A high-density and high-confinement tokamak plasma regime for fusion energy.

The tokamak approach, utilizing a toroidal magnetic field configuration to confine a hot plasma, is one of the most promising designs for developing reactors that can exploit nuclear fusion to generate electrical energy1,2. To reach the goal of an economical reactor, most tokamak reactor designs3-10 simultaneously require reaching a plasma line-averaged density above an empirical limit-the so-called Greenwald density11-and attaining an energy confinement quality better than the standard high-confinement mode12,13. However, such an operating regime has never been verified in experiments. In addition, a long-standing challenge in the high-confinement mode has been the compatibility between a high-performance core and avoiding large, transient edge perturbations that can cause very high heat loads on the plasma-facing-components in tokamaks. Here we report the demonstration of stable tokamak plasmas with a line-averaged density approximately 20% above the Greenwald density and an energy confinement quality of approximately 50% better than the standard high-confinement mode, which was realized by taking advantage of the enhanced suppression of turbulent transport granted by high density-gradients in the high-poloidal-beta scenario14,15. Furthermore, our experimental results show an integration of very low edge transient perturbations with the high normalized density and confinement core. The operating regime we report supports some critical requirements in many fusion reactor designs all over the world and opens a potential avenue to an operating point for producing economically attractive fusion energy.

Observation of a multimode plasma response and its relationship to density pumpout and edge-localized mode suppression.

Density pumpout and edge-localized mode (ELM) suppression by applied n=2 magnetic fields in low-collisionality DIII-D plasmas are shown to be correlated with the magnitude of the plasma response driven on the high-field side (HFS) of the magnetic axis but not the low-field side (LFS) midplane. These distinct responses are a direct measurement of a multimodal magnetic plasma response, with each structure preferentially excited by a different n=2 applied spectrum and preferentially detected on the LFS or HFS. Ideal and resistive magneto-hydrodynamic (MHD) calculations find that the LFS measurement is primarily sensitive to the excitation of stable kink modes, while the HFS measurement is primarily sensitive to resonant currents (whether fully shielding or partially penetrated). The resonant currents are themselves strongly modified by kink excitation, with the optimal applied field pitch for pumpout and ELM suppression significantly differing from equilibrium field alignment.

Tokamak operation with safety factor q95 < 2 via control of MHD stability.

Magnetic feedback control of the resistive-wall mode has enabled the DIII-D tokamak to access stable operation at safety factor q(95) = 1.9 in divertor plasmas for 150 instability growth times. Magnetohydrodynamic stability sets a hard, disruptive limit on the minimum edge safety factor achievable in a tokamak, or on the maximum plasma current at a given toroidal magnetic field. In tokamaks with a divertor, the limit occurs at q(95) = 2, as confirmed in DIII-D. Since the energy confinement time scales linearly with current, this also bounds the performance of a fusion reactor. DIII-D has overcome this limit, opening a whole new high-current regime not accessible before. This result brings significant possible benefits in terms of fusion performance, but it also extends resistive-wall mode physics and its control to conditions never explored before. In present experiments, the q(95) < 2 operation is eventually halted by voltage limits reached in the feedback power supplies, not by intrinsic physics issues. Improvements to power supplies and to control algorithms have the potential to further extend this regime.

Abundance, distribution and habitat characteristics of winter skate Leucoraja ocellata in the southern Gulf of St Lawrence: a population on the brink of extirpation?

Abundance indices of southern Gulf Leucoraja ocellata residing in Northumberland Strait, Canada, declined from 2001 to 2005, but increased during 2006 to 2008. Catch rates in 2009 were the lowest in the time series. The size of the area occupied in Northumberland Strait varied with changes in the abundance indices. Leucoraja ocellata were primarily caught in the north-west half of the strait over sandy to gravelly seabed; a near total absence was documented from the eastern half despite suitable habitat and a previously established presence documented during research surveys conducted before 2000. In Northumberland Strait, L. ocellata occupied shallow (50% cumulative occurrence = 12 m) and warm (50% cumulative occurrence = 16·5° C) coastal waters and were not present in the cold (<1° C, >35 m) intermediate layer. Abundance and distribution data highlight the need for continuing studies to monitor the status of this population, which is classified as endangered by the IUCN and Committee on the Status of Endangered Wildlife in Canada.

