Global bifurcation at isolated singular points of the Hadamard derivative.

Consider [Formula: see text] such that F(λ, 0) = 0 for all [Formula: see text], where X and Y are Banach spaces. Bifurcation from the line [Formula: see text] of trivial solutions is investigated in cases where F(λ, · ) need not be Fréchet differentiable at 0. The main results provide sufficient conditions for µ to be a bifurcation point and yield global information about the connected component of [Formula: see text] containing (µ, 0). Some necessary conditions for bifurcation are also formulated. The abstract results are used to treat several singular boundary value problems for which Fréchet differentiability is not available. This article is part of the theme issue 'Topological degree and fixed point theories in differential and difference equations'.

Skiing and snowboarding head injury: A retrospective centre-based study and implications for helmet test standards.

BACKGROUND: Head injury occurs in up to 47% of skiing or snowboarding injuries and is the predominant cause of death in these sports. In most existing literature reporting injury type and prevalence, head injury mechanisms are underreported. Thus, protective equipment design relies on safety evaluation test protocols that are likely oversimplified. This study aims to characterize severity and mechanism of head injuries suffered while skiing and snowboarding in a form appropriate to supplement existing helmet evaluation methods. METHODS: A 6-year, multicentre, retrospective clinical record review used emergency databases from two major trauma centres and Coroner's reports to identify relevant cases which indicated head impact. Records were investigated to understand the relationships between helmet use, injury type and severity, and injury mechanism. Descriptive statistics and odds ratios aided interpretation of the data. FINDINGS: The snow sport head injury database included 766 cases. "Simple fall", "jump impact" and "impact with object" were the most common injury mechanisms while concussion was observed to be the most common injury type. Compared to "edge catch", moderate or serious head injury was more common for "fall from height" (OR = 4.69; 95% CI = 1.44-16.23; P = 0.05), "jump impact" (OR = 3.18; 95% CI = 1.48-7.26; P = 0.01) and "impact with object" (OR = 2.44; 95% CI = 1.14-5.56; P = 0.05). Occipital head impact was associated with increased odds of concussion (OR = 7.46; 95% CI = 4.55-12.56; P = 0.001). INTERPRETATION: Snow sport head injury mechanisms are complex and cannot be represented through a single impact scenario. By relating clinical data to injury mechanism, improved evaluation methods for protective measures and ultimately better protection can be achieved.

Injuries at the Whistler Sliding Center: a 4-year retrospective study.

BACKGROUND: The Whistler Sliding Centre (WSC) in British Columbia, Canada, has played host to many events including the 2010 Winter Olympics. This study was performed to better understand sliding sport incident (crash, coming off sled, etc) and injury prevalence and provide novel insights into the effect of slider experience and track-specific influences on injury risk and severity. METHODS: Track documentation and medical records over 4 years (2007 track inception to 2011) were used to form 3 databases, including over 43,200 runs (all sliding disciplines). Statistics were generated relating incident and injury to start location, crash location and slider experience as well as to understand injury characteristics. RESULTS: Overall injury rate was found to be 0.5%, with more severe injury occurring in <0.1% of the total number of runs. More frequent and severe injuries were observed at lower track locations. Of 2605 different sliders, 73.6% performed 1-29 runs down the track. Increased slider experience was generally found to reduce the frequency of injury. Lacerations, abrasions and contusions represented 52% of all injuries. A fatality represented the most severe injury on the track and was the result of track ejection. CONCLUSIONS: By investigating the influence of start location, incident location and slider experience on incident and injury frequency and severity, a better understanding has been achieved of the inherent risks involved in sliding sports. Incident monitoring, with particular focus on track ejection, should be an emphasis of sliding tracks.

Relapsing acute adult epiglottitis following hypophysectomy.

Adult epiglottitis is an uncommon disease that may become fatal because of sudden airway obstruction. Recurrent adult epiglottitis has been reported rarely in the literature. We present a case of relapsing epiglottitis in a patient with corticosteroid insufficiency secondary to pituitary surgery. It is the first case to highlight this infection occurring in a relapsing manner in a patient with pituitary-adrenocortical insufficiency on long-term steroid replacement therapy.

Epithelioid sarcoma with metastatic spread to the tongue.

