A sustained high-temperature fusion plasma regime facilitated by fast ions.

Nuclear fusion is one of the most attractive alternatives to carbon-dependent energy sources1. Harnessing energy from nuclear fusion in a large reactor scale, however, still presents many scientific challenges despite the many years of research and steady advances in magnetic confinement approaches. State-of-the-art magnetic fusion devices cannot yet achieve a sustainable fusion performance, which requires a high temperature above 100 million kelvin and sufficient control of instabilities to ensure steady-state operation on the order of tens of seconds2,3. Here we report experiments at the Korea Superconducting Tokamak Advanced Research4 device producing a plasma fusion regime that satisfies most of the above requirements: thanks to abundant fast ions stabilizing the core plasma turbulence, we generate plasmas at a temperature of 100 million kelvin lasting up to 20 seconds without plasma edge instabilities or impurity accumulation. A low plasma density combined with a moderate input power for operation is key to establishing this regime by preserving a high fraction of fast ions. This regime is rarely subject to disruption and can be sustained reliably even without a sophisticated control, and thus represents a promising path towards commercial fusion reactors.

Intrinsic rotation driven by non-Maxwellian equilibria in Tokamak plasmas.

The effect of small deviations from a Maxwellian equilibrium on turbulent momentum transport in tokamak plasmas is considered. These non-Maxwellian features, arising from diamagnetic effects, introduce a strong dependence of the radial flux of cocurrent toroidal angular momentum on collisionality: As the plasma goes from nearly collisionless to weakly collisional, the flux reverses direction from radially inward to outward. This indicates a collisionality-dependent transition from peaked to hollow rotation profiles, consistent with experimental observations of intrinsic rotation.

Therapeutic effects of stem cells and substrate reduction in juvenile Sandhoff mice.

Sandhoff Disease (SD) involves the CNS accumulation of ganglioside GM2 and asialo-GM2 (GA2) due to inherited defects in the ß-subunit gene of ß-hexosaminidase A and B (Hexb gene). Substrate reduction therapy, utilizing imino sugar N-butyldeoxygalactonojirimycin (NB-DGJ), reduces ganglioside biosynthesis and levels of stored GM2 in SD mice. Intracranial transplantation of Neural Stem Cells (NSCs) can provide enzymatic cross correction, to help reduce ganglioside storage and extend life. Here we tested the effect of NSCs and NB-DGJ, alone and together, on brain ß-hexosaminidase activity, GM2, and GA2 content in juvenile SD mice. The SD mice received either cerebral NSC transplantation at post-natal day 0 (p-0), intraperitoneal injection of NB-DGJ (500 mg/kg/day) from p-9 to p-15, or received dual treatments. The brains were analyzed at p-15. ß-galactosidase staining confirmed engraftment of lacZ-expressing NSCs in the cerebral cortex. Compared to untreated and sham-treated SD controls, NSC treatment alone provided a slight increase in Hex activity and significantly decreased GA2 content. However, NSCs had no effect on GM2 content when analyzed at p-15. NB-DGJ alone had no effect on Hex activity, but significantly reduced GM2 and GA2 content. Hex activity was slightly elevated in the NSC + drug-treated mice. GM2 and GA2 content in the dual treated mice were similar to that of the NB-DGJ treated mice. These data indicate that NB-DGJ alone was more effective in targeting storage in juvenile SD mice than were NSCs alone. No additive or synergistic effect between NSC and drug was found in these juvenile SD mice.

Metformin can activate imidazoline I-2 receptors to lower plasma glucose in type 1-like diabetic rats.

Metformin is widely used in clinic for handling the diabetic disorders. However, action mechanisms of metformin remain obscure. It has recently been indicated that guanidinium derivatives are ligands to activate type-2 imidazoline receptors (I-2 receptors) that can improve diabetes through increment in skeletal muscle glucose uptake. Also, activation of I-2 receptors can increase the release of ß-endorphin in diabetic animals. Because metformin is a guanidinium derivative, we were interested in the effect of metformin on I-2 receptors. In the present study, the marked blood glucose-lowering action of metformin in streptozotocin-induced type-1 like diabetes rats was blocked by specific I-2 receptor antagonist, BU224, in a dose-dependent manner. Also, the increase of ß-endorphin release by metformin was blocked by BU224 in same manner. A specific competition between metformin and BU224 was observed in isolated adrenal medulla. Otherwise, amiloride at the dose sufficient to block I-2A receptor abolished the metformin-induced ß-endorphin release, but only the blood glucose-lowering action of metformin was markedly reduced. In addition, the blood glucose-lowering action of metformin in bilateral adrenalectomized rats was diminished by amiloride at higher doses. These results suggest that metformin might activate imidazoline I-2 receptors while I-2A receptors link the increase of ß-endorphin release and I-2B receptors couple to the other actions for lowering of blood glucose in type-1 like diabetic rats.

