Paradoxical Reduction Research Articles

Torpedo Formation and Purkinje Cell Loss: Modeling their Relationship in Cerebellar Disease

Torpedo formation and Purkinje cell (PC) loss represent standard and inter-related cerebellar responses to injury. Surprisingly, the nature of their relationship has not been carefully characterized across a range of normal and disease states. Are brains with more torpedoes expected to have fewer PCs? We quantified torpedoes and PCs in four groups: essential tremor (ET), spinocerebellar ataxia (SCA), multiple system atrophy-cerebellar (MSA-C), and controls. Brains from 100 individuals (58 ET, 27 controls, 7 SCA, 8 MSA-C) were available at the New York Brain Bank. After complete neuropathological assessment, a standard parasagittal neocerebellar block was harvested; a 7-μm thick section was stained with Luxol fast blue/hematoxylin and eosin; and torpedoes and PCs were quantified. For a given PC count, SCA and MSA-C cases often had higher torpedo counts than ET cases or controls. Furthermore, the relationship between torpedo and PC counts was complex. The correlation between torpedo and PC counts was negative in ET cases (i.e., individuals with more torpedoes had fewer PCs [i.e., more PC loss]) whereas the relationship was positive in MSA-C cases (i.e., individuals with fewer PCs [i.e., more PC loss] had fewer torpedoes). Patients with SCA showed both patterns. When all diagnostic groups were combined, the correlation was best fit by a quadratic (i.e., parabolic) model rather than a simple linear model; this model incorporated data on the negative correlation in ET cases, the mixed results in SCA cases, and the positive correlation in MSA-C cases (r = 0.636). The relationship between torpedo and PC counts was complex and heterogeneous across a range of cerebellar disease states, and was best characterized by a quadratic rather than a simple model. With more severe cerebellar disease, torpedoes can be quite numerous and are likely a common feature of surviving PCs, but eventually, dramatic loss of PC leads to a paradoxical reduction in observable torpedoes.

Paradoxical reduction in HDL-C with fenofibrate and thiazolidinedione therapy in type 2 diabetes: the ACCORD Lipid Trial.

OBJECTIVETo determine the occurrence of extremely low HDL cholesterol (HDL-C) among participants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid Trial and to examine the relationship of this finding with treatment with fenofibrate and thiazolidinedione (TZD).RESEARCH DESIGN AND METHODSThe ACCORD Lipid Trial was a randomized, double-blind, placebo-controlled study conducted in patients with type 2 diabetes at 77 clinical centers across the U.S. and Canada in a 5,518-patient subset of the larger 10,251 ACCORD Glycemia Trial. Patients were enrolled from 11 January 2001 to 29 October 2005 and followed until the end of study visits between 1 March and 30 June 2009. Follow-up in the ACCORD Lipid Trial was 4–8 years (mean 4.7 years). Patients were treated with blinded fenofibrate or placebo on a background of simvastatin therapy. The main outcome measures for these descriptive, post hoc analyses was the occurrence of extremely low HDL-C (defined as <25 mg/dL [0.647 mmol/L]) during the trial.RESULTSAmong ACCORD Lipid Trial participants, the occurrence of extremely low HDL-C ever during study follow-up was 106% higher among those randomized to fenofibrate (10.1% fenofibrate vs. 4.9% placebo, P < 0.001). The occurrence of low HDL-C was associated with concurrent treatment with fenofibrate and TZD (7.0% for both vs. 2.2% for neither at 48 months postrandomization).CONCLUSIONSIdiosyncratic and marked reduction in HDL-C can occur in some patients treated with both fenofibrate and TZD. Practitioners should recognize this important potential idiosyncratic reaction and take appropriate corrective action.

