The life cycle of the steroidogenic acute regulatory (StAR) protein: from transcription through proteolysis

The Steroidogenic Acute Regulatory (StAR) protein is a mitochondrial protein required for the transport of cholesterol substrate to the P450scc enzyme located in the inner mitochondrial membranes of steroid producing cells. This study suggests that the acute regulation of the rodent StAR gene in the ovary is mediated by two factors, C/EBPbeta and GATA-4. Once translated, the StAR precursor protein is either imported into the mitochondria, or it is rapidly degraded in the cytosol. We predicted that in order to perpetuate StAR activity cycles, imported StAR should turn over rapidly to avoid a potentially harmful accumulation of the protein in sub-mitochondrial compartments. Pulse-chase experiments in metabolically labeled cells showed that: (a) the turnover rate of mature mitochondrial StAR protein (30 kDa) is much faster (t(1/2) = 4-5 h) than that of other mitochondrial proteins; (b) dissipation of the inner membrane potential (-delta psi) by carbonyl cyanide m-chlorophenylhydrazone (mCCCP) accelerates the mitochondrial degradation of StAR; (c) unexpectedly, the mitochondrial degradation of StAR is inhibited by MG132 and lactacystin, but not by epoxomicin. Furthermore, StAR degradation becomes inhibitor-resistant two hours after import. Therefore, these studies suggest a bi-phasic route of StAR turnover in the mitochondria. Shortly after import, StAR is degraded by inhibitor-sensitive protease(s) (phase I), whereas at later times, StAR turnover proceeds to completion through an MG132-resistant proteolytic activity (phase II). Collectively, this study defines StAR as a unique protein that can authentically be used to probe multiple proteolytic activities in mammalian mitochondria.     

Glucose metabolism: key endogenous regulator of β-cell replication and survival

Recent studies in mice have shown that pancreatic β-cells have a significant potential for regeneration, suggesting that regenerative therapy for diabetes is feasible. Genetic lineage tracing studies indicate that β-cell regeneration is based on the replication of fully differentiated, insulin-positive β-cells. Thus, a major challenge for this field is to identify and enhance the molecular pathways that control β-cell replication and mass. We review evidence, from human genetics and mouse models, that glucose is a major signal for β-cell replication. The mitogenic effect of blood glucose is transmitted via glucose metabolism within β-cells, and through a signalling cascade that resembles the pathway for glucose-stimulated insulin secretion. We introduce the concept that the individual β-cell workload, defined as the amount of insulin that an individual β-cell must secrete to maintain euglycaemia, is the primary determinant of replication, survival and mass. We also propose that a cell-autonomous pathway, similar to that regulating replication, appears to be responsible for at least some of the toxic effects of glucose on β-cells. Understanding and uncoupling the mitogenic and toxic effects of glucose metabolism on β-cells may allow for the development of effective regenerative therapies for diabetes.     

Biometric parameters of the hand as an index of schizophrenia—A preliminary study

Since abnormalities in distal upper limb development are among the minor physical anomalies associated with schizophrenia we attempted to determine whether patients with schizophrenia can be identified on the basis of specific morphologic and dermatoglyphic features of the hand. Photographs and prints of the hands of 38 patients with schizophrenia and those of 42 control subjects were evaluated and graded on 13 biometric parameters. Results were statistically evaluated. A combination of three of the parameters was found to have good predicting abilities to distinguish between schizophrenics and controls. Subjects having high values in these three parameters were found to have a higher propensity to be defined as schizophrenics. In order to define a simple rule for classifying subjects we chose a criterion of having a value of 3 (in a scale from 1 to 3) in at least one of these three discriminating variables. This rule yielded an overall accuracy of 81.2%. Among controls, 85.7% of subjects did not fulfill such criteria, while 14.3% were defined as false positives. Among schizophrenics 76.3% achieved this condition while 23.7% were false negatives. The technique's objectivity and ease of application could facilitate the diagnosis of this disease.     

Hydrogen Peroxide in Exhaled Breath Condensate (EBC) vs Eosinophil Count in Induced Sputum (IS) in Parenchymal vs Airways Lung Diseases"

We compared exhaled breath condensate (EBC) and induced sputum (IS) for assessing inflammation in pulmonary diseases in patients with obstructive lung disease (n = 20), persistent cough >6 months (n = 20), interstitial lung disease (n = 25) and controls (n = 10). EBC was collected by suspending a Teflon perfluoroalkoxy tube installed in an ice-filled container and connected to a polypropylene test tube. IS was recovered after 20’ inhalation of 3% saline with an ultrasonic nebulizer, and 300 cells were differentially counted in cytospin Giemsa-stained slides. H₂0₂ was measured by a method based on oxidation of phenolsulfonphthalein (phenol red) mediated by horseradish peroxidases and H₂0₂. Pulmonary function tests were performed by conventional methods. H₂0₂ levels in EBC and % eosinophils in IS were significantly different between groups. A positive and significant correlation was found between % eosinophils in IS and the levels of H₂0₂ in EBC for each group and for all patients combined.     

Low Incidence of Postoperative Leaks When Using Small-Diameter Calibrated Bougies During Laparoscopic Sleeve Gastrectomy: A Retrospective Cohort Study

Background

Laparoscopic sleeve gastrectomy (LSG) is a well-established bariatric procedure. A staple line leak is a recognized complication of LSG. Bougie size has been suggested to impact leak rates. In this study, we evaluate the impact of using 32–34F bougie sizes with LSG on early postoperative outcomes including staple line leaks within our practice.

