescents ages 11–18 from 7 societies (M = 14.5 years, SD = 2.0 years; 51% boys). Using CBCL and YSR data, we asked the following questions: (a) Do parents report more problems for their adolescent children than the adolescents report about themselves? (b) How do cross-informant correlations (rs) for scale scores differ by problem type and by society? (c) How well do parents and adolescents, on average, agree regarding which problems they rate as low, medium, or high? (d) How does within-dyad item agreement vary within and between societies? (e) How do societies vary in dichotomous cross-informant agreement with respect to the deviance status of the adolescents? CBCL and YSR scores were quite similar, with small and inconsistent informant effects across societies. Cross-informant rs averaged .47 across scales and societies. On average, parents and adolescents agreed well regarding which problem items received low, medium, or high ratings (M r = .87). Mean within-dyad item agreement was moderate across all societies, but dyadic agreement varied widely within every society. In most societies, adolescent noncorroboration of parent-reported deviance was more common than parental noncorroboration of adolescent-reported deviance. Overall, somewhat better parent–adolescent agreement and more consistency in agreement patterns across diverse societies were found in these seven clinical samples than in population samples studied using the same methods.     

Parvalbumin interneuron loss mediates repeated anesthesia-induced memory deficits in mice

Repeated or prolonged, but not short-term, general anesthesia during the early postnatal period causes long-lasting impairments in memory formation in various species. The mechanisms underlying long-lasting impairment in cognitive function are poorly understood. Here, we show that repeated general anesthesia in postnatal mice induces preferential apoptosis and subsequent loss of parvalbumin-positive inhibitory interneurons in the hippocampus. Each parvalbumin interneuron controls the activity of multiple pyramidal excitatory neurons, thereby regulating neuronal circuits and memory consolidation. Preventing the loss of parvalbumin neurons by deleting a proapoptotic protein, mitochondrial anchored protein ligase (MAPL), selectively in parvalbumin neurons rescued anesthesia-induced deficits in pyramidal cell inhibition and hippocampus-dependent long-term memory. Conversely, partial depletion of parvalbumin neurons in neonates was sufficient to engender long-lasting memory impairment. Thus, loss of parvalbumin interneurons in postnatal mice following repeated general anesthesia critically contributes to memory deficits in adulthood.     

Involvement of NF-kappaB in the response of embryonic cells to methotrexate

The involvement of NF-kappaB in the regulation of the apoptotic process was demonstrated previously, however, its exact role has not been established yet. In order to unravel mechanisms underlying teratogen-induced cell death, we tried in our present study to assess the involvement of the p65 subunit of NF-kappaB in the response of mouse embryonic fibroblasts (MEFs) to the anti-cancer drug methotrexate (MTX), using p65 knockout MEFs (p65(-/-)). Indeed, this cell line was found to be more susceptible to the exposure to MTX, demonstrated by more profound changes in cell survival, cell cycle, proliferation and the percentage of apoptotic or necrotic cells, as compared to wild type (WT) MEFs. Also, a different pattern of intracellular localization of p65 in WT cells as well as IkappaBalpha and Bax in both cell lines was detected in response to MTX. Altogether, our results implicate the p65 subunit of NF-kappaB to play an important role in the response of embryonic cells to MTX.     

The need for routine bleomycin test dosing in the 21st century

OBJECTIVE: To review the clinical evidence for routine use of bleomycin test dosing. DATA SOURCES: English-language review articles, references from retrieved articles, case reports, and clinical trials were identified from a MEDLINE literature search (1966-July 2005). Key search terms included bleomycin, test dose, anaphylactic reactions, and hypersensitivity. Information from an unpublished E-mail survey, the manufacturer, and the Internet was also used. DATA SYNTHESIS: Early clinical trials and isolated case reports suggest that bleomycin-induced acute hypersensitivity reactions occur in 1% of patients with lymphoma and <0.5% of those with solid tumors. The reactions are mainly characterized by high-grade fever, chills, hypotension, and in a few cases, cardiovascular collapse, which can lead to death. The exact mechanism of these reactions is unclear, but is thought to be related to the release of endogenous pyrogens from the host cells. Evidence does not suggest any correlation between doses and the onset or severity of the reactions. Supportive care, including hydration, steroids, antipyretics, and antihistamines, may resolve the symptoms. However, it may not completely prevent recurrences. CONCLUSIONS: The incidence of acute hypersensitivity or hyperpyrexic reactions associated with bleomycin is very low, but the reaction is potentially fatal. Clinicians should monitor their patients for any signs and symptoms of acute hyperpyrexic reactions during bleomycin administration. Since the onset of the reactions can occur with any dose of bleomycin and at any time, routine test dosing does not seem to predict when drug reactions may occur.     

DSC and EPR investigations on effects of cholesterol component on molecular interactions between paclitaxel and phospholipid within lipid bilayer membrane

Differential scanning calorimetry (DSC) and electron paramagnetic resonance spectroscopy (EPR) were applied to investigate effects of cholesterol component on molecular interactions between paclitaxel, which is one of the best antineoplastic agents found from nature, and dipalmitoylphosphatidylcholine (DPPC) within lipid bilayer vesicles (liposomes), which could also be used as a model cell membrane. DSC analysis showed that incorporation of paclitaxel into the DPPC bilayer causes a reduction in the cooperativity of bilayer phase transition, leading to a looser and more flexible bilayer structure. Including cholesterol component in the DPPC/paclitaxel mixed bilayer can facilitate the molecular interaction between paclitaxel and lipid and make the tertiary system more stable. EPR analysis demonstrated that both of paclitaxel and cholesterol have fluidization effect on the DPPC bilayer membranes although cholesterol has more significant effect than paclitaxel does. The reduction kinetics of nitroxides by ascorbic acid showed that paclitaxel can inhibit the reaction by blocking the diffusion of either the ascorbic acid or nitroxide molecules since the reaction is tested to be a first order one. Cholesterol can remarkably increase the reduction reaction speed. This research may provide useful information for optimizing liposomal formulation of the drug as well as for understanding the pharmacology of paclitaxel.     

Quality improvement pilot program for vulnerable elderly surgical patients

The elderly are a growing surgical population with more comorbidities and less physiological reserve compared with nonelderly patients. The objective of our study was to implement a quality improvement pilot program targeting the specific needs of the elderly. We prospectively enrolled consecutive patients aged 65 years or older undergoing inpatient general or vascular surgery operations. Patients completed a preoperative assessment including the Vulnerable Elder Survey (VES) to determine baseline functional status and incidence of polypharmacy (five or more medications). They were interviewed postdischarge Day 2 and Day 30 for changes in functional status. An intervention was implemented consisting of an elderly-specific postoperative order set and preoperative risk reports sent to the surgical team with instructions to order physical therapy consults and home health nursing on discharge for VES 3 or greater and geriatrics consults for patients with polypharmacy. The elderly-specific order set was used for 71 per cent of the postintervention group. There were no differences in the percentage of participants receiving physical therapy, geriatric, or home health nursing consults between the two groups. The postintervention group had significantly better functional status on postdischarge Day 30 (P < 0.01). Our preliminary data suggest that individualizing care for elderly patients is feasible and may improve postoperative outcomes.