Paradoxical Effect of Gonadotrophin‐Inhibiting Hormone to Negatively Regulate Neuropeptide Y Neurones in Mouse Arcuate Nucleus

Regulation of reproduction and energy homeostasis are linked, although our understanding of the central neural mechanisms subserving this connection is incomplete. Gonadotrophin-inhibiting hormone (GnIH) is a neuropeptide that negatively regulates reproduction and stimulates food intake. Neuropeptide Y (NPY) and products of the pro-opiomelanocortin (POMC) precursor (β-endorphin melanocortins) are appetite regulating peptides produced in the neurones of the arcuate nucleus; these peptides also regulate reproduction. In the present study, we determined the effects of GnIH on NPY and POMC neurones. Using brain slices from mice with transgenes for fluorescent tags in the two types of neurone and patch clamp electrophysiology, a predominant inhibitory effect of GnIH was observed. GnIH (100 nM) inhibited the firing rate in POMC cells, confirming the results of previous studies and consistent with the stimulatory effect of GnIH on food intake. Paradoxically (i.e. because both GnIH and NPY stimulate food intake), GnIH also had a predominantly inhibitory effect on action potential activity in NPY cells. GnIH also inhibited the secretion of NPY and α-melanocyte-stimulating hormone secretion in incubated hypothalamic blocks. GnIH (100 ng) injected into the cerebral ventricles of mice did not increase the number of NPY cells that were positively immunostained for c-Fos. Finally, dual label immunocytochemistry showed that 20% of NPY neurones had close contacts from GnIH fibres/varicosities. In conclusion, we confirm a negative effect of GnIH on POMC cells and demonstrate a paradoxical reduction of electrophysiological and functional activity in NPY cells.

Low-carbohydrate and high-fat intake can manage obesity and associated conditions: Occasional survey

This study analyses 127 communications from individuals self-reporting their weight change following adoption of a low-carbohydrate, high-fat (LCHF) eating plan. Total combined self-reported weight loss was 1 900 kg (range 5 kg gain to 84 kg loss). The mean ± standard deviation weight loss of 15 (±12) kg is among the largest yet described. Sixteen subjects reported the LCHF 'cured' (i.e. medications no longer required) one or more of their medical conditions, most commonly type 2 diabetes mellitus (T2DM) (n=14), hypertension (n=8) and hypercholesterolaemia (n=7). Another 9 subjects with either type 1 diabetes mellitus or T2DM reduced medications as did 7 patients with hypertension; 8 no longer suffered from irritable bowel syndrome. These data show that significant and rapid weight loss is possible on an unsupervised eating plan that severely restricts daily carbohydrate intake to approximately &lt;75 g/day. Better weight loss on a carbohydrate-restricted LCHF eating plan than on an iso-caloric high-carbohydrate, low-fat (HCLF) diet is well described in the literature, probably due to a paradoxical reduction of hunger by carbohydrate restriction. A randomised controlled clinical trial is urgently required to disprove the hypothesis that the LCHF eating plan can reverse cases of T2DM, metabolic syndrome and hypertension without pharmacotherapy.

Murine dendritic cell rapamycin-resistant and rictor-independent mTOR controls IL-10, B7-H1, and regulatory T-cell induction

AbstractMammalian target of rapamycin (mTOR) is an important, yet poorly understood integrative kinase that regulates immune cell function. mTOR functions in 2 independent complexes: mTOR complex (mTORC) 1 and 2. The immunosuppressant rapamycin (RAPA) inhibits mTORC1 but not mTORC2 and causes a paradoxical reduction in anti-inflammatory interleukin (IL) 10 and B7-homolog 1 (B7-H1) expression by dendritic cells (DCs). Using catalytic mTOR inhibitors and DCs lacking mTORC2, we show that restraint of signal transducer and activator of transcription 3–mediated IL-10 and B7-H1 expression during DC maturation involves a RAPA-insensitive and mTORC2-independent mTOR mechanism. Relatedly, catalytic mTOR inhibition promotes B7-H1–dependent and IL-1β–dependent DC induction of regulatory T cells (Tregs). Thus, we define an immunoregulatory pathway in which RAPA-sensitive mTORC1 in DCs promotes effector T-cell expansion and RAPA-insensitive mTORC1 restrains Treg induction. These findings identify the first known RAPA-insensitive mTOR pathway that is not mediated solely by mTORC2 and have implications for the use of catalytic mTOR inhibitors in inflammatory disease settings.

