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Myasthenic crisis (MC) is a life-threatening condition for patients with myasthenia gravis (MG). Seronegative patients represent around 10–15% of MG, but data on outcome of seronegative MCs are lacking. We performed a subgroup analysis of patients who presented with MC with either acetylcholine-receptor-antibody-positive MG (AChR-MG) or seronegative MG between 2006 and 2015 in a retrospective German multicenter study. We identified 15 seronegative MG patients with 17 MCs and 142 AChR-MG with 159 MCs. Seronegative MCs were younger (54.3 ± 14.5 vs 66.5 ± 16.3 years; p = 0.0037), had a higher rate of thymus hyperplasia (29.4% vs 3.1%; p = 0.0009), and were more likely to be female (58.8% vs 37.7%; p = 0.12) compared to AChR-MCs. Time between diagnosis of MG and MC was significantly longer in seronegative patients (8.2 ± 7.6 vs 3.1 ± 4.4 years; p < 0.0001). We found no differences in duration of mechanical ventilation (16.2 ± 15.8 vs 16.5 ± 15.9 days; p = 0.94) and length of stay at intensive care unit (17.6 ± 15.2 vs 17.8 ± 15.4 days; p = 0.96), or in-hospital mortality (11.8% vs. 10.1%; p = 0.69). We conclude that MC in seronegative MG affects younger patients after a longer period of disease, but that crisis treatment efficacy and outcome do not differ compared to AChR-MCs. [ABSTRACT FROM AUTHOR]

Background: We aimed to determine the association between seizure termination and side effects of isoflurane for the treatment of refractory status epilepticus (RSE) and super-refractory status epilepticus (SRSE) in neurointensive care units (neuro-ICUs). Methods: This was a multicenter retrospective study of patients with RSE/SRSE treated with isoflurane for status epilepticus termination admitted to the neuro-ICUs of nine German university centers during 2011–2018. Results: We identified 45 patients who received isoflurane for the treatment of RSE/SRSE. During isoflurane treatment, electroencephalograms showed no epileptiform discharges in 33 of 41 (80%) patients, and burst suppression pattern was achieved in 29 of 41 patients (71%). RSE/SRSE was finally terminated after treatment with isoflurane in 23 of 45 patients (51%) for the entire group and in 13 of 45 patients (29%) without additional therapy. Lengths of stay in the hospital and in the neuro-ICU were significantly extended in cases of ongoing status epilepticus under isoflurane treatment (p = 0.01 for length of stay in the hospital, p = 0.049 for length in the neuro-ICU). During isoflurane treatment, side effects were reported in 40 of 45 patients (89%) and mainly included hypotension (n = 40, 89%) and/or infection (n = 20, 44%). Whether side effects occurred did not affect the outcome at discharge. Of 22 patients with follow-up magnetic resonance imaging, 2 patients (9%) showed progressive magnetic resonance imaging alterations that were considered to be potentially associated with RSE/SRSE itself or with isoflurane therapy. Conclusions: Isoflurane was associated with a good effect in stopping RSE/SRSE. Nevertheless, establishing remission remained difficult. Side effects were common but without effect on the outcome at discharge. [ABSTRACT FROM AUTHOR]

Myasthenic crisis (MC) is a life-threatening condition for patients with myasthenia gravis (MG). Muscle-specific kinase-antibodies (MuSK-ABs) are detected in ~ 6% of MG, but data on outcome of MuSK-MCs are still lacking. We made a subgroup analysis of patients who presented with MC with either acetylcholine-receptor-antibody positive MG (AchR-MG) or MuSK-MG between 2006 and 2015 in a retrospective German multicenter study. We identified 19 MuSK-AB associated MCs in 15 patients and 161 MCs in 144 patients with AchR-ABs only. In contrast to patients with AchR-AB, MuSK-AB patients were more often female (p = 0.05, OR = 2.74) and classified as Myasthenia Gravis Foundation of America-class IV before crisis (p = 0.04, OR = 3.25). MuSK-AB patients suffer more often from multiple chronic disease (p = 0.016, OR = 4.87) and were treated more invasively in terms of plasma exchanging therapies (not significant). The number of days of mechanical ventilation (MV) (43.0 ± 53.1 vs. 17.4 ± 18; p < 0.0001), days on an intensive care unit (ICU) (45.3 ± 49.5 vs. 21.2 ± 19.7; p < 0.0001), and hospital-length of stay (LOS) (55.9 ± 47.6 vs. 28.8 ± 20.9 days; p < 0.0001) were significantly increased in MuSK-MC. Remarkable is that these changes were mainly due to patients with MusK-ABs only, whereas patients' outcome with both antibodies was similar to AchR-MCs. Furthermore, our data showed a shortened duration of MV after treatment with plasma exchanging therapies compared to treatment with intravenous immunoglobulin in MuSK-MCs. We conclude that MuSK-AB-status is associated with a longer need of MV, ICU-LOS, and hospital-LOS in MC, and therefore recommend early initiation of a disease-specific therapy. [ABSTRACT FROM AUTHOR]

