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ABSTRACTLipotoxicity is a form of cellular stress caused by the accumulation of lipids resulting in mitochondrial dysfunction and insulin resistance in muscle. Previously, we demonstrated that the mitophagy receptor BNIP3L/Nix is responsive to lipotoxicity and accumulates in response to a high-fat (HF) feeding. To provide a better understanding of this observation, we undertook gene expression array and shot-gun metabolomics studies in soleus muscle from rodents on an HF diet. Interestingly, we observed a modest reduction in several autophagy-related genes. Moreover, we observed alterations in the fatty acyl composition of cardiolipins and phosphatidic acids. Given the reported roles of these phospholipids and BNIP3L in mitochondrial dynamics, we investigated aberrant mitochondrial turnover as a mechanism of impaired myocyte insulin signaling. In a series of gain-of-function and loss-of-function experiments in rodent and human myotubes, we demonstrate that BNIP3L accumulation triggers mitochondrial depolarization, calcium-dependent activation of DNM1L/DRP1, and mitophagy. In addition, BNIP3L can inhibit insulin signaling through activation of MTOR-RPS6KB/p70S6 kinase inhibition of IRS1, which is contingent on phosphatidic acids and RHEB. Finally, we demonstrate that BNIP3L-induced mitophagy and impaired glucose uptake can be reversed by direct phosphorylation of BNIP3L by PRKA/PKA, leading to the translocation of BNIP3L from the mitochondria and sarcoplasmic reticulum to the cytosol. These findings provide insight into the role of BNIP3L, mitochondrial turnover, and impaired myocyte insulin signaling during an overfed state when overall autophagy-related gene expression is reduced. Furthermore, our data suggest a mechanism by which exercise or pharmacological activation of PRKA may overcome myocyte insulin resistance.Abbreviations:BCL2: B cell leukemia/lymphoma 2; BNIP3L/Nix: BCL2/adenovirus E1B interacting protein 3-like; DNM1L/DRP1: dynamin 1-like; FUNDC1: FUN14 domain containing 1; IRS1: insulin receptor substrate 1; MAP1LC3A/LC3: microtubule-associated protein 1 light chain 3 alpha; MFN1: mitofusin 1; MFN2: mitofusin 2; MTOR: mechanistic target of rapamycin kinase; OPA1: OPA1 mitochondrial dynamin like GTPase; PDE4i: phosphodiesterase 4 inhibitor; PLD1: phospholipase D1; PLD6: phospholipase D family member 6; PRKA/PKA: protein kinase, AMP-activated; PRKCD/PKCδ: protein kinase C, delta; PRKCQ/PKCθ: protein kinase C, theta; RHEB: Ras homolog enriched in brain; RPS6KB/p70S6K: ribosomal protein S6 kinase; SQSTM1/p62: sequestosome 1; YWHAB/14-3-3β: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein beta

Background: Obesity often originates in early life, and is linked to excess sugar intake. Nonnutritive sweeteners (NNS) are widely consumed as “healthier” alternatives to sugar, yet recent evidence suggests NNS may adversely influence weight gain and metabolic health. The impact of NNS during critical periods of early development has rarely been studied. We investigated the effect of prenatal NNS exposure on postnatal adiposity and adipocyte development. Methods: In the CHILD birth cohort (N= 2298), we assessed maternal NNS beverage intake during pregnancy and child body composition at 3 years, controlling for maternal BMI and other potential confounders. To investigate causal mechanisms, we fed NNS to pregnant C57BL6J mice at doses relevant to human consumption (42 mg/kg/day aspartame or 6.3 mg/kg/day sucralose), and assessed offspring until 12 weeks of age for: body weight, adiposity, adipose tissue morphology and gene expression, glucose and insulin tolerance. We also studied the effect of sucralose on lipid accumulation and gene expression in cultured 3T3-L1 pre-adipocyte cells. Results: In the CHILD cohort, children born to mothers who regularly consumed NNS beverages had elevated body mass index (mean z-score difference +0.23, 95% CI 0.05–0.42 for daily vs. no consumption, adjusted for maternal BMI). In mice, maternal NNS caused elevated body weight, adiposity, and insulin resistance in offspring, especially in males (e.g., 47% and 15% increase in body fat for aspartame and sucralose vs. controls, p< 0.001). In cultured adipocytes, sucralose exposure at early stages of differentiation caused increased lipid accumulation and expression of adipocyte differentiation genes (e.g., C/EBP-α, FABP4, and FASN). These genes were also upregulated in adipose tissue of male mouse offspring born to sucralose-fed dams. Conclusion: By triangulating evidence from humans, mice, and cultured adipocytes, this study provides new evidence that maternal NNS consumption during pregnancy may program obesity risk in offspring through effects on adiposity and adipocyte differentiation.