Abstract 444: The Liver-Specific Role of Sortilin in VLDL Secretion

Introduction Sortilin, the protein product of the SORT1 gene, is a multi-ligand sorting receptor involved in Golgi to lysosome trafficking that is expressed in multiple tissues. Genome-wide association studies have shown an association between elevated SORT1 expression in human liver and a reduction in low-density lipoprotein cholesterol (LDL-C) and in myocardial infarction (MI) risk. Our lab has previously shown liver specific sortilin overexpression in mice reduces LDL by facilitating LDL plasma clearance and by promoting the lysosomal degradation of very-low density lipoprotein (VLDL). Interestingly, we and others have also shown that total body Sort1 deficiency in mice is associated with a paradoxical reduction in VLDL secretion (48%, P = 0.004). One major difference is that the overexpression studies were hepatic specific whereas the loss-of-function studies were in total body knockout (KO) mice. Methods/Results We used liver-specific Sort1 conditional KO mice and reconstitution of hepatic Sort1 in total body KO mice to further probe the specific role of hepatic sortilin in VLDL secretion. Sort1 fl/fl mice were injected with a control adeno-associated virus (AAV) or an AAV expressing Cre recombinase driven by a liver specific promoter and in vivo VLDL secretion studies were performed. Liver-specific Sort1 deletion reduced VLDL secretion by 51% (P = 0.005). We also used AAV to test the hypothesis that sortilin serves as a chaperone to facilitate VLDL secretion. Sort1 reconstitution in total body Sort1 KO mice reduced VLDL secretion by 29% (P = 0.002). Interestingly, expression of a sortilin mutant that cannot traffic to the lysosome but does traffic to the plasma membrane increased VLDL secretion by 88% (P = 0.001). Conclusion These findings suggest that liver-specificity is not responsible for the paradoxical reduction in secretion seen in the total body Sort1 KO mouse, which is reproduced in the hepatic-specific sortilin KO mouse. The differential effects of wild-type and lysosomal defective sortilin on VLDL secretion and are consistent with a model in which sortilin serves a dual function in VLDL trafficking, with low levels of sortilin facilitating VLDL export and higher levels of sortilin promoting pre-secretory lysosomal VLDL degradation.

Patients with sickle cell anemia on simple chronic transfusion protocol show sex differences for hemodynamic and hematologic responses to transfusion

Chronic transfusion therapy (CTT) is a mainstay for stroke prophylaxis in sickle cell anemia, but its effects on hemodynamics are poorly characterized. Transfusion improves oxygen-carrying capacity, reducing demands for high cardiac output, while decreasing hemoglobin (Hb)S%, reticulocyte count, and hemolysis. We hypothesized that transfusion would improve oxygen-carrying capacity, but that would be counteracted by a decrease in cardiac output due to increased hematocrit (Hct) and vascular resistance, leaving oxygen delivery unchanged. To test this hypothesis, we examined patients on CTT immediately before transfusion and again 12 to 120 hours after transfusion, using echocardiography and near infrared spectroscopy. Comparable increases in Hb and Hct and decreases in reticulocyte count and HbS with transfusion were observed in all patients, but males had a larger rebound of HbS%, reticulocyte count, and free Hb levels between transfusions. In males, transfusion decreased heart rate by 12%, stroke volume by 15%, and cardiac index by 24% while estimates for pulmonary and systemic vascular resistance increased, culminating in 6% decrease in oxygen delivery. In contrast, stroke volume and cardiac index and systemic and pulmonary vascular resistance did not change in women after transfusion, such that oxygen delivery improved 17%. In our sample population, males exhibit a paradoxical reduction in oxygen delivery in response to transfusion because the increase in vascular resistance is larger than the increase in oxygen capacity. This may result from an inability to adequately suppress their HbS% between transfusion cycles.