Frequent infusions of intravenous factor VIII (FVIII) are required to prevent bleeding associated with hemophilia A. To reduce the treatment burden, recombinant FVIII with a longer half-life was developed without changing the protein structure. FVIII-polyethylene glycol (PEG) conjugates were prepared using an enzymatic process coupling PEG (ranging from 10 to 80 kDa) selectively to a unique O-linked glycan in the FVIII B-domain. Binding to von Willebrand factor (VWF) was maintained for all conjugates. Upon cleavage by thrombin, the B-domain and the associated PEG were released, generating activated FVIII (FVIIIa) with the same primary structure and specific activity as native FVIIIa. In both FVIII- and VWF-deficient mice, the half-life was found to increase with the size of PEG. In vivo potency and efficacy of FVIII conjugated with a 40-kDa PEG (N8-GP) and unmodified FVIII were not different. N8-GP had a longer duration of effect in FVIII-deficient mouse models, approximately a twofold prolonged half-life in mice, rabbits, and cynomolgus monkeys; however, the prolongation was less pronounced in rats. Binding capacity of N8-GP on human monocyte-derived dendritic cells was reduced compared with unmodified FVIII, resulting in several-fold reduced cellular uptake. In conclusion, NB-GP has the potential to offer efficacious prevention and treatment of bleeds in hemophilia A at reduced dosing frequency. [ABSTRACT FROM AUTHOR]

Background: Reports in the literature have linked high acetabular inclination angles to increased wear of ceramic-on-ceramic bearings. However, many of these studies were only conducted in vitro and did not address the clinical relevance of such findings. Questions/purposes: We therefore determined: (1) whether the cup inclination angle influences survival or function in patients with ceramic-on-ceramic implants; (2) the incidence of radiolucencies, osteolysis, and subsidence of ceramic-on-ceramic implants; and (3) whether the survival rate higher for ceramic-on-ceramic THAs than for conventional metal-on-polyethylene THAs. Methods: We retrospectively reviewed 537 THAs performed in 512 prospectively followed patients having THA between October 1996 and October 2000. Eleven patients (12 hips) were lost to followup before 2 years, leaving 501 patients (525 THAs); of these, 421 were alumina ceramic-on-ceramic articulations and 104 cobalt-chromium-on-polyethylene. The mean age was 54 years. We determined acetabular cup inclination angles, Harris hip scores, Health-Status-Questionnaire-12 scores, and presence and location of any radiolucencies, osteolysis, or radiographic subsidence. We compared survival using the Kaplan-Meier method. The minimum followup was 24 months (mean, 59 months; range, 24-120 months). Results: Twenty-two of the 424 THAs (4.2%) were revised. We observed no difference in clinical or radiographic outcomes with respect to cup inclination angles. Radiographically, two loose acetabular components and two femoral components had subsided. The 5-year survival rate was slightly higher for ceramic-on-ceramic bearings (98%) than for metal-on-polyethylene (92%). Conclusions: Although there may be a link between acetabular inclination angles and wear rates as reported by some authors, we found no differences in patient function or radiographic survivorship using alumina-on-alumina articulations. Level of Evidence: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. [ABSTRACT FROM AUTHOR]

The primary goals of this critical literature review were to determine whether revision rates of primary total hip arthroplasty in patients with osteonecrosis differ based on the underlying associated risk factors and diagnoses, whether the outcomes of this procedure have improved over the past two decades, and to compare outcomes based on study level of evidence. A systematic literature review yielded 67 reports representing 3,277 hips in 2,593 patients who had a total hip arthroplasty for osteonecrosis of the femoral head. Stratification of outcomes by associated risk factors or diagnoses revealed significantly lower revision rates in patients with idiopathic disease, systemic lupus erythematosus, and after heart transplant, and significantly higher rates in patients with sickle cell disease, Gaucher disease, or after renal failure and/or transplant. There was a significant decrease in revision rates between patients operated upon before 1990 versus those in 1990 or later, with rates of 17% and 3%, respectively. The results for arthroplasties performed in 1990 or later were similar to those for all hips in publicly reported national joint registries. Certain risk factors were associated with higher revision rates in patients with osteonecrosis who were treated by total hip arthroplasty. However, most patients (82%) do not have these associated negative risk factors. Overall, this critical literature review provides evidence that osteonecrosis itself, or when associated with the most common risk factors and/or diagnoses, is not associated with poor outcomes in total hip arthroplasty. [ABSTRACT FROM AUTHOR]

Despite increasing understanding of the pathophysiology of achalasia, the etiology of this esophageal motility disorder remains largely unknown. However, the occurrence of familial achalasia and its association with well-defined genetic syndromes suggest the involvement of genetic factors. Mutant mouse models display gastrointestinal disturbances that are similar to those observed in achalasia patients. The candidate gene approach has revealed some promising results; however, it has not established conclusive links to specific genes so far. The aim of this review was to summarize current knowledge of the genetics of achalasia. We also discuss the extent to which our understanding of achalasia is likely to be enhanced through future molecular genetic research. [ABSTRACT FROM AUTHOR]

We present a Monte Carlo algorithm that generates points randomly and uniformly on a set of arbitrary surfaces. The algorithm is completely general and only requires the geometry modeling software to provide the intersection points of an arbitrary line with the surface being sampled. We demonstrate the algorithm using the Geant4 Monte Carlo simulation toolkit. The efficiency of the sampling algorithm is discussed, along with various options in the implementation and example applications. [ABSTRACT FROM AUTHOR]