Epithelioid sarcoma (ES) is a rare tumour that seldom presents to the otolaryngologist. It typically occurs in the extremities of young adolescents; however, it has the capability of metastasizing, often to the lungs or skin. The diagnosis is by histopathological examination and immunohistochemistry. We present a case of metastatic ES occuring in the tongue, a tumour not reported previously in the English literature.

Spontaneous intracranial hypotension due to thoracic disc herniation. Case report.

Spontaneous intracranial hypotension is frequently idiopathic. The authors report on a patient presenting with symptomatic intracranial hypotension caused by a transdural calcified thoracic disc herniation. Cranial magnetic resonance (MR) imaging revealed classic signs of intracranial hypotension, and a combination of spinal MR and computerized tomography myelography confirmed a mid-thoracic transdural calcified herniated disc as the cause. The patient was treated with an epidural blood patch and burr hole drainage of the subdural effusion on two occasions. Postoperatively the headache resolved and there was no neurological deficit. Thoracic disc herniation may be a cause of spontaneous intracranial hypotension.

Altered GLUT1 and GLUT3 gene expression and subcellular redistribution of GLUT4: protein in muscle from patients with acanthosis nigricans and severe insulin resistance.

Multiple isoforms of glucose transporters are found in muscle, the tissue that normally accounts for 85% of insulin-stimulated glucose uptake. Glucose uptake into muscle cells in the fasting state is mediated primarily by GLUT1 and GLUT3 glucose transporters, whereas postprandial (insulin-stimulated) and exercise-related increments in muscle glucose uptake are mediated primarily by GLUT4. To determine if glucose transporters are abnormally expressed in muscle from insulin-resistant subjects, muscle samples were obtained from 10 normal subjects and 6 obese, nondiabetic subjects with severe insulin resistance and acanthosis nigricans. Both GLUT4 total protein and mRNA were normal in the insulin-resistant subjects. Muscle GLUT3 protein and mRNA were lower than controls by 62% and 71%, respectively. GLUT1 mRNA was twice normal, whereas GLUT1 protein content was not significantly increased. GLUT4 protein was markedly redistributed to the muscle plasma membrane in subjects with severe insulin resistance compared with normals (92% v 40% GLUT4 in plasma membrane-enriched fractions, P <.001), whereas the percentage of GLUT1 and GLUT3 protein found in the plasma membrane-enriched fractions was not different from controls. These data document differences in the expression of genes for GLUT1 and GLUT3 in muscle from normal and insulin-resistant subjects. Further, insulin resistance with fasting hyperinsulinemia was associated with a redistribution of GLUT4 to the muscle cell surface with no change in total GLUT4 protein. These data suggest that glucose transporter gene expression and their basal distribution in human muscle are related to insulin resistance and could be determinants of whole body insulin responsiveness.

GLUT-3 expression in human skeletal muscle.

Muscle biopsy homogenates contain GLUT-3 mRNA and protein. Before these studies, it was unclear where GLUT-3 was located in muscle tissue. In situ hybridization using a midmolecule probe demonstrated GLUT-3 within all muscle fibers. Fluorescent-tagged antibody reacting with affinity-purified antibody directed at the carboxy-terminus demonstrated GLUT-3 protein in all fibers. Slow-twitch muscle fibers, identified by NADH-tetrazolium reductase staining, possessed more GLUT-3 protein than fast-twitch fibers. Electron microscopy using affinity-purified primary antibody and gold particle-tagged second antibody showed that the majority of GLUT-3 was in association with triads and transverse tubules inside the fiber. Strong GLUT-3 signals were seen in association with the few nerves that traversed muscle sections. Electron microscopic evaluation of human peripheral nerve demonstrated GLUT-3 within the axon, with many of the particles related to mitochondria. GLUT-3 protein was found in myelin but not in Schwann cells. GLUT-1 protein was not present in nerve cells, axons, myelin, or Schwann cells but was seen at the surface of the peripheral nerve in the perineurium. These studies demonstrated that GLUT-3 mRNA and protein are expressed throughout normal human skeletal muscle, but the protein is predominantly found in the triads of slow-twitch muscle fibers.

Therapy focused on lowering postprandial glucose, not fasting glucose, may be superior for lowering HbA1c. IOEZ Study Group.