Membrane stability and methaemoglobin content of human erythrocytes incubated in aqueous leaf extract of Nicotiana tabacum product

The present study seeks to ascertain membrane stability and methaemoglobin content (%MetHb) of human erythrocytes suspended in aqueous leaf extract of N. tabacum. Erythrocyte membrane stability (%EMS) and %MetHb were measured by spectrophotometric method. Erythrocytes incubated in the five experimental concentrations of N. tabacum exhibited higher tendency to haemolyze in phosphate buffered saline solution [PBS] &gt; 0.54 g/100 mL, whereas erythrocytes incubated in aqueous extracts of [N. tabaccum] = 0.4 and 0.8 mg/100 mL showed relatively lower level of haemolysis in [PBS] &lt; 0.54 g/100 mL, compared with the control samples. Experimental [N. tabacum] = 2.0 mg/100 mL caused destabilization of erythrocyte membrane by 13.3%. %MetHb of control and erythrocytes treated with aqueous extracts of N. tabacum ranged between 0.58 ± 0.09 and 1.89 ± 0.12%. Specifically, erythrocytes treated with [N. tabacum] = 0.4 mg/100 mL gave %MetHb = 0.59 ± 0.08; p &lt; 0.05. Experimental [N. tabacum] = 2.0 mg/100 mL engendered a paradoxical reduction in erythrocyte %MetHb = 0.58 ± 0.09; p &gt; 0.05. The medium negative correlation (r = −0.62421) between MCF and %MetHb was an indication that N. tabacum destabilizing effect, exemplified by [N. tabacum] = 0.2 mg/100 mL; %MetHb = 0.58 ± 0.09; %EMS = −13.3, was not an oxidative process, but by mechanical perturbation by constituents of the plant extract on erythrocyte membrane structural components. Erythrocyte %MetHb in the presence of the five experimental [N. tabacum] = 0.4 − 2.0 mg/100 mL did not cause toxic methaemoglobinemia in vitro.

Response selection in prosaccades, antisaccades, and other volitional saccades

Saccades made to the opposite side of a visual stimulus (antisaccades) and to central cues (simple volitional saccades) both require active response selection but whether the mechanisms of response selection differ between these tasks is unclear. Response selection can be assessed by increasing the number of response alternatives: this leads to increased reaction times when response selection is more demanding. We compared the reaction times of prosaccades, antisaccades, saccades cued by a central arrow, and saccades cued by a central number, in blocks of either two or six possible responses. In the two-response blocks, reaction times were fastest for prosaccades and antisaccades, and slowest for arrow-cued and number-cued saccades. Increasing response alternatives from two to six caused a paradoxical reduction in reaction times of prosaccades, had no effect on arrow-cued saccades, and led to a large increase in reaction times of number-cued saccades. For antisaccade reaction times, the effect of increasing response alternatives was intermediate, greater than that for arrow-cued saccades but less than that for number-cued saccades. We suggest that this pattern of results may reflect two components of saccadic processing: (a) response triggering, which is more rapid with a peripheral stimulus as in the prosaccade and antisaccade tasks and (b) response selection, which is more demanding for the antisaccade and number-cued saccade tasks, and more automatic when there is direct stimulus-response mapping as with prosaccades, or over-learned symbols as with arrow-cued saccades.

Book Reviews

At a time when smartphones, smart-homes, smart-cities, wearables, factories, etc., are becoming increasingly omnipresent, shall we also expect technological progress in artificial intelligence (AI) to result in the emergence of smart-governments and nations? The field of AI, and more broadly the development of artificial cognitive machines, is making breathtaking advances. A significant increase in computing power is enabling the rapid adoption of a new paradigm of AI, whereby cognitive machines are no longer programmed line by line, instruction by instruction, but instead are now capable of learning autonomously, thereby continuously developing themselves. The new paradigm is unleashing extraordinary progress in a wide range of applications, from healthcare to transportation and even the justice system; at the same time, these new forms of intelligence are making decisions in complex ways that escape the limits of human comprehension.The technological transformation driven by artificial cognitive machines is already beginning to have far reaching consequences, some unintended, at a scale and pace which exceeds even that of the first and second industrial revolutions. This paper aims to discuss these implications, both with an ontological and epistemological perspective, to assess the potential challenges for the systemic viability of democratic societies: a fundamental change in the nature of economic wealth creation, which could raise significant social tensions, combined with the paradoxical reduction in the effectiveness of human communication. It then explores the potential role of artificial cognitive machines to address its own challenges, introducing the idea of a future brain for public governance, understanding brain as an emergent property resulting from the interaction of human agents and AI systems created to address the priorities of social organizations.