Maturity, size at age and predator-prey relationships of winter skate Leucoraja ocellata in the southern Gulf of St Lawrence: potentially an undescribed endemic facing extirpation.

The goals of this study were to document the size and age structure, size at maturity, ovarian fecundity and diet of the endangered population of winter skate Leucoraja ocellata that resides in the southern Gulf of St Lawrence (SGSL). The maximum size observed for SGSL L. ocellata was 68 cm total length (LT ) but >99% of animals caught were <60 cm LT . Fifty per cent of male and female L. ocellata were fully mature at 40 and 42 cm LT , respectively, age c. 5 years. The oldest individual caught was age 11 years, but 98% of the 561 individuals examined were ≤age 8 years, indicating a short reproductive life span. Ovarian fecundity was low; no more than 29 ova >10 mm diameter were ever observed. At 40 cm LT , the diet changed from one dominated by shrimp Crangon septemspinosa and gammarid amphipods to one dominated by fishes (mainly sand lance Ammodytes spp. and rainbow smelt Osmerus mordax) and Atlantic rock crab Cancer irroratus. Sufficient differences were observed between SGSL L. ocellata and other populations in their size-at-maturity pattern and maximum size to propose the taxonomic re-evaluation of the population.

Evidence for the importance of trapped particle resonances for resistive wall mode stability in high beta tokamak plasmas.

Active measurements of the plasma stability in tokamak plasmas reveal the importance of kinetic resonances for resistive wall mode stability. The rotation dependence of the magnetic plasma response to externally applied quasistatic n=1 magnetic fields clearly shows the signatures of an interaction between the resistive wall mode and the precession and bounce motions of trapped thermal ions, as predicted by a perturbative model of plasma stability including kinetic effects. The identification of the stabilization mechanism is an essential step towards quantitative predictions for the prospects of "passive" resistive wall mode stabilization, i.e., without the use of an "active" feedback system, in fusion-alpha heated plasmas.

Presence of CD3+ and CD79a+ Lymphocytes in the Pituitary Gland of Dogs at Post-mortem Examination.

Hypophysitis has been reported occasionally in dogs, with most cases resembling primary lymphocytic hypophysitis in man. Although it is generally assumed that lymphocytes are not present normally in the canine pituitary gland, few studies have investigated this hypothesis. However, lymphocytes are recognized in the pituitary gland of people and horses without signs of pituitary disease. It is unknown to what degree lymphocyte infiltration of the pituitary gland might occur as an incidental finding in dogs. The aim of the present study was to investigate the presence and distribution of lymphocytes in the pituitary gland of dogs without clinical suspicion of pituitary disease. Twenty dogs were subjected to routine necropsy examination. Formalin-fixed and paraffin wax-embedded sections of pituitary were stained with haematoxylin and eosin (HE) or subjected to immunohistochemistry (IHC) using primary antibodies specific for the T-cell marker CD3 and the B-cell marker CD79a. The number of CD3+ and CD79a+ cells per area unit (CPA) was determined for different pituitary regions. Two dogs had extensive neoplastic lesions in the pituitary gland and were excluded from analysis. In the remaining 18 dogs, occasional scattered CD3+ cells were found in the pituitary gland. There was a significant difference in CD3+ CPA between pituitary regions (P = 0.001). The highest CD3+ CPA was found in the pars tuberalis (median 41.3 cells/mm2, interquartile range 20.9-50.5 cells/mm2). In six of the 18 dogs (33%), CD79a+ cells were detected in small number (median total cell number 0 cells/section, interquartile range 0-1.0 cells/section). This study shows that T cell, and fewer B cells, may be found in the pituitary gland of dogs without clinical suspicion of pituitary disease. Regional difference in T-cell density, with the highest CD3+ CPA in the pars tuberalis, may imply regional immunoregulatory functions in the canine pituitary gland.