OBJECTIVE: To compare the overall efficacy of combination therapies focused on fasting or postprandial blood glucose in patients with type 2 diabetes not adequately controlled with oral sulfonylurea agents alone. RESEARCH DESIGN AND METHODS: A total of 135 patients were randomly assigned for 3 months to 1 of 3 combination regimens with glyburide (G) that addressed postprandial blood glucose with insulin lispro (L+G), premeal blood glucose with metformin (M+G), or fasting blood glucose (FBG) with bedtime NPH insulin (NPH+G). RESULTS: At end point, HbA1c was significantly lower with all therapies (P = 0.001) and was significantly lower for L+G (7.68+/-0.88%) compared with either NPH+G (8.51+/-1.38%, P = 0.003) or M+G (8.31+/-1.31%, P = 0.025). FBG at end point was significantly lower for NPH+G (8.49+/-2.36 mmol/l) compared with either L+G (10.57+/-1.97 mmol/l, P = 0.001) or M+G (9.69+/-2.89 mmol/l, P = 0.029). The mean 2-h postprandial glucose after a test meal was significantly lower for L+G (10.87+/-2.88 mmol/l) versus NPH+G (12.21+/-3.12 mmol/, P = 0.052) or versus M+G (12.72+/-3.26 mmol/l, P = 0.009). The overall rate of hypoglycemia (episodes per 30 days) was low and not statistically significant between groups (P = 0.156). CONCLUSIONS: Adding a second antihyperglycemic agent, regardless of its timing of action, lowers HbA1c and glucose values. However, when insulin lispro was used to focus on postprandial blood glucose, there was a greater impact on overall metabolic control. These data support the importance of lowering postprandial blood glucose to optimize overall glycemic control and thus improve long-term outcomes.

Comparison of GLUT1, GLUT3, and GLUT4 mRNA and the subcellular distribution of their proteins in normal human muscle.

Basal, "insulin-independent" glucose uptake into skeletal muscle is provided by glucose transporters positioned at the plasma membrane. The relative amount of the three glucose transporters expressed in muscle has not been previously quantified. Using a combination of qualitative and quantitative ribonuclease protection assay (RPA) methods, we found in normal human muscle that GLUT1, GLUT3, and GLUT4 mRNA were expressed at 90 +/- 10, 46 +/- 4, and 156 +/- 12 copies/ng RNA, respectively. Muscle was fractionated by DNase digestion and differential sedimentation into membrane fractions enriched in plasma membranes (PM) or low-density microsomes (LDM). GLUT1 and GLUT4 proteins were distributed 57% to 67% in LDM, whereas GLUT3 protein was at least 88% in the PM-enriched fractions. These data suggest that basal glucose uptake into resting human muscle could be provided in part by each of these three isoforms.

Inactivity amplifies the catabolic response of skeletal muscle to cortisol.

Severe injury or trauma is accompanied by both hypercortisolemia and prolonged inactivity or bed rest (BR). Trauma and BR alone each result in a loss of muscle nitrogen, albeit through different metabolic alterations. Although BR alone can result in a 2-3% loss of lean body mass, the effects of severe trauma can be 2- to 3-fold greater. We investigated the combined effects of hypercortisolemia and prolonged inactivity on muscle protein metabolism in healthy volunteers. Six males were studied before and after 14 days of strict BR using a model based on arteriovenous sampling and muscle biopsy. Fractional synthesis and breakdown rates of skeletal muscle protein were also directly calculated. Each assessment of protein metabolism was conducted during a 12-h infusion of hydrocortisone sodium succinate (120 microg/kg x h), resulting in blood cortisol concentrations that mimic severe injury (approximately 31 microg/dL). After 14 days of strict BR, hypercortisolemia increased phenylalanine efflux from muscle by 3-fold (P < 0.05). The augmented negative amino acid balance was the result of an increased muscle protein breakdown (P < 0.05) without a concomitant change in muscle protein synthesis. Muscle efflux of glutamine and alanine increased significantly after bed rest due to a significant increase in de novo synthesis (P < 0.05). Thus, inactivity sensitizes skeletal muscle to the catabolic effects of hypercortisolemia. Furthermore, these effects on healthy volunteers are analogous to those seen after severe injury.

GLUT3 protein and mRNA in autopsy muscle specimens.