Ischemia–reperfusion injury is a leading cause of acute renal failure and a major determinant in the outcome of kidney transplantation. Here we explored systemic gene therapy with a modified adenovirus expressing Interleukin (IL)-13, a cytokine with strong anti-inflammatory and cytoprotective properties. When ischemia was induced we found that the IL-13 receptor is expressed in both the normal and experimental kidneys. Prior to the induction of ischemia, rats received adenovirus-IL-13, control adenovirus or saline. IL-13 plasma levels increased more than 50-fold in adenovirus-IL-13 treated animals, confirming successful IL-13 gene delivery. Histological analysis showed decreased tubular epithelial cell damage with adenovirus-IL-13 therapy, accompanied by reduced kidney injury molecule-1 expression. Interstitial infiltration by neutrophils and macrophages was reduced by half as was interstitial fibrosis and expression of α-smooth muscle actin. IL-13 treatment significantly diminished the expression of E-selectin, IL-8, MIP-2, TNF-α and MCP-1 mRNA. These results suggest that the use of systemic IL-13 gene therapy may be useful in reducing renal tubulointerstitial damage and inflammation caused by ischemia–reperfusion.Kidney International (2008) 73, 1364–1373; doi:10.1038/ki.2008.18; published online 19 March 2008; [ABSTRACT FROM AUTHOR]

Discusses a molecular basis for the regulation of caspases by viral and endogenous inhibitors. Background on caspases; General mechanisms of protease inhibition; Discussion of several caspase inhibitors and how or when to use them.

Studies the activation of the apoptotic initiator caspase 9, a critical step in the induction of apoptosis. Fundamental ways in which protease zymogens are maintained in an inactive conformation; Protease caspase 9 conformation and structure; Active and inactive catalytic domains.

This study was conducted to evaluate the short- and long-term clinical and angiographic results of implantation of a flexible, coiled stainless steel stent, the Freedom Coronary Stent. During the study period this stent was used as an alternative to the Palmaz-Schatz PS153 coronary stent in long or tortuous lesions. The study was designed as a prospectively planned outcome analysis. Implantation of Freedom stents was attempted in 62 consecutive patients (56% males, mean age 63 ± 10 years) with a total of 65 coronary lesions. Indications for stent implantation were: restenosis, 8%; recoil, 26%; visible dissection, 32%; threatening occlusion, 15%; chronic total occlusion, 18%. The average stent length was 30 ± 16 mm and 67% of the lesions were type C. Rate of successful stent implantation, acute complications, angiographic restenosis after 6 months and major cardiac events (death, myocardial infarction, target vessel revascularization) during follow-up were assessed. The success rate of stent implantation was 94%. One patient died after an emergency bypass operation and one patient suffered a subacute stent thrombosis, which was successfully treated with re-percutaneous transluminal coronary angioplasty (PTCA). There were no Q- or non-Q myocardial infarctions. Clinical follow-up was carried out in 56 patients (97%) and 57 vessels were assessed by angiography (93%). Mean length of the follow-up period was 6.8 ± 2.3 months. During the 6 months' follow-up period, one patient died, two patients suffered an acute non-Q myocardial infarction and eight patients had revascularization of the target vessel. Major cardiac event rate for all patients where stent implantation was intended was 23%. Angina CCS class declined from 3.0 ± 0.9 to 1.1 ± 0.8 (p < 0.01) before PTCA to follow-up. Overall restenosis rate was 28%. In 14 lesions with a stented segment length of <20 mm, the restenosis rate was 21%; in 31 lesions with a stented segment length ≥20 and <30 mm, the restenosis rate was 26%; and in 13 lesions with a stented segment length of ≥30 mm, the restenosis rate was 42%. Although there was a high procedural success rate after implantation of the Freedom stent in long or tortuous lesions, problems with high restenosis rates in long lesions remain unresolved. [ABSTRACT FROM AUTHOR]

Studies the hydrolytic properties of carboxypeptidase Y. Preparation of mutant enzymes; Determination of kinetic parameters; pH dependence of the catalytic parameters; Kinetic parameters; Significance of C-terminal in catalysis.

Looks at the World Health Organization's Action Programme on Essential Drugs and its aim to train and teach pharmacotherapy to medical students. Results of training; Conclusion.

Irrational prescribing is a habit which is difficult to cure. However, prevention is possible and for this reason the WHO Action Programme on Essential Drugs aims to improve the teaching of pharmacotherapy to medical students. The impact of a short problem-based training course in pharmacotherapy, using a WHO manual on the principles of rational prescribing, was measured in an international multi-centre randomised controlled study of 219 undergraduate medical students in Groningen (Netherlands), Kathmandu (Nepal), Lagos (Nigeria), Newcastle (Australia), New Delhi (India), San Francisco (USA), and Yogyakarta (Japan). The manual and the course presented the students, who were about to enter the clinical phase of their studies, with a normative model for pharmacotherapeutic reasoning in which they were taught to generate a "standard" pharmacotherapeutic approach to common disorders, resulting in a set of first-choice drugs called P(ersonal)-drugs. The students were then taught how to apply this set of P-drugs to specific patient problems on the symptomatic treatment of pain, using a six-step problem-solving routine. The impact of the course was measured by tests before training, immediately after, and six months later. After the course, students from the study group performed significantly better than controls in all patient problems presented (p < 0.05). The students not only remembered how to solve old problems, but they could also apply their skills to new problems. Both retention and transfer effect were maintained at least six months after the training session in all seven medical schools. In view of the impossibility of teaching students all basic knowledge on the thousands of drugs available, this approach seems to be an efficient way of teaching rational prescribing. However, the method should be accompanied by a change in teaching methods away from the habit of transferring knowledge about the drugs towards problem-based teaching of therapeutic reasoning. [ABSTRACT FROM AUTHOR]

Investigates carboxypeptidase Y (CPD-Y)-catalyzed transacylation reactions. Applicability of CPD-Y mutants in transacylation reactions; Transpeptidation reactions with wild-type CPD-Y; Binding of amino acid nucleophiles prior to their attack on the acyl-enzyme intermediate; Binding of the C-terminal carboxylate group of peptide substrates.

