Effects of various physical treatment methods on arteriolar vasomotion and microhemodynamic functional characteristics in case of deficient regulation of organ blood flow. Results of a placebo-controlled, double-blind study.
As part of a placebo-controlled study, high-resolution measurement methods were used to examine, on the basis of representative functional characteristics of microcirculation, whether and to what extent six different, commercially available, physical treatment devices were suitable for influencing, through complementary therapy, deficient blood-flow regulation. Of the six commercially available devices tested, two proved to be ineffective and three not effective enough to be therapeutically relevant. Only in one device was it possible to show a complementary-therapeutic effect: the device uses a specific, biorhythmically defined stimulus for vasomotion.


Maternal plasma folate impacts differential DNA methylation in an epigenome-wide meta-analysis of newborns.
Folate is vital for fetal development. Periconceptional folic acid supplementation and food fortification are recommended to prevent neural tube defects. Mechanisms whereby periconceptional folate influences normal development and disease are poorly understood: epigenetics may be involved. We examine the association between maternal plasma folate during pregnancy and epigenome-wide DNA methylation using Illumina's HumanMethyl450 Beadchip in 1,988 newborns from two European cohorts. Here we report the combined covariate-adjusted results using meta-analysis and employ pathway and gene expression analyses. Four-hundred forty-three CpGs (320 genes) are significantly associated with maternal plasma folate levels during pregnancy (false discovery rate 5%); 48 are significant after Bonferroni correction. Most genes are not known for folate biology, including APC2, GRM8, SLC16A12, OPCML, PRPH, LHX1, KLK4 and PRSS21. Some relate to birth defects other than neural tube defects, neurological functions or varied aspects of embryonic development. These findings may inform how maternal folate impacts the developing epigenome and health outcomes in offspring.


Accumulation of beneficial mutations in one dimension.
When beneficial mutations are relatively common, competition between multiple unfixed mutations can reduce the rate of fixation in well-mixed asexual populations. We introduce a one-dimensional model with a steady accumulation of beneficial mutations. We find a transition between periodic selection and multiple-mutation regimes. In the multiple-mutation regime, the increase of fitness along the lattice bears a striking similarity to surface growth phenomena, with power-law growth and saturation of the interface width. We also find significant differences compared to the well-mixed model. In our lattice model, the transition between regimes happens at a much lower mutation rate due to slower fixation times in one dimension. Also, the rate of fixation is reduced with increasing mutation rate due to the more intense competition, and it saturates with large population size.


A community-based comprehensive intervention to reduce cardiovascular risk in hypertension (HOPE 4): a cluster-randomised controlled trial.
Hypertension is the leading cause of cardiovascular disease globally. Despite proven benefits, hypertension control is poor. We hypothesised that a comprehensive approach to lowering blood pressure and other risk factors, informed by detailed analysis of local barriers, would be superior to usual care in individuals with poorly controlled or newly diagnosed hypertension. We tested whether a model of care involving non-physician health workers (NPHWs), primary care physicians, family, and the provision of effective medications, could substantially reduce cardiovascular disease risk. HOPE 4 was an open, community-based, cluster-randomised controlled trial involving 1371 individuals with new or poorly controlled hypertension from 30 communities (defined as townships) in Colombia and Malaysia. 16 communities were randomly assigned to control (usual care, n=727), and 14 (n=644) to the intervention. After community screening, the intervention included treatment of cardiovascular disease risk factors by NPHWs using tablet computer-based simplified management algorithms and counselling programmes; free antihypertensive and statin medications recommended by NPHWs but supervised by physicians; and support from a family member or friend (treatment supporter) to improve adherence to medications and healthy behaviours. The primary outcome was the change in Framingham Risk Score 10-year cardiovascular disease risk estimate at 12 months between intervention and control participants. The HOPE 4 trial is registered at ClinicalTrials.gov, NCT01826019. All communities completed 12-month follow-up (data on 97% of living participants, n=1299). The reduction in Framingham Risk Score for 10-year cardiovascular disease risk was -6·40% (95% CI 8·00 to -4·80) in the control group and -11·17% (-12·88 to -9·47) in the intervention group, with a difference of change of -4·78% (95% CI -7·11 to -2·44, p<0·0001). There was an absolute 11·45 mm Hg (95% CI -14·94 to -7·97) greater reduction in systolic blood pressure, and a 0·41 mmol/L (95% CI -0·60 to -0·23) reduction in LDL with the intervention group (both p<0·0001). Change in blood pressure control status (<140 mm Hg) was 69% in the intervention group versus 30% in the control group (p<0·0001). There were no safety concerns with the intervention. A comprehensive model of care led by NPHWs, involving primary care physicians and family that was informed by local context, substantially improved blood pressure control and cardiovascular disease risk. This strategy is effective, pragmatic, and has the potential to substantially reduce cardiovascular disease compared with current strategies that are typically physician based. Canadian Institutes of Health Research; Grand Challenges Canada; Ontario SPOR Support Unit and the Ontario Ministry of Health and Long-Term Care; Boehringer Ingelheim; Department of Management of Non-Communicable Diseases, WHO; and Population Health Research Institute. VIDEO ABSTRACT.