GLUT3 is expressed in rat muscle, but this glucose transporter protein has not been identified previously in adult human skeletal muscle. We quantified the rapidity of disappearance of mRNA and protein from human skeletal muscle at room temperature and at 4 degrees C. Fifty percent of the immunologically detectable GLUT3 protein disappeared by 1 hour at 20 degrees C and by 2 hours at 4 degrees C. mRNA for GLUT3 was decreased 50% by 2.2 hours at 20 degrees C and by 24 hours at 4 degrees C. Half of the measurable mRNAs for GLUT4, glyceraldehyde 3-phosphate dehydrogenase (GAPDH), alpha-actin, and beta-myosin disappeared by 0.8 to 2.1 hours at 20 degrees C and by 5.0 to 16.6 hours at 4 degrees C. Previous conclusions that GLUT3 is not expressed in human muscle were likely drawn because of artifacts related to degradation of GLUT3 protein in the specimens prior to study. Because of the rapid degradation of protein and mRNA, autopsy specimens of muscle must be obtained within 6 hours of death, and even then, protein and mRNA data will likely dramatically underestimate their expression in fresh muscle. Some previously published conclusions and recommendations regarding autopsy specimens are not stringent enough to consistently yield useful protein and mRNA.

Specific binding and growth-promoting activity of insulin in endometrial cancer cells in culture.

OBJECTIVE: Insulin is known to be mitogenic to a variety of cells in culture. The purpose of this study was to investigate the possible role of insulin in the growth and development of endometrial cancers. STUDY DESIGN: Specific binding and growth effects of insulin were studied in 5 different human endometrial cancer cell lines derived from cancers with different degrees of differentiation: HEC-1-A and HEC-1-B (from a moderately well-differentiated adenocarcinoma), RL95-2 (from a moderately well-differentiated adenosquamous carcinoma), KLE (from poorly differentiated carcinoma), and AN3 CA (from a metastatic undifferentiated endometrial carcinoma). The receptors were further characterized by competitive binding and chemical cross-linking studies. RESULTS: Binding studies with 125I-insulin revealed the presence of high-affinity binding sites for insulin on all the 5 cell lines. Binding of insulin was found to be highly specific. Competitive binding studies with 125I-insulin revealed that insulin was most effective in displacing the labeled hormone, whereas insulin-like growth factor-I and insulin-like growth factor-II competed for binding only at very high concentrations. Scatchard analysis of the binding data revealed that the association constant for the high-affinity binding sites ranged from 0.72 to 1.91 x 10(9) L/mol. Estrogen-receptor-negative cell lines HEC-1-A and HEC-1-B had the highest number of insulin receptors, whereas the estrogen-receptor-positive cell line RL95-2 had the least number of receptors. The effect of insulin on cell proliferation was studied by monitoring cell number and incorporating [3H]thymidine into deoxyribonucleic acid of the cells. Insulin stimulated cell growth of all the cell lines. CONCLUSIONS: The results of this study indicate the potential role of hyperinsulinemia in the growth and development of endometrial cancer.

Quantification of insulin in dried blood spots.

A method has been developed in which the concentrations of insulin in dried blood spots on filter paper can be estimated. The technique involves elution of blood from the paper, evaporation, and rehydration in assay buffer. The resuspended samples are then assayed by radioimmunoassay. The ratio of control plasma to control dried blood spot insulin values is used as a conversion factor for unknown samples on paper to express the dried blood spot insulin concentration in plasma equivalents. Intra-assay variability was 14%, and interassay variability was 25%, but the elution conversion factor had a variability of about 40% among individuals. This technique has substantial advantages for field studies, but elevated values should be confirmed by a venous plasma sample measurement in a conventional radioimmunoassay.

Acanthosis nigricans as a risk factor for non-insulin dependent diabetes mellitus.

The prevalences of obesity and of non-insulin dependent diabetes mellitus (NIDDM) have increased in the United States population over the past two decades, and thus diabetes prevention has become a major concern of public health agencies such as the National Institutes of Health. Identification of individuals at risk for diabetes is an essential first step in designing and implementing intervention programs. Insulin resistance is the hallmark of the pathophysiology of NIDDM. Subjects with hyperinsulinemia, impaired glucose tolerance, or gestational diabetes are well accepted as being at high risk for diabetes. We propose that the easily identifiable skin lesion, acanthosis nigricans, is common in the major minority groups in the United States and that its presence is a surrogate for laboratory-determined hyperinsulinemia.