A case of atrioventricular block (Wenckebach type) induced by sugammadex

To the Editor: Summadex is a muscle relaxant antagonist that reverses muscle relaxation by binding to muscle relaxants. There is almost no known noteworthy adverse reaction to this drug, although there have been some reports of QT prolongation on electrocardiogram (ECG) induced by summadex [1–3]. We recently encountered a case who developed seconddegree atrioventricular block (Wenckebach type) after having received sugammadex. A 21-year-old female patient (height 165 cm, body weight 47 kg) had no noteworthy previous disease history, and preoperative tests revealed no abnormalities of the ECG, serum electrolytes, or other factors. Surgery for resection of nevus pigmentosus of the brachium and face was scheduled. Anesthesia was induced with propofol (100 mg) and rocuronium (40 mg) and maintained with oxygen (40 %), sevoflurane (1.5 %), and remifentanil (0.02 lg/kg/min). The surgeon gave locally 6 ml 1 % lidocaine mixed with 1:200,000 epinephrine to maintain a bloodless surgical field with local anesthesia. Circulation dynamics remained stable intraoperatively. The operation lasted for 60 min. At the completion of the operation, when consciousness was restored, sugammadex (200 mg) was administered. Before tracheal extubation, the patient showed ECG changes consistent with second-degree atrioventricular block (Wenckebach type) (Fig. 1). There were no changes of the heart rate, blood pressure, or SpO2 after the administration of sugammadex as compared with preadministration values. When the course of atrioventricular block was followed, the block converted to firstdegree atrioventricular block within 3 min and to normal sinus rhythm within a few more minutes. In this young patient for whom no particular problem was detected in preoperative tests, second-degree atrioventricular block (Wenckebach type) developed after a dose of sugammadex. Sugammadex binds to muscle relaxants, forming an inactive complex (inclusion compound), thereby effectively removing the muscle relaxant from the neuromuscular junction. Features of sugammadex that are advantageous over the conventional anticholinesterase agents include the lack of a ceiling effect, capability of the drug to reverse even deep muscle relaxation, the slight effects of acid–base balance, body temperature, or anesthetic agents on the drug’s actions, rapid manifestation of action, lack of muscarinic receptor stimulation, and lack of paradoxical reduction of the muscle strength [1–4]. Known adverse reactions to sugammadex include nausea/vomiting, cough, and hypotension. Anaphylaxis and QT prolongation have been reported as serious adverse reactions to this drug [1– 3]. QT prolongation is considered to show no association with the dose level of sugammadex [5]. Tachycardia and bradycardia, for example, often appear when the patient emerges from anesthesia following treatment with anticholinesterase agents or sugammadex [1–4]. However, it is rare for atrioventricular block to develop in a patient with no organic heart disease emerging from anesthesia. Y. Osaka (&) N. Shimada M. Satou T. Masuda T. Ando Y. Kozono M. Shimada Department of Anesthesiology, Tokyo Metropolitan Ohtsuka Hospital, 2-8-1 Minami-ohtsuka, Toshima-ku, Tokyo 170-8476, Japan e-mail: bluesapphire1226@gmail.com

Paradoxical reduction in cardiac O‐GlcNAcylation following short‐term high fat feeding