Tau protein hyperphosphorylation and aggregation are key pathological events in neurodegenerative tauopathies such as Alzheimer's disease. Interestingly, seasonal hibernators show extensive tau hyperphosphorylation during torpor, i.e., the hypothermic and hypometabolic state of hibernation, which is completely reversed during arousal. Torpor-associated mechanisms that reverse tau hyperphosphorylation may be of therapeutic relevance, however, it is currently not known to what extent they apply to human tau. Here we addressed this issue using daily torpor in wildtype mice that express mouse tau (mtau) and in mice that lack mtau expression and instead express human tau (htau). AT8, AT100 and Ser396 immunoblotting and immunohistochemistry were used to assess tau (hyper)phosphorylation at clinically relevant phosphorylation sites. We found that torpor robustly and reversibly increases the levels of phosphorylated tau in both mtau and htau mice. Immunohistochemistry revealed four brain areas that show prominent tau phosphorylation: the hippocampus, posterior parietal cortex, piriform cortex and cortical amygdala. Whereas wildtype mice primarily showed increased levels of diffusely organized hyperphosphorylated tau during torpor, htau mice contained clear somato-dendritic accumulations of AT8 reactivity resembling tau pre-tangles as observed in the Alzheimer brain. Interestingly, AT8-positive accumulations disappeared upon arousal, and tau phosphorylation levels at 24 h after arousal were lower than observed at baseline, suggesting a beneficial effect of torpor-arousal cycles on preexisting hyperphosphorylated tau. In conclusion, daily torpor in mice offers a quick and standardized method to study tau phosphorylation, accumulation and clearance in mouse models relevant for neurodegeneration, as well as opportunities to discover new targets for the treatment of human tauopathies. [ABSTRACT FROM AUTHOR]

Some protease inhibitors use uncommon mechanisms to restrain the activity of their target enzymes. A recent paper in Chemistry and Biology () demonstrates a curious mechanism of inhibition of a caspase, relying on principles of native peptide ligation. [Copyright &y& Elsevier]

A synthetic approach to two regioisomeric π‐electron extended [1,4]thiaborins annulated with two benzothiophene units has been developed. The central thiaborin rings of the boracycles obtained exhibit different electronic properties; this is reflected in their different aromatic characters, boron Lewis acidity and UV‐vis spectroscopic behavior. Thiaborins were converted to boron dipyrromethene (BODIPY) complexes. Their emission spectra exhibit two distinct bands resulting from 1LE and 1CT transitions. Strong near‐infrared phosphorescence in Zeonex thin films at 77 K indicates efficient intersystem crossing and the formation of triplet states. Separation of HOMO and LUMO orbitals between boracyclic and BODIPY moieties facilitates electron transfer to a 1CT state followed by a transition to the 3LE triplet state located on the ligand. These unique properties of spiro thiaborin‐BODIPY complexes were explored for their application as singlet‐oxygen photosensitizers. They show excellent photocatalytic performance with singlet oxygen quantum yields reaching 77 % and full conversion of the model organic substrate achieved after 1.5 h with only 0.05 % mol catalyst load. [ABSTRACT FROM AUTHOR]

An abstract of the study "Increased Myogenic Tone in Mesenteric Artery in Chronic Heart Failure Involves Transactivation of EGF Receptor via AT1 Receptor," by Y. Xu and colleagues is presented.

A response by H. R. Andersen and colleagues to a letter to the editor about their article "A Comparison of Coronary Angioplasty With Fibrinolytic Therapy in Acute Myocardial Infarction," in an issue of the "New England Journal of Medicine" is presented.

Background: For the treatment of myocardial infarction with ST-segment elevation, primary angioplasty is considered superior to fibrinolysis for patients who are admitted to hospitals with angioplasty facilities. Whether this benefit is maintained for patients who require transportation from a community hospital to a center where invasive treatment is available is uncertain. Methods: We randomly assigned 1572 patients with acute myocardial infarction to treatment with angioplasty or accelerated treatment with intravenous alteplase; 1129 patients were enrolled at 24 referral hospitals and 443 patients at 5 invasive-treatment centers. The primary study end point was a composite of death, clinical evidence of reinfarction, or disabling stroke at 30 days. Results: Among patients who underwent randomization at referral hospitals, the primary end point was reached in 8.5 percent of the patients in the angioplasty group, as compared with 14.2 percent of those in the fibrinolysis group (P=0.002). The results were similar among patients who were enrolled at invasive-treatment centers: 6.7 percent of the patients in the angioplasty group reached the primary end point, as compared with 12.3 percent in the fibrinolysis group (P=0.05). Among all patients, the better outcome after angioplasty was driven primarily by a reduction in the rate of reinfarction (1.6 percent in the angioplasty group vs. 6.3 percent in the fibrinolysis group, P<0.001); no significant differences were observed in the rate of death (6.6 percent vs. 7.8 percent, P=0.35) or the rate of stroke (1.1 percent vs. 2.0 percent, P=0.15). Ninety-six percent of patients were transferred from referral hospitals to an invasive-treatment center within two hours. Conclusions: A strategy for reperfusion involving the transfer of patients to an invasive-treatment center for primary angioplasty is superior to on-site fibrinolysis, provided that the transfer takes two hours or less. N Engl J Med 2003;349:733-42. [ABSTRACT FROM AUTHOR]

Deals with a study which aimed to find the optimal antiproteinuric dose of the angiotensin II antagonist losartan. Methodology used in the study; Results and conclusion.