BACKGROUND:It is unclear whether intrauterine exposure to maternal diabetes is associated with risk factors for cardiovascular disease and related end points in adulthood. We examined this potential association in a population-based birth cohort followed up to age 35 years.METHODS:We performed a cohort study of offspring born between 1979 and 2005 (n= 293 546) and followed until March 2015 in Manitoba, Canada, using registry-based administrative data. The primary exposures were intrauterine exposure to gestational diabetes and type 2 diabetes mellitus. The primary outcome was a composite measure of incident cardiovascular disease events, and the secondary outcome was a composite of risk factors for cardiovascular disease in offspring followed up to age 35 years.RESULTS:The cohort provided 3 628 576 person-years of data (mean age at latest follow-up 20.5 [standard deviation 6.4] years, 49.3% female); 2765 (0.9%) of the offspring experienced a cardiovascular disease end point, and 12 673 (4.3%) experienced a cardiovascular disease risk factor. After propensity score matching, the hazard for cardiovascular disease end points was elevated in offspring exposed to gestational diabetes (adjusted hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.12–1.79) but not type 2 diabetes (adjusted HR 1.40, 95% CI 0.98–2.01). A similar association was observed for cardiovascular disease risk factors (gestational diabetes: adjusted HR 1.92, 95% CI 1.75–2.11; type 2 diabetes: adjusted HR 3.40, 95% CI 3.00–3.85).INTERPRETATION:Intrauterine exposure to maternal diabetes was associated with higher morbidity and risk related to cardiovascular disease among offspring up to 35 years of age.

Fetal exposure to gestational diabetes mellitus (GDM) and poor postnatal diet are strong risk factors for type 2 diabetes development later in life, but the mechanisms connecting GDM exposure to offspring metabolic health remains unclear. In this study, we aimed to determine how GDM interacts with the postnatal diet to affect islet function in the offspring as well as characterize the gene expression changes in the islets. GDM was induced in female rats using a high-fat, high-sucrose (HFS) diet, and litters from lean or GDM dams were weaned onto a low-fat (LF) or HFS diet. Compared with the lean control offspring, GDM exposure reduced glucose-stimulated insulin secretion in islets isolated from 15-week-old offspring, which was additively worsened when GDM exposure was combined with postnatal HFS diet consumption. In the HFS diet-fed offspring of lean dams, islet size and number increased, an adaptation that was not observed in the HFS diet-fed offspring of GDM dams. Islet gene expression in the offspring of GDM dams was altered in such categories as inflammation (e.g., Il1b, Ccl2), mitochondrial function/oxidative stress resistance (e.g., Atp5f1, Sod2), and ribosomal proteins (e.g., Rps6, Rps14). These results demonstrate that GDM exposure induced marked changes in gene expression in the male young adult rat offspring that cumulatively interact to worsen islet function, whole-body glucose homeostasis, and adaptations to HFS diets.

Myocardin is a transcriptional co-activator required for cardiovascular development, but also promotes cardiomyocyte survival through an unclear molecular mechanism. Mitochondrial permeability transition is implicated in necrosis, while pore closure is required for mitochondrial maturation during cardiac development. We show that loss of myocardin function leads to subendocardial necrosis at E9.5, concurrent with elevated expression of the death gene Nix. Mechanistically, we demonstrate that myocardin knockdown reduces microRNA-133a levels to allow Nix accumulation, leading to mitochondrial permeability transition, reduced mitochondrial respiration, and necrosis. Myocardin knockdown elicits calcium release from the endo/sarcoplasmic reticulum with mitochondrial calcium accumulation, while restoration of microRNA-133a function, or knockdown of Nix rescues calcium perturbations. We observed reduced myocardin and elevated Nix expression within the infarct border-zone following coronary ligation. These findings identify a myocardin-regulated pathway that maintains calcium homeostasis and mitochondrial function during development, and is attenuated during ischemic heart disease. Given the diverse role of Nix and microRNA-133a, these findings may have broader implications to metabolic disease and cancer.

