Mechanisms of disease: adipocytokines and visceral adipose tissue--emerging role in intestinal and mesenteric diseases

Adipose tissue has long been regarded as a passive type of connective tissue that stores energy as triglycerides and releases energy as free fatty acids, however, this point of view has now changed. The wide variety of products expressed and secreted by adipose tissue, such as adiponectin, leptin, and resistin, mean that the total adipose tissue mass can be defined as a real endocrine organ. The anatomic, metabolic and biochemical characteristics of visceral adipose tissue make it interesting in the context of intestinal and mesenteric diseases. These characteristics include increased lipolysis, venous drainage via the portal vein and local glucocorticoid excess owing to the specific expression of 11-beta-hydroxysteroid-dehydrogenase type 1. In this review, the role of the visceral adipose tissue and its secretory products in intestinal and mesenteric diseases is systematically reviewed, with special focus on 'creeping fat' in Crohn's disease and mesenteric panniculitis.     

PTEN permits acute increases in D3-phosphoinositide levels following TCR stimulation but inhibits distal signaling events by reducing the basal activity of Akt

Phosphoinositide 3-kinase (PI3K) is important in TCR signaling. PI3K generates phosphatidylinositol 3, 4, 5-trisphosphate (PI-3,4,5-P3), which regulates membrane localization and/or activity of multiple signaling proteins. PTEN (phosphatase and tensin homologue deleted on chromosome 10) opposes PI3K, reversing this reaction. Maintaining the balance between these two enzymes is important for normal T cell function. Here we use the PTEN-null Jurkat T cell line to address the role of PTEN in modulating proximal and distal TCR-signaling events. PTEN expression at levels that restored low basal Akt phosphorylation (an indicator of PI-3,4,5-P3 levels), but which were not themselves cytotoxic, had minimal effect on TCR-stimulated activation of phospholipase Cgamma1 and Ca2+ flux, but reduced the duration of extracellular signal-regulated kinase (Erk) activation. Distal signaling events, including nuclear factor of activated T cells (NFAT) activation, CD69 expression and IL-2 production, were all inhibited by PTEN expression. Notably, PTEN did not block TCR-stimulated PI-3,4,5-P3 accumulation. The effect of PTEN on distal TCR signaling events was strongly correlated with the loss of the constitutive Akt activation and glycogen synthase kinase-3 (GSK3) inhibition that is typical of Jurkat cells, and could be reversed by expression of activated Akt or pharmacologic inhibition of GSK3. These results suggest that PTEN acts in T cells primarily to control basal PI-3,4,5-P3 levels, rather than opposing PI3K acutely during TCR stimulation.     

Neuromonitoring in thyroid surgery: prospective evaluation of intraoperative electrophysiological responses for the prediction of recurrent laryngeal nerve injury

OBJECTIVE: We evaluated the ability of neuromonitoring to predict postoperative outcome in patients undergoing thyroid surgery for different indications. SUMMARY BACKGROUND DATA: Neuromonitoring has been advocated to reduce the risk of vocal cord palsy and to predict postoperative vocal cord function. METHODS: Three hundred twenty-eight patients (502 nerves at risk) were studied prospectively at a single center. Neuromonitoring was performed with the Neurosign 100 device by transligamental placement of the recording electrode into the vocalis muscles. Cumulative distribution of stimulation thresholds was determined by stepwise decreases in current (1 mA to 0.05 mA) for both the vagus and the recurrent nerve. Patients were grouped according to surgical risk (benign and malignant disease, reoperation for benign and for malignant disease). RESULTS: If the electrophysiological response was correlated to postoperative vocal cord function, the sensitivity of neuromonitoring was modest (86% in surgery for benign disease) to low (25% in reoperation for malignant disease); the positive predictive value was modest (overall rate 62%) but acceptable (87%) if corrected for technical problems. Specificity and negative predictive values were high (ie, overall >95%). Stimulation thresholds were not augmented in 11 patients, in whom postoperative palsy developed despite normal intraoperative recordings. Similarly, an electrical field response was elicited in 14 of 21 patients with preoperative vocal cord palsy. Electromyographic recordings did not reveal an abnormal amplitude or a decline in nerve conduction velocity. CONCLUSIONS: Neuromonitoring is useful for identifying the recurrent laryngeal nerve, in particular if the anatomic situation is complicated by prior surgery, large tissue masses, aberrant nerve course. However, neuromonitoring does not reliably predict postoperative outcome.     