Background: There are limited data on the incidence, clinical implications, and predisposing factors of transcatheter heart valve (THV) thrombosis following transcatheter aortic valve replacement (TAVR).Objectives: The authors assessed the incidence, potential predictors, and clinical implications of THV thrombosis as determined by contrast-enhanced multidetector computed tomography (MDCT) after TAVR.Methods: Among 460 consecutive patients who underwent TAVR with the Edwards Sapien XT or Sapien 3 (Edwards Lifesciences, Irvine, California) THV, 405 (88%) underwent MDCT in addition to transthoracic and transesophageal echocardiography 1 to 3 months post-TAVR. MDCT scans were evaluated for hypoattenuated leaflet thickening that indicated THV thrombosis.Results: MDCT verified THV thrombosis in 28 of 405 (7%) patients. A total of 23 patients had subclinical THV thrombosis, whereas 5 (18%) patients experienced clinically overt obstructive THV thrombosis. THV thrombosis risk did not differ among different generations of THVs (8% vs. 6%; p = 0.42). The risk of THV thrombosis in patients who did not receive warfarin was higher compared with patients who received warfarin (10.7% vs. 1.8%; risk ratio [RR]: 6.09; 95% confidence interval [CI]: 1.86 to 19.84). A larger THV was associated with an increased risk of THV thrombosis (p = 0.03). In multivariable analysis, a 29-mm THV (RR: 2.89; 95% CI: 1.44 to 5.80) and no post-TAVR warfarin treatment (RR: 5.46; 95% CI: 1.68 to 17.7) independently predicted THV thrombosis. Treatment with warfarin effectively reverted THV thrombosis and normalized THV function in 85% of patients as documented by follow-up transesophageal echocardiography and MDCT.Conclusions: Incidence of THV thrombosis in this large study was 7%. A larger THV size may predispose to THV thrombosis, whereas treatment with warfarin appears to have a protective effect. Although often subclinical, THV thrombosis may have important clinical implications. [ABSTRACT FROM AUTHOR]

Acute kidney injury (AKI) develops frequently in the course of patients with sepsis and strongly associates with in-hospital mortality. However, diagnosing AKI involves a considerable lag-time because it depends on assessing an increase in serum creatinine, and offers no insight in the underlying pathophysiology. Consequently, identifying a set of proteins reflecting the development of AKI may improve earlier recognition of AKI and the understanding of its pathophysiology. A targeted plasma proteomic approach was performed in early sepsis patients with and without subsequent AKI development in a matched pair design (n = 19 each). Principal component analysis identified 53 proteins associated with development of AKI, which were further analysed using Enrichr gene ontology and pathway analysis. Nine differentially expressed proteins from the targeted proteomics were increased among patients who subsequently developed AKI and correlated with principal components, namely CALCA, CALR, CA12, CLEC1A, PTK7, KIM-1, NPPC, NUCB2 and PGF. We demonstrated the biological insight in the development of AKI in early sepsis compared to non-AKI sepsis. [ABSTRACT FROM AUTHOR]

Data substantiating the optimal patient body temperature during cooling procedures in cardiac operations are currently unavailable. To explore the optimal temperature strategy, we examined the association between temperature management and survival among patients during cardiopulmonary bypass assisted coronary artery bypass grafting (CABG) procedures on 30-days and 5-year postoperative survival. Adult patients (n = 5,672, 23.6% female and mean (SD) age of 66 (10) years) operated between 1997 and 2015 were included, with continuous measured intraoperative nasopharyngeal temperatures. The association between mortality and patient characteristics, laboratory parameters, the lowest intraoperative plateau temperature and intraoperative cooling/rewarming rates were examined by multivariate Cox regression analysis. Machine learning-based cluster analysis was used to identify patient subgroups based on pre-cooling parameters and explore whether specific subgroups benefitted from a particular temperature management. Mild hypothermia (32–35°C) was independently associated with improved 30-days and 5-year survival compared to patients in other temperature categories regardless of operation year. 30 days and 5-year survival were 98% and 88% in the mild hypothermia group, whereas it amounted 93% and 80% in the severe hypothermia (<30°C). Normothermia (35–37°C) showed the lowest survival after 30 days and 5 years amounting 93% and 72%, respectively. Cluster analysis identified 8 distinct patient subgroups principally defined by gender, age, kidney function and weight. The full cohort and all patient subgroups displayed the highest survival at a temperature of 32°C. Given these associations, further prospective randomized controlled trials are needed to ascertain optimal patient temperatures during CPB. [ABSTRACT FROM AUTHOR]