IMPORTANCE: The consumption of artificial sweeteners has increased substantially in recent decades, including among pregnant women. Animal studies suggest that exposure to artificial sweeteners in utero may predispose offspring to develop obesity; however, to our knowledge, this has never been studied in humans. OBJECTIVE: To determine whether maternal consumption of artificially sweetened beverages during pregnancy is associated with infant body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]). DESIGN, SETTING, AND PARTICIPANTS: This cohort study included 3033 mother-infant dyads from the Canadian Healthy Infant Longitudinal Development (CHILD) Study, a population-based birth cohort that recruited healthy pregnant women from 2009 to 2012. Women completed dietary assessments during pregnancy, and their infants’ BMI was measured at 1 year of age (n = 2686; 89% follow-up). Statistical analysis for this study used data collected after the first year of follow-up, which was completed in October 2013. The data analysis was conducted in August 2015. EXPOSURES: Maternal consumption of artificially sweetened beverages and sugar-sweetened beverages during pregnancy, determined by a food frequency questionnaire. MAIN OUTCOMES AND MEASURES: Infant BMI z score and risk of overweight at 1 year of age, determined from objective anthropometric measurements and defined according to World Health Organization reference standards. RESULTS: The mean (SD) age of the 3033 pregnant women was 32.4 (4.7) years, and their mean (SD) BMI was 24.8 (5.4). The mean (SD) infant BMI z score at 1 year of age was 0.19 (1.05), and 5.1% of infants were overweight. More than a quarter of women (29.5%) consumed artificially sweetened beverages during pregnancy, including 5.1% who reported daily consumption. Compared with no consumption, daily consumption of artificially sweetened beverages was associated with a 0.20-unit increase in infant BMI z score (adjusted 95% CI, 0.02-0.38) and a 2-fold higher risk of infant overweight at 1 year of age (adjusted odds ratio, 2.19; 95% CI, 1.23-3.88). These effects were not explained by maternal BMI, diet quality, total energy intake, or other obesity risk factors. There were no comparable associations for sugar-sweetened beverages. CONCLUSIONS AND RELEVANCE: To our knowledge, we provide the first human evidence that maternal consumption of artificial sweeteners during pregnancy may influence infant BMI. Given the current epidemic of childhood obesity and widespread use of artificial sweeteners, further research is warranted to confirm our findings and investigate the underlying biological mechanisms, with the ultimate goal of informing evidence-based dietary recommendations for pregnant women.

In pancreatic β-cells, controlling the levels of reactive oxygen species (ROS) is critical to counter oxidative stress, dysfunction and death under nutrient excess. Moreover, the fine-tuning of ROS and redox balance is important in the regulation of normal β-cell physiology. We recently demonstrated that Bcl-2 and Bcl-xL, in addition to promoting survival, suppress β-cell glucose metabolism and insulin secretion. Here, we tested the hypothesis that the nonapoptotic roles of endogenous Bcl-2 extend to the regulation of β-cell ROS and redox balance. We exposed mouse islet cells and MIN6 cells to the Bcl-2/Bcl-xLantagonist Compound 6 and the Bcl-2-specific antagonist ABT-199 and evaluated ROS levels, Ca2+responses, respiratory control, superoxide dismutase activity and cell death. Both acute glucose stimulation and the inhibition of endogenous Bcl-2 progressively increased peroxides and stimulated superoxide dismutase activity in mouse islets. Importantly, conditional β-cell knockout of Bcl-2 amplified glucose-induced formation of peroxides. Bcl-2 antagonism also induced a mitochondrial proton leak that was prevented by the antioxidant N-acetyl-L-cysteine and, therefore, secondary to redox changes. We further established that the proton leak was independent of uncoupling protein 2 but partly mediated by the mitochondrial permeability transition pore. Acutely, inhibitor-induced peroxides promoted Ca2+influx, whereas under prolonged Bcl inhibition, the elevated ROS was required for induction of β-cell apoptosis. In conclusion, our data reveal that endogenous Bcl-2 modulates moment-to-moment ROS signaling and suppresses a redox-regulated mitochondrial proton leak in β-cells. These noncanonical roles of Bcl-2 may be important for β-cell function and survival under conditions of high metabolic demand.

