First Accurate Normalization of the ß-delayed α Decay of

The ^{12}C(α,γ)^{16}O reaction plays a central role in astrophysics, but its cross section at energies relevant for astrophysical applications is only poorly constrained by laboratory data. The reduced α width, γ_{11}, of the bound 1^{-} level in ^{16}O is particularly important to determine the cross section. The magnitude of γ_{11} is determined via sub-Coulomb α-transfer reactions or the ß-delayed α decay of ^{16}N, but the latter approach is presently hampered by the lack of sufficiently precise data on the ß-decay branching ratios. Here we report improved branching ratios for the bound 1^{-} level [b_{ß,11}=(5.02±0.10)×10^{-2}] and for ß-delayed α emission [b_{ßα}=(1.59±0.06)×10^{-5}]. Our value for b_{ßα} is 33% larger than previously held, leading to a substantial increase in γ_{11}. Our revised value for γ_{11} is in good agreement with the value obtained in α-transfer studies and the weighted average of the two gives a robust and precise determination of γ_{11}, which provides significantly improved constraints on the ^{12}C(α,γ) cross section in the energy range relevant to hydrostatic He burning.

(97)(37)Rb(60): The Cornerstone of the Region of Deformation around A ∼ 100 [corrected].

Excited states of the neutron-rich nuclei (97,99)Rb were populated for the first time using the multistep Coulomb excitation of radioactive beams. Comparisons of the results with particle-rotor model calculations provide clear identification for the ground-state rotational band of (97)Rb as being built on the πg(9/2) [431] 3/2(+) Nilsson-model configuration. The ground-state excitation spectra of the Rb isotopes show a marked distinction between single-particle-like structures below N=60 and rotational bands above. The present study defines the limits of the deformed region around A∼100 and indicates that the deformation of (97)Rb is essentially the same as that observed well inside the deformed region. It further highlights the power of the Coulomb-excitation technique for obtaining spectroscopic information far from stability. The (99)Rb case demonstrates the challenges of studies with very short-lived postaccelerated radioactive beams.

Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial.

AIM: Inhibition of diacylglycerol acyltransferase 1 (DGAT1) is a potential treatment modality for patients with type 2 diabetes mellitus and obesity, based on preclinical data suggesting it is associated with insulin sensitization and weight loss. This randomized, placebo-controlled, phase 1 study in 62 overweight or obese men explored the effects and tolerability of AZD7687, a reversible and selective DGAT1 inhibitor. METHODS: Multiple doses of AZD7687 (1, 2.5, 5, 10 and 20 mg/day, n = 6 or n = 12 for each) or placebo (n = 20) were administered for 1 week. Postprandial serum triacylglycerol (TAG) was measured for 8 h after a standardized 45% fat meal. Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) were measured and a paracetamol challenge was performed to assess gastric emptying. RESULTS: Dose-dependent reductions in postprandial serum TAG were demonstrated with AZD7687 doses ≥5 mg compared with placebo (p < 0.01). Significant (p < 0.001) increases in plasma GLP-1 and PYY levels were seen at these doses, but no clear effect on gastric emptying was demonstrated at the end of treatment. With AZD7687 doses >5 mg/day, gastrointestinal (GI) side effects increased; 11/18 of these participants discontinued treatment owing to diarrhoea. CONCLUSIONS: Altered lipid handling and hormone secretion in the gut were demonstrated during 1-week treatment with the DGAT1 inhibitor AZD7687. However, the apparent lack of therapeutic window owing to GI side effects of AZD7687, particularly diarrhoea, makes the utility of DGAT1 inhibition as a novel treatment for diabetes and obesity questionable.

Ozone exposure enhances mast-cell inflammation in asthmatic airways despite inhaled corticosteroid therapy.