Faecal calprotectin or lactoferrin can identify postoperative recurrence in Crohn's disease.

BACKGROUND: Identifying Crohn's disease recurrence in symptomatic patients after ileocaecal resection is difficult. The aim of this study was to evaluate faecal concentrations of granulocyte degradation products in this setting. METHODS: A postoperative cohort of 13 patients was followed prospectively for 1 year with regular faecal calprotectin (FC) and lactoferrin (FL) measurements. A second postoperative cohort (median 24 months after resection) of 104 patients provided a single stool sample. Faecal measurements were compared with symptom diaries, the Harvey Bradshaw Index, endoscopic examination, C-reactive protein and platelet measurement. RESULTS: In the uncomplicated course, both markers normalized within 2 months. Both FC and FL correlated significantly with Harvey Bradshaw Index (P < 0.001). Twenty-eight patients with severely clinically active disease had high mean(s.e.) levels of FC (661.1(119.1) microg/g) and FL (116.6(32.2) microg/g); and 43 with clinically inactive disease had low levels of FC (70.2(27.1) microg/g) and FL (5.9(2.4) microg/g). In patients with mild to moderately clinically active disease, FC and FL identified individuals with and without recurrent inflammatory disease. Faecal markers were more accurate at predicting clinical disease activity than C-reactive protein, platelet count or endoscopic appearance. CONCLUSION: FC and FL are non-invasive tests that can help to identify disease recurrence in symptomatic postoperative patients.

Cushing's disease in dogs and humans.

BACKGROUND: Cushing's disease (CD) is a common endocrinological disorder in dogs with an estimated incidence of 1 to 2 cases/1,000 dogs/year. This is in contrast to humans in whom CD is rare. The clinical presentation of CD, however, is highly similar between dogs and humans, with characteristic signs, such as abdominal obesity, weight gain, fatigue, muscle atrophy and skin changes. Canine CD may therefore serve as an animal model for human CD, especially since therapeutic canine hypophysectomy can generate substantial amounts of primary corticotroph adenoma tissue for in vitro research purposes. In a recent study, we found that dopamine (DA) D(2) and somatostatin (SS) receptor subtypes are well expressed in canine corticotroph adenomas, but there are some distinct differences compared with the expression profile observed in human CD. These differences need to be considered when using canine CD as a model to evaluate the efficacy of novel DA/SS compounds for potential use in human CD. CASE REPORT: This case involves an 8-year-old female dog that developed signs of exercise intolerance, muscle weakness and polyuria/polydipsia due to an adrenocorticotropic hormone-secreting pituitary adenoma. The dog underwent curative transsphenoidal hypophysectomy and has remained in complete remission in the 3.5 years since surgery.

Expression and functional analysis of dopamine receptor subtype 2 and somatostatin receptor subtypes in canine cushing's disease.

Cushing's disease (CD) is a severe disorder characterized by chronic hypercortisolism due to an ACTH-secreting pituitary adenoma. Transsphenoidal adenomectomy is the treatment of choice in humans with CD, but recurrences occur frequently. Finding an effective and safe medical treatment for CD may improve long-term clinical outcome. The recent demonstration of expression of somatostatin receptor subtypes (mainly sst5) and dopamine receptor subtype 2 (D2) in human corticotroph adenomas offers the possibility for medical treatment of CD with novel somatostatin analogs and dopamine agonists. Investigation of the effects of these drugs is hampered by the low incidence of CD in humans. Interestingly, CD is a frequent disorder in dogs with striking clinical similarities with CD in humans. Therefore, we investigated the expression and functional role of D2 and somatostatin receptors in corticotroph adenoma cells from 13 dogs with active CD that underwent therapeutic hypophysectomy and normal anterior pituitary cells from five dogs. Quantitative RT-PCR and immunohistochemistry revealed that both in CD and normal anterior pituitary, sst2 was the predominant receptor subtype expressed, whereas D2 was modestly expressed and sst5 was expressed only at very low levels. In primary cultures of canine adenomas (n = 7), the sst2-preferring agonist octreotide also showed the strongest ACTH-suppressive effects. In conclusion, canine corticotroph adenomas provide an interesting model to study CD, but differences in somatostatin and dopamine receptor expression between humans and dogs should be taken into account when using dogs with CD as a model to evaluate efficacy of novel somatostatin analogs and dopamine agonists for human CD.