Mobilization of hepatic triacylglycerol stores provides substrates for mitochondrial β-oxidation and assembly of VLDLs; however, the identity of lipolytic enzymes involved in the regulation of this process remains largely unknown. Arylacetamide deacetylase (AADA) shares homology with hormone-sensitive lipase and therefore could potentially participate in hepatic lipid metabolism, including the regulation of hepatic triacylglycerol levels. We have established McArdle-RH7777 (rat hepatoma) cell lines stably expressing mouse AADA cDNA and performed metabolic labeling as well as lipid mass analyses. Expression of AADA cDNA in McArdle-RH7777 cells significantly reduced intracellular triacylglycerol levels and apolipoprotein B secretion and increased fatty acid oxidation.

Mobilization of hepatic triacylglycerol stores provides substrates for mitochondrial β-oxidation and assembly of VLDLs; however, the identity of lipolytic enzymes involved in the regulation of this process remains largely unknown. Arylacetamide deacetylase (AADA) shares homology with hormone-sensitive lipase and therefore could potentially participate in hepatic lipid metabolism, including the regulation of hepatic triacylglycerol levels. We have established McArdle-RH7777 (rat hepatoma) cell lines stably expressing mouse AADA cDNA and performed metabolic labeling as well as lipid mass analyses. Expression of AADA cDNA in McArdle-RH7777 cells significantly reduced intracellular triacylglycerol levels and apolipoprotein B secretion and increased fatty acid oxidation.

A recent cycle of a General Electric boiling water reactor performed two beginning-of-cycle local cold criticals. The eigenvalues estimated by the core simulator were 0.99826 and 1.00610. The large spread in them (= 0.00784) is a source of concern, and it is studied here. An analysis process is developed using statistical techniques, where first a transfer function relating the core observable Y(eigenvalue) to various factors (X’s) is established. Engineering judgment is used to recognize the best candidates for X’s. They are identified as power-weighted assembly k∞’s of selected assemblies around the withdrawn rods. These are a small subset of many X’s that could potentially influence Y. However, the intention here is not to do a comprehensive study by accounting for all the X’s. Rather, the scope is to demonstrate that the process developed is reasonable and to show its applicability to performing detailed studies. Variability in X’s is obtained by perturbing nodal k∞’s since they directly influence the buckling term in the quasi-two-group diffusion equation model of the core simulator. Any perturbations introduced in them are bounded by standard well-established uncertainties. The resulting perturbations in the X’s may not necessarily be directly correlated to physical attributes, but they encompass numerous biases and uncertainties credited to input and modeling uncertainties. The “vital few” from the “unimportant many” X’s are determined, and then they are subgrouped according to assembly type, location, exposure, and control rod insertion. The goal is to study how the subgroups influence Yin order to have a better understanding of the variability observed in it.