Chronic high fat feeding (HFF) leads to hyperglycemia which elevates cardiac O‐linked B‐N‐acetylglucosamine glycosylation (O‐GlcNAcylation) of mitochondrial proteins and leads to reduced oxidative phosphorylation. This impairs the hearts ability to oxidize surplus fatty acids perpetuating substrate toxicity associated with lipid excess. We evaluated short‐term HFF on C57BL/6 cardiac O‐GlcNAcylation and mitochondrial function. Following 20 wk HFF, mice were obese (49.12 +/− 0.73 vs. 31.82 +/− 0.95 mg; n=10), but had similar fasting blood glucose (13.98 +/− 1.45 vs. 16.56 +/− 0.91 mM; n=10). High‐resolution respirometry exhibited increased state 3 oxygen consumption supported by complex I substrates in HFF permeabilized cardiac fibers (288.82 +/− 24.81 vs. 188.80 +/− 16.48 pmol/s/mgww; n=8). This was associated with ~1.5‐fold greater mitochondrial density in the HFF group as determined by electron microscopy (n=5). Additionally, global O‐GlcNAcylation decreased ~7‐fold in the HFF mice (n=6) and immunoprecipitation experiments show complex I subunit NDUFA9 O‐GlcNAcylation is reduced ~2.5‐fold (n=6). In conclusion, prior to the onset of hyperglycemia, cardiac mitochondrial oxidative phosphorylation increases to accommodate excess substrate availability due, in part, to enhanced mitochondrial density and decreased O‐GlcNAcylated NDUFA9. This work was supported by CIHR, AHFMR, CDA and HSF.

Glutathione Peroxidase-1 Primes Pro-Inflammatory Cytokine Production after LPS Challenge In Vivo

Reactive oxygen species produced during the innate immune response to LPS are important agents of anti-pathogen defence but may also cause oxidative lung damage. Glutathione peroxidase-1 (gpx-1) is an anti-oxidant enzyme that may protect lungs from such damage. We assessed the in vivo importance of gpx-1 in LPS-induced lung inflammation. Male wild-type (WT) or gpx-1 deficient (gpx-1−/−) mice were treated intranasally with PBS or 10 µg LPS and killed 3 and 24 h post LPS. Lungs were lavaged with PBS and then harvested for inflammatory marker expression. LPS caused an intense neutrophilia in WT BALF evident 3 and 24 h post challenge that was reduced in gpx-1−/− mice. In addition, LPS-treated gpx-1−/− mice had significantly fewer macrophages than LPS-treated WT mice. To understand the basis for this paradoxical reduction we assessed inflammatory cytokines and proteases at protein and transcript levels. MMP-9 expression and net gelatinase activity in BALF of gpx-1−/− mice treated with LPS for 3 and 24 h was no different to that found in LPS-treated WT mice. BALF from LPS-treated gpx-1−/− mice (3 h) had less TNF-α, MIP-2 and GM-CSF protein than LPS-treated WT mice. In contrast, LPS-induced increases in TNF-α, MIP-2 and GM-CSF mRNA expression in WT mice were similar to those observed in gpx-1−/− mice. These attenuated protein levels were unexpectedly not mirrored by reduced mRNA transcripts but were associated with increased 20S proteasome expression. Thus, these data suggest that gpx-1 primes pro-inflammatory cytokine production after LPS challenge in vivo.

Impact of body mass index in the results after primary angioplasty in patients with ST segment elevation acute myocardial infarction

Obese patients submitted to elective coronary angioplasty have a paradoxical reduction in hospital and long-term mortality. In primary angioplasty setting, the relation with Body Mass Index (BMI) is less studied. To evaluate the impact of obesity in the results after ST-segment elevation acute myocardial infarction treated by primary angioplasty. Study of 539 consecutive patients with ST-segment elevation acute myocardial infarction (STEMI) submitted to primary angioplasty. We evaluated in-hospital, 30-day and one-year all-cause mortality according to BMI: 'normal', <25 kg/m(2); 'overweight', 25-29.9 kg/m(2) and 'obese', ≥ 30 kg/m(2). Obese patients were younger, had more hypertension and hyperlipidemia. There were no differences in previous cardiac history and hospital data. In-hospital mortality was 8.0% for patients with normal BMI, 4.4% for overweight patients and 5.9% for obese patients (P=0.296). At 30 days, 9.6%, 5.2% and 6.9% (P=0.212) and at first year, 11.2%, 5.2% and 6.9% (P=0.064), respectively. Overweight was the only group with decreased risk (OR: 0.44, 95% CI: 0.21-0.90, P=0.015), even after adjustment for confounding variables (OR: 0.37, 95% CI: 0.15-0.95, P=0.038). Overweight patients had a better prognosis after primary angioplasty for STEMI compared with other BMI groups.