Notch signaling regulates endocrine cell specification in the zebrafish anterior pituitary.
The vertebrate pituitary gland is a key endocrine control organ that contains six distinct hormone secreting cell types. In this study, we analyzed the role of direct cell-to-cell Delta-Notch signaling in zebrafish anterior pituitary cell type specification. We demonstrate that initial formation of the anterior pituitary placode is independent of Notch signaling. Later however, loss of Notch signaling in mind bomb (mib) mutant embryos or by DAPT treatment leads to increased numbers of lactotropes and loss of corticotropes in the anterior pars distalis (APD), increased number of thyrotropes and loss of somatotrope cell types in the posterior pars distalis (PPD), and fewer melanotropes in the posterior region of the adenohypophysis, the pars intermedia (PI). Conversely, Notch gain of function leads to the opposite result, loss of lactotrope and thyrotrope cell specification, and an increased number of corticotropes, melanotropes, and gonadotropes in the pituitary. Our results suggest that Notch acts on placodal cells, presumably as a permissive signal, to regulate progenitor cell specification to hormone secreting cell types. We propose that Notch mediated lateral inhibition regulates the relative numbers of specified hormone cell types in the three pituitary subdomains.


Electrocardiographically gated multi-detector row CT for assessment of valvular morphology and calcification in aortic stenosis.
To evaluate the applicability and image quality of nonenhanced and contrast material-enhanced multi-detector row computed tomography (CT) combined with retrospective electrocardiographic (ECG) gating for visualization of the aortic valve, determination of aortic valve morphology and diameter of the aortic valve annulus, and assessment of the degree of valvular calcification in patients with aortic valve stenosis, as compared with results of surgery and echocardiography. Prior to surgical valve replacement, 25 patients with aortic valve stenosis and sinus rhythm underwent nonenhanced (n = 15) and contrast-enhanced (n = 25) retrospectively ECG-gated multi-detector row CT. Two readers working in consensus evaluated image quality and assessed valvular morphology and the degree of valvular calcification. In addition, the diameter of the aortic valve annulus was measured. Results were compared with surgical and echocardiographic findings by using the paired sign test, kappa statistics, and the method of Bland and Altman. The aortic valve could be visualized nearly free of motion artifacts on all multi-detector row CT images. Image quality and diagnostic confidence for classification of aortic valve morphology were significantly superior on contrast-enhanced rather than nonenhanced images (P =.004 and P =.006, respectively). Nonenhanced and contrast-enhanced CT showed good agreement with surgical findings with regard to quantification of the degree of aortic valve calcification (kappa = 0.77 and kappa = 0.74, respectively). Measurement of the diameter of the aortic valve annulus was more reliable on contrast-enhanced images. Contrast-enhanced retrospectively ECG-gated multi-detector row CT allows determination of aortic valve morphology, measurement of the diameter of the aortic valve annulus, and assessment of the degree of aortic valve calcification in patients with aortic stenosis.