Hepatic VLDL (very-low-density lipoprotein) assembly is a complex process that is largely regulated by the provision of lipid for apolipoprotein B assembly. Intracellular stored TAG (triacylglycerol) undergoes an initial lipolysis followed by re-esterification of the lipolytic products to form TAG prior to their incorporation into a VLDL particle. TGH (TAG hydrolase) is a lipase that hydrolyses intracellular TAG within the hepatocyte. We have utilized both dexamethasone-injected mouse and primary hepatocyte models to address whether stimulation of TAG biosynthesis by the synthetic glucocorticoid, dexamethasone, altered hepatic lipolysis and re-esterification and the provision of stored TAG for lipoprotein secretion. Dexamethasone treatment resulted in decreased TGH expression, primarily due to a dexamethasone-induced decrease in TGH mRNA stability. The expression and activities of diacylglycerol acyltransferases 1 and 2 were stimulated by dexamethasone. The combination of reduced intracellular TAG lipolysis and increased TAG biosynthesis contributed to the accumulation of TAG within the livers of dexamethasone-injected mice. The rate of hepatic TAG secretion in dexamethasonetreated mice was maintained at similar levels as in control mice. Our data demonstrate that stimulation of de novo TAG synthesis by dexamethasone increased the proportion of secreted TAG that was derived from de novo sources, while the utilization of stored TAG for secretion was reduced. The results show that, during markedly increased TAG synthesis, some TAGs are diverted from the cytosolic storage pool and are utilized directly for VLDL assembly within the endoplasmic reticulum lumen.

In the science and technology policy literature that emerged in the early 1980s, it was held that, while public support for science is appropriate, public support for technology development represents an unproductive use of public resources. The perspective that emerges in my recent book, Technology, Growth and Development: An Induced Innovation Perspective (Oxford, 2002) is quite different. Government has played an important role in technology development and transfer in almost every US industry that has become competitive on a global scale.

The development and introduction of transgenically modified organisms to enhance crop and animal production has generated considerable controversy about potential food safety and environmental impacts. The introduction, in tropical Latin America and Asia, of high yielding varieties of wheat, maize and rice beginning in the late 1960s was also controversial. Critics argued that the new technology was biased against the poor – it would make the rich richer and the poor poorer. In this paper, I review the equity andproductivity impacts of the "green revolution" technology and draw several inferences about evaluation of the effects of the new biotechnologies in agricultural production.

Thirteen-lined ground squirrels (Spermophilus tridecemlineatus) exploit the low-temperature activity of pancreatic triacylglycerol lipase (PTL) during hibernation. Lipolytic activity at body temperatures associated with hibernation was examined using recombinant ground squirrel and human PTLs expressed in yeast. Both the human and ground squirrel enzymes displayed high activity at temperatures as low as 0°C and showed Q10values of 1.2–1.5 over a range of 37–7°C. These studies indicate that low-temperature lipolysis is a general property of PTL and does not require protein modifications unique to mammalian cells and/or the hibernating state. Western blots show elevated levels of PTL protein during hibernation in both heart and white adipose tissue (WAT). Significant increases in PTL gene expression are seen in heart, WAT, and testes; but not in pancreas, where PTL mRNA levels are highest. Upregulation of PTL in testes is also accompanied by expression of the PTL-specific cofactor, colipase. The multi-tissue expression of PTL during hibernation supports its role as a key enzyme that shows high activity at low temperatures.

The purpose of this study was to evaluate the degree of functional recovery in adult rats with completely transected spinal cord following experimental treatment regimens that include implantation of peripheral nerve segments and local application of acidic fibroblast growth factor (aFGF). Rats were randomly divided to five groups: (1) spinal cord transection, (2) spinal cord transection and aFGF treatment, (3) spinal cord transection and peripheral nerve grafts, (4) spinal cord transection, aFGF treatment, and peripheral nerve grafts, and (5) sham control (laminectomy only). The locomotor behavior of all rats was analyzed by the Basso, Beattie and Bresnahan (BBB) open field locomotor test over the six months survival time. Immunohistochemisty for neurofilament protein, and somatosensory (SSEP) and motor evoked potentials (MEP) were used to evaluate axon growth across the damage site following the different treatments. The results show four principal findings: (1) Only the combination of peripheral nerve grafts and aFGF treatment improved hindlimb locomotor function after spinal cord transection. (2) The SSEP and MEP demonstrated electrophysiological evidence of both sensory and motor information crossing the damaged site, but only in the combined nerve grafts and aFGF treatment rats. (3) Immunostaining demonstrated neurofilament positive axons extending through the graft area and into distal end of spinal cord, but only in the group with combined nerve grafts and aFGF treatment. (4) Retransection of group 4 rats eliminated the behavioral recovery, MEP, and SSEP responses, indicating that the improvement of hindlimb locomotor activity came from supraspinal control. These results demonstrate the ability of the repair strategy combining peripheral nerve grafts and aFGF treatment to facilitate the regeneration of spinal ascending and descending tracts and also recovery of motor behavior following spinal cord injury.

