bluuebunny/crossref_metadata_2025 huggingface dataset:
Searching for somatic mutations in McCune–Albright syndrome: a comparative study of the peptidic nucleic acid versus the nested PCR method based on 148 DNA samples
Authors: Kalfa N , Philibert P , Audran F , Ecochard A , Hannon T , Lumbroso S , Sultan C
Published: November 2006

Background: Activating mutations of the Gsα gene (GNAS), which encodes for the α-subunit of the stimulatory G protein, have been identified in patients with McCune–Albright syndrome (MAS). Accuracy and sensitivity in the molecular diagnosis of MAS is mandatory for optimal therapeutic strategy and adapted follow-up, especially for incomplete clinical forms of MAS. To date, the highly sensitive nested PCR method with intermediary digestion by a restriction enzyme at the mutation site is one of the most widely used techniques. This study evaluated a new diagnostic method using a peptidic nucleic acid (PNA) and compared it with the nested PCR method.

Material and methods: One hundred and forty-eight DNA samples from eighty-eight patients presenting clinical symptoms compatible with MAS were included. The DNA samples were mainly obtained from peripheral blood, ovarian tissue or cyst liquid, and bone lesions. The nested PCR method required 4 days. PNA clamping required 1.5 days and utilized the higher thermal stability and specificity of PNA–DNA coupling to inhibit PCR product formation. Direct sequencing was subsequently performed in all cases.

Results: The sensitivity of mutation detection was 54% (n = 80) for nested PCR and 46.6% (n = 69) for PNA (P > 0.05). The 11 cases where PNA failed to detect the mutation were mainly incomplete and atypical clinical forms of MAS (n = 10/11). The cost per sample was 50 euros for PNA clamping versus 136 euros for nested PCR.

Conclusion: PNA clamping is a rapid, reliable, and economical method to diagnose MAS. It should be the first-line diagnostic method, although negative results, especially for incomplete clinical forms of MAS, should be confirmed by nested PCR.
Serum sex hormone and plasma homocysteine levels in middle-aged and elderly men
Authors: Pour Hamid Reza Nakhai , Grobbee Diederick E , Muller Majon , Emmelot-Vonk Marielle , van der Schouw Yvonne T
Published: November 2006

Objective: To investigate whether circulating levels of testosterone (total, bioavailable), estradiol (total, bioavailable), and DHEA sulfate (DHEAS) are associated with fasting plasma homocysteine (tHcy) levels in middle-aged and elderly men.

Design: A population-based sample of 400 independently living men between 40 and 80 years of age in a cross-sectional study.

Methods: Total testosterone, sex hormone binding globulin (SHBG), and total estradiol were measured by RIA methods and bioavailable testosterone and estradiol were calculated. DHEAS was measured using an immunometric technique. Fasting homocysteine was measured by fluorescence polarization immunoassay. Anthropometric characteristics were also measured and two standardized questionnaires completed, including life-style factors and diet. Linear regression analysis adjusted for age, body mass index (BMI), creatinine clearance, and mean visceral fat was used to assess the association of endogenous sex hormones and fasting plasma homocysteine levels.

Results: After adjustment for age, BMI, creatinine clearance, and mean visceral fat no statistically significant association was observed between testosterone (total, bioavailable), DHEAS, and estradiol (total, bioavailable)levels with natural log tHcy (β = −2 × 10−3; 95% confidence intervals (CI) −9 × 10−3; 5 × 10−3), (β = −4 × 10−3; 95% CI −18 × 10−3; 9 × 10−3), (β = 3 × 10−3; 95% CI −6 × 10−3; 12 × 10−3), (β = −9.3 × 10−5; 95% CI −1 × 10−3; 1 × 10−3), and (β = 0.00; 95% CI −3 × 10−3; 2 × 10−3) respectively. Additional adjustment for smoking, alcohol intake, daily physical activity, diabetes mellitus, and hypertension did not change these findings.

Conclusion: The results of our study do not support a direct role for circulating sex hormone levels in the regulation of fasting plasma tHcy concentrations in middle-aged and elderly men.
Selective parathyroid venous sampling in patients with complicated hyperparathyroidism
Authors: Ogilvie C M , Brown P L , Matson M , Dacie J , Reznek R H , Britton K , Carpenter R , Berney D , Drake W M , Jenkins P J , Chew S L , Monson J P
Published: November 2006

Objective: The role of preoperative localisation of abnormal parathyroid glands remains controversial but is particularly relevant to the management of patients with recurrent or persistent hyperparathyroidism and familial syndromes. We report our experience of the use of selective parathyroid venous sampling (PVS) in the localisation of parathyroid disease in such patients.

Design: We report a retrospective 10-year experience (n = 27) of the use of PVS in complicated primary hyperparathyroidism and contrast the use of PVS with neck ultrasound, magnetic resonance imaging (MRI), computed tomography (CT) and sestamibi imaging modalities.

Results: In 14 out of 25 patients who underwent surgery PVS results were completely concordant with surgical and histological findings and 88% of patients achieved post-operative cure. Out of 13 patients referred after previous failed surgery, 12 underwent further surgery which was curative in 9. In total PVS yielded useful positive (n = 13) and/or negative information (n = 6) in 19 out of 25 patients undergoing surgery. Using histology as the gold standard, 59% of PVS studies were entirely consistent with histology, as compared with 39% of ultrasound scans, 36% of sestamibi scans and 17% of MRI/CT scans.

