Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones

Activation of peroxisome proliferator-activated receptor gamma (PPARgamma) by thiazolidinediones (TZDs) improves insulin resistance by increasing insulin-stimulated glucose disposal in skeletal muscle. It remains debatable whether the effect of TZDs on muscle is direct or indirect via adipose tissue. We therefore generated mice with muscle-specific PPARgamma knockout (MuPPARgammaKO) using Cre/loxP recombination. Interestingly, MuPPARgammaKO mice developed excess adiposity despite reduced dietary intake. Although insulin-stimulated glucose uptake in muscle was not impaired, MuPPARgammaKO mice had whole-body insulin resistance with a 36% reduction (P < 0.05) in the glucose infusion rate required to maintain euglycemia during hyperinsulinemic clamp, primarily due to dramatic impairment in hepatic insulin action. When placed on a high-fat diet, MuPPARgammaKO mice developed hyperinsulinemia and impaired glucose homeostasis identical to controls. Simultaneous treatment with TZD ameliorated these high fat-induced defects in MuPPARgammaKO mice to a degree identical to controls. There was also altered expression of several lipid metabolism genes in the muscle of MuPPARgammaKO mice. Thus, muscle PPARgamma is not required for the antidiabetic effects of TZDs, but has a hitherto unsuspected role for maintenance of normal adiposity, whole-body insulin sensitivity, and hepatic insulin action. The tissue crosstalk mediating these effects is perhaps due to altered lipid metabolism in muscle.     

Is faster better? Impact of operative time on postoperative outcomes after VATS anatomical pulmonary resection

BackgroundVideo-assisted thoracic surgery (VATS) is now the preferred approach for standard anatomical pulmonary resections. This study evaluates the impact of operative time (OT) on post-operative outcomes after VATS anatomical pulmonary resection for non-small cell lung cancer (NSCLC).MethodsWe retrospectively reviewed all consecutive patients undergoing VATS lobectomy or segmentectomy for NSCLC between November 2010 and December 2019. Postoperative outcomes were compared between short (<150 minutes) and long (≥150 minutes) OT groups. A multivariable analysis was performed to identify predictors of long OT and overall post-operative complications.ResultsA total of 670 patients underwent lobectomy (n=496, 74%) or segmentectomy (n=174, 26%) for NSCLC. Mediastinal lymph node dissection was performed in 621 patients (92.7%). The median OT was 141 minutes (SD: 47 minutes) and 387 patients (57.8%) were operated within 150 minutes. Neoadjuvant chemotherapy was given in 25 patients (3.7%). Conversion thoracotomy was realized in 40 patients (6%). Shorter OT was significantly associated with decreased post-operative overall complication rate (30% vs. 41%; P=0.003), shorter median length of drainage (3 vs. 4 days; P<0.001) and shorter median length of hospital stay (6 vs. 7 days; P<0.001). On multivariable analysis, long OT (≥150 minutes) (OR 1.64, P=0.006), ASA score >2 (OR 1.87, P=0.001), FEV₁ <80% (OR 1.47, P=0.046) and DLCO <80% (OR 1.5, P=0.045) were significantly associated with postoperative complications. Two predictors of long OT were identified: neoadjuvant chemotherapy (OR 3.11, P=0.01) and lobectomy (OR 1.5, P=0.032).ConclusionsA prolonged OT is significantly associated with postoperative complications in our collective of patients undergoing VATS anatomical pulmonary resection.     

Occurrence and course of suicidality during short-term treatment of late-life depression

BACKGROUND: Elderly persons (> or =65 years) have the highest rate of suicide; still, little is known about the occurrence, course, and responsivity of suicidal ideation during treatment of depression in late life and how suicidality affects treatment response. METHODS: This study was undertaken to determine (1) how suicidal ideation changes during short-term depression treatment and (2) whether treatment response differs among 3 groups of patients based on their levels of suicidality at baseline and during treatment (those with a recent suicide attempt or current suicidal ideation [high-risk group; n = 46], those with recurrent thoughts of death [moderate-risk group; n = 143], or those with no suicide attempt, suicidal ideation, or thoughts of death [low-risk group; n = 206]). This is a secondary analysis of pooled data from 3 treatment studies of late-life major depression. Participants were 395 elderly persons with a current major depressive episode, treated as inpatients or outpatients under protocolized conditions with paroxetine hydrochloride or nortriptyline hydrochloride, with or without interpersonal psychotherapy. Changes in suicidal ideation over time, rate of responses, and time to response in each group were compared. RESULTS: Suicidal ideation decreased rapidly early in the course of treatment, with more gradual change thereafter. At the beginning of treatment, 77.5% of the patients reported suicidal ideation, thoughts of death, or feelings that life is empty. After 12 weeks of treatment, suicidal ideation had resolved in all treated patients; 4.6% still reported thoughts of death. However, 6-week (P =.001) and 12-week (P =.02) rates of response were significantly lower in high-risk patients than in low- and moderate-risk patients. High- and moderate-risk patients needed a significantly (P<.001) longer time to respond than low-risk patients (median time to response, 6 and 5 vs 3 weeks). CONCLUSIONS: While suicidal ideation resolves rapidly, the resolution of thoughts about death is more gradual. Suicidal elderly persons with depression require special attention during depression treatment because they have a lower response rate and need a longer time to respond.     