This study developed a slice culture model system to study axonal regeneration after spinal cord injury. This model was tested in studies of the roles of acidic fibroblast growth factor (aFGF) and peripheral nerve segments in axonal growth between pieces of spinal cord. Transverse sections of P15–P18 Sprague-Dawley rat spinal cord were collected for organotypic slice cultures. Group I consisted of two slices of spinal cord in contact with each other during the culture period. Group II consisted of two slices that were separated by 3 mm and connected by two segments of intercostal nerves. Group III consisted of single slices for studies of neuron survival. Some cultures from each group included aFGF in the culture medium. Bromodeoxyuridine (BrdU) was included in the medium for some cultures. The results showed three principal findings. First, counts of neurofilament-positive cells demonstrated that treatment with aFGF significantly increased the number of surviving neurons in culture. Second, neurofilament immunostaining and DiI tracing demonstrated axons crossing the junction between the two pieces of spinal cord or growing through the intercostal nerve segments, and these axons were seen only in cultures with aFGF treatment. Third, few cells were double stained for neurofilament and BrdU, and these were found only with aFGF treatment. These results demonstrate that (1) organotypic slice cultures present a useful model to study regeneration from spinal cord injury, (2) aFGF rescues neurons and promotes axonal growth in these cultures, and (3) segments of intercostal nerves promote axon growth between slices of spinal cord.

Treatment of rats with thyroxine has been shown to elevate the biosynthesis and content of cardiolipin in the heart [Cao, Cheng, Angel and Hatch (1995) Biochim. Biophys. Acta 1256, 241-244]. Treatment with thyroxine resulted in a 1.8-fold increase (P < 0.025) in [1-14C]linoleate and a 1.7-fold increase (P < 0.025) in [1-14C]oleate incorporated into cardiolipin in perfused hearts, compared with controls. The mechanism for the elevation in incorporation of unsaturated fatty acids into cardiolipin was a 1.6-fold (P < 0.025) increase in mitochondrial monolysocardiolipin acyltransferase activity. The results demonstrate that the acylation of cardiac monolysocardiolipin is regulated by thyroid hormone. Thus an elevation in cardiolipin biosynthesis is accompanied by an elevation in monolysocardiolipin acyltransferase activity to maintain the appropriate molecular species composition of cardiolipin in the cardiac mitochondrial membrane. We postulate that monolysocardiolipin acyltransferase might be a rate-limiting enzyme for the molecular remodelling of cardiolipin in the heart.

As with most other management skills, anyone can learn assertive behaviour. This article introduces some of the main concepts of assertiveness, and offers some practical techniques for approaching a variety of workplace situations-be you a shrinking violet or a savage beast.

Tafazzin (TAZ) is a cardiolipin (CL) biosynthetic enzyme important for maintaining mitochondrial function. TAZ affects both the species and content of CL in the inner mitochondrial membrane, which are essential for normal cellular respiration. In pancreatic β cells, mitochondrial function is closely associated with insulin secretion. However, the role of TAZ and CL in the secretion of insulin from pancreatic islets remains unknown. Male 4-month-old doxycycline-inducible TAZ knock-down (KD) mice and wild-type littermate controls were used. Immunohistochemistry was used to assess β-cell morphology in whole pancreas sections, whereas ex vivo insulin secretion, CL content, RNA-sequencing analysis, and mitochondrial oxygen consumption were measured from isolated islet preparations. Ex vivo insulin secretion under nonstimulatory low-glucose concentrations was reduced ~52% from islets isolated from TAZ KD mice. Mitochondrial oxygen consumption under low-glucose conditions was also reduced ~58% in islets from TAZ KD animals. TAZ deficiency in pancreatic islets was associated with significant alteration in CL molecular species and elevated polyunsaturated fatty acid CL content. In addition, RNA-sequencing of isolated islets showed that TAZ KD increased expression of extracellular matrix genes, which are linked to pancreatic fibrosis, activated stellate cells, and impaired β-cell function. These data indicate a novel role for TAZ in regulating pancreatic islet function, particularly under low-glucose conditions.