Conclusions: PVS is a valuable adjunct to MRI/CT and sestamibi scanning in selected patients with complicated hyperparathyroidism when performed in an experienced unit.
Effect of Eucaloric High- and Low-Sucrose Diets With Identical Macronutrient Profile on Insulin Resistance and Vascular Risk
Authors: Black R. Neil A. , Spence Michelle , McMahon Ross O. , Cuskelly Geraldine J. , Ennis Cieran N. , McCance David R. , Young Ian S. , Bell Patrick M. , Hunter Steven J.
Published: November 2006

The long-term impact of dietary carbohydrate type, in particular sucrose, on insulin resistance and the development of diabetes and atherosclerosis is not established. Current guidelines for the healthy population advise restriction of sucrose intake. We investigated the effect of high- versus low-sucrose diet (25 vs. 10%, respectively, of total energy intake) in 13 healthy subjects aged 33 ± 3 years (mean ± SE), BMI 26.6 ± 0.9 kg/m2, in a randomized crossover design with sequential 6-week dietary interventions separated by a 4-week washout. Weight maintenance, eucaloric diets with identical macronutrient profiles and fiber content were designed. All food was weighed and distributed. Insulin action was assessed using a two-step euglycemic clamp; glycemic profiles were assessed by the continuous glucose monitoring system and vascular compliance by pulse-wave analysis. There was no change in weight across the study. Peripheral glucose uptake and suppression of endogenous glucose production were similar after each diet. Glycemic profiles and measures of vascular compliance did not change. A rise in total and LDL cholesterol was observed. In this study, a high-sucrose intake as part of an eucaloric, weight-maintaining diet had no detrimental effect on insulin sensitivity, glycemic profiles, or measures of vascular compliance in healthy nondiabetic subjects.
Lipin Deficiency Impairs Diurnal Metabolic Fuel Switching
Authors: Xu Jun , Lee W.N. Paul , Phan Jack , Saad Mohammed F. , Reue Karen , Kurland Irwin J.
Published: November 2006

Fatty liver is a common feature of both obesity and lipodystrophy, reflecting compromised adipose tissue function. The lipin-deficient fatty liver dystrophy (fld) mouse is an exception, as there is lipodystrophy without a fatty liver. Using a combination of indirect calorimetry and stable-isotope flux phenotyping, we determined that fld mice exhibit abnormal fuel utilization throughout the diurnal cycle, with increased glucose oxidation near the end of the fasting period and increased fatty acid oxidation during the feeding period. The mechanisms underlying these alterations include a twofold increase compared with wild-type mice in tissue glycogen storage during the fed state, a 40% reduction in hepatic glucose production in the fasted state, and a 27-fold increase in de novo fatty acid synthesis in liver during the fed state. Thus, the inability to store energy in adipose tissue in the fld mouse leads to a compensatory increase in glycogen storage for use during the fasting period and reliance upon hepatic fatty acid synthesis to provide fuel for peripheral tissues during the fed state. The increase in hepatic fatty acid synthesis and peripheral utilization provides a potential mechanism to ameliorate fatty liver in the fld that would otherwise occur as a consequence of adipose tissue dysfunction.
Glucagon Receptor Knockout Mice Display Increased Insulin Sensitivity and Impaired β-Cell Function
Authors: Sørensen Heidi , Winzell Maria Sörhede , Brand Christian L. , Fosgerau Keld , Gelling Richard W. , Nishimura Erica , Ahren Bo
Published: November 2006

In previous studies, glucagon receptor knockout mice (Gcgr−/−) display reduced blood glucose and increased glucose tolerance, with hyperglucagonemia and increased levels of glucagon-like peptide (GLP)-1. However, the role of glucagon receptor signaling for the regulation of islet function and insulin sensitivity is unknown. We therefore explored β-cell function and insulin sensitivity in Gcgr−/− and wild-type mice. The steady-state glucose infusion rate during hyperinsulinemic-euglycemic clamp was elevated in Gcgr−/− mice, indicating enhanced insulin sensitivity. Furthermore, the acute insulin response (AIR) to intravenous glucose was higher in Gcgr−/− mice. The augmented AIR to glucose was blunted by the GLP-1 receptor antagonist, exendin-3. In contrast, AIR to intravenous administration of other secretagogues was either not affected (carbachol) or significantly reduced (arginine, cholecystokinin octapeptide) in Gcgr−/− mice. In islets isolated from Gcgr−/− mice, the insulin responses to glucose and several insulin secretagogues were all significantly blunted compared with wild-type mice. Furthermore, glucose oxidation was reduced in islets from Gcgr−/− mice. In conclusion, the present study shows that glucagon signaling is required for normal β-cell function and that insulin action is improved when disrupting the signal. In vivo, augmented GLP-1 levels compensate for the impaired β-cell function in Gcgr−/− mice.
C-Peptide Reverses Nociceptive Neuropathy in Type 1 Diabetes
Authors: Kamiya Hideki , Zhang Weixian , Ekberg Karin , Wahren John , Sima Anders A.F.
Published: November 2006