Deficiencies in Cystathionine‐β‐synthase (CBS) lead to hyperhomocysteinemia (HHCy), which is considered a risk factor for cardiovascular, bone and neurological disease. Moreover, CBS is important for the production of cysteine, hydrogen sulfide (H2S) and glutathione. Studying the biological role of CBS in adult mice has been severely hampered by embryological disturbances and perinatal mortality. To overcome these issues and assess the effects of whole‐body CBS deficiency in adult mice, we engineered and characterized a Cre‐inducible Cbs knockout model during ageing. No perinatal mortality occurred before Cbs−/− induction at 10 weeks of age. Mice were followed until 90 weeks of age and ablation of Cbs was confirmed in liver and kidney but not in brain. Severe HHCy was observed in Cbs−/− (289 ± 58 µM) but not in Cbs+/− or control mice (<10 µM). Cbs−/− showed impaired growth, facial alopecia, endothelial dysfunction in absence of increased mortality, and signs of liver or kidney damage. CBS expression in skin localized to sebaceous glands and epidermis, suggesting local effects of Cbs−/− on alopecia. Cbs−/− showed increased markers of oxidative stress and senescence but expression of other H2S producing enzymes (CSE and 3‐MST) was not affected. CBS deficiency severely impaired H2S production capacity in liver, but not in brain or kidney. In summary, Cbs−/− mice presented a mild phenotype without mortality despite severe HHCy. The findings demonstrate that HHCy is not directly linked to development of end organ damage. [ABSTRACT FROM AUTHOR]

Background: The most significant source of background in direct dark matter searches are neutrons that scatter elastically from nuclei in the detector's sensitive volume. Experimental data for the elastic scattering cross section of neutrons from argon and neon, which are target materials of interest to the dark matter community, were previously unavailable. Purpose: Measure the differential cross section for elastic scattering of neutrons from argon and neon in the energy range relevant to backgrounds from (a, n) reactions in direct dark matter searches. Method: Cross-section data were taken at the Triangle Universities Nuclear Laboratory (TUNL) using the neutron time-of-flight technique. These data were fit using the spherical optical model. Results: The differential cross section for elastic scatting of neutrons from neon at 5.0 and 8.0 MeV and argon at 6.0 MeV was measured. Optical-model parameters for the elastic scattering reactions were determined from the best fit to these data. The total elastic scattering cross section for neon was found to differ by 6% at 5.0 MeV and 13% at 8.0 MeV from global optical-model predictions. Compared to a local optical model for 40Ar, the elastic scattering cross section was found to differ from the data by 8% at 6.0 MeV. Conclusions: These new data are important for improving Monte Carlo simulations and background estimates for direct dark matter searches and for benchmarking optical models of neutron elastic scattering from these nuclei. [ABSTRACT FROM AUTHOR]

Abstract: A highly segmented coaxial HPGe detector was operated in a low background counting facility for over 1 year to experimentally evaluate possible segmentation strategies for the proposed Majorana neutrino-less double-beta decay experiment. Segmentation schemes were evaluated on their ability to reject multi-segment events while retaining single-segment events. To quantify a segmentation scheme''s acceptance efficiency the percentage of peak area due to single segment events was calculated for peaks located in the energy region 911–2614keV. Single interaction site events were represented by the double-escape peak from the 2614keV decay in 208Tl located at 1592keV. In spite of its prototypical nature, the detector performed well under realistic operating conditions and required only minimal human interaction. Though the energy resolution for events with interactions in multiple segments was impacted by inter-segment cross-talk, the implementation of a cross-talk correlation matrix restored acceptable resolution. Additionally, simulations utilizing the MaGe simulation package were performed and found to be in good agreement with experimental observations verifying the external nature of the background radiation. [Copyright &y& Elsevier]

Abstract: Using simulations to understand backgrounds from muon-induced neutrons is important in designing next-generation low-background underground experiments. Validation of relevant physics within the Geant4 simulation package has been completed by comparing to data from two recent experiments. Verification focused on the production and propagation of neutrons at energies important to underground experiments. Discrepancies were observed between experimental data and the simulation. Techniques were explored to correct for these discrepancies. [Copyright &y& Elsevier]

Photoactive yellow protein (PYP) from Halorhodospira halophila is a soluble 14 kDa blue-light photoreceptor. It absorbs light via its para-coumaric acid chromophore (pCA), which is covalently attached to Cys69 and is believed to be involved in the negative phototactic response of the organism to blue light. The complete structure (including H atoms) of PYP has been determined in D2O-soaked crystals through the application of joint X-ray (1.1 Å) and neutron (2.5 Å) structure refinement in combination with cross-validated maximum-likelihood simulated annealing. The resulting XN structure reveals that the phenolate O atom of pCA accepts deuterons from Glu46 Oℇ2 and Tyr42 Oη in two unusually short hydrogen bonds. This arrangement is stabilized by the donation of a deuteron from Thr50 Oγ1 to Tyr42 Oη. However, the deuteron position between pCA and Tyr42 is only partially occupied. Thus, this atom may also interact with Thr50, possibly being disordered or fluctuating between the two bonds. [ABSTRACT FROM AUTHOR]