Inhibition of insulin degrading enzyme by racecadotril in the brain of Wistar rats.

Racecadotril is an enkephalinase inhibitor used to treat abdominal discomfort in the clinic. The blood-glucose lowering action of racecadotril has been observed in rats; however, the mechanisms remain obscure. 8-week-old Wistar rats were intravenously injected with racecadotril and the levels of insulin in the brain were measured. Additionally, brain homogenates were co-incubated with racecadotril or thiorphan to evaluate insulin degrading enzyme (IDE) activity. Otherwise, rats were pretreated by intracerebroventricular (i. c. v.) injection of insulin antibody or glibenclamide at a dose sufficient to inhibit K (ATP) channels prior to injection of racecadotril. Moreover, rats were vagotomized to evaluate the role of the cholinergic nerve. Racecadotril significantly decreased the plasma glucose in rats; this action of racecadotril was abolished by i. c. v. pretreatment with insulin antibody or glibenclamide. Also, i. c. v. injection of thiorphan, the active form of racecadotril, lowered blood glucose, but this effect disappeared in the presence of the insulin antibody. In rat brain homogenates, racecadotril and thiorphan inhibited IDE activity and increased the cerebral insulin level. The blood-glucose lowering action of racecadotril or thiorphan was diminished in vagotomized rats. Our results suggest that racecadotril lowers blood glucose mainly through inhibition of IDE activity and increases endogenous insulin in the brain. Subsequently, the increased insulin might activate insulin receptor, which opens the K (ATP) channel and induces peripheral insulin release through the vagal nerve. Thus, we provide the new finding that racecadotril has the ability to inhibit IDE in rat brain.

Regulation of pancreatic beta-cell growth and survival by the serine/threonine protein kinase Akt1/PKBalpha.

The physiological performance of an organ depends on an interplay between changes in cellular function and organ size, determined by cell growth, proliferation and death. Nowhere is this more evident than in the endocrine pancreas, where disturbances in function or mass result in severe disease. Recently, the insulin signal-transduction pathway has been implicated in both the regulation of hormone secretion from beta cells in mammals as well as the determination of cell and organ size in Drosophila melanogaster. A prominent mediator of the actions of insulin and insulin-like growth factor 1 (IGF-1) is the 3'-phosphoinositide-dependent protein kinase Akt, also known as protein kinase B (PKB). Here we report that overexpression of active Akt1 in the mouse beta cell substantially affects compartment size and function. There was a significant increase in both beta-cell size and total islet mass, accompanied by improved glucose tolerance and complete resistance to experimental diabetes.

Successfully treated multicentric Castleman's disease with renal thrombotic microangiopathy using rituximab and corticosteroid.

Thrombotic microangiopathy (TMA) is a rare renal complication accompanied with Castleman's disease. We report the first case of TMA combined plasma cell type multicentric Castleman's disease (MCD) which was successfully treated with rituximab and corticosteroid. A previously healthy 60-year-old Korean man was admitted due to acute renal failure, thrombocytopenia, and multiple lymphadenopathies. The result of lymph node biopsy was plasma cell type Castleman's disease and TMA was revealed by kidney biopsy. After treatment with rituximab, prednisolone and temporary hemodialysis, complete remission was achieved. The combination of corticosteroid and rituximab was associated with improvement for this patient.

Evaluation of methods to estimate glomerular filtration rate versus actual drug clearance in patients with chronic spinal cord injury.

STUDY DESIGN: A retrospective chart review. OBJECTIVES: To evaluate different methods of estimating renal function compared with patient-specific vancomycin and aminoglycoside (AG) clearance (CL(DRUG)) in patients with spinal cord injury (SCI), and to develop a new equation to more accurately estimate glomerular filtration rate (GFR) in SCI patients in order to optimize dosing for vancomycin and AG. SETTING: Veterans Affairs medical center in California, United States of America, tertiary care facility with the largest inpatient SCI center in the VA system. METHODS: Retrospective data collection from patient records. Pharmacokinetic analysis was performed to obtain actual CL(DRUG,) which is compared with different methods of estimating GFR.A total of 310 patients were initially assessed; however, only 141 patients met the inclusion criteria, had a diagnosis of chronic SCI, and received vancomycin or AG with at least one drug level at steady state from January to December of 2008. RESULTS: All four equations evaluated to estimate GFR significantly overestimated CL(DRUG): the Modification of Diet in Renal Disease equation by 141%, Cockcroft-Gault equation by 83%, Chronic Kidney Disease Epidemiology Collaboration equation by 82% and 24-h endogenous creatinine clearance by 71% (P<0.001). The modified Cockcroft-Gault equation (CL(M)) showed improvement, however, still overestimated CL(DRUG) by 39% (P<0.001). Thus, a new equation for SCI (CL(SCI)) was developed which underestimated CL(DRUG) by <5% (P=0.16). CONCLUSION: Compared with different methods of estimating GFR, CL(SCI)=2.3 × x (0.7) (x equals CL(M) in ml min(-1)) more accurately estimates CL(DRUG) in chronic SCI patients.