We examined the therapeutic effects of C-peptide on established nociceptive neuropathy in type 1 diabetic BB/Wor rats. Nociceptive nerve function, unmyelinated sural nerve fiber and dorsal root ganglion (DRG) cell morphometry, nociceptive peptide content, and the expression of neurotrophic factors and their receptors were investigated. C-peptide was administered either as a continuous subcutaneous replacement dose via osmopumps or a replacement dose given once daily by subcutaneous injection. Diabetic rats were treated from 4 to 7 months of diabetes and were compared with control and untreated diabetic rats of 4- and 7-month duration. Osmopump delivery but not subcutaneous injection improved hyperalgesia and restored the diabetes-induced reduction of unmyelinated fiber number (P < 0.01) and mean axonal size (P < 0.05) in the sural nerve. High-affinity nerve growth factor (NGF) receptor (NGFR-TrkA) expression in DRGs was significantly reduced at 4 months (P < 0.01). Insulin receptor and IGF-I receptor (IGF-IR) expressions in DRGs and NGF content in sciatic nerve were significantly decreased in 7-month diabetic rats (P < 0.01, 0.05, and 0.005, respectively). Osmopump delivery prevented the decline of NGFR-TrkA, insulin receptor (P < 0.05), and IGF-IR (P < 0.005) expressions in DRGs and improved NGF content (P < 0.05) in sciatic nerve. However, subcutaneous injection had only marginal effects on morphometric and molecular changes in diabetic rats. We conclude that C-peptide exerts beneficial therapeutic effects on diabetic nociceptive neuropathy and that optimal effects require maintenance of physiological C-peptide concentrations for a major proportion of the day.
Tau Is Hyperphosphorylated at Multiple Sites in Mouse Brain In Vivo After Streptozotocin-Induced Insulin Deficiency
Authors: Clodfelder-Miller Buffie J. , Zmijewska Anna A. , Johnson Gail V.W. , Jope Richard S.
Published: November 2006

Deficient signaling by insulin, as occurs in diabetes, is associated with impaired brain function, and diabetes is associated with an increased prevalence of Alzheimer’s disease. One of the hallmark pathological characteristics of Alzheimer’s disease is the presence of neurofibrillary tangles containing hyperphosphorylated tau, a microtubule-associated protein. Therefore, we tested the hypothesis that insulin depletion caused by administration of streptozotocin may cause tau hyperphosphorylation in mouse brain by using site-specific phosphorylation-dependent tau antibodies to obtain precise identification of the phosphorylation of tau on individual residues. A massive (fivefold average increase) and widespread at multiple residues (detected with eight different phosphorylation-dependent tau antibodies) increase in the phosphorylation of tau was found in mouse cerebral cortex and hippocampus within 3 days of insulin depletion by streptozotocin treatment. This hyperphosphorylation of tau at some sites was rapidly reversible by peripheral insulin administration. Examination of several kinases that phosphorylate tau indicated that they were unlikely to account for the widespread hyperphosphorylation of tau caused by streptozotocin treatment, but there was a large decrease in mouse brain protein phosphatase 2A activity, which is known to mediate tau phosphorylation. These results show that insulin deficiency causes rapid and large increases in tau phosphorylation, a condition that could prime tau for the neuropathology of Alzheimer’s disease, thereby contributing to the increased susceptibility to Alzheimer’s disease caused by diabetes.
Effects of Rimonabant (SR141716) on Fasting-Induced Hypothalamic-Pituitary-Adrenal Axis and Neuronal Activation in Lean and Obese Zucker Rats
Authors: Doyon Christian , Denis Raphaël G. , Baraboi Elena-Dana , Samson Pierre , Lalonde Josée , Deshaies Yves , Richard Denis
Published: November 2006

The effects of the cannabinoid-1 receptor (CB1) antagonist rimonabant on energy metabolism and fasting-induced hypothalamic-pituitary-adrenal (HPA) axis and neuronal activation were investigated. Lean and obese Zucker rats were treated orally with a daily dose of 10 mg/kg rimonabant for 14 days. A comprehensive energy balance profile based on whole-carcass analyses further demonstrated the potential of CB1 antagonists for decreasing energy gain through reducing food intake and potentially increasing brown adipose tissue thermogenesis. Rimonabant also reduced plasma glucose, insulin, and homeostasis model assessment of insulin resistance, which further confirms the ability of CB1 antagonists to improve insulin sensitivity. To test the hypothesis that rimonabant attenuates the effect of fasting on HPA axis activation in the obese Zucker model, rats were either ad libitum–fed or food-deprived for 8 h. Contrary to expectation, rimonabant increased basal circulating corticosterone levels and enhanced the HPA axis response to food deprivation in obese rats. Rimonabant also exacerbated the neuronal activation seen in the arcuate nucleus (ARC) after short-term deprivation. In conclusion, the present study demonstrates that CB1 blockade does not prevent the hypersensitivity to food deprivation occurring at the level of HPA axis and ARC activation in the obese Zucker rats. This, however, does not prevent CB1 antagonism from exerting beneficial effects on energy and glucose metabolism.
Sodium-Coupled Glucose Cotransporters Contribute to Hypothalamic Glucose Sensing
Authors: O’Malley Dervla , Reimann Frank , Simpson Anna K. , Gribble Fiona M.
Published: November 2006

Specialized neurons within the hypothalamus have the ability to sense and respond to changes in ambient glucose concentrations. We investigated the mechanisms underlying glucose-triggered activity in glucose-excited neurons, using primary cultures of rat hypothalamic neurons monitored by fluorescence calcium imaging. We found that 35% (738 of 2,139) of the neurons were excited by increasing glucose from 3 to 15 mmol/l, but only 9% (6 of 64) of these glucose-excited neurons were activated by tolbutamide, suggesting the involvement of a ATP-sensitive K+ channel–independent mechanism. α-Methylglucopyranoside (αMDG; 12 mmol/l), a nonmetabolizable substrate of sodium glucose cotransporters (SGLTs), mimicked the effect of high glucose in 67% of glucose-excited neurons, and both glucose- and αMDG-triggered excitation were blocked by Na+ removal or by the SGLT inhibitor phloridzin (100 nmol/l). In the presence of 0.5 mmol/l glucose and tolbutamide, responses could also be triggered by 3.5 mmol/l αMDG, supporting a role for an SGLT-associated mechanism at low as well as high substrate concentrations. Using RT-PCR, we detected SGLT1, SGLT3a, and SGLT3b in both cultured neurons and adult rat hypothalamus. Our findings suggest a novel role for SGLTs in glucose sensing by hypothalamic glucose-excited neurons.
Reduced Expression of Gi in Erythrocytes of Humans With Type 2 Diabetes Is Associated With Impairment of Both cAMP Generation and ATP Release
Authors: Sprague Randy S. , Stephenson Alan H. , Bowles Elizabeth A. , Stumpf Madelyn S. , Lonigro Andrew J.
Published: November 2006