International Law, COVID-19 and Feminist Engagement with the United Nations Security Council: The End of the Affair?
The gendered implications of COVID-19, in particular in terms of gender-based violence and the gendered division of care work, have secured some prominence, and ignited discussion about prospects for a 'feminist recovery'. In international law terms, feminist calls for a response to the pandemic have privileged the United Nations Security Council (UNSC), conditioned-I argue-by two decades of the pursuit of the Women, Peace and Security (WPS) agenda through the UNSC. The deficiencies of the UNSC response, as characterised by the Resolution 2532 adopted to address the pandemic, manifest yet again the identified deficiencies of the WPS agenda at the UNSC, namely fragmentation, securitisation, efficacy and legitimacy. What Resolution 2532 does bring, however, is new clarity about the underlying reasons for the repeated and enduring nature of these deficiencies at the UNSC. Specifically, the COVID-19 'crisis' is powerful in exposing the deficiencies of the crisis framework in which the UNSC operates. My reflections draw on insights from Hilary Charlesworth's seminal contribution 'International Law: A Discipline of Crisis' to argue that, instead of conceding the 'crisis' framework to the pandemic by prioritising the UNSC, a 'feminist recovery' must instead follow Charlesworth's exhortation to refocus on an international law of the everyday.


Laparoscopic removal of gonads in women with abnormal karyotypes.
The objective of this study was to evaluate if laparoscopy can be an acceptable alternative to laparotomy for gonadectomy in women with gonadal dysgenesis (46,XY karyotype or 45,X karyotype with evidence of hyperandrogenism). We retrospectively analyzed five cases of gonadal dysgenesis that were managed by laparoscopic gonadectomy. All five patients underwent laparoscopic gonadectomy performed at a day surgery unit of a university medical center without any complications and were discharged the same day. The average operative time was 72 minutes (range, 35-95), the average blood loss was 20 mL, and the average cost was $4,380. We conclude that laparoscopic gonadectomy is a safe, effective and economical procedure to perform on patients with Y chromosomes or evidence of abnormal gonads. Laparoscopy should be accepted as the treatment of choice in these patients by physicians experienced in pelviscopic surgery.


Conversion of the Abdominal Aortic and Junctional Tourniquet (AAJT) to Infrarenal Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) Is Practical in a Swine Hemorrhage Model.
Two methods of controlling pelvic and inguinal hemorrhage are the Abdominal Aortic and Junctional Tourniquet (AAJT; Compression Works) and resuscitative endovascular balloon occlusion of the aorta (REBOA). The AAJT can be applied quickly, but prolonged use may damage the bowel, inhibit ventilation, and obstruct surgical access. REBOA requires technical proficiency but avoids many of the complications associated with the AAJT. Conversion of the AAJT to REBOA would allow for field hemorrhage control with mitigation of the morbidity associated with prolonged AAJT use. Yorkshire male swine (n = 17; 70-90kg) underwent controlled 40% hemorrhage. Subsequently, AAJT was placed on the abdomen, midline, 2cm superior to the ilium, and inflated. After 1 hour, the animals were allocated to an additional 30 minutes of AAJT inflation (continuous AAJT occlusion [CAO]), REBOA placement with the AAJT inflated (overlapping aortic occlusion [OAO]), or REBOA placement following AAJT removal (sequential aortic occlusion [SAO]). Following removal, animals were observed for 3.5 hours. No statistically significant differences in survival, blood pressure, or laboratory values were found following intervention. Conversion to REBOA was successful in all animals but one in the OAO group. REBOA placement time was 4.3 ± 2.9 minutes for OAO and 4.1 ± 1.8 minutes for SAO (p = .909). No animal had observable intestinal injury. Conversion of the AAJT to infrarenal REBOA is practical and effective, but access may be difficult while the AAJT is applied.


Unintentional Firearm Injury Deaths Among Children and Adolescents Aged 0-17 Years - National Violent Death Reporting System, United States, 2003-2021.
In the United States, unintentional injury is the fourth leading cause of death among infants (i.e., children aged <1 year) and is the top cause of death among children and adolescents aged 1-17 years; firearms are a leading injury method. Unsecured firearms (e.g., unlocked and loaded) are associated with risk for unintentional childhood firearm injury death. Data recorded during 2003-2021 by the National Violent Death Reporting System (NVDRS) from 49 states, the District of Columbia, and Puerto Rico were used to characterize unintentional firearm injury deaths of U.S. infants, children, and adolescents aged 0-17 years (referred to as children in this report). NVDRS identified 1,262 unintentional firearm injury deaths among children aged 0-17 years: the largest percentage (33%) of these deaths were among children aged 11-15 years, followed by 29% among those aged 0-5 years, 24% among those aged 16-17 years, and 14% among persons aged 6-10 years. Overall, 83% of unintentional firearm injury deaths occurred among boys. The majority (85%) of victims were fatally injured at a house or apartment, including 56% in their own home. Approximately one half (53%) of fatal unintentional firearm injuries to children were inflicted by others; 38% were self-inflicted. In 9% of incidents, it was unknown whether the injury was self- or other-inflicted. Approximately two thirds (67%) of shooters were playing with or showing the firearm to others when it discharged. Overall, firearms used in unintentional injury deaths were often stored loaded (74%) and unlocked (76%) and were most commonly accessed from nightstands and other sleeping areas (30%). Unintentional firearm injury deaths of children are preventable. Secured firearm storage practices (e.g., storing firearms locked, unloaded, and separate from ammunition) have been identified as protective factors against child firearm injuries and deaths, underscoring the importance of policymakers, health care professionals (e.g., pediatricians), and others partnering with parents, caregivers, and firearm owners to promote secure firearm storage.