Cold-impaired cardiac performance in rats is only partially overcome by cold acclimation

The consequences of acute hypothermia include impaired cardiovascular performance, ultimately leading to circulatory collapse. We examined the extent to which this results from intrinsic limitations to cardiac performance or physiological dysregulation/autonomic imbalance, and whether chronic cold exposure could ameliorate the impaired function. Wistar rats were held at a 12 h:12 h light:dark (L:D) photoperiod and room temperature (21°C; euthermic controls), or exposed to a simulated onset of winter in an environmental chamber by progressive acclimation to 1 h:23 h L:D and 4°C over 4 weeks. In vivo, acute cold exposure (core temperature, T(b)=25°C) resulted in hypotension (approximately -20%) due to low cardiac output (approximately -30%) accompanying a bradycardia (approximately -50%). Cold acclimation (CA) induced only partial compensation for this challenge, including increased coronary flow at T(b)=37°C (but not at T(b)=25°C), maintenance of ventricular capillarity and altered sympathovagal balance (increased low:high frequency in power spectral analysis, PSA), suggesting physiological responses alone were insufficient to maintain cardiovascular performance. However, PSA showed maintenance of cardiorespiratory coupling on acute cold exposure in both groups. Ex vivo cardiac performance revealed no change in intrinsic heart rate, but a mechanical impairment of cardiac function at low temperatures following CA. While CA involved an increased capacity for β-oxidation, there was a paradoxical reduction in developed pressure as a result of adrenergic down-regulation. These data suggest that integrated plasticity is the key to cardiovascular accommodation of chronic exposure to a cold environment, but with the potential for improvement by intervention, for example with agents such as non-catecholamine inotropes.

Indirect modulation of neuronal excitability and synaptic transmission in the hippocampus by activation of proteinase-activated receptor-2.

Proteinase-activated receptor-2 (PAR2) is widely expressed in the CNS under normal physiological conditions. However, its potential role in modulating neuronal excitability and synaptic transmission remains to be determined. Here, we have investigated whether PAR2 activation modulates synaptic activity in the hippocampus. PAR2 activation and its effect on the hippocampus were examined in rat primary cultures and acute slices using whole cell patch clamp and standard extracellular recordings, respectively. PAR2 activation leads to a depolarization of hippocampal neurones and a paradoxical reduction in the occurrence of synaptically driven spontaneous action potentials (APs). PAR2-induced neuronal depolarization was abolished following either the inhibition of astrocytic function or antagonism of ionotropic glutamate receptors whilst the PAR2-induced decrease in AP frequency was also reduced when astrocytic function was inhibited. Furthermore, when examined in acute hippocampal slices, PAR2 activation induced a profound long-term depression of synaptic transmission that was dependent on NMDA receptor activation and was sensitive to disruption of astrocytic function. These novel findings show that PAR2 activation indirectly inhibits hippocampal synaptic activity and indicate that these receptors may play an active role in modulating normal physiological CNS function, in addition to their role in pathophysiological disorders.

Surgical Revascularization Reverses Cerebral Cortical Thinning in Patients With Severe Cerebrovascular Steno-Occlusive Disease

Chronic deficiencies in regional blood flow lead to cerebral cortical thinning without evidence of gross tissue loss at the same time as potentially negatively impacting on neurological and cognitive performance. This is most pronounced in patients with severe occlusive cerebrovascular disease in whom affected brain areas exhibit "steal physiology," a paradoxical reduction of cerebral blood flow in response to a global vasodilatory stimulus intended to increase blood flow. We tested whether surgical brain revascularization that eliminates steal physiology can reverse cortical thinning. We identified 29 patients from our database who had undergone brain revascularization with pre- and postoperative studies of cerebrovascular reactivity using blood oxygen(ation) level-dependent MRI and whose preoperative study exhibited steal physiology without MRI-evident structural abnormalities. Cortical thickness in regions corresponding to steal physiology, and where applicable corresponding areas in the normal hemisphere, were measured using Freesurfer software. At an average of 11 months after surgery, cortical thickness increased in every successfully revascularized hemisphere (n=30). Mean cortical thickness in the revascularized regions increased by 5.1% (from 2.40 ± 0.03 to 2.53 ± 0.03; P<0.0001). Successful regional revascularization and reversal of steal physiology is followed by restoration of cortical thickness.