Human erythrocytes, by virtue of their ability to release ATP in response to physiological stimuli, have been proposed to participate in the regulation of local blood flow. A signal transduction pathway that relates these stimuli to ATP release has been described and includes the heterotrimeric G protein Gi and adenylyl cyclase (AC). In this cell, Gi activation results in increases in cAMP and, ultimately, ATP release. It has been reported that Gi expression is decreased in animal models of diabetes and in platelets of humans with type 2 diabetes. Here, we report that Gi2 expression is selectively decreased in erythrocytes of humans with type 2 diabetes and that this defect is associated with reductions in cAMP accumulation and ATP release in response to incubation of erythrocytes with mastoparan 7 (10 μmol/l), an activator of Gi. Importantly, this defect in ATP release correlates inversely with the adequacy of glycemic control as determined by levels of HbA1c (A1C). These results demonstrate that in erythrocytes of humans with type 2 diabetes, both Gi expression and ATP release in response to mastoparan 7 are impaired, which is consistent with the hypothesis that this defect in erythrocyte physiology could contribute to the vascular disease associated with this clinical condition.
Leptin Regulation of the Anorexic Response to Glucagon-Like Peptide-1 Receptor Stimulation
Authors: Williams Diana L. , Baskin Denis G. , Schwartz Michael W.
Published: November 2006

Leptin reduces food intake in part by enhancing satiety responses to gastrointestinal signals produced in response to food consumption. Glucagon-like peptide 1 (GLP-1), secreted by the intestine when nutrients enter the gut, is one such putative satiety signal. To investigate whether leptin enhances the anorexic effects of GLP-1, rats received either saline or a subthreshold dose of leptin before intraperitoneal injection of either GLP-1 or Exendin-4 (Ex4; a GLP-1 receptor agonist). Leptin pretreatment strongly enhanced anorexia and weight loss induced by GLP-1 or Ex4 over 24 h. Conversely, fasting attenuated the anorexic response to GLP-1 or Ex4 treatment via a leptin-dependent mechanism, as demonstrated by our finding that the effect of fasting was reversed by physiological leptin replacement. As expected, Ex4 induced expression of c-Fos protein, a marker of neuronal activation, in hindbrain areas that process afferent input from satiety signals, including the nucleus of the solitary tract and area postrema. Unexpectedly, leptin pretreatment blocked this response. These findings identify physiological variation of plasma leptin levels as a potent regulator of GLP-1 receptor-mediated food intake suppression and suggest that the underlying mechanism is distinct from that which mediates interactions between leptin and other satiety signals.
Polymorphism in the Transcription Factor 7-Like 2 (TCF7L2) Gene Is Associated With Reduced Insulin Secretion in Nondiabetic Women
Authors: Munoz Julian , Lok Kerry H. , Gower Barbara A. , Fernandez Jose R. , Hunter Gary R. , Lara-Castro Cristina , De Luca Maria , Garvey W. Timothy
Published: November 2006

Recently, the transcription factor 7-like 2 (TCF7L2) gene on chromosome 10q25.2 has been linked with type 2 diabetes among Caucasians, with disease associations noted for single nucleotide polymorphisms (SNPs) rs12255372 and rs7903146. To investigate mechanisms by which TCF7L2 could contribute to type 2 diabetes, we examined the effects of these SNPs on clinical and metabolic traits affecting glucose homeostasis in 256 nondiabetic female subjects (138 European Americans and 118 African Americans) aged 7–57 years. Outcomes included BMI, percent body fat, insulin sensitivity (Si), acute insulin response to glucose (AIRg), and the disposition index (DI). Homozygosity for the minor allele (TT) of SNP rs12255372 occurred in 9% of individuals and was associated with a 31% reduction in DI values in a recessive model. The at-risk allele TT was also associated with lower AIRg adjusted for Si in both ethnic groups, whereas rs12255372 genotype was not associated with measures of adiposity or with Si. The T allele of rs12255372 was also associated with increased prevalence of impaired fasting glucose. Genotypes at rs7903146 were not associated with any metabolic trait. Lower Si and higher AIRg observed in the African-American compared with the European-American subgroup could not be explained by the TCF7L2 genotype. Our data suggest that the TCF7L2 gene is an important factor regulating insulin secretion, which could explain its association with type 2 diabetes.
Peroxisome Proliferator–Activated Receptor-α and Glucocorticoids Interactively Regulate Insulin Secretion During Pregnancy
Authors: Holness Mark J. , Greenwood Gemma K. , Smith Nicholas D. , Sugden Mary C.
Published: November 2006