Nonsustained effect of short-term bisphosphonate therapy on bone turnover three years after renal transplantation

BACKGROUND: We recently showed that two doses of 4 mg of zoledronic acid (ZOL) ameliorated the bone loss and improved bone histology within the first six months after kidney transplantation. The aim of the present study was to evaluate whether this early short-term intervention exhibited a sustained bone-sparing effect. METHODS: A homogenous group of 20 de novo renal transplant recipients were equally randomized to two infusions of 4 mg of ZOL or placebo at two weeks and three months after engraftment. Patients were followed up for three years by sequential determination of bone densitometry and specific biochemical markers. RESULTS: From month six to three years after transplantation, both treatment groups exhibited an improvement of bone mineralization. Femoral neck bone mineral density z-scores increased statistically significantly from -1.3 (2.6) to -0.2 (3.6) in the placebo group and from -1.6 (2.9) to -1.2 (1.9) in the ZOL group (median, range). Biochemical parameters of osteoblast activity such as osteocalcin and bone-specific alkaline phosphatase did not increase significantly in both groups. Osteoprotegerin, a marker of osteoclast inhibition, was significantly elevated over the first six months in the ZOL group, but decreased to similar levels, as in the placebo group, over the next two and a half years. Other markers of osteoclast activity such as c-telopeptide of type 1 collagen, calcitonin, and intact parathyroid hormone were not different between six months and three years in either group. CONCLUSION: The early bone-sparing effect of short-term ZOL therapy confers no sustained benefit versus placebo at three year post-transplantation.     

Relative Carnitine Deficiency in Autism

A random retrospective chart review was conducted to document serum carnitine levels on 100 children with autism. Concurrently drawn serum pyruvate, lactate, ammonia, and alanine levels were also available in many of these children. Values of free and total carnitine (p < 0.001), and pyruvate (p=0.006) were significantly reduced while ammonia and alanine levels were considerably elevated (p < 0.001) in our autistic subjects. The relative carnitine deficiency in these patients, accompanied by slight elevations in lactate and significant elevations in alanine and ammonia levels, is suggestive of mild mitochondrial dysfunction. It is hypothesized that a mitochondrial defect may be the origin of the carnitine deficiency in these autistic children.     

Treatment effects of methylphenidate on cognitive functioning in children with mental retardation and ADHD

OBJECTIVE: Cognitive effects of stimulant medication were investigated in children with mental retardation (MR) and attention-deficit/hyperactivity disorder (ADHD). METHOD: Performance on tasks tapping sustained attention, visual and auditory selective attention, inhibition, and immediate memory was assessed for 24 children (mean age 10.9 years) during a placebo-controlled, double-blind, crossover treatment trial with 0.15, 0.30, and 0.60 mg/kg b.i.d. dosages of methylphenidate (MPH). RESULTS: Successively higher MPH doses were associated with consistent gains in cognitive task performance, with optimal performance noted at the highest dose. Analysis of dose-response curves revealed significant linear components of trend on measures tapping sustained attention, visual selective attention, auditory selective attention, as well as two tasks tapping inhibition/impulsivity: delay of gratification and match-to-sample. No evidence of a curvilinear dose-response relationship emerged for any measure. CONCLUSIONS: Inattention and disinhibition/impulsivity decline with MPH treatment in children with ADHD/MR, and consistent with the Multimodal Treatment Study of ADHD, higher MPH doses are most effective. These findings also suggest that cognitive testing, together with behavioral and medical assessment, can be an effective tool in assessing stimulant response in children with ADHD/MR.