No protective role for hypoxic pulmonary vasoconstriction in severe hypergravity-induced arterial hypoxemia

Supine subjects exposed to hypergravity show a marked arterial desaturation. Previous work from our laboratory has also shown a paradoxical reduction of lung perfusion in dependent lung regions in supine subjects exposed to hypergravity. We reasoned that the increased lung weight during hypergravity caused either direct compression of the blood vessels in the dependent lung tissue or that poor regional ventilation caused reduced perfusion through hypoxic pulmonary vasoconstriction (HPV). The objective of this study was to evaluate the importance of HPV through measurements of arterial oxygenation during exposure to hypergravity with normal and attenuated HPV. A further increased arterial desaturation during hypergravity with attenuated HPV would support the hypothesis that HPV contributes to the paradoxical redistribution of regional perfusion. In a two-phased randomized study we first exposed 12 healthy subjects to 5 G while supine during two single-blinded conditions; control and after 50 mg sildenafil p.o.. In a second phase, 12 supine subjects were exposed to 5 G during three single-blinded conditions; control, after 100 mg sildenafil p.o. and after inhalation of 10 μg iloprost. There was a substantial arterial desaturation by 5-30% units in all subjects with no or only minor differences between conditions. The results speak against HPV as a principal mechanism for the hypergravity-induced reduction of lung perfusion in dependent lung regions in supine humans.

Evaluating demand side measures in simulation models for the power market

Increased energy efficiency is one of the pillars for reducing CO 2 emissions. However, in models for the electricity market like unit commitment and dispatch models, increased efficiency of demand results in a paradoxical apparent reduction of the total economic surplus. The reason is that these are partial models for the electricity market, which do not take into account the effect of the changes in other markets. This paper shows how the calculation of the consumer surplus in the electricity market should be corrected to take into account the effect in other markets. In different cases we study shifts in the demand curve that are caused by increased energy efficiency, reduced cost for substitutes to electricity and real-time monitoring of demand, and we derive the necessary correction. The correction can easily be included in existing simulation models, and makes it possible to assess the effect of changes in demand on economic surplus.

Regulation of the Matriptase-Prostasin Cell Surface Proteolytic Cascade by Hepatocyte Growth Factor Activator Inhibitor-1 during Epidermal Differentiation

Matriptase, a membrane-tethered serine protease, plays essential roles in epidermal differentiation and barrier function, largely mediated via its activation of prostasin, a glycosylphosphatidylinositol-anchored serine protease. Matriptase activity is tightly regulated by its inhibitor hepatocyte growth factor activator inhibitor-1 (HAI-1) such that free active matriptase is only briefly available to act on its substrates. In the current study we provide evidence for how matriptase activates prostasin under this tight control by HAI-1. When primary human keratinocytes are induced to differentiate in a skin organotypic culture model, both matriptase and prostasin are constitutively activated and then inhibited by HAI-1. These processes also occur in HaCaT human keratinocytes when matriptase activation is induced by exposure of the cells to a pH 6.0 buffer. Using this acid-inducible activation system we demonstrate that prostatin activation is suppressed by matriptase knockdown and by blocking matriptase activation with sodium chloride, suggesting that prostatin activation is dependent on matriptase in this system. Kinetics studies further reveal that the timing of autoactivation of matriptase, prostasin activation, and inhibition of both enzymes by HAI-1 binding are closely correlated. These data suggest that, during epidermal differentiation, the matriptase-prostasin proteolytic cascade is tightly regulated by two mechanisms: 1) prostasin activation temporally coupled to matriptase autoactivation and 2) HAI-1 rapidly inhibiting not only active matriptase but also active prostasin, resulting in an extremely brief window of opportunity for both active matriptase and active prostasin to act on their substrates.