Seventy-nine subjects from 14 centers in eight English National Health Service Trusts recorded their levels of preoperative and postoperative pain and perceived change in pain on 100-mm visual analog scales before and after scalpel debridement of painful plantar hyperkeratosis. A significant reduction in pain was reported following treatment, and there were highly significant differences between the preoperative and postoperative scores. There were no age- or sex-related differences in any of the preoperative, postoperative, or perceived-change scores. The objective data support the anecdotal evidence that scalpel debridement of painful plantar hyperkeratosis is immediately effective in the palliative management of such patients.

Abstract.: Spider Lamb Syndrome (SLS) is a semi-lethal congenital disorder, causing severe skeletal abnormalities in sheep. The syndrome has now been disseminated into several sheep breeds in the United States, Canada, and Australia. The mode of inheritance for SLS is autosomal recessive, making the identification and culling of carrier animals difficult due to their normal phenotype. Two large pedigrees segregating for the SLS mutation were established, and a genome scan with genetic markers from previously published genome maps of cattle and sheep was used to map the locus causing SLS. Genetic linkage between SLS and several microsatellite markers, OarJMP8, McM214, OarJMP12, and BL1038, was detected, thereby mapping the SLS locus to the telomeric end of ovine Chromosome (Chr) 6. Alignment of ovine Chr 6 with its evolutionary ortholog, human Chr 4, revealed a positional candidate gene, fibroblast growth factor receptor 3 (FGFR3).

The authors characterize magnetic resonance (MR) features of oligodendroglioma that permit diagnosis. These features may be used to guide MR stereotactic biopsies.

Cadmium is known to dissociate myocardial excitation-contraction coupling and to depress the excitability of the cardiac conduction system in vitro(1-7). Short-term feeding experiments concluding that cadmium increases conduction time through the atrioventricular node-His-Purkinje system have partially extended these in vitroobservations to in vivo systems (8, 9). Although the cadmium content of the heart increases with age and exposure (10-14), the effects of cadmium have not been systematically analyzed for possible significance as a contributing factor to degenerative heart disease. This preliminary study was undertaken to investigate electrocardiographical, biochemical, and morphological changes in mammalian hearts associated with long-term, low-level cadmium feeding.Methods.Eighteen weanling female rats of the Long-Evans strain were obtained and housed as described (15). They received a special rye-based, low-cadmium diet and deionized water fortified with Mn, Co, Cu, Zn, and Mo, as described by Schroeder and Vinton (16), for a total of 24 months when all were sacrificed. For half of them, cadmium acetate was added to the water to provide a final concentration of five parts per million (ppm) cadmium; for the half which served as controls, no cadmium was added; however, they were otherwise treated identically (16).For 16 rats (8 cadmium-fed and 8 control), indirect systolic pressures were determined 12, 18, and 21 months after weaning. Eight of the rats (4 cadmium-fed and 4 control) were studied electrocardiographically and their blood pressures determined directly after which they were sacrificed so that the various parts of the heart could be assayed for cadmium and zinc. The phosphate spectrum of hearts from the eight remaining rats (4 cadmium-fed and 4 control) were analyzed by phosphorus nuclear magnetic resonance spectroscopy (31P NMR). In addition hearts from a pair of rats not otherwise studied (1 cadmium-fed and 1 control) were examined by electron microscopy.

In the study of rapidity distributions of charged pions produced ine+e- annihilation at 29 GeV, we observe a significant dip in the rapidity distributions aty˜0 for events with low sphericity. A comparison of data with several QCD-based phenomenological models strongly suggests that this structure is related to the emission of multiple soft and/or collinear gluons.