Expression and mutation analysis of Tpit in the canine pituitary gland and corticotroph adenomas.

Pituitary-dependent hyperadrenocorticism (PDH) in dogs is caused by a pituitary corticotroph adenoma. Although PDH is a common disorder in dogs, little is known about the underlying pathogenesis. In the pituitary glands of humans and mice, the pro-opiomelanocortin (POMC)-expressing cell lineages, the corticotrophs and melanotrophs, have a specific marker in common, the T-box transcription factor Tpit (Tbx19), which is obligate for POMC expression. Tpit also regulates the late differentiation of the corticotrophs and melanotrophs, and therefore may contribute to the pathogenesis of the corticotroph adenomas. The aim of this study was to perform an expression and mutation analysis of Tpit in the normal canine pituitary and in corticotroph adenomas. The distribution of the Tpit protein in the pituitary gland was studied with immunohistochemistry and the expression of the gene with RT-PCR. The coding region of Tpit cDNA from 14 dogs with PDH was screened for mutations. Tpit was expressed in corticotroph and melanotroph cells of the normal and adenomatous canine pituitary, and remained present in non-adenomatous corticotrophs of pituitaries from PDH dogs. No tumor-specific mutation in the Tpit cDNA from the corticotroph adenomas was found. However, a missense polymorphism in the highly conserved DNA-binding domain, the T-box, was discovered in one dog. It is concluded that Tpit can be used as a reliable marker for the corticotroph and melanotroph cells in the canine pituitary tissue and that mutations in the Tpit gene are unlikely to play a major role in the pathogenesis of canine corticotroph adenomas.

Plasma profiles of adrenocorticotropic hormone, cortisol, alpha-melanocyte-stimulating hormone, and growth hormone in dogs with pituitary-dependent hyperadrenocorticism before and after hypophysectomy.

The 6-h plasma profiles of adrenocorticotropic hormone (ACTH), cortisol, alpha-melanocyte-stimulating hormone (alpha-MSH), and GH were studied in 17 dogs with pituitary-dependent hyperadrenocorticism (PDH) before and after hypophysectomy. The aim of the study was to investigate the relation between the hormone profile characteristics and recurrence of PDH after surgery. The hormones were secreted in a pulsatile fashion. The basal plasma cortisol concentration and area under the curve (AUC) for cortisol were significantly higher in the PDH cases than in eight controls. The characteristics of the plasma profiles of ACTH and alpha-MSH were not significantly different between the PDH cases and the controls. In the PDH cases, less GH was secreted in pulses than in the controls, but the difference was not significant. The basal plasma cortisol concentration, the AUC for ACTH and cortisol, and the pulse frequency of ACTH and cortisol decreased significantly after hypophysectomy for the group of PDH cases. The basal plasma concentrations of ACTH and alpha-MSH, the AUC for alpha-MSH, and the characteristics of the plasma GH profiles of the PDH cases remained unchanged after hypophysectomy. No pulses of alpha-MSH were observed after hypophysectomy. The co-occurrence between the ACTH and cortisol pulses decreased significantly with hypophysectomy. The postoperative pulse frequency of ACTH was the only characteristic with predictive value for the recurrence of PDH after hypophysectomy. The results of this study demonstrate that ACTH, cortisol, alpha-MSH, and GH are secreted in a pulsatile fashion in dogs with PDH. Hypophysectomy effectively reduces the secretion of ACTH and cortisol. The presence of ACTH pulses after hypophysectomy is a risk factor for the recurrence of hyperadrenocorticism.