Novel Protein Biomarkers of Monoamine Metabolism Defects Correlate with Disease Severity.
Genetic defects of monoamine neurotransmitters are rare neurological diseases amenable to treatment with variable response. They are major causes of early parkinsonism and other spectrum of movement disorders including dopa-responsive dystonia. The objective of this study was to conduct proteomic studies in cerebrospinal fluid (CSF) samples of patients with monoamine defects to detect biomarkers involved in pathophysiology, clinical phenotypes, and treatment response. A total of 90 patients from diverse centers of the International Working Group on Neurotransmitter Related Disorders were included in the study (37 untreated before CSF collection, 48 treated and 5 unknown at the collection time). Clinical and molecular metadata were related to the protein abundances in the CSF. Concentrations of 4 proteins were significantly altered, detected by mass spectrometry, and confirmed by immunoassays. First, decreased levels of apolipoprotein D were found in severe cases of aromatic L-amino acid decarboxylase deficiency. Second, low levels of apolipoprotein H were observed in patients with the severe phenotype of tyrosine hydroxylase deficiency, whereas increased concentrations of oligodendrocyte myelin glycoprotein were found in the same subset of patients with tyrosine hydroxylase deficiency. Third, decreased levels of collagen6A3 were observed in treated patients with tetrahydrobiopterin deficiency. This study with the largest cohort of patients with monoamine defects studied so far reports the proteomic characterization of CSF and identifies 4 novel biomarkers that bring new insights into the consequences of early dopaminergic deprivation in the developing brain. They open new possibilities to understand their role in the pathophysiology of these disorders, and they may serve as potential predictors of disease severity and therapies. © 2020 International Parkinson and Movement Disorder Society.


The adjuvant effect of TLR agonists on CD4(+) effector T cells is under the indirect control of regulatory T cells.
TLR agonists have been suggested to directly impact Tregs, thereby enhancing or reversing their suppressive function. Here, in order to select TLR agonists leading to potent effector T-cell responses, while minimizing Treg inhibitory function, we used a model antigen, covalently linked to an inert delivery system, combined with a large panel of TLR agonists, for the immunization of mice with an attenuated/depleted or intact Treg subset. We observed that the negative modulation of effector CD4(+) T cells exerted by Tregs cannot be circumvented, whatever the TLR agonist used as adjuvant. To better understand the impact of TLR agonists on Tregs, we investigated (i) the TLR expression profile of highly purified CD4(+) Foxp3(+) Tregs, at steady state or subsequent to in vivo activation by TLR agonists and (ii) the Treg phenotype after in vivo and in vitro activation by TLR agonists. Our results demonstrate that TLR agonists, as single signal inducers, are not able to directly activate Tregs. The phenotypic Treg activation observed in vivo, following TLR administration, does not result from cross-talk with conventional T cells but is rather a consequence of the interaction with other immune cell type(s).


