K2P2.1 is a regulator of inflammatory cell responses in idiopathic inflammatory myopathies.

K2P2.1 (TREK1), a two-pore domain potassium channel, has emerged as regulator of leukocyte transmigration into the central nervous system. In the context of skeletal muscle, immune cell infiltration constitutes the pathogenic hallmark of idiopathic inflammatory myopathies (IIMs). However, the underlying mechanisms remain to be elucidated. In this study, we investigated the role of K2P2.1 in the autoimmune response of IIMs. We detected K2P2.1 expression in primary skeletal muscle and endothelial cells of murine and human origin. We observed an increased pro-inflammatory cell response, adhesion and transmigration by pharmacological blockade or genetic deletion of K2P2.1 in vitro and in in vivo myositis mouse models. Of note, our findings were not restricted to endothelial cells as skeletal muscle cells with impaired K2P2.1 function also demonstrated a strong pro-inflammatory response. Conversely, these features were abrogated by activation of K2P2.1 and improved the disease course of a myositis mouse model. In humans, K2P2.1 expression was diminished in IIM patients compared to non-diseased controls arguing for the translatability of our findings. In summary, K2P2.1 may regulate the inflammatory response of skeletal muscle. Further research is required to understand whether K2P2.1 could serve as novel therapeutic target.

The grey - green spectrum: A review of coastal protection interventions.

In the face of uncertainties around coastal management and climate change, coastal engineering interventions need to be able to adapt to changing conditions. Nature-based solutions and other non-traditional, integrated interventions are gaining traction. However, system-based views are not yet embedded into coastal management strategies. Moreover, the differences in coastal interventions, ranging from hard ('grey') to nature-based ('green') infrastructure remain understudied. In coastal management it is therefore challenging to work with the grey-green spectrum of interventions with clarity and focus, and to produce results that can be evaluated. The objective of this paper was to examine whether there is a common understanding of: the characteristics and differences between grey and green infrastructure, where interventions sit on this spectrum, and the resilience of grey versus green infrastructure. We conducted an integrative literature review of the grey-green spectrum of coastal infrastructure. We examined 105 coastal protection case studies and expanded the double-insurance framework to ensure an integrative approach, looking at both external and internal factors of resilience. Our review showed that external factors are typically used to characterise the grey-green spectrum. However, although useful, they do not facilitate a holistic comparison of alternative interventions. The additional consideration of internal factors (response diversity, multifunctionality, modularity and adaptive, participatory governance) bridges this gap. The review showed that dikes, reefs, saltmarshes, sand nourishment and dunes span a wider segment of the grey-green spectrum than they are generally categorised in. Furthermore, resilient solutions for adaptation are unlikely to be exclusively engineered or natural, but tend to be a mix of the two at different spatial scales (micro, meso, macro and mega). Our review therefore suggests that coastal planners benefit from a more diverse range of options when they consider the incorporation of grey and green interventions in the context of each spatial scale. We propose that internal resilience should be accounted for when infrastructure options are comparatively evaluated. This consideration brings attention to the ways in which the grey-hybrid-green spectrum of infrastructure enhances value for people.

Distant regions underpin interregional flows of cultural ecosystem services provided by birds and mammals.

Ecosystem service assessments rarely consider flows between distant regions. Hence, telecoupling effects such as conservation burdens in distant ecosystems are ignored. We identified service-providing species for two cultural ecosystem services (existence and bequest, and birdwatching) and two receiving, i.e. benefitting, regions (Germany, the Netherlands). We delineated and analysed sending, i.e. service-providing, regions on a global scale. The proportion of service-providing species with distant habitats was higher for birdwatching (Germany: 58.6%, Netherlands: 59.4%), than for existence and bequest (Germany: 49.3%, Netherlands: 57.1%). Hotspots of sending regions were predominantly situated in tropical and subtropical grasslands, savannas and shrublands and were significantly more threatened and poorer than the global mean. Hotspot protection levels for flows to Germany were higher than the global mean, and lower for the Dutch hotspots. Our findings increase understanding on how distant regions underpin ecosystem services and necessitate interregional assessment as well as conservation efforts.