'Smoking': use of cigarettes, cigars and blunts among Southeast Asian American youth and young adults.

Increased use of cigars has been noted among youth, as well as use of blunts (hollowed-out cigars filled with marijuana). Three types of relationships have been previously hypothesized between use of tobacco and marijuana in substance use progression. We aimed to assess these relationships for Southeast Asian American youth and adults in an urban population. We conducted in-person interviews with 164 Southeast Asians, smokers and non-smokers, in two low-income urban communities in Northern California, collecting both quantitative and qualitative data. Analysis of the quantitative data indicated distinct use patterns for blunts, cigars and other forms of marijuana in terms of associations with generation in the United States. The use of these items was also found to be related: ever having smoked cigarettes or blunts increased the risk of ever having smoked the other three items. Qualitative data found indications of all three hypothesized relationships between tobacco and marijuana for youths but not for older adults. For youths in the study, 'smoking' was found to constitute a social construct within which use of cigarettes, cigars and blunts were somewhat interchangeable. Youths in similar settings may initiate into and progress through smoking as an activity domain rather than any one of these items.

Functional role of caspase-1 and caspase-3 in an ALS transgenic mouse model.

Mutations in the copper/zinc superoxide dismutase (SOD1) gene produce an animal model of familial amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. To test a new therapeutic strategy for ALS, we examined the effect of caspase inhibition in transgenic mice expressing mutant human SOD1 with a substitution of glycine to alanine in position 93 (mSOD1(G93A)). Intracerebroventricular administration of zVAD-fmk, a broad caspase inhibitor, delays disease onset and mortality. Moreover, zVAD-fmk inhibits caspase-1 activity as well as caspase-1 and caspase-3 mRNA up-regulation, providing evidence for a non-cell-autonomous pathway regulating caspase expression. Caspases play an instrumental role in neurodegeneration in transgenic mSOD1(G93A) mice, which suggests that caspase inhibition may have a protective role in ALS.

Fate of the micropenis and constitutional small penis: do they grow to normalcy in puberty?

INTRODUCTION: Penile length is an important indicator of male sexual development. Scarce data were reported on penile length measurements in children comparing changes between prepuberty and puberty for the small penile issue with long-term follow-up. OBJECTIVE: The purpose of this study was to investigate the possibility of catch-up growth of the penile length of boys with a small penis in the long-term follow-up. STUDY DESIGN: From April 2001 to December 2016, 27 boys who visited the outpatient clinic owing to a small penis, without any chromosomal anomalies and other genital disorder, were investigated retrospectively. Micropenis is defined as 2.5 standard deviations less than the mean stretched penile length (SPL) of age. Periodic penile length, testicular volume, hormonal levels (serum testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH)), and bone age were measured. Pubertal development was recorded by using the Tanner scale. The effect of hormonal therapy and the factors attributable to the increment of the penile length were evaluated. RESULTS: The mean age at the first visit was 9.8 years (5-12 years) and that at puberty was 12.6 years (10-16 years). The length of the penis at the initial visit was 4.0 ± 0.8 cm (2.5-6.0) and at puberty, 7.3 ± 1.8 cm (4.0-12.0). Nine patients diagnosed with micropenis no longer had a micropenis in puberty. The less the age-matched SPL, the more the increment of SPL that was observed (rho = - 0.548, P = 0.003). The mean increment of SPL in the hormonal therapy group (11 boys) and the non-hormonal therapy group (16 boys) was not statistically different (43.5 ± 22. 9% vs 41.5 ± 21.6%, respectively, P = 0.497). DISCUSSION: This study explains how much the growth of a small penis catches up in puberty. From the point of view of the increment of SPL, the increment was higher in boys who belonged to the smaller penis group. Hormonal therapy does not attribute to an increase in the length after long-term follow-up. Limitations of this study were its retrospective origin with a small number of patients in a single center. CONCLUSION: Catch-up growth of the small penis at puberty was accomplished in most children with a small penis before puberty. Hormonal treatment was not significantly correlated with the penile length increment in the long-term follow-up.