Excited-State Tautomerization of 7-Azaindole in Nonpolar Solution: A Theoretical Study Based on Liquid-Phase Potential Surfaces of Mean Force.
Excited state tautomerization of a 7-azaindole (7AI) complex with one methanol molecule in heptane was studied using variational transition state theory including multidimensional tunneling (VTST/MT) with the dielectric continuum model for the solvent effect. Electronic structures and energies for reactants and transition state (TS) in solution were computed at the complete active space self-consistent field (CASSCF) level with second-order multireference perturbation theory (MRPT2) to take into consideration of dynamic electron correlation. The polarizable continuum model using the integral equation formalism (IEFPCM) and the SMD model were used for the excited-state solvent effect. Excited-state surfaces of potential of the mean force in solution were generated for the first time at the MRPT2//SMD/CASSCF(10,9)/6-31G(d,p) level. The position of TS on the reaction coordinate substantially depended on the dynamic electron correlation. The two protons in the excited-state tautomerization were transferred in a concerted but asynchronous process. Calculated HH/DD kinetic isotope effect (KIE) and the ratio of Arrhenius pre-exponential factors, A(HH)/A(DD), agreed very well with the corresponding experimental values. The shape of the adiabatic energy surfaces in the excited-state strongly depended on the position of isotopes due to the asynchronicity of the reaction path, and the tunneling effect was essential for reproducing experimental KIEs. The pyrrolic proton moved a twice longer distance by tunneling than the hydroxyl proton in the most probable tunneling path at 292 K. This study strongly suggests that the mechanism of the excited-state double proton transfer in heptane is triggered by proton transfer from the pyrrolic nitrogen of 7AI to alcohol (protolytic pathway), rather than by proton transfer from alcohol to the pyridine nitrogen of 7AI (solvolytic pathway).


Confocal unstable-resonator semiconductor laser.
GaAs/GaAlAs heterostructure lasers with a monolithic confocal unstable resonator were demonstrated. The curved mirrors satisfying the confocal condition were fabricated by etching. Close to threshold, the lasers operate in a single lateral mode with a nearly collimated output beam. A single-lobe far-field intensity distribution as narrow as 1.9 degrees full width at half maximum was measured.


Physical training improves motor performance in people with dementia: a randomized controlled trial.
To determine whether a specific, standardized training regimen can improve muscle strength and physical functioning in people with dementia. Double-blinded, randomized, controlled trial with 3-month intervention and 3-month follow-up period in 2006 to 2009. Outpatient geriatric rehabilitation. Individuals with confirmed mild to moderate dementia, no severe somatic or psychological disease, and ability to walk 10 m. Most participants were still living independently with or without supportive care. Supervised, progressive resistance and functional group training for 3 months specifically developed for people with dementia (intervention, n = 62) compared with a low-intensity motor placebo activity (control, n = 60). Primary outcome measures were one-repetition maximum in a leg press device for maximal strength and duration of the five-chair-stand test for functional performance. Secondary outcome measures were assessed for a number of established parameters for maximal strength, physical function, and physical activity. Training significantly improved both primary outcomes (percentage change from baseline: maximal strength, intervention group (IG): +51.5 ± 41.5 kg vs control group (CG): -1.0 ± 28.9 kg, P < .001; functional performance, IG: -25.9 ± 15.1 seconds vs CG: +11.3 ± 60.4 seconds, P < .001). Secondary analysis confirmed effects for all strength and functional parameters. Training gains were partly sustained during follow-up. Low baseline performance on motor tasks but not cognitive impairment predicted positive training response. Physical activity increased significantly during the intervention (P < .001). The intensive, dementia-adjusted training was feasible and substantially improved motor performance in frail, older people with dementia and may represent a model for structured rehabilitation or outpatient training.


Initial Upper Palaeolithic humans in Europe had recent Neanderthal ancestry.
Modern humans appeared in Europe by at least 45,000 years ago1-5, but the extent of their interactions with Neanderthals, who disappeared by about 40,000 years ago6, and their relationship to the broader expansion of modern humans outside Africa are poorly understood. Here we present genome-wide data from three individuals dated to between 45,930 and 42,580 years ago from Bacho Kiro Cave, Bulgaria1,2. They are the earliest Late Pleistocene modern humans known to have been recovered in Europe so far, and were found in association with an Initial Upper Palaeolithic artefact assemblage. Unlike two previously studied individuals of similar ages from Romania7 and Siberia8 who did not contribute detectably to later populations, these individuals are more closely related to present-day and ancient populations in East Asia and the Americas than to later west Eurasian populations. This indicates that they belonged to a modern human migration into Europe that was not previously known from the genetic record, and provides evidence that there was at least some continuity between the earliest modern humans in Europe and later people in Eurasia. Moreover, we find that all three individuals had Neanderthal ancestors a few generations back in their family history, confirming that the first European modern humans mixed with Neanderthals and suggesting that such mixing could have been common.