We evaluated the impact of peroxisome proliferator–activated receptor (PPAR)α activation and dexamethasone treatment on islet adaptations to the distinct metabolic challenges of fasting and pregnancy, situations where lipid handling is modified to conserve glucose. PPARα activation (24 h) in vivo did not affect glucose-stimulated insulin secretion (GSIS) in nonpregnant female rats in the fasted state, although fasting suppressed GSIS. Dexamethasone treatment (5 days) of nonpregnant rats lowered the glucose threshold and augmented GSIS at high glucose; the former effect was selectively opposed by PPARα activation. Pregnancy-induced changes in GSIS were opposed by PPARα activation at day 19 of pregnancy. Dexamethasone treatment from day 14 to 19 of pregnancy did not modify the GSIS profile of perifused islets from 19-day pregnant rats but rendered the islet GSIS profile refractory to PPARα activation. During sustained hyperglycemia in vivo, dexamethasone treatment augmented GSIS in nonpregnant rats but limited further modification of GSIS by pregnancy. We propose that the effect of PPARα activation to oppose lowering of the glucose threshold for GSIS by glucocorticoids is important as part of the fasting adaptation, and modulation of the islet GSIS profile by glucocorticoids toward term facilitates the transition of maternal islet function from the metabolic demands of pregnancy to those imposed after parturition.
Fatty Acid Transport Protein 1 Is Required for Nonshivering Thermogenesis in Brown Adipose Tissue
Authors: Wu Qiwei , Kazantzis Melissa , Doege Holger , Ortegon Angelica M. , Tsang Bernice , Falcon Alaric , Stahl Andreas
Published: November 2006

Nonshivering thermogenesis in brown adipose tissue (BAT) generates heat through the uncoupling of mitochondrial β-oxidation from ATP production. The principal energy source for this process is fatty acids that are either synthesized de novo in BAT or are imported from circulation. How uptake of fatty acids is mediated and regulated has remained unclear. Here, we show that fatty acid transport protein (FATP)1 is expressed on the plasma membrane of BAT and is upregulated in response to cold stimuli, concomitant with an increase in the rate of fatty acid uptake. In FATP1-null animals, basal fatty acid uptake is reduced and remains unchanged following cold exposure. As a consequence, FATP1 knockout (KO) animals display smaller lipid droplets in BAT and fail to defend their core body temperature at 4°C, despite elevated serum free fatty acid levels. Similarly, FATP1 is expressed by the BAT-derived cell line HIB-1B upon differentiation, and both fatty acid uptake and FATP1 protein levels are rapidly elevated following isoproterenol stimulation. Stimulation of fatty uptake by isoproterenol required both protein kinase A and mitogen-activated kinase signaling and is completely dependent on FATP1 expression, as small-hairpin RNA–mediated knock down of FATP1 abrogated the effect.
Probe-Independent and Direct Quantification of Insulin mRNA and Growth Hormone mRNA in Enriched Cell Preparations
Authors: Van Lommel Leentje , Janssens Kristel , Quintens Roel , Tsukamoto Katsura , Vander Mierde Dirk , Lemaire Katleen , Denef Carl , Jonas Jean-Christophe , Martens Geert , Pipeleers Daniel , Schuit Frans C.
Published: November 2006

Task division in multicellular organisms ensures that differentiated cell types produce cell-specific proteins that fulfill tasks for the whole organism. In some cases, the encoded mRNA species is so abundant that it represents a sizeable fraction of total mRNA in the cell. In this study, we have used a probe- and primer-free technique to quantify such abundant mRNA species in order to assess regulatory effects of in vitro and in vivo conditions. As a first example, we were able to quantify the regulation of proinsulin mRNA abundance in β-cells by food intake or by the glucose concentration in tissue culture. The second example of application of this technique is the effect of corticosteroids on growth hormone mRNA in enriched somatrotrophs. It is anticipated that other examples exist in which measurement of very abundant mRNAs in dedicated cells will help to understand biological processes, monitor disease states, or assist biotechnological manufacturing procedures.
Comparative Analysis of Insulin Gene Promoters
Authors: Hay Colin W. , Docherty Kevin
Published: November 2006

DNA sequences that regulate expression of the insulin gene are located within a region spanning ∼400 bp that flank the transcription start site. This region, the insulin promoter, contains a number of cis-acting elements that bind transcription factors, some of which are expressed only in the β-cell and a few other endocrine or neural cell types, while others have a widespread tissue distribution. The sequencing of the genome of a number of species has allowed us to examine the manner in which the insulin promoter has evolved over a 450 million–year period. The major findings are that the A-box sites that bind PDX-1 are among the most highly conserved regulatory sequences, and that the conservation of the C1, E1, and CRE sequences emphasize the importance of MafA, E47/β2, and cAMP-associated regulation. The review also reveals that of all the insulin gene promoters studied, the rodent insulin promoters are considerably dissimilar to the human, leading to the conclusion that extreme care should be taken when extrapolating rodent-based data on the insulin gene to humans.
The Leptin-Deficient (ob/ob) Mouse
Authors: Drel Viktor R. , Mashtalir Nazar , Ilnytska Olga , Shin Jeho , Li Fei , Lyzogubov Valeriy V. , Obrosova Irina G.
Published: November 2006