: ObjectivesA randomized trial was done to compare single-chamber atrial (AAI) and dual-chamber (DDD) pacing in patients with sick sinus syndrome (SSS). Primary end points were changes in left atrial (LA) size and left ventricular (LV) size and function as measured by M-mode echocardiography.: BackgroundIn patients with SSS and normal atrioventricular conduction, it is still not clear whether the optimal pacing mode is AAI or DDD pacing.: MethodsA total of 177 consecutive patients (mean age 74 ± 9 years, 73 men) were randomized to treatment with one of three rate-adaptive (R) pacemakers: AAIR (n = 54), DDDR with a short atrioventricular delay (n = 60) (DDDR-s), or DDDR with a fixed long atrioventricular delay (n = 63) (DDDR-l). Before pacemaker implantation and at each follow-up, M-mode echocardiography was done to measure LA and LV diameters. Left ventricular fractional shortening (LVFS) was calculated. Analysis was on an intention-to-treat basis.: ResultsMean follow-up was 2.9 ± 1.1 years. In the AAIR group, no significant changes were observed in LA or LV diameters or LVFS from baseline to last follow-up. In both DDDR groups, LA diameter increased significantly (p < 0.05), and in the DDDR-s group, LVFS decreased significantly (p < 0.01). Atrial fibrillation was significantly less common in the AAIR group, 7.4% versus 23.3% in the DDDR-s group versus 17.5% in the DDDR-l group (p = 0.03, log-rank test). Mortality, thromboembolism, and congestive heart failure did not differ between groups.: ConclusionsDuring a mean follow-up of 2.9 ± 1.1 years, DDDR pacing causes increased LA diameter, and DDDR pacing with a short atrioventricular delay also causes decreased LVFS. No changes occur in LA or LV diameters or LVFS during AAIR pacing. Atrial fibrillation is significantly less common during AAIR pacing. [Copyright &y& Elsevier]

Expresses the full-length precursor of the Arg-specific caspase relative from the bacterium Porphyromonas gingivalis, Arg-gingipain-B, and shows that it contains N- and C-terminal extensions that render a low amount of latency. Substantially active zymogen; Requirement of three sequential autolytic processing steps at the N and C terminus for full activity; N-propeptide as intramolecular chaperone rather than an inhibitory peptide.

Examines the synthesis of Pr[sub 8]Ru[sub 12]Al[sub 49]Si[sub 9](Al[sub x]Si[sub 12-x] and Sm[sub 8]Ru[sub 12]Al[sub 49]Si[sub 9](Al[sub x]Si[sub 12-x]), where x is approximately 4, derived from Sm, Pr, Ru and Si in molten aluminum at 800 to 1000 degree centigrade in sealed fused silica tubes. Single-crystal X-ray crystallography; Charge transport properties.

Several human inhibitor of apoptosis (IAP) family proteins function by directly inhibiting specific caspases in a mechanism that does not require IAP cleavage. In this study, however, we demonstrate that endogenous XIAP is cleaved into two fragments during apoptosis induced by the tumor necrosis factor family member Fas (CD95). The two fragments produced comprise the baculoviral inhibitory repeat (BIR) 1 and 2 domains (BIR1-2) and the BIR3 and RING (BIR3-Ring) domains of XIAP. Overexpression of the BIR1-2 fragment inhibits Fas-induced apoptosis, albeit at significantly reduced efficiency compared with full-length XIAP. In contrast, overexpression of the BIR3-Ring fragment results in a slight enhancement of Fas-directed apoptosis. Thus, cleavage of XIAP may be one mechanism by which cell death programs circumvent the anti-apoptotic barrier posed by XIAP. Interestingly, ectopic expression of the BIR3-Ring fragment resulted in nearly complete protection from Bax-induced apoptosis. Use of purified recombinant proteins revealed that BIR3-Ring is a specific inhibitor of caspase-9 whereas BIR1-2 is specific for caspases 3 and 7. Therefore XIAP possesses two different caspase inhibitory activities which can be attributed to distinct domains within XIAP. These data may provide an explanation for why IAPs have evolved with multiple BIR domains. [ABSTRACT FROM AUTHOR]

The worldwide shortage of medical-grade ventilators is a well-known issue, that has become one of the central topics during the COVID-19 pandemic. Given that these machines are expensive and have long lead times, one approach is to vacate them for patients in critical conditions while patients with mild to moderate symptoms are treated with stripped-down ventilators. We propose a mass-producible solution that can create such ventilators with minimum effort. The central part is a module that can be attached to CPAP machines and repurpose them as low-pressure ventilators. Here, we describe the concept and first measurements which underline the potential of our solution. Our approach may serve as a starting point for open-access ventilator technologies. [ABSTRACT FROM AUTHOR]

Presents research which concluded that caspases can be directly regulated by protein phosphorylation. What caspases are; Induction of phosphorylation of pro-caspase-9 (pro-Casp9) in cells; Defective cytochrome c-induced proteolytic processing of pro-Casp9; Protease activity of Akt phosphorylated recombinant Casp9; Behavior of mutant pro-Casp9(Ser196Ala); Akt-resistant induction of apoptosis.

Inhibitor of apoptosis (IAP) gene products play an evolutionarily conserved role in regulating programmed cell death in diverse species ranging from insects to humans. Human XIAP, cIAP1 and cIAP2 are direct inhibitors of at least two members of the caspase family of cell death proteases: caspase-3 and caspase-7. Here we compared the mechanism by which IAPs interfere with activation of caspase-3 and other effector caspases in cytosolic extracts where caspase activation was initiated by caspase-8, a proximal protease activated by ligation of TNF-family receptors, or by cytochrome c, which is released from mitochondria into the cytosol during apoptosis. These studies demonstrate that XIAP, cIAP1 and cIAP2 can prevent the proteolytic processing of pro­caspases -3, -6 and -7 by blocking the cytochrome c-induced activation of procaspase-9. In contrast, these IAP family proteins did not prevent caspase-8-induced proteolytic activation of pro-caspase-3; however, they subsequently inhibited active caspase-3 directly, thus blocking downstream apoptotic events such as further activation of caspases. These findings demonstrate that IAPs can suppress different apoptotic pathways by inhibiting distinct caspases and identify pro-caspase-9 as a new target for IAP-mediated inhibition of apoptosis. [ABSTRACT FROM AUTHOR]