Asthmatics are recognised to be more susceptible than healthy individuals to adverse health effects caused by exposure to the common air pollutant ozone. Ozone has been reported to induce airway neutrophilia in mild asthmatics, but little is known about how it affects the airways of asthmatic subjects on inhaled corticosteroids. We hypothesised that ozone exposure would exacerbate the pre-existent asthmatic airway inflammation despite regular inhaled corticosteroid treatment. Therefore, we exposed subjects with persistent asthma on inhaled corticosteroid therapy to 0.2 ppm ozone or filtered air for 2 h, on 2 separate occasions. Lung function was evaluated before and immediately after exposure, while bronchoscopy was performed 18 h post exposure. Compared to filtered air, ozone exposure increased airway resistance. Ozone significantly enhanced neutrophil numbers and myeloperoxidase levels in airway lavages, and induced a fourfold increase in bronchial mucosal mast cell numbers. The present findings indicate that ozone worsened asthmatic airway inflammation and offer a possible biological explanation for the epidemiological findings of increased need for rescue medication and hospitalisation in asthmatic people following exposure to ambient ozone.

Hormone-sensitive lipase and monoacylglycerol lipase are both required for complete degradation of adipocyte triacylglycerol.

The respective roles of monoacylglycerol lipase and hormone-sensitive lipase in the sequential hydrolysis of adipose tissue triacylglycerols have been examined. An adipose tissue preparation, containing both lipases in approximately the same proportion as in the intact tissue, hydrolyzed emulsified tri- or dioleoylglycerol to fatty acids and glycerol, with little accumulation of di- or monooleoylglycerol. Selective removal of the monoacylglycerol lipase by immunoprecipitation markedly reduced the glycerol release. Isolated hormone-sensitive lipase hydrolyzed acylglycerols with a marked accumulation of monoacylglycerol in accordance with the positional specificity of this enzyme (Fredrikson, G. and Belfrage, P. (1983) J. Biol. Chem. 258, 14253-14256). Addition of increasing amounts of isolated monoacylglycerol lipase led to a corresponding increase in glycerol release, due to hydrolysis of the monoacylglycerols formed. The reaction proceeded to completion when the relative proportion of the two lipases was similar to that in the intact tissue. These findings indicate that hormone-sensitive lipase catalyzes the hydrolysis of triacylglycerol in the rate-limiting step of adipose tissues lipolysis, and of the resulting diacylglycerol, whereas the action of monoacylglycerol lipase is required in the final hydrolysis of the 2-monoacylglycerols produced.

Enzymes catalyzing the hydrolysis of long-chain monoacyglycerols in rat adipose tissue.

Acetone-ether preparations of epididymal fat pads from fasted or fed rats contained two enzymes catalyzing the hydrolysis of long-chain monoacylglycerols. The enzymes were identified as monoacylglycerol lipase (Tornqvist, H. and Belfrage, P., (1976) J. Biol Chem. 251, 813--819) and lipoprotein lipase by their apparent pI values after electrofocusing in non-ionic detergent, selective inhibition properties, substrate specificity and positional specificity. It was estimated that monoacylglycerol lipase accounted for about 90% of the total monoacylglycerol-hydrolyzing activity in acetone-ether preparations from fasted and 70% from fed rats. Its enzyme activity did not change with the nutritional state in contrast to that of lipoprotein lipase. The latter enzyme hydrolyzed 2-monoacylglycerols at a much lower rate than the 1(3)-isomers. Monoacylglycerol lipase was located almost entirely in the adipocytes, thus most of the enzyme activity towards monoacylglycerols in the adipose tissue was found in this site. Fractionated sucrose homogenates of rat epididymal fat pads also contained a third enzyme with monoacylglycerol-hydrolyzing activity, identified as hormone-sensitive lipase by its pI, selective inhibition properties and substrate specificity. It was estimated that hormone-sensitive lipase accounted for less than 20% of the total activity against monoacylglycerols in these tissue preparations from fasted rats. Over-all quantitative estimations emphasized the dominant role of monoacylglycerol lipase over the other two enzymes in the hydrolysis of monoacylglycerols.