Whereas functional, metabolic, neurotrophic, and morphological abnormalities of peripheral diabetic neuropathy (PDN) have been extensively explored in streptozotocin-induced diabetic rats and mice (models of type 1 diabetes), insufficient information is available on manifestations and pathogenetic mechanisms of PDN in type 2 diabetic models. The latter could constitute a problem for clinical trial design because the vast majority of subjects with diabetes have type 2 (non–insulin dependent) diabetes. This study was aimed at characterization of PDN in leptin-deficient (ob/ob) mice, a model of type 2 diabetes with relatively mild hyperglycemia and obesity. ob/ob mice (∼11 weeks old) clearly developed manifest sciatic motor nerve conduction velocity (MNCV) and hind-limb digital sensory nerve conduction velocity (SNCV) deficits, thermal hypoalgesia, tactile allodynia, and a remarkable (∼78%) loss of intraepidermal nerve fibers. They also had increased sorbitol pathway activity in the sciatic nerve and increased nitrotyrosine and poly(ADP-ribose) immunofluorescence in the sciatic nerve, spinal cord, and dorsal root ganglion (DRG). Aldose reductase inhibition with fidarestat (16 mg · kg−1 · d−1), administered to ob/ob mice for 6 weeks starting from 5 weeks of age, was associated with preservation of normal MNCV and SNCV and alleviation of thermal hypoalgesia and intraepidermal nerve fiber loss but not tactile allodynia. Sciatic nerve nitrotyrosine immunofluorescence and the number of poly(ADP-ribose)–positive nuclei in sciatic nerve, spinal cord, and DRGs of fidarestat-treated ob/ob mice did not differ from those in nondiabetic controls. In conclusion, the leptin-deficient ob/ob mouse is a new animal model that develops both large motor and sensory fiber and small sensory fiber PDN and responds to pathogenetic treatment. The results support the role for increased aldose reductase activity in functional and structural changes of PDN in type 2 diabetes.
Effects of type and number of impellers and liquid viscosity on the power characteristics of mechanically agitated gas—liquid systems
Authors: Adamiak R. , Karcz J.
Published: November 2006

Effect of the type and number of high-speed impellers installed on a common shaft on the power characteristics was investigated in water and glucose solutions of different concentration. Different configurations of the Rushton or Smith turbines, pitched blade turbines, propeller, and A 315 impeller were tested. Measurements of power consumption were carried out within the transitional and turbulent regime of the fluid flow using the strain gauge method. Baffled agitated vessels with inner diameter of 0.288 m and 0.634 m were used for the experiments. Liquid height in the vessels was equal to the vessel diameter or it was twice higher. The relative power consumption was compared for different configurations of the impellers.
Modelling of composting of food waste in a column reactor
Authors: Briški F. , Vuković M. , Papa K. , Gomzi Z. , Domanovac T.
Published: November 2006

The composting of organic solid waste, the mixture of fruit and vegetable leftovers enriched with night soil, was investigated in a closed thermally insulated reactor. It was found that 80.9 % of the original substrate biodegraded after 14 days. A mathematical model of the column reactor was proposed where the biodegradation rate of the organic solid waste was described using simple n-thorder kinetics. A good prediction of process performance was obtained using the proposed kinetics and experimentally obtained reaction heat.
Electrical resistivity and photoluminescence of lead iodide crystals
Authors: Matuchová M. , Žďánský K. , Svatuška M. , Zavadil J. , Procházková O.
Published: November 2006

Direct synthesis of lead iodide, a promising material for X-ray and γ detectors operating at room temperature, was developed and optimized. The influence of admixture of rare earth elements Ce, Ho, Gd, Yb, Er, and Tb in concentrations 0.05–0.5 at. % on the quality of prepared PbI2 was investigated. Zone melting was employed in order to increase the lead iodide purity. Electrical and optical properties of PbI2 samples were assessed on the basis of the measurement of electrical resistivity and low-temperature photoluminescence. The electrical resistivity of synthesized samples varied from 109 Ω cm to 1011 Ω cm and occasionally it was increased up to 1013 Ω cm.
Theoretical study of solvent effect on π-EDA complexation II. Complex between TCNE and two benzene molecules
Authors: Kysel’ O. , Juhász G. , Mach P. , Košík G.
Published: November 2006

Formation of tetracyanoethylene—benzene 1: 1 and 1: 2 complexes was modeled using the Møller—Plesset second-order theory (MP2) and polarized continuum model (PCM). The MP2 calculated geometry of 1: 1 complex presents a plane-parallel C 2υ sandwich structure with interplanar distance 3.05 × 10−10 m, while the 1: 2 complex has D 2h geometry where the planparallel distance is equal to 3.09 × 10−10 m. The MP2 calculations indicate that the main part of formation enthalpy in both complexes is dispersion energy due to intermolecular electron correlation. The calculations also show that the formation entropy destabilizes both complexes since from the two constituent molecules one complex molecule arises. The MP2/6-31G* procedure showed to be a suitable tool for the estimation of the relative importance of 1: 2 complexation compared to the 1: 1 complexation. In the gas phase the ratio of the equilibrium constants of both complexes K 1:2/K 1:1 = 0.09 was calculated. The presence of solvent, treated by the PCM, further destabilized the 1: 2 complex with respect to the 1: 1 complex. The ratio K 1:2/K 1:1 in CH2Cl2 calculated by the PCM method was 0.022, i.e. the 1: 2 complex was almost 50 times less stable than the 1: 1 complex, which is in agreement with available experimental data. According to the calculations, solvent always destabilizes complex with respect to the isolated (solvated) components.

It was also found that charge polarization in the 1: 2 complex with respect to that in the 1: 1 complex was not strictly additive due to the presence of the second benzene molecule in the 1: 2 complex. Non-additive were also formation enthalpy, entropy, polarizability, charge transfer from donors to acceptor molecule and other properties. This fact is caused by a slightly changed interaction between constituent molecules in the 1: 2 complex in comparison with the 1: 1 complex as well as by the interaction between benzene molecules in the 1: 2 complex which is missing in the 1: 1 complex.