Methods

This is a retrospective cohort analysis of a prospectively maintained database of all LSG procedures performed between January 2012 and December 2018 at a single medical center. Data collected and analyzed included bougie size, postoperative leak rate, need for re-operation, 12-month excess weight loss, and 30-day morbidity and mortality.

Results

During the study period, 3153 patients underwent LSG, of whom 1977 (62.7%) were female. Mean age and body mass index (BMI) were 42.9 ± 12.2 years (range 15–76 years) and 42.4 ± 5.2 kg/m² (range 27–73), respectively. No intraoperative complications or mortality occurred. There was one case of perioperative mortality due to bleeding (0.03%). Early postoperative adverse events occurred in 131 patients (4.1%): 17 leaks (0.5%), 75 bleeds (2.4%), and 39 (1.2%) other.

Conclusion

The use of smaller-sized (32–34F) bougies had no impact on staple line leaks in the hands of experienced bariatric surgeons at a high-volume center.

     

Acute Cholecystitis Complicating Unrelated Disease: Etiological Considerations

The phenomenon of acute cholecystitis complicating an unrelated operation has been reported with increasing frequency, and may be preceded by a variety of operative procedures and a lack of previous biliary tract symptoms. Among eight such patients treated by us, seven developed acute cholecystitis postoperatively, and in one it was discovered during operation for bleeding duodenal ulcer. Two patients had undergone wide excision of the breast; two, highly selective vagotomy; one, nephrolithotomy; one, truncal vagotomy and gastroenterostomy; and one, left hemicolectomy and colostomy. In three patients, urgent cholecystectomy was performed, and four were treated conservatively with subsequent elective cholecystectomy. Histopathological studies revealed acute and chronic cholecystitis in all eight patients and cholelithiasis in four. One patient died in septic shock. Numerous contributing factors have been suggested, including hypovolemia and biliary stasis, as well as the presence of stones. It would appear that chronic cholecystitis or other biliary pathology, as found in our eight patients, is a major factor in the development of this manifestation.     

Are adult patients with Laron syndrome osteopenic? A comparison between dual-energy X-ray absorptiometry and volumetric bone densities

Severe short stature resulting from a deficiency in IGF-I is a prominent feature of Laron syndrome (LS). Although low bone mineral density (BMD) has been noted in LS patients examined by dual energy x-ray absorptiometry (DEXA), this technique does not take volume into account and may therefore underestimate the true bone density in patients with small bones. The aim of the present study was to evaluate the BMD yielded by DEXA in our LS patients using estimated volumetric values. Volumetric density was calculated with the following formulas: bone mineral apparent density (BMAD) = bone mineral content (BMC)/(area)(3/2) for the lumbar spine and BMAD = BMC/area(2) for the femoral neck. The study sample included 12 patients (mean age, 43.9 yr; mean height, 123.7 cm). Findings were compared with 10 osteopenic subjects without developmental abnormalities (mean age, 56 yr; mean height, 164.8 cm) and 10 healthy control subjects matched for sex and age to the LS patients (mean height, 165.5 cm). BMAD in the LS group was 0.201 +/- 0.02 g/cm(3) at the lumbar spine and 0.201 +/- 0.04 g/cm(3) at the femoral neck; corresponding values for the osteopenic group were 0.130 +/- 0.01 and 0.140 +/- 0.01 g/cm(3), and for the controls, 0.178 +/- 0.03 and 0.192 +/- 0.02 g/cm(3). Although areal BMD was significantly lower in the LS and osteopenic subjects compared with controls (P < 0.02) at both the lumbar spine and femoral neck, BMAD was low (P < 0.01) in the osteopenic group only. In conclusion, DEXA does not seem to be a reliable measure of osteoporosis in patients with LS.     

Non-alcoholic fatty liver disease--a common and benign finding in octogenarian patients.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), a common entity in the general population, has been shown to be linked with insulin resistance and metabolic syndrome. Several of the components of the metabolic syndrome are more common in the aged population. The aims of the current study were to determine in the aged, the prevalence and the clinical presentation of NAFLD, as well as the relation to the underlying metabolic abnormalities. METHOD: In this prospective study, we evaluated 91 octogenarians with a mean age of 85.56+/-3.76 years, who were admitted to the rehabilitation departments of a geriatric hospital. Clinical evaluation included: abdominal ultrasound (US), fasting glucose and lipid levels, serum liver enzymes, ferritin, iron and transferrin saturation. Elderly patients with NAFLD were compared with 46 young patients with NAFLD. RESULTS: NAFLD diagnosed by US was a common finding in this aged population, is present in 42/91 patients (46.2%). No significant differences were observed between the patients with or without NAFLD in the following: age, gender, chronic illnesses, anthropometric parameters, lipid profile, fasting glucose levels, metabolic syndrome prevalence, serum levels of transaminases, ferritin and iron. Young patients with NAFLD had significantly higher serum levels of triglycerides and a significantly higher prevalence of glucose intolerance, obesity and the metabolic syndrome compared with the elderly patients with NAFLD. CONCLUSIONS: NAFLD was a common finding in our group of elderly patients and the prevalence was higher than reported in the general population. In contrast to the well-described association between the metabolic syndrome and NAFLD in the general population, we did not find this association in the aged group. In addition, none of the patients had stigmata of advanced liver disease. These data suggest that NAFLD is a common and benign finding in the elderly population, but is not associated with the metabolic syndrome.