Removal of nonionic detergent from proteins fractionated by electrofocusing.

The nonionic detergent Nonipol TD 12 (an alkyl polyoxyethylene alcohol) has been removed from solubilised proteins after their fractionation by electrofocusing. Following electrofocusing in nonionic detergent an anionic or cationic detergent was added to the focussing medium and the focusing was allowed to continue. The ionic detergent formed mixed micelles with the nonionic detergent. Thus charged, the mixed micelles migrated to either electrode, removing nonionic detergent from the fractionated proteins. Applying this technique to an adipose tissue preparation, detergent-inhibited activity of a lipolytic enzyme was restored and the binding of adenosine 3':5'-cyclic monophosphate (cyclic AMP) to a protein kinase was increased.

Evidence for the key role of the adipocyte cGMP-inhibited cAMP phosphodiesterase in the antilipolytic action of insulin.

Enhancement of cAMP degradation by increased cGMP-inhibited cAMP phosphodiesterase (cGI-PDE) activity is thought to be an important component of the mechanism whereby insulin counteracts catecholamine-induced lipolysis in adipocytes. In this study the selective cGI-PDE inhibitor OPC3911 was used to evaluate this role of cGI-PDE activation in intact rat adipocytes with special reference to changes in cAMP levels measured as cAMP-dependent protein kinase (cAMP-PK) activity ratios. OPC3911 completely blocked (IC50 = 0.3 microM) the maximal inhibitory effect of insulin on noradrenaline-induced lipolysis and the net dephosphorylation of hormone-sensitive lipase and other intracellular target proteins for insulin action, whereas insulin-induced lipogenesis was not changed. The effect of OPC3911 on cAMP-PK activity ratios at different levels of lipolysis achieved by noradrenaline stimulation revealed that the reduction of cAMP-PK caused by 1 nM insulin was completely blocked by 3 microM OPC3911. The effect of OPC3911 was not due to an excessive increase in cellular cAMP resulting in 'supramaximal' lipolysis unresponsive to insulin. These data demonstrate that reduction in cAMP levels by the activation of cGI-PDE may be sufficient to account for the antilipolytic action of insulin.

Insulin and cortisol promote leptin production in cultured human fat cells.

The aim of this study was to investigate the regulation of leptin expression and production in cultured human adipocytes using the model of in vitro differentiated human adipocytes. Freshly isolated human preadipocytes did not exhibit significant leptin mRNA and protein levels as assessed by reverse transcriptase (RT)-polymerase chain reaction (PCR) and radioimmunoassay (RIA). However, during differentiation induced by a defined adipogenic serum-free medium, cellular leptin mRNA and leptin protein released into the medium increased considerably in accordance with the cellular lipid accumulation. In fully differentiated human fat cells, insulin provoked a dose-dependent rise in leptin protein. Cortisol at a near physiological concentration of 10(-8) mol/l was found to potentiate this insulin effect by almost threefold. Removal of insulin and cortisol, respectively, was followed by a rapid decrease in leptin expression, which was reversible after readdition of the hormones. These results clearly indicate that both insulin and cortisol are potent and possibly physiological regulators of leptin expression in human adipose tissue.

Effects of tyrosine kinase inhibitors on tyrosine phosphorylations and the insulin-like effects in response to human growth hormone in isolated rat adipocytes.