Acanthosis nigricans.

Acanthosis nigricans is a lesion affecting localized areas of the skin in persons with obesity and/or hyperinsulinemia. Roughening of the skin correlates with histological papilomatosis and the apparent darkening is due to hyperkeratosis. Biochemical mechanisms for developing this hyperplastic lesion are unclear, but likely involve local cutaneous growth factors. Cross sectional surveys of unselected populations have demonstrated that young children have low prevalences of obesity and acanthosis nigricans, but the prevalences of both increase with increasing age until plateaus are reached after the age of ten. Nearly 40% of Native American teenagers have acanthosis nigricans, whereas about 13% of African American, 6% of Hispanic, and less than 1% of white, non-Hispanic children aged 10-19 have clinically apparent acanthosis nigricans. We conclude that the presence of this skin lesion is a clinical surrogate of laboratory-documented hyperinsulinemia. Acanthosis nigricans identifies a subgroup within an ethnic group who have the highest insulin concentration, the most severe insulin resistance, and thus the highest risk for the development of type 2 diabetes.

Hyperinsulinemia and acanthosis nigricans in African Americans.

Compared with the US white, non-Hispanic population, the African-American population has a nearly two-fold higher prevalence of noninsulin-dependent diabetes mellitus (NIDDM). Obesity, which usually precedes NIDDM, is associated with the skin lesion acanthosis nigricans in African Americans. This study was undertaken to determine what the relationship of acanthosis nigricans was to hyperinsulinemia, a major risk factor for NIDDM. Eighty-nine African-American subjects with acanthosis nigricans and 25 others without the skin lesion were evaluated using oral glucose tolerance testing and responsiveness to insulin. Noninsulin-dependent diabetes mellitus was present in 19 of the subjects with acanthosis nigricans. The prevalence of NIDDM in this group increased with increasing age, reaching 50% among those in their 40s. Fasting plasma insulin concentration was in direct proportion to the severity of the acanthosis nigricans involvement of the neck. These data suggest that among African Americans, this skin lesion is a marker for hyperinsulinemia and insulin resistance. Furthermore, the presence of acanthosis nigricans identifies a subset with a much higher prevalence of NIDDM than is present in African Americans in the general population.

Effect of adding a sulfonylurea in patients with non-insulin-dependent diabetes mellitus previously well controlled with insulin.

OBJECTIVE: To determine whether insulin-requiring patients with non-insulin-dependent diabetes mellitus (NIDDM) and good glycemic control would benefit in weight control, serum lipid concentrations, or blood pressure from a reduction in exogenous insulin treatment. METHODS: Eighteen patients with well-controlled NIDDM who required insulin therapy were entered into a randomized, placebo-controlled, double-blind, crossover study of the addition for 12 weeks of treatment with a second-generation sulfonylurea agent (micronized glyburide). RESULTS: The mean fasting plasma glucose at entry was 7.00 +/- 0.22 mmol/L and at the end of the 12-week treatment phase was 7.67 +/- 0.39 mmol/L with placebo and 7.28 +/- 0.44 mmol/L with active drug. Hemoglobin A(1c) was unchanged during the study (7.5 +/- 0.2% at entry, 7.5 +/- 0.3% with placebo, and 7.4 +/- 0.3% with active drug). Addition of the orally administered agent resulted in a 29% decrease in exogenous insulin requirements and a 37% increase in 24-hour urinary C-peptide excretion. Patients had no change in weight after 12 weeks of either placebo or active drug. Plasma cholesterol levels declined slightly during the study, but they did not differ significantly during drug and placebo treatment. Blood pressure was unchanged in both the subjects with and without hypertension. CONCLUSION: In patients with NIDDM and good glycemic control with insulin treatment, a glyburide-related increase in endogenous insulin secretion caused a proportionate decrease in exogenous insulin requirements. With continued good glycemic control, however, the orally administered agent showed no additional benefit on weight, blood pressure, plasma triglycerides, or low-density lipoprotein or high-density lipoprotein cholesterol.