Placentas from a clinical study group of 446 high-risk pregnancies and 108 normal pregnancies were cultured for Mycoplasma hominis and Ureaplasma urealyticum and examined histologically. Results were compared and correlated with the clinical history. The recovery rate of U urealyticum, but not of M hominis, was significantly higher in the clinical study than in the control group. Isolation of both mycoplasmas was associated with polymorphonuclear leukocyte infiltration of placental membranes, fetal surface, and umbilical cord. Recovery of mycoplasma was significantly higher with prolonged membrane rupture, spontaneous abortion, stillbirth, and early neonatal death. Isolation of U urealyticum, but not of M hominis, was associated with prematurity, lower birth weight, and intrauterine growth retardation. (Obstet Gynecol 56475, 1980)

This study assessed the ability of functional magnetic stimulation (FMS) to activate the respiratory muscles in dogs. With the animal supine, FMS of the phrenic nerves using a high‐speed magnetic stimulator was performed by placing a round magnetic coil (MC) at the carotid triangle. Following hyperventilation‐induced apnea, changes in volume (ΔV) and airway pressure (ΔP) against an occluded airway were determined. FMS of the phrenic nerves produced substantial inspired function (ΔV = 373 ± 20.5 mL and ΔP = −20 ± 2.0 cm H2O). After bilateral phrenectomies, maximal inspired ΔV (219 ± 12.2 mL) and ΔP (−10 ± 1.0 cm H2O) were produced when the MC was placed near the C6–C7 spinous processes, while maximal expired ΔV (−199 ± 22.5 mL) and ΔP (11 ± 2.3 cm H2O) were produced following stimulation near the T9–T10 spinous processes. We conclude: (1) FMS of either the phrenic or upper intercostal nerves results in inspired volume production; (2) FMS of the lower intercostal nerves generates expired volume production; and (3) FMS of the respiratory muscles may be a useful noninvasive tool for artificial ventilation and assisted cough in patients with spinal cord injuries or other neurological disorders. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:1048–1057, 1998.

Normal phase preparative and semi-preparative liquid chromatography were used to isolate fractions of varying polarity from corn, soybean and sunflowerseed oils. Reported here is the composition of one fraction, less polar than triglycerides, determined by isolating the individual «peaks» of a semi-preparative separation using as starting material the mix of compounds obtained from a large scale separation. These peaks were then analyzed by high performance liquid chromatography (LC) gas chromatography (GC), mass-spectrometry (MS) with and without GC, in both electron impact (EI) and chemical ionization (CI) modes, and carbon-13 nuclear magnetic resonance (NMR) spectroscopy. Semi-quantitative data were obtained for many of the components found in these semi-preparative isolates including hydrocarbons, steryl esters, triterpenyl esters, phytyl esters and geranylgeranyl esters. The weight percent and composition of the preparative fraction differed substantially among the three oils. Corn oil had the greatest amount, at 1.25% of the starting oil, and was composed mostly of steryl and triterpenyl esters. Sunflowerseed oil, at 0.7%, and soybean oil, at 0.3%, showed greater variety in that branched chain esters were included with the steryl/triterpenyl distributions.

At some stage in their career, most managers have to deal with unsatisfactory behaviour from their subordinates. Disciplinary procedures can be a minefield, and even experienced human resources managers can get caught out if a case goes to an industrial tribunal. Fortunately for the average engineering manager, especially anyone not regularly involved in personnel issues, ACAS publishes guidelines for disciplinary procedures, suitable for both managers and employees. This article outlines the main features of the guidelines, and their implications for managers, whether they are HRM experts or not.

An advertising campaign for a well-known software company urged everyone to: `work smarter, not harder. Most `smart' people do not need computer programs to make them effective; they make the best possible use of their time by planning their work. This article describes some time and personal techniques that allow anyone to work `smarter': the need for `harder' then becomes optional.

• In a series of clinical studies of a combined measles (Schwarz strain), mumps (Jeryl Lynn strain), and rubella (Cendehill strain) vaccine, 1,481 children received the vaccine or a placebo. The vaccine did not cause any significant reactions. The frequencies of mild, transient fever or rash or both in triple-susceptible vaccinees were similar to those that follow use of Schwarz strain measles vaccine alone. Measles, mumps, and rubella seroconversion rates in triple-susceptible vaccinees ranged from 95% to 100%. Geometric mean antibody titers were as high as those that usually result from use of these same virus strains as monovalent vaccines.(Am J Dis Child 129:1408-1412, 1975)