RING-dependent tumor suppression and G2/M arrest induced by the TRC8 hereditary kidney cancer gene.

TRC8/RNF139 and von Hippel-Lindau (VHL) both encode E3 ubiquitin (Ub) ligases mutated in clear-cell renal carcinomas (ccRCC). VHL, inactivated in nearly 70% of ccRCCs, is a tumor suppressor encoding the targeting subunit for a Ub ligase complex that downregulates hypoxia-inducible factor-alpha. TRC8/RNF139 is a putative tumor suppressor containing a sterol-sensing domain and a RING-H2 motif essential for Ub ligase activity. Here we report that human kidney cells are growth inhibited by TRC8. Inhibition is manifested by G2/M arrest, decreased DNA synthesis and increased apoptosis and is dependent upon the Ub ligase activity of the RING domain. Tumor formation in a nude mouse model is inhibited by TRC8 in a RING-dependent manner. Expression of TRC8 represses genes involved in cholesterol and fatty acid biosynthesis that are transcriptionally regulated by the sterol response element binding proteins (SREBPs). Expression of activated SREBP-1a partially restores the growth of TRC8-inhibited cells. These data suggest that TRC8 modulation of SREBP activity comprises a novel regulatory link between growth control and the cholesterol/lipid homeostasis pathway.

Comorbidities Can Predict Mortality of Kidney Transplant Recipients: Comparison With the Charlson Comorbidity Index.

BACKGROUND: Comorbid conditions are important in the survival of kidney transplant recipients. The weights assigned to comorbidities to predict survival may vary based on the type of index disease and advances in the management of comorbidities. We aimed to develop a modified Charlson comorbidity index (CCI) in renal allograft recipients (mCCI-KT), thereby improving risk stratification for mortality. METHODS: A total of 3765 recipients in a multicenter cohort were included to develop a comorbidity score. The weights of the comorbidities, per the CCI, were recalibrated using a Cox proportional hazards model. RESULTS: Peripheral vascular disease, liver disease, myocardial infarction, and diabetes in the CCI were selected from the Cox proportional hazards model. Thus, the mCCI-KT included 4 comorbidities with recalibrated severity weights. Whereas the CCI did not discriminate for survival, the mCCI-KT provided significant discrimination for survival using the Kaplan-Meier method and Cox regression analysis. The mCCI-KT showed modest increases in c-statistics (0.54 vs 0.52, P = .001) and improved net mortality risk reclassification by 16.3% (95% confidence interval, 3.2-29.4; P = .015) relative to the CCI. CONCLUSION: The mCCI-KT stratifies the risk for mortality in renal allograft recipients better than the CCI, suggesting that it may be a preferred index for use in clinical practice.

Residual symptomatic superior oblique palsy.

PURPOSE: To determine the outcome of patients treated for residual symptomatic hyperdeviations, in a tertiary referral centre, following a previous weakening procedure of the ipsilateral Inferior Oblique (IO) muscle in Superior Oblique (SO) palsy. METHODS: A retrospective review of 37 patients seen over 6 years at one institution who had remained symptomatic from a SO palsy despite having had an initial weakening procedure to their ipsilateral IO (myectomy or recession). Median age was 19 years (range 3 to 56 years). Information recorded included pre- and postoperative deviation and ocular motility findings, preoperative symptoms, findings at the time of surgery, and outcome. RESULTS: Nine patients underwent repeat weakening surgery (disinsertion) on the ipsilateral IO only. Thirteen patients underwent strengthening surgery on the ipsilateral SO only. Nine patients had surgery on both the ipsilateral IO and SO. Six patients had surgery on the ipsilateral IO with either horizontal or vertical rectus surgery. Nine (24%) patients remained symptomatic after their initial procedure and are regarded as initial failures. Four of these patients had masked bilateral IO weakness. Five patients required additional surgery. At final outcome, 84% were discharged with resolution of their symptoms. CONCLUSIONS: In the light of these findings we suggest an approach for the management of these patients. This should always include exploring a previously operated ipsilateral IO. Despite this, patients should be warned that they have a 1 in 4 chance of needing further surgery to achieve adequate ocular motility.

Baclofen for patients with congenital periodic alternating nystagmus.