Multitemperature (15, 100, 150, 200, 300, 450, 600, 900 K) single crystal neutron diffraction data on the type I clathrate Ba[sub 8]Ga[sub 16]Si[sub 30] are reported. For the framework atoms reciprocal space structural refinements give total occupancies in the unit cell of Ga/Si=3.8/2.2, 1.8/14.2, 10.2/13.8 for the 6c, 16i, and 24k sites respectively, thus showing that Ga avoids the tetrahedral 16i positions. The guest atom displacement parameters obtained from structure factor fitting are analyzed with semianharmonic Einstein models giving Einstein temperatures (Θ[sub E]) of 69(1), 98(7), and 124(2) K for Ba(2)[sub (100)], Ba(2)[sub [100]], and Ba(1), respectively. The analysis furthermore suggests that all guest atoms are structurally disordered, and the disorder appears to be temperature dependent with increased host-guest interaction at high temperatures. The structure factors are subsequently used in the maximum entropy method calculations to obtain direct space nuclear densities. These are modeled with anharmonic one-particle potential models to fourth order. Even at elevated temperatures anharmonicity is limited indicating that the low thermal conductivity of the clathrate has a different origin. © 2002 American Institute of Physics. [ABSTRACT FROM AUTHOR]

Invited for the cover of this issue are Krzysztof Durka and co‐workers at Warsaw University of Technology, University of Warsaw, Silesian University of Technology and Heinrich‐Heine‐Universität. The image depicts the generation of singlet oxygen by the BODIPY photosensitizer. Read the full text of the article at 10.1002/chem.202300680. [ABSTRACT FROM AUTHOR]

Invited for the cover of this issue are Krzysztof Durka and co‐workers at Warsaw University of Technology, University of Warsaw, Silesian University of Technology and Heinrich‐Heine‐Universität. The image depicts the generation of singlet oxygen by the BODIPY photosensitizer. Read the full text of the article at 10.1002/chem.202300680.“The presented strategy is universal, as it opens up new possibilities for the development of efficient photoactive materials for applications in medicine, catalysis and decontamination of pollutants.” This and more about the story behind the front cover can be found in the article at 10.1002/chem.202300680). [ABSTRACT FROM AUTHOR]

Boron, heterocycles, luminescence, photooxidation, structure-property relationship The structures in the left and right corners of the doors are those of bis(benzothienylo)[1,4]thiaborins - basic building blocks of BODIPY. Keywords: boron; heterocycles; luminescence; photooxidation; structure-property relationship EN boron heterocycles luminescence photooxidation structure-property relationship 1 1 1 07/03/23 20230627 NES 230627 B Singlet oxygen is generated b by the BODIPY photosensitizer, whose X-ray structure is shown in the central part of the picture. [Extracted from the article]

Epicutaneous allergen-specific immunotherapy ( EPIT) is proposed as an alternative route for allergen-specific immunotherapy ( AIT). The induction of allergen-specific blocking IgG antibodies represents an important mechanism underlying AIT, but has not been investigated for EPIT. Here, we compared the induction of allergen-specific blocking IgG in outbred guinea pigs which had been immunized with recombinant birch pollen allergen Bet v 1 using patch delivery system ( PDS) with or without heat-labile toxin ( LT) from Escherichia coli or subcutaneously with aluminum hydroxide (Alum)-adsorbed rBet v 1. Only subcutaneous immunization with Alum-adsorbed rBet v 1 and epicutaneous administration of rBet v 1 with PDS in combination with LT from E. coli induced allergen-specific IgG antibodies blocking allergic patients' IgE, but not immunization with rBet v 1 via PDS alone. Our results suggest that patch vaccination with rBet v 1 in combination with LT may be a promising strategy for allergen-specific immunotherapy against birch pollen allergy. [ABSTRACT FROM AUTHOR]

Spin-crossover crystals show multi-step responses to femtosecond light excitation. The local molecular photo-switching from low to high spin states occurs on the sub-picosecond timescale. It is followed by additional conversion due to elastic (ns) and thermal (μs) effects. In [Fe(phen)2(NCS)2] crystals discussed herein, the thermal switching can be made unobtrusive for the investigation of cooperative elastic switching. We evidence a cooperative transformation induced by lattice expansion through elastic coupling between molecules in the crystal, where up to 3 molecules are transformed per photon. [ABSTRACT FROM AUTHOR]

Lysine residues are implicated in driving the ligand binding to the LDL receptor family. However, it has remained unclear how specificity is regulated. Using coagulation factor VIII as a model ligand, we now study the contribution of individual lysine residues in the interaction with the largest member of the LDL receptor family, low-density lipoprotein receptor-related protein (LRP1). Using hydrogen-deuterium exchange mass spectrometry (HDX-MS) and SPR interaction analysis on a library of lysine replacement variants as two independent approaches, we demonstrate that the interaction between factor VIII (FVIII) and LRP1 occurs over an extended surface containing multiple lysine residues. None of the individual lysine residues account completely for LRP1 binding, suggesting an additive binding model. Together with structural docking studies, our data suggest that FVIII interacts with LRP1 via an extended surface of multiple lysine residues that starts at the bottom of the C1 domain and winds around the FVIII molecule. [ABSTRACT FROM AUTHOR]