The leukemia inhibitory factor receptor gene is not involved in the etiology of pituitary dwarfism in German shepherd dogs.

Pituitary dwarfism in German shepherd dogs is characterized by combined pituitary hormone deficiency (CPHD) and intrapituitary cyst formation. Activation of the leukemia inhibitory factor (LIF)-LIF receptor (LIFR) signal transduction pathway results in a similar phenotype in (transgenic) mice. We therefore assessed the role of the LIFR in the etiology of pituitary dwarfism in German shepherd dogs. A polymorphic microsatellite marker (UULIFR) was used to analyze the segregation of the LIFR gene in 22 German shepherd dogs from 4 pedigrees, each including one dwarf. There was no allelic association between UULIFR and the dwarfism phenotype. Based on our findings LIFR was excluded as a candidate gene for CPHD.

Naturally Occurring Adrenocortical Insufficiency--An Epidemiological Study Based on a Swedish-Insured Dog Population of 525,028 Dogs.

BACKGROUND: Naturally occurring adrenocortical insufficiency (NOAI) in dogs is considered an uncommon disease with good prognosis with hormonal replacement treatment. However, there are no epidemiological studies with estimates for the general dog population. OBJECTIVES: To investigate the epidemiological characteristics of NOAI in a large population of insured dogs. ANIMALS: Data were derived from 525,028 client-owned dogs insured by a Swedish insurance company representing 2,364,652 dog-years at risk (DYAR) during the period between 1995-2006. METHODS: Retrospective cohort study. Incidence rates, prevalences, and relative risks for dogs with NOAI (AI with no previous claim for hypercortisolism), were calculated for the whole dog population, and for subgroups divided by breed and sex. Mortality rates were calculated and compared in dogs with NOAI and the remaining dogs overall. RESULTS: In total 534 dogs were identified with NOAI. The overall incidence was 2.3 cases per 10,000 DYAR. The relative risk of disease was significantly higher in the Portuguese Water Dog, Standard Poodle, Bearded Collie, Cairn Terrier, and Cocker Spaniel compared with other breeds combined. Female dogs overall were at higher risk of developing AI than male dogs (RR 1.85; 95% CI, 1.55-2.22; P < .001). The relative risk of death was 1.9 times higher in dogs with NOAI than in dogs overall. CONCLUSION AND CLINICAL IMPORTANCE: The data supports the existence of breed-specific differences in incidence rates of NOAI in dogs.

Spatial and temporal analysis of DIII-D 3D magnetic diagnostic data.

An extensive set of magnetic diagnostics in DIII-D is aimed at measuring non-axisymmetric "3D" features of tokamak plasmas, with typical amplitudes ∼10-3 to 10-5 of the total magnetic field. We describe hardware and software techniques used at DIII-D to condition the individual signals and analysis to estimate the spatial structure from an ensemble of discrete measurements. Applications of the analysis include detection of non-rotating MHD instabilities, plasma control, and validation of MHD stability and 3D equilibrium models.

The prognostic value of perioperative profiles of ACTH and cortisol for recurrence after transsphenoidal hypophysectomy in dogs with corticotroph adenomas.

BACKGROUND: Transsphenoidal hypophysectomy is an effective treatment for dogs with pituitary-dependent hypercortisolism (PDH). However, long-term recurrence of hypercortisolism is a well-recognized problem, indicating the need for reliable prognostic indicators. OBJECTIVES: The aim of this study was to evaluate the prognostic value of perioperative plasma ACTH and cortisol concentrations for identifying recurrence of hypercortisolism after transsphenoidal hypophysectomy. ANIMALS: A total of 112 dogs with PDH that underwent transsphenoidal hypophysectomy met the inclusion criteria of the study. METHODS: Hormone concentrations were measured preoperatively and 1-5 hours after surgery. Both absolute hormone concentrations and postoperative concentrations normalized to preoperative concentrations were included in analyses. The prognostic value of hormone concentrations was studied with Cox's proportional hazard analysis. RESULTS: Median follow-up and disease-free period were 1096 days and 896 days, respectively. Twenty-eight percent of patients had recurrence, with a median disease-free period of 588 days. Both absolute and normalized postoperative cortisol concentrations were significantly higher in dogs with recurrence than in dogs without recurrence. High ACTH 5 hours after surgery, high cortisol 1 and 4 hours after surgery, high normalized ACTH 3 hours after surgery, high normalized cortisol 4 hours after surgery and the random slope of cortisol were associated with a shorter disease-free period. CONCLUSIONS AND CLINICAL IMPORTANCE: Individual perioperative hormone curves provide valuable information about the risk of recurrence after hypophysectomy. However, because no single cutoff point could be identified, combination with other variables, such as the pituitary height/brain area (P/B) ratio, is still needed to obtain a good estimate of the risk for recurrence of hypercortisolism after hypophysectomy.