Recent data suggest involvement of the Janus tyrosine kinase-2 (JAK2) in human GH-induced tyrosine phosphorylation of the GH receptor and the insulin receptor substrates 1 and 2 (IRS-1 and IRS-2), leading to activation of the phosphatidylinositol 3-kinase and the acute insulin-like effects in primary rat adipocytes. To investigate the functional role of this kinase, we screened a number of tyrosine kinase inhibitors for their ability to inhibit three rapid effects of GH on primary adipocytes: increased lipogenesis, inhibition of noradrenaline-induced lipolysis, and promotion of JAK2 tyrosine phosphorylation. Only staurosporine was found to inhibit all three effects. The inhibition of lipogenesis and antilipolysis exhibited the same staurosporine dose dependency (IC50, approximately 40 nM) as inhibition of JAK2 and IRS-1 tyrosine phosphorylation as well as binding of the p85 subunit of phosphatidylinositol 3-kinase to IRS-1 and IRS-2. The unidentified cytosolic tyrosine-phosphorylated protein pp95, in contrast, was not affected, suggesting that it is not phosphorylated primarily by JAK2. Protein kinase C does not seem to be directly involved in the insulin-like effects, because the selective protein kinase C inhibitor calphostin C had no effect at levels up to 100 nM above which unspecific cellular effects occurred. Methyl-2,5-dihydroxy cinnamate inhibited GH-induced lipogenesis from [3-3H]glucose and nonstimulated lipogenesis from [2-14C]-pyruvate and [3H]acetate, but was without effect on GH-induced 2-deoxy-D-[1-3H]glucose uptake, JAK2 phosphorylation and antilipolysis, suggesting unspecific effects on mitochondrial metabolism rather than a direct effect on the GH-mediated signal. Tyrphostin 25 and herbimycin A had no effect on any of the parameters studied, except for a slight increase in JAK2 phosphorylation in response to tyrphostin 25. In summary, these data support the role for JAK2 in mediating the insulin-like effects of GH in adipocytes.

Tyrosine phosphorylation of the growth hormone (GH) receptor and Janus tyrosine kinase-2 is involved in the insulin-like actions of GH in primary rat adipocytes.

The nature of tyrosine phosphorylations induced by GH in relation to the insulin-like metabolic effects in primary rat adipocytes was investigated. Unlike other cells, e.g. 3T3-F442A fibroblast, in which GH is believed to initiate cell differentiation through activation of the Janus tyrosine kinase-2 (JAK2), the adipocytes are metabolically active and fully differentiated cells that do not proliferate. Thus, it cannot be assumed that the same molecular mechanisms relay the acute insulin-like effects of GH. In adipocytes responsive to these effects, we found that GH induced tyrosine phosphorylation of a 114-kilodalton membrane protein, identified as the GH receptor, and a 130-kilodalton cytosolic protein, identified as JAK2. In contrast, these phosphorylations were not seen in adipocytes refractory to these effects of GH. The GH concentration dependency (ED50,1-2 nM) of these phosphorylations coincided with the increase in lipogenesis and the decrease in noradrenaline-induced lipolysis caused by the hormone. In analogy with the effects of insulin, the onset of phosphorylation was rapid (t1/2, < 1 min) and preceded the metabolic responses. The observations that a small fraction of the receptor pool became tyrosine phosphorylated and that the level of phosphorylation induced by GH decreased at higher GH concentrations agree with the concept that GH-induced dimerization of the receptor is necessary for signal transduction. We conclude that tyrosine phosphorylation of JAK2 and the GH receptor seems to be involved in the signal transduction mechanism leading to the insulin-like effects of GH in adipocytes. Importantly, the signal pathways for GH and insulin clearly differ at the receptor level, but seem to converge at or before the level of insulin receptor substrate 1 or 2 phosphorylation that has been shown to occur in response to both of these hormones.

Exon-intron organization and chromosomal localization of the mouse monoglyceride lipase gene.

Monoglyceride lipase (MGL) functions together with hormone-sensitive lipase to hydrolyze intracellular triglyceride stores of adipocytes and other cells to fatty acids and glycerol. In addition, MGL presumably complements lipoprotein lipase in completing the hydrolysis of monoglycerides resulting from degradation of lipoprotein triglycerides. Cosmid clones containing the mouse MGL gene were isolated from a genomic library using the coding region of the mouse MGL cDNA as probe. Characterization of the clones obtained revealed that the mouse gene contains the coding sequence for MGL on seven exons, including a large terminal exon of approximately 2.6 kb containing the stop codon and the complete 3' untranslated region. Two different 5' leader sequences, diverging 21 bp upstream of the predicted translation initiation codon, were isolated from a mouse adipocyte cDNA library. Western blot analysis of different mouse tissues revealed protein size heterogeneities. The amino acid sequence derived from human MGL cDNA clones showed 84% identity with mouse MGL. The mouse MGL gene was mapped to chromosome 6 in a region with known homology to human chromosome 3q21.