Isolation of Primary Murine Skeletal Muscle Microvascular Endothelial Cells.

The endothelial cells of skeletal muscle capillaries (muscle microvascular endothelial cells, MMEC) build up the barrier between blood stream and skeletal muscles regulating the exchange of fluids and nutrients as well as the immune response against infectious agents by controlling immune cell migration. For these functions, MMEC form a functional "myovascular unit" (MVU), with further cell types, such as fibroblasts, pericytes and skeletal muscle cells. Consequently, a dysfunction of MMEC and therefore the MVU contributes to a vast variety of myopathies. However, regulatory mechanisms of MMEC in health and disease remain insufficiently understood and their elucidation precedes more specific treatments for myopathies. The isolation and in-depth investigation of primary MMEC functions in the context of the MVU might facilitate a better understanding of these processes. This article provides a protocol to isolate primary murine MMEC of the skeletal muscle by mechanical and enzymatic dissociation including purification and culture maintenance steps.

Mortality outcomes in patients transfused with fresher versus older red blood cells: a meta-analysis.

BACKGROUND: Among transfused patients, the effect of the duration of red blood cell storage on mortality remains unclear. This study aims to compare the mortality of patients who were transfused with fresher versus older red blood cells. METHODS: We performed an updated systematic search in the CENTRAL, MEDLINE, EMBASE and CINAHL databases, from January 2015 to October 2016. RCTs of hospitalized patients of any age comparing transfusion of fresher versus older red blood cells were eligible. We used a random-effects model to calculate pooled risk ratios (RRs) with corresponding 95% confidence interval (CI). RESULTS: We identified 14 randomized trials that enrolled 26 374 participants. All-cause mortality occurred in 1219 of 9531 (12·8%) patients who received a transfusion of fresher red blood cells and 1810 of 16 843 (10·7%) in those who received older red blood cells (RR: 1·04, 95% CI: 0·98-1·12, P = 0·90, I2 = 0%, high certainty for ruling out benefit of fresh blood, moderate certainty for ruling out harm of fresh blood). In six studies, in-hospital death occurred in 691 of 7479 (9·2%) patients receiving fresher red cells and 1291 of 14 757 (8·8%) receiving older red cells (RR: 1·06, 95% CI: 0·97-1·15, P = 0·81, I2 = 0%, high certainty for ruling out benefit of fresh blood, moderate certainty for ruling out harm of fresh blood). CONCLUSION: Transfusion of fresher red blood cells does not reduce overall or in-hospital mortality when compared with older red blood cells. Our results support the practice of transfusing patients with the oldest red blood cells available in the blood bank.

HIV-1 and intestinal helminth review update: updating a Cochrane Review and building the case for treatment and has the time come to test and treat?

Intestinal helminth infection activates and dysregulates the immune system and impacts the host's capacity to respond to illness. Such neglected tropical infections exact the greatest burden on resource-limited settings and there appears to be considerable overlapping epidemiology with HIV-1 and other high-burden infections and illnesses in such settings. Recent limited yet controlled RCT evidence suggests a potentially beneficial therapeutic effect when persons co-infected with soil-transmitted worms and HIV-1, are treated with albendazole. The positive impact on CD4+ counts and plasma RNA levels appears to delay HIV-1 progression. The evidence-base has been conflicting and the unequivocal evidence needed to support large-scale de-worming remains lacking. The recent RCT by Walson and colleagues provides the first real tantalizing evidence of a beneficial impact of worm treatment and adds to a prior Cochrane review that was inconclusive. Further controlled, longer duration and larger trial arm designs that are minimally biased and comparable, are needed to provide the conclusive evidence needed yet the case for de-worming in delaying high-burden illnesses such as HIV-1 has been made much stronger.

Zymogen activation in a reconstituted pancreatic acinar cell system.