Congenital disorder of glycosylation type 1a in a macrosomic 16-month-old boy with an atypical phenotype and homozygosity of the N216I mutation

We report on a 16-month-old boy with congenital disorder of glycosylation type 1a (CDG-1a; OMIM 212065) showing an atypical phenotype. Whereas failure to thrive is known to be a prominent feature in this condition, our patient developed postnatal macrosomia with increase of weight, length and occipitofrontal circumference (OFC) above the 95th percentile within his 1st year of life. Thereafter, weight and length were close to the 90th and OFC at the 50th percentiles. In contrast to other CDG-1a patients, the child did not have abnormal fat pads or inverted nipples; but unusual eyebrows were present. CDG-1a was confirmed by isoelectric focusing of serum transferrin and measurement of phosphomannomutase activity in leucocytes and cultured fibroblasts (residual activity <5% of controls). Mutation analysis of the phosphomannomutase 2 gene ( PMM2) revealed homozygosity for a 647A>T (N216I) mutation in our patient and heterozygosity in his consanguineous parents. Conclusion:this is the first report of macrosomia and of homozygosity for the 647A>T (N216I) mutation in a patient with congenital disorder of glycosylation type 1a which may allow further phenotype/genotype comparisons.Abbreviations BMI body mass index - CDG congenital disorder of glycosylation - OFC occipitofrontal circumference - PMM2 phosphomannomutase 2 gene     

Grape seed proanthocyanidins improved cardiac recovery during reperfusion after ischemia in isolated rat hearts

BACKGROUND: Increasing evidence shows that red wine consumption has cardioprotective effects. These effects have been attributed to the polyphenolic compounds in grapes. OBJECTIVE: We studied the effects of red grape seed proanthocyanidins on the recovery of postischemic function in isolated rat hearts. DESIGN: Two groups of rats were fed different doses of proanthocyanidin-rich extract for 3 wk and another group was untreated and served as controls. The animals were then anesthetized and the hearts were isolated and subjected to 30 min of ischemia followed by 2 h of reperfusion. Coronary effluents were collected during the third minute of reperfusion for measurement of oxygen free radicals by using electron spin resonance spectroscopy. RESULTS: In rats treated with 50 and 100 mg grape seed proanthocyanidins/kg, the incidence of reperfusion-induced ventricular fibrillation was reduced from its control value of 92% to 42% and 25%, respectively (P < 0.05 for both). The incidence of ventricular tachycardia showed the same pattern. In rats treated with 100 mg proanthocyanidins/kg, the recovery of coronary flow, aortic flow, and developed pressure after 60 min of reperfusion was improved by 32% +/- 8%, 98% +/- 8%, and 37% +/- 3%, respectively (P < 0.05 for all) compared with untreated control rats. Electron spin resonance studies indicated that proanthocyanidins significantly inhibited the formation of oxygen free radicals. In rats treated with 100 mg proanthocyanidins/kg, free radical intensity was reduced by 75% +/- 7% (P < 0.05) compared with the control rats. CONCLUSION: Grape seed proanthocyanidins have cardioprotective effects against reperfusion-induced injury via their ability to reduce or remove, directly or indirectly, free radicals in myocardium that is reperfused after ischemia.     

Morphological changes in the lower esophageal sphincter influencing the result of antireflux surgical interventions in chronic gastroesophageal reflux disease

BACKGROUND/AIMS: It is still unclear whether long-term reflux episodes result in morphological changes in the lower esophageal sphincter or not. If the answer is supposedly yes, do these changes influence the postoperative functional results following antireflux surgery? METHODOLOGY: Between 1 January 2002 and 2004, we performed antireflux surgery on 85 patients. Muscle samples were taken from the lower esophageal sphincter (LES) in 57 patients on operation. Patients with endoscopic findings of moderate or severe reflux esophagitis--Los Angeles B, C, D--were excluded. Control samples were obtained from muscle tissue at the gastroesophageal junction that had been removed from 16 patients undergoing gastric or esophageal resection. Histologic (hematoxylin and eosin and Giemsa), and immunohistologic (S-100 Protein, NCL-SERCA2, alpha-SMA) and electronmicroscopic analysis were used to evaluate the specimens. The number of smooth muscle cell nuclei in these intraoperative biopsies was used to compare the results of antireflux operations (Visick I and II-III). RESULTS: In 19% (11/57) of the reflux-type LES muscle samples perivascular inflammatory infiltration has been noted and in 6 of these cases (6/57 = 11%) this has incorporated marked intramuscular and adventitial granulocyte infiltration. In one patient (1/57 = 2%) eosinophil infiltration of the myenteric plexus and the ganglion has been revealed. Significantly lower Schwann and smooth muscle cell count could be detected in LES muscle samples taken from patients with GERD (p < 0.05). The analysis of the values of the 9 patients in Visick groups II and III at two months after surgery, has shown a significant decrease in the number of smooth muscle cell nuclei as compared to those patients in Visick group I (p < 0.01). CONCLUSIONS: Our results draw attention to the morphological changes occurring in the LES muscles of reflux patients. The enteric ganglionitis induced by GERD may result in various functional esophageal diseases. The histologic changes--that very much resemble hypertrophy--developing in LES muscles may serve as a reason for symptoms after antireflux surgery, presumably for the most common complaint of dysphagia.