Essential role of phosphatidylinositol 3-kinase in insulin-induced activation and phosphorylation of the cGMP-inhibited cAMP phosphodiesterase in rat adipocytes. Studies using the selective inhibitor wortmannin.

Incubation of rat adipocytes with wortmannin, a potent and selective phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor, completely blocked the antilipolytic action of insulin (IC50 = 100 nM), the insulin-induced activation and phosphorylation of cGMP-inhibited cAMP phosphodiesterase (cGI-PDE) as well as the activation of the insulin-stimulated cGI-PDE kinase (IC50 = 10-30 nM). No direct effects of the inhibitor on the insulin-stimulated cGI-PDE kinase, the cGI-PDE and the hormone-sensitive lipase were observed. These data suggest that activation of PI 3-kinase upstream of the insulin-stimulated cGI-PDE kinase in the antilipolytic insulin signalchain has an essential role for insulin-induced cGI-PDE activation/phosphorylation and anti-lipolysis.

Shoulder function in patients with unoperated anterior shoulder instability.

A functional analysis, including Rowe score and measurements of isokinetic peak torque and range of motion of the shoulder, and a subjective assessment were performed in 26 consecutive patients (23 males and 3 females) with unoperated anterior shoulder instability. Patients experienced the initial dislocation at an average age of 23 +/- 8 years and 58% occurred during sports activity. No patient had gone through any controlled rehabilitation program. In this study, an average of 7 years (range, 1 to 28) had passed since the initial dislocation. Fifty-nine percent of the patients complained of markedly reduced ability to perform in sports because of instability, impaired strength, decreased range of motion, and pain induced by activity. The majority (65%) of the patients reported instability only during physical activity. The average Rowe score was 68 +/- 14 on a scale of 100. In comparison with the healthy side, the injured shoulder had a significantly lower isokinetic peak torque during abduction and internal rotation, as well as a reduced range of motion in extension, abduction, and external rotation, but not in flexion. The severity of impairment (Rowe score, deficit in range of motion, and peak torque) was not related to the number of dislocations sustained or to the duration of instability.

Identification and some characteristics of the enzyme protein of the hormone-sensitive lipase from rat adipose tissue.

A tri-, di-, and monoacylglycerol-hydrolyzing enzyme from rat adipose tissue has been detergent-solubilized and separated from monoacylglycerol lipase (H. Tornqvist and P. Belfrage, 1976, J. Biol. Chem. 251, 813-819) and lipoprotein lipase by use of ion-exchange chromatography, broad and narrow pH range electrofocusing and gel chromatography. The final preparation contained several different proteins. One of these, with an apparent minimum molecular weight of 86,000 by SDS-gel electrophoresis, was identified as the enzyme protein of hormone-sensitive lipase: a) the enzyme activity was reproducibly stimulated 50-100% by incubation with cyclic AMP-dependent protein kinase, cyclic AMP and ATP-Mg2+; b) the relative intensity of the Mw 86,000 protein band, and only this, closely paralleled the enzyme activity during narrow pH range electrofocusing and during subsequent gel chromatography of the electrofocusing enzyme peak fraction; c) only the Mw 86,000 protein extensively incorporated 32p from [gamma-32P]ATP after incubation with protein kinase and cyclic AMP. The pI of the enzyme was 6.7, it had the same Stokes radius on Sephadex G 200 as IgG and was 50% inactivated by 10 micron HgCl2, 20 micron PCMB, 50 micron DFP, 10 mM NaF and non-ionic detergents above their critical micellar concentration.