Characterization of anergy to the superantigen Staphylococcus enterotoxin B.
In vivo administration of superantigens leads to activation and subsequent depletion or anergy of T cells expressing defined V beta-T cell receptors (TCR). Superantigens have therefore become intensively studied tools for examining parameters of immunoregulation and they may represent model antigens for pathogenic agents. An HIV-encoded superantigen has for example been implicated in the dramatic loss of helper T cells in AIDS. We investigated the response of V beta 8+ T cells in mice after primary and secondary exposure to the superantigen Staphylococcus Enterotoxin B (SEB).


Blood-brain barrier transport and neuroprotective potential of blackberry-digested polyphenols: an in vitro study.
Epidemiological and intervention studies have attempted to link the health effects of a diet rich in fruits and vegetables with the consumption of polyphenols and their impact in neurodegenerative diseases. Studies have shown that polyphenols can cross the intestinal barrier and reach concentrations in the bloodstream able to exert effects in vivo. However, the effective uptake of polyphenols into the brain is still regarded with some reservations. Here we describe a combination of approaches to examine the putative transport of blackberry-digested polyphenols (BDP) across the blood-brain barrier (BBB) and ultimate evaluation of their neuroprotective effects. BDP was obtained by in vitro digestion of blackberry extract and BDP major aglycones (hBDP) were obtained by enzymatic hydrolysis. Chemical characterization and BBB transport of extracts were evaluated by LC-MSn. BBB transport and cytoprotection of both extracts was assessed in HBMEC monolayers. Neuroprotective potential of BDP was assessed in NT2-derived 3D co-cultures of neurons and astrocytes and in primary mouse cerebellar granule cells. BDP-modulated genes were evaluated by microarray analysis. Components from BDP and hBDP were shown to be transported across the BBB. Physiologically relevant concentrations of both extracts were cytoprotective at endothelial level and BDP was neuroprotective in primary neurons and in an advanced 3D cell model. The major canonical pathways involved in the neuroprotective effect of BDP were unveiled, including mTOR signaling and the unfolded protein response pathway. Genes such as ASNS and ATF5 emerged as novel BDP-modulated targets. BBB transport of BDP and hBDP components reinforces the health benefits of a diet rich in polyphenols in neurodegenerative disorders. Our results suggest some novel pathways and genes that may be involved in the neuroprotective mechanism of the BDP polyphenol components.


RHIPILIA COPPEJANSII, A NEW CORAL REEF-ASSOCIATED SPECIES FROM GUAM (BRYOPSIDALES, CHLOROPHYTA)(1).
The new species Rhipilia coppejansii is described from Guam. This species, which has the external appearance of a Chlorodesmis species, features tenacula upon microscopical examination, a diagnostic character of Rhipilia. This unique morphology, along with the tufA and rbcL data presented herein, set this species apart from others in the respective genera. Phylogenetic analyses show that the taxon is nested within the Rhipiliaceae. We discuss the diversity and possible adaptation of morphological types in the Udoteaceae and Rhipiliaceae.


Ab initio derivation of multi-orbital extended Hubbard model for molecular crystals.
From configuration interaction (CI) ab initio calculations, we derive an effective two-orbital extended Hubbard model based on the gerade (g) and ungerade (u) molecular orbitals (MOs) of the charge-transfer molecular conductor (TTM-TTP)I(3) and the single-component molecular conductor [Au(tmdt)(2)]. First, by focusing on the isolated molecule, we determine the parameters for the model Hamiltonian so as to reproduce the CI Hamiltonian matrix. Next, we extend the analysis to two neighboring molecule pairs in the crystal and we perform similar calculations to evaluate the inter-molecular interactions. From the resulting tight-binding parameters, we analyze the band structure to confirm that two bands overlap and mix in together, supporting the multi-band feature. Furthermore, using a fragment decomposition, we derive the effective model based on the fragment MOs and show that the staking TTM-TTP molecules can be described by the zig-zag two-leg ladder with the inter-molecular transfer integral being larger than the intra-fragment transfer integral within the molecule. The inter-site interactions between the fragments follow a Coulomb law, supporting the fragment decomposition strategy.