Preliminary CIS/6-31G* theoretical study regarding a few first-electron (electron charge transfer) transitions in both complexes indicates the presence of Frenkel excitn and Davydov transition energy splitting in the 1: 2 “supercomplex” with the first allowed π → π* absorption transition at λ = 355 nm, while the first allowed transition in the case of 1: 1 complex was characterized by λ = 392 nm with the oscillator strength only half of that of the 1: 2 complex, which is in agreement with experiment. These unexpected large hypso-and hypochromic effects predicted by the theory could allow to overcome difficulties of the experimental determination of the 1: 2 complexation.
Corporate Strategies of Busines Groups in the Wake of Competitive Shocks: Lessons from Argentina
Authors: Fracchia Eduardo , Mesquita Luiz F.
Published: November 2006

Conventional economic and management theories explain that business groups facing market liberalization policy reforms (i.e., competitive shocks) would have incentives to reduce corporate portfolios and increase internationalization. We empirically examine the strategic responses of Argentine business groups and, through an inductive theory building process, propose refinements to this theory. We argue that such a strategy process is moderated not only by differences in market forces set out by policy reforms across different economic segments but also by the path dependency of resources and capabilities as well as management decision‐making style of individual business groups. We discuss implications for theory and practice.
Corporate Governance and the Mondragón Cooperatives
Authors: Surroca Jordi , García‐Cestona Miguel A. , Santamaria Lluís
Published: November 2006

This paper builds upon recent advances in the corporate governance framework to extend and complement the economic literature on producer cooperatives. We argue that the problem of governance in a cooperative is twofold and consists in designing mechanisms and setting up institutions that (1) encourage workers to define a goal that maximizes workers’ welfare and (2) induce managers to pursue and internalize such a broad goal. When compared to capital‐controlled firms, the agency problems become more complex and harder to solve in the cooperative framework. As empirical evidence of this problem and its corresponding solution, we illustrate the case of the Mondragón cooperatives, explaining in detail the incentive system and the control mechanisms now in place in this successful business group. The study of the governance architecture of Mondragón may help us to propose solutions to traditional problems of the cooperative firm and to reach a better understanding of both the governance of cooperatives and corporate governance in general.
COVID-19 Rebound After VV116 vs Nirmatrelvir-Ritonavir Treatment
Authors: Yang Zhitao , Xu Yu , Zheng Ruizhi , Ye Lei , Lv Gang , Cao Zhujun , Han Rulai , Li Mian , Zhu Yuanyue , Cao Qiuyu , Ding Yi , Wang Jiqiu , Tan Yun , Liu Feng , Wei Dong , Tan Wei , Jiang Weiwei , Sun Jing , Sun Shouyue , Shao Jie , Deng Yang , Gao Weiyi , Wang Weiqing , Zhao Ren , Qiu Liping , Chen Erzhen , Zhang Xinxin , Wang Shengyue , Ning Guang , Xu Yiping , Bi Yufang
Published: March 2024

Importance

With the widespread use of anti–SARS-CoV-2 drugs, accumulating data have revealed potential viral load rebound after treatment.

Objective

To compare COVID-19 rebound after a standard 5-day course of antiviral treatment with VV116 vs nirmatrelvir-ritonavir.

Design, Setting, and Participants

This is a single-center, investigator-blinded, randomized clinical trial conducted in Shanghai, China. Adult patients with mild-to-moderate COVID-19 and within 5 days of SARS-CoV-2 infection were enrolled between December 20, 2022, and January 19, 2023, and randomly allocated to receive either VV116 or nirmatrelvir-ritonavir.

Interventions

Participants in the VV116 treatment group received oral 600-mg VV116 tablets every 12 hours on day 1 and 300 mg every 12 hours on days 2 through 5. Participants in the nirmatrelvir-ritonavir treatment group received oral nirmatrelvir-ritonavir tablets with 300 mg of nirmatrelvir plus 100 mg of ritonavir every 12 hours for 5 days. Participants were followed up every other day until day 28 and every week until day 60.

Main Outcomes and Measures

The primary outcome was viral load rebound (VLR), defined as a half-log increase in viral RNA copies per milliliter compared with treatment completion. Secondary outcomes included a reduction in the cycle threshold value of 1.5 or more, time until VLR, and symptom rebound, defined as an increase of more than 2 points in symptom score compared with treatment completion. The primary outcome and secondary outcomes were analyzed using the full analysis set. Sensitivity analyses were conducted using the per protocol set. Adverse events were analyzed using the safety analysis set.

Results

The full analysis set included 345 participants (mean [SD] age, 53.2 [16.8] years; 175 [50.7%] were men) who received VV116 (n = 165) or nirmatrelvir-ritonavir (n = 180). Viral load rebound occurred in 33 patients (20.0%) in the VV116 group and 39 patients (21.7%) in the nirmatrelvir-ritonavir group (P = .70). Symptom rebound occurred in 41 of 160 patients (25.6%) in the VV116 group and 40 of 163 patients (24.5%) in the nirmatrelvir-ritonavir group (P = .82). Viral whole-genome sequencing of 24 rebound cases revealed the same lineage at baseline and at viral load rebound in each case.

Conclusions and Relevance

In this randomized clinical trial of patients with mild-to-moderate COVID-19, viral load rebound and symptom rebound were both common after a standard 5-day course of treatment with either VV116 or nirmatrelvir-ritonavir. Prolongation of treatment duration might be investigated to reduce COVID-19 rebound.

Trial Registration

Chinese Clinical Trial Registry Identifier: ChiCTR2200066811
Bright Light Therapy as Add-On to Inpatient Treatment in Youth With Moderate to Severe Depression
Authors: Legenbauer Tanja , Kirschbaum-Lesch Inken , Jörke Carina , Kölch Michael , Reis Olaf , Berger Christoph , Dück Alexander , Schulte-Markwort Michael , Becker-Hebly Inga , Bienioschek Stefanie , Schroth Jennifer , Ruckes Christian , Deuster Oliver , Holtmann Martin
Published: March 2024

Importance

Major depressive disorder is one of the most common mental disorders among adolescents, entailing severe, long-term psychosocial impairment and a high risk of chronicity. In view of the large number of patients requiring treatment, along with insufficient treatment responses with small effect sizes, innovative adjunctive treatment strategies are urgently needed.