Mononuclear leukocyte cyclic adenosine monophosphate responses in psoriasis are normal.

It has been proposed that immune dysfunction in psoriasis is a consequence of aberrant cyclic nucleotide metabolism. We have examined cyclic AMP responses to isoprenaline, histamine, and prostaglandin E2 in peripheral blood mononuclear leukocytes from patients with psoriasis, in the presence and absence of a potent cyclic AMP phosphodiesterase inhibitor. Stimulated and basal cyclic AMP levels in mononuclear leukocytes from psoriatics did not differ from those observed in mononuclear leukocytes from normal subjects, irrespective of the stimulant employed, either in the presence or in the absence of the phosphodiesterase inhibitor. These findings do not support the hypothesis that psoriasis is associated with either impaired beta-adrenergic reactivity or a more generalized abnormality of mononuclear leukocyte cyclic nucleotide metabolism.

Cerebral vasocapacitance and TIAs.

We report the vasocapacitance of the cerebral circulation, as determined by cerebral blood flow reactivity to induced hypercapnia using fluoromethane positron emission tomography, in 32 patients with unilateral anterior circulation transient ischemic attacks. A hemodynamic subset of eight patients, defined based on exertional, positional, orthostatic, or cardiac dysrhythmic induction of symptomatology, is characterized by multiple (median, 4.5 attacks per patient), brief (median, 2.5 minutes per attack), continued episodes of hemispheric ischemia including focal limb shaking. Symptomatic middle cerebral artery flow territories show significantly lower (p less than 0.04) and more asymmetric (p = 0.036) vasodilatory responses in the hemodynamic subset. Although ipsilateral internal carotid artery occlusion is more prevalent in the hemodynamic subset, the features of age, mean arterial blood pressure, carbon dioxide values, serum glucose, serum hematocrit, and number or type of risk factors do not differ significantly between groups. These studies of vasocapacitance help validate clinical criteria for cerebral hemodynamic events with an objective physiologic measurement.

Early changes in tumor metabolism after treatment: the effects of stereotactic radiotherapy.

Four patients with intracranial neoplasms, two with malignant gliomas and two with brain metastases, were treated with stereotactic radiotherapy. Patients received between 15 and 27.5 Gray of photon irradiation to the central tumor target point; the 80% isodose line covered the periphery of the tumor as determined by contrast enhanced computed tomography. Patients underwent a sequence of three Positron Emission Tomographic scans using [18F]-fluorodeoxyglucose (PET-FDG)--a baseline scan the day before treatment, and follow-up scans 1 and 7 days after treatment. Ratios between the maximal tumor regional cerebral metabolic rate for glucose (rCMRGlu) (T*) and the contralateral remote white matter rCMRGlu (RW), that is, the glucose uptake ratio (T*/RW), were calculated. The percent change in ratios relative to each patient's baseline scan were calculated. Ratios increased 25% to 42% 1 day post-radiotherapy, then decreased to between 10% above and 12% below the baseline value 7 days post-radiotherapy. The T*/RW increased acutely after stereotactic radiotherapy in a fashion similar to that previously described following chemotherapy with a complex multi-drug regimen. A common metabolic pathway may underlie the increase in T*/RW after these different treatments.