Tibia nonunions treated by interlocked nailing: increased risk of infection after previous external fixation.

Eighteen patients, mean age 36 years (range of 22-76 years), with tibia-shaft nonunions were treated with interlocked nailing. There were 12 nonunions originally treated with either cast, lag screws, plate, or Ender nails (nine closed, two open grade I and one grade II injury). The remaining six nonunions, all open fractures (five grade II and one grade III injury) initially received external fixation. After removal of the fixator, 72 days postinjury (range of 58-111 days), there was a delay of 218 days (range of 112-449 days) before the nailing procedure in those patients primarily treated with external fixation. All 12 nonunions not primarily treated with external fixation healed without complications after nailing within 17 weeks (range of 12-24 weeks). All six nonunions primarily treated with external fixation had temporary pin-tract infections, which healed after pin extraction. Two of the nonunions healed without any complication, whereas four developed intramedullary infection with the same bacteria as from the pin-tract site. Although the number of patients is small in this report, there is an apparently high incidence of intramedullary infection in the group originally treated with external fixation. The sequential procedure of external fixation followed by intramedullary nailing is, therefore, not recommended in the treatment of open tibia fractures.

Telemedicine in Sweden--a diffusion study.

A survey of telemedicine use in Sweden was carried out. The response rate by hospital management was high at almost 90%. Sixty per cent of hospitals were involved in some kind of telemedicine activity in Sweden, with a further 15% planning telemedicine implementation. In rural areas of north Sweden good links exist between primary and secondary care. In the more populated southern region good links exist between the county hospitals and specialist university hospitals. Fifty-four per cent of telemedicine applications were used for specialist consultations, 13% for consultation between paramedics and hospitals and 10% for rounds. Teleradiology was the most frequent service.

The potential of telemedicine: barriers, incentives and possibilities in the implementation phase.

Between 1998 and 1999, the Swedish Institute for Health Services Development (Spri) evaluated three applications in which specialist competence was being accessed via telemedicine. The results indicated that these kinds of application can be cost-effective in an organization well adapted to new technology and that telemedicine can improve continuity of care for patients. However, the new technology was seldom supported by the old organization and better education and technical support are needed. In a study called 'Incentives and Implementation', the Federation of Swedish County Councils interviewed people in Swedish health-care with a lot of experience of telemedicine. The interviewees agreed that telemedicine was likely to affect the whole structure of health-care. Peripheral competence was expected to increase and referral patterns to change, as well as the functions of the personnel and the hospitals. New working conditions and methods of work were expected to be made possible by telemedicine and health-care was expected to become more process oriented, partly because patients are likely to be more demanding and better informed. To be able to utilize this potential, health-care managers will have to show more interest in and commitment to telemedicine. Old organizational patterns must be called into question and be developed along with information technology and telemedicine. It is also important to give priority to training in telemedicine for physicians and nurses.

The operative treatment of fractures of the distal radius is increasing: results from a nationwide Swedish study.

The aim of this study was to investigate the epidemiology of fractures of the distal radius in the Swedish population and to review the methods used to treat them between 2005 and 2010. The study population consisted of every patient in Sweden who was diagnosed with a fracture of the wrist between 1 January 2005 and 31 December 2010. There were 177 893 fractures of the distal radius. The incidence rate in the total population was 32 per 10 000 person-years. The mean age of the patients was 44 years (0 to 104). The proportion of fractures treated operatively increased from 16% in 2005 to 20% in 2010. The incidence rate for plate fixation in the adult population increased 3.61 fold. The incidence rate for external fixation decreased by 67%. The change was greatest in the 50 years to 74 years age group. In Sweden, there is an increasing tendency to operate on fractures of the distal radius. The previously reported increase in the use of plating is confirmed: it has increased more than threefold over a five-year period.