Objective

To investigate whether the effect of adolescent psychiatric inpatient treatment as usual for major depressive disorder can be enhanced by simultaneous use of morning bright light therapy.

Design, Setting, and Participants

This was a double-blind, placebo-controlled randomized parallel-group trial with enrollment between March 2018 and November 2020 and follow-up completed in May 2021. The study took place among inpatients at 4 university hospitals for child and adolescent psychiatry across Germany. Of 248 eligible youth aged 12 to 18 years fulfilling ICD-10 criteria for major depressive disorder, 227 were randomized to bright light therapy (n = 116) or placebo red light (n = 111); 151 participants completed the study.

Interventions

Up to 20 sessions of either morning bright light therapy with an intensity of 10 000 lux or placebo red light (100 lux) in addition to multimodal inpatient treatment as usual over 4 weeks.

Main Outcomes and Measures

The primary outcome was the change in Beck Depression Inventory-II (BDI-II) score from baseline to posttreatment in the intention-to-treat sample.

Results

Among the 224 patients included in the intention-to-treat analyses (192 girls and 32 boys; mean [SD] age, 15.5 [1.4] years), the mean (SD) BDI-II score at baseline was 37.3 (8.7). BDI-II scores were significantly reduced after 4 weeks (postassessment) by a mean of −7.5 (95% CI, −9.0 to −6.0; Hedges g = 0.71). Bright light therapy had no impact on this change (no significant group × time effect). Loss to follow-up was 31% (n = 69) at 16 weeks and 49% (n = 110) at 28 weeks. There were 10 serious adverse events throughout the whole trial, which were not considered related to study treatment.

Conclusions and Relevance

The findings in this study did not indicate superiority of bright light therapy over placebo red light therapy in a large sample of adolescent inpatients with moderate or severe major depressive disorder. Both groups benefited equally from treatment as usual, showing relevant symptom reduction.

Trial Registration

German Clinical Trials Register: DRKS00013188
Accreditation Council for Graduate Medical Education Milestone Training Ratings and Surgeons’ Early Outcomes
Authors: Smith Brigitte K. , Yamazaki Kenji , Tekian Ara , Brooke Benjamin S. , Mitchell Erica L. , Park Yoon Soo , Holmboe Eric S. , Hamstra Stanley J.
Published: March 2024

Importance

National data on the development of competence during training have been reported using the Accreditation Council for Graduate Medical Education (ACGME) Milestones system. It is now possible to consider longitudinal analyses that link Milestone ratings during training to patient outcomes data of recent graduates.

Objective

To evaluate the association of in-training ACGME Milestone ratings in a surgical specialty with subsequent complication rates following a commonly performed operation, endovascular aortic aneurysm repair (EVAR).

Design, Setting, and Participants

This study of patient outcomes followed EVAR in the Vascular Quality Initiative (VQI) registry (4213 admissions from 208 hospitals treated by 327 surgeons). All surgeons included in this study graduated from ACGME-accredited training programs from 2015 through 2019 and had Milestone ratings 6 months prior to graduation. Data were analyzed from December 1, 2021, through September 15, 2023. Because Milestone ratings can vary with program, they were corrected for program effect using a deviation score from the program mean.

Exposure

Milestone ratings assigned to individual trainees 6 months prior to graduation, based on judgments of surgical competence.

Main Outcomes and Measures

Surgical complications following EVAR for patients treated by recent graduates during the index hospitalization, obtained using the nationwide Society for Vascular Surgery Patient Safety Organization’s VQI registry, which includes 929 participating centers in 49 US states.

Results

The study included outcomes for 4213 patients (mean [SD] age, 73.25 [8.74] years; 3379 male participants [80.2%]). Postoperative complications included 9.5% major (400 of 4213 cases) and 30.2% minor (1274 of 4213 cases) complications. After adjusting for patient risk factors and site of training, a significant association was identified between individual Milestone ratings of surgical trainees and major complications in early surgical practice in programs with lower mean Milestone ratings (odds ratio, 0.50; 95% CI; 0.27-0.95).

Conclusions and Relevance

In this study, Milestone assessments of surgical trainees were associated with subsequent clinical outcomes in their early career. Although these findings represent one surgical specialty, they suggest Milestone ratings can be used in any specialty to identify trainees at risk for future adverse patient outcomes when applying the same theory and methodology. Milestones data should inform data-driven educational interventions and trainee remediation to optimize future patient outcomes.
Thermodynamic Assessment of the Mo–Si System
Authors: Czerny Andreas Klaus , Ma Wenhao , Hausner Clemens Simon , Franke Peter , Rohde Magnus , Seifert Hans Jürgen
Published: March 2024

The binary system Mo–Si is reassessed based on previously reported findings that the phase shows a deficiency in Si and to take into account experimental data on the heat capacities of the Mo silicides. The last aspect in particular has been neglected in previous assessments of the system. Experimental studies are carried out which confirm that the phase is deficient in Si in every alloy analyzed, with an average Si content of 23 at%. The thermodynamic description of this phase is adjusted accordingly and the parameters of the system are optimized. Two alternative possible descriptions are presented for the phase . It is shown that the calculated binary phase diagram agrees well with experimental data, like liquidus and solidus temperatures as well as homogeneity ranges of the phases, where applicable, for both datasets. Likewise, thermophysical data like enthalpies of the formation of the silicides are adequately described.