Pathological activation of digestive zymogens within the pancreatic acinar cell initiates acute pancreatitis. Cytosolic events regulate this activation within intracellular compartments of unclear identity. In an in vivo model of acute pancreatitis, zymogen activation was detected in both zymogen granule-enriched and microsomal cellular fractions. To examine the mechanism of this activation in vitro, a reconstituted system was developed using pancreatic cytosol, a zymogen granule-enriched fraction, and a microsomal fraction. Addition of cytosol to either particulate fraction resulted in a prominent increase in both trypsin and chymotrypsin activities. The percentage of the pool of trypsinogen and chymotrypsinogen activated was about twofold and sixfold greater, respectively, in the microsomal than in the zymogen granule-enriched fraction. Activation of chymotrypsinogen but not trypsinogen was significantly enhanced by ATP (5 mM) but not by the inactive ATP analog AMP-PNP. The processing of procarboxypeptidase B to its mature form also demonstrated a requirement for ATP and cytosol. E64d, an inhibitor of cathepsin B, a thiol protease that can activate trypsin, completely inhibited trypsin activity but did not affect chymotrypsin activity or carboxypeptidase B generation. These studies demonstrate that both zymogen granule-enriched and microsomal fractions from the pancreas can support cytosol-dependent zymogen activation. A component of the activation of some zymogens, such as chymotrypsinogen and procarboxypeptidase, may depend on ATP but not on trypsin or cathepsin B.

Colorectal cancer screening: video-reviewed flexible sigmoidoscopy by nurse endoscopists--a Canadian community-based perspective.

BACKGROUND: Colorectal cancer (CRC) is the third most common incident cancer and the second most fatal cancer in Canada. Flexible sigmoidoscopy (FS) is one of the modalities under consideration for CRC screening. The present series reports on a screening program of FS performed by nonphysician endoscopists in a Canadian community setting, with video review of procedures by physicians and recommendation of follow-up colonoscopy where polyps are identified. RESULTS: Five hundred twenty-five, average-risk, asymptomatic patients were examined. After exclusion of inappropriate referrals, 488 remained for analysis. The duration and extent of examination were comparable with those of previous studies elsewhere. Compliance with suggested follow-up was 97.3%. Polyps were identified at FS in 15.4% of examinees. In 8.2% of patients, the polyps were neoplastic at subsequent histology. Four malignant lesions were detected, all at an early stage. There were no complications of FS. INTERPRETATION: This report shows that FS can be carried out safely and effectively by nonphysician personnel in a community setting in Canada. The manpower cost for nonphysician operators is considerably less than that for specialist physician endoscopists. This approach deserves consideration in cost effectiveness analyses of CRC screening.

Medication side effects in anxious patients: negative placebo responses?

The purpose of the present study was to detect any problems among anxious patients in switching from alprazolam to extended release alprazolam. Fifty-four patients with an anxiety disorder, stabilized on alprazolam, entered the study. During the first 2 weeks, all patients took alprazolam as usual. During the second 2 weeks, they all took the same dosage of the extended release formulation. They were evaluated weekly with standard clinical measures and were asked to report any adverse medical events. The clinical measures showed modest, steady improvement over the course of the study. Patients reporting adverse medical events increased from 26% of the sample to 60% after the switch of dosage forms. Most of these events were anxiety-like (48%) or sedative (37%). Patients who developed sedative events took slightly higher mean doses of alprazolam. Patients who developed anxiety-like events had higher baseline scores on the Somatization, Anxiety and Phobia clusters of the SCL-90. The results suggest that more anxious patients confronted with a change of regimen commonly generate anxiety symptoms that they attribute to the medication, i.e., negative placebo responses, perhaps especially if they have a tendency toward somatization. A study designed to sort out pharmacological and psychological effects and further explore the mechanisms at work is indicated.

Management of panic disorders.

Panic disorders are medical conditions requiring an eclectic treatment approach that often combines pharmacotherapeutics with education, cognitive-behavior therapy, and psychodynamic therapy. This article focuses on the management of medication within this framework. The medications that have been found to be effective include tricyclic antidepressants, fluoxetine, monoamine oxidase inhibitors, and higher potency benzodiazepines. Although alprazolam is the most studied medication and acts very rapidly, each type of medication has unique advantages and liabilities. The general treatment strategy with all the medications is to start with a low dose and increase it slowly until side effects develop or panic attacks cease. The treatment approach should be oriented toward a chronic illness that often requires long-term medication.

Alprazolam treatment for panic disorders.