PURPOSE: To describe the clinical effect of baclofen on a group of patients with congenital periodic alternating nystagmus. METHODS: A retrospective review of case notes was carried out of all patients with congenital periodic alternating nystagmus (PAN) treated with baclofen between 1999 and 2004. Eight patients were identified, 6 males and 2 females with a mean age of 21 years (range 9 to 34 years). Clinical data were recorded for all patients pre- and post-treatment with the GABA agonist baclofen. Adverse effects of the treatment were recorded and a questionnaire was constructed to evaluate patient satisfaction with the treatment. RESULTS: All 8 patients had an abnormal head posture (AHP) before treatment which improved following treatment in 4 patients, one of whom had recurrence following treatment withdrawal. Binocular Snellen visual acuity (VA) improved by one line in 4 cases, while none of the other 4 patients suffered any loss of vision from the treatment. Three of the eight patients have continued on treatment long-term, in one case for 6 years. In the other five, treatment was withdrawn due to side effects in 4 cases, and in the fifth due to a lack of effect. The most commonly reported side effect was drowsiness, which occurred in 3 patients. Using a patient-centered survey, complete responses were obtained from 6 of the 8 patients treated. Five patients were either pleased or very pleased that they had tried the treatment. The reasons given were: improved vision or head posture, an appreciation of slowing of ocular movements, improved cosmesis and improved confidence. CONCLUSIONS: Baclofen may be effective in a select group of patients with congenital PAN and a trial of treatment may be worthwhile, prior to considering surgical intervention in this condition.

A semiconductor photon-sorter.

Obtaining substantial nonlinear effects at the single-photon level is a considerable challenge that holds great potential for quantum optical measurements and information processing. Of the progress that has been made in recent years one of the most promising methods is to scatter coherent light from quantum emitters, imprinting quantum correlations onto the photons. We report effective interactions between photons, controlled by a single semiconductor quantum dot that is weakly coupled to a monolithic cavity. We show that the nonlinearity of a transition modifies the counting statistics of a Poissonian beam, sorting the photons in number. This is used to create strong correlations between detection events and to create polarization-correlated photons from an uncorrelated stream using a single spin. These results pave the way for semiconductor optical switches operated by single quanta of light.

Calpains play a role in insulin secretion and action.

Studies of the genetic basis of type 2 diabetes suggest that variation in the calpain-10 gene affects susceptibility to this common disorder, raising the possibility that calpain-sensitive pathways may play a role in regulating insulin secretion and/or action. Calpains are ubiquitously expressed cysteine proteases that are thought to regulate a variety of normal cellular functions. Here, we report that short-term (4-h) exposure to the cell-permeable calpain inhibitors calpain inhibitor II and E-64-d increases the insulin secretory response to glucose in mouse pancreatic islets. This dose-dependent effect is observed at glucose concentrations above 8 mmol/l. This effect was also seen with other calpain inhibitors with different mechanisms of action but not with cathepsin inhibitors or other protease inhibitors. Enhancement of insulin secretion with short-term exposure to calpain inhibitors is not mediated by increased responses in intracellular Ca2+ or increased glucose metabolism in islets but by accelerated exocytosis of insulin granules. In muscle strips and adipocytes, exposure to both calpain inhibitor II and E-64-d reduced insulin-mediated glucose transport. Incorporation of glucose into glycogen in muscle also was reduced. These results are consistent with a role for calpains in the regulation of insulin secretion and insulin action.

Aromatic-aromatic interactions in the zinc finger motif. Analysis of the two-dimensional nuclear magnetic resonance structure of a mutant domain.

The folding and stability of globular proteins are determined by a variety of chemical mechanisms, including hydrogen bonds, salt bridges and the hydrophobic effect. Of particular interest are weakly polar interactions involving aromatic rings, which are proposed to regulate the geometry of closely packed protein interiors. Such interactions reflect the electrostatic contribution of pi-electrons and, unlike van der Waals' interactions and the hydrophobic effect, may, in principle, introduce a directional force in a protein's hydrophobic core. Although the weakly polar hypothesis is supported by a statistical analysis of protein structures, the general importance of such contributions to protein folding and stability is unclear. Here, we show the presence of alternative aromatic-aromatic interactions in the two-dimensional nuclear magnetic resonance structure of a mutant Zn finger. Changes in aromatic packing lead in turn to local and non-local differences between the structures of a wild-type and mutant domain. The results provide insight into the evolution of Zn finger sequences and have implications for understanding how geometric relationships may be chemically encoded in a simple sequence template.

Hearing voices and seeing pictures.

I have been living with a psychiatric disorder, schizophrenia, for 2 decades. I will relate how important medication is to the treatment of this illness. I will also relate how important the assessment of the level of medication to be used is to recovery. Specifically, I will explain how I learned to manage hallucinations and delusions and also how I acquired an experience which I refer to as spiritual, mystical and psychic.