Office records of 27 private patients who were treated with alprazolam for panic disorders were evaluated by a second psychiatrist. Alprazolam treatment led to a complete remission of panic attacks in 85% of the patients; panics ceased within an average of 6 days, at a mean dose of 2.2 mg/day. In addition, alprazolam was found to bring about a complete absence of phobic avoidance behavior in 21 of the 23 agoraphobic patients in the group. This is the first study to demonstrate the efficacy of medication alone as a treatment for agoraphobia.

Plasma norepinephrine and dopamine-beta-hydroxylase activity in schizophrenia.

Plasma norepinephrine (NE) and dopamine-beta-hydroxylase (DBH) activity may be altered by changes in posture, pulse rate, and BP. Twenty-three drug-free schizophrenic, ten schizoaffective, and 24 normal control subjects, and a separate group of eight schizophrenic patients treated with chlorpromazine hydrochloride and haloperidol comprised the sample. Drug-free schizophrenic patients showed higher plasma NE levels while standing and higher pulse rates when supine and standing than normal subjects. Following chlorpromazine therapy, but not following haloperidol treatment, plasma NE level increased with patients supine and standing, pulse rate increased with patients standing, and systolic BP decreased with patients standing. These findings suggest (1) a decreased peripheral alpha-adrenergic postsynaptic receptor sensitivity in schizophrenia and (2) a peripheral alpha-adrenergic blocking mechanism in chlorpromazine-induced hypotension.

Lithium treatment in post-psychotic depression.

Six of eleven drug-free schizophrenic patients who were depressed following remission of their illness showed a significant decrease in their depressive symptomatology during a double-blind, placebo substitution lithium trial. Traditional indicators of prognosis did not predict lithium response in this small sample; the schizophrenic patients tolerated the lithium well. Lithium should be studied further in a larger patient sample as an adjunct in the treatment of post-psychotic depression, which frequently is treatment resistant.

Effects of dopamine blockade on gonadotropins and testosterone in men.

The authors found that plasma luteinizing hormone (LH), prolactin, and testosterone were initially normal in nine acutely psychotic males with schizophrenia or schizo-affective disorder; follicle-stimulating hormone (FSH) was normal in eight of the nine. When patients were treated with pimozide, a relatively specific dopamine receptor blocker, there were statistically significant declines in FSH and LH, although levels remained within normal limits. Prolactin rose significantly, but testosterone did not change. The observed reductions in FSH and LH concentrations are consistent with the hypotheses that dopamine and/or prolactin play a role in gonadotropin secretion. The maintenance of normal levels of gonadotropins and testosterone, however, suggests that these patients possessed relatively normal hypothalamic-pituitary-gonadal axis function before and during a course of neuroleptic treatment.

Serum calcium and magnesium levels in schizophrenia. II. Possible relationship to extrapyramidal symptoms.

The relationship between serum calcium and magnesium levels and neuroleptic-induced extrapyramidal symptoms (EPS) was studied in schizophrenic patients. The 16 patients in whom EPS developed had a significantly lower mean drug-free calcium level than the six patients in whom EPS did not develop. In patients in whom EPS developed, drug-free serum calcium and magnesium levels together correlated significantly with the neuroleptic dosage at which EPS first developed; lower calcium and magnesium values predicted EPS at lower dosages. We have previously shown that both serum calcium and magnesium levels were significantly lower during neuroleptic treatment than in the drug-free state. In this study, a similar trend was observed, but the calcium value tended to be, and the magnesium value was significantly lower at the onset of neuroleptic-induced EPS than during the mean of an entire pimozide trial.

Antipsychotic effects of lithium in schizophrenia.

The lithium carbonate therapy of 13 psychotic schizophrenic patients was evaluated in a placebo-controlled three-week study that was double-blind. Seven of the 13 patients were less psychotic while receiving lithium; 4 of these 7 patients relapsed after lithium withdrawal. Patients who improved during the third week on lithium could be differentiated from nonresponders on the basis of their improvement during the first week. Clinical factors such as diagnosis, prognosis, and symptoms failed to predict responders from nonresponders. To the authors' knowledge, this is the first controlled study to yield positive results with schizophrenic patients treated with lithium alone.