Venous thromboembolism prophylaxis in patients undergoing cranial neurosurgery: a systematic review and meta-analysis.
Randomized clinical trials (RCTs) have usually supported using heparin prophylaxis against venous thromboembolism (VTE) in patients undergoing cranial neurosurgery. The tradeoff between benefit and bleeding risk, however, has not been adequately characterized. To conduct a systematic review and meta-analysis assessing the extent to which low-dose unfractionated heparin (LDUH) or low-molecular-weight heparin (LMWH) prophylaxis reduces the rate of VTE and increases the rate of intracerebral hemorrhage (ICH) and other bleeding in patients undergoing elective cranial neurosurgery. We selected RCTs that evaluated LDUH or LMWH prophylaxis of VTE in patients undergoing elective cranial neurosurgery. A meta-analysis assessing heparins vs no heparin (either with or without mechanical methods) was performed. Eight RCTs were identified. Six RCTs involving 1170 patients evaluated LDUH or LMWH vs a control group. Five of 6 trials found a significant reduction in the risk of symptomatic and asymptomatic VTE with heparin prophylaxis. The pooled risk ratio was 0.58 (95% confidence interval, 0.45-0.75). ICH was more common in those receiving heparin, but not statistically significantly. For every 1000 patients who receive heparin prophylaxis, 91 VTE events will be prevented (approximately 35 of which are proximal deep vein thrombosis or pulmonary embolism and 9 to 18 of which are symptomatic), whereas 7 ICHs and 28 more minor bleeds will occur. Heparin prophylaxis for patients undergoing elective cranial neurosurgery reduces the risk of VTE but may also increase bleeding risks with a ratio of serious or symptomatic VTE relative to serious bleeding that is only slightly favorable.


QTL for resistance to root lesion nematode (Pratylenchus thornei) from a synthetic hexaploid wheat source.
A whole genome average interval mapping approach identified eight QTL associated with P. thornei resistance in a DH population from a cross between the synthetic-derived wheat Sokoll and cultivar Krichauff. Pratylenchus thornei are migratory nematodes that feed and reproduce within the wheat root cortex, causing cell death (lesions) resulting in severe yield reductions globally. Genotypic selection using molecular markers closely linked to Pratylenchus resistance genes will accelerate the development of new resistant cultivars by reducing the need for laborious and expensive resistance phenotyping. A doubled haploid wheat population (150 lines) from a cross between the synthetic-derived cultivar Sokoll (P. thornei resistant) and cultivar Krichauff (P. thornei moderately susceptible) was used to identify quantitative trait loci (QTL) associated with P. thornei resistance. The resistance identified in the glasshouse was validated in a field trial. A genetic map was constructed using Diversity Array Technology and the QTL regions identified were further targeted with simple sequence repeat (SSR) and single-nucleotide polymorphism (SNP) markers. Six significant and two suggestive P. thornei resistance QTL were detected using a whole genome average interval mapping approach. Three QTL were identified on chromosome 2B, two on chromosome 6D, and a single QTL on each of chromosomes 2A, 2D and 5D. The QTL on chromosomes 2BS and 6DS mapped to locations previously identified to be associated with Pratylenchus resistance. Together, the QTL on 2B (QRlnt.sk-2B.1-2B.3) and 6D (QRlnt.sk-6D.1 and 6D.2) explained 30 and 48 % of the genotypic variation, respectively. Flanking PCR-based markers based on SSRs and SNPs were developed for the major QTL on 2B and 6D and provide a cost-effective high-throughput tool for marker-assisted breeding of wheat with improved P. thornei resistance.


Fatigue life of preceramic soldered and postceramic soldered joints.
This research investigated the fatigue life (ie, the number of cycles of a given stress that can be sustained by a sample prior to catastrophic failure) of metal ceramic soldering. One metal ceramic alloy was joined using four postceramic solders and one preceramic solder. All specimens received appropriate heat treatment simulating ceramic application although no porcelain was applied. Five specimens were fabricated for each solder type, and a 35,000 psi (241.4 MPa) fatigue stress was applied to each solder joint during specimen testing. The test variable was the number of stress cycles required to fail each specimen. The postceramic solders exhibited significantly higher fatigue lives than did the preceramic solder. Scanning electron microscope analysis showed that the preceramic solder not only exhibited a larger grain size, but also showed micropores between these grains.


Intracardiac Metastases Detected by 18F-FSPG PET/CT.
PET/CT imaging is frequently used for cancer diagnosis and restaging as metabolically active cells, including cancer, utilize glucose for proliferation. F-FDG is the most commonly utilized radiopharmaceutical in PET/CT imaging. Limitations of F-FDG imaging include intense physiologic uptake in benign tissues such as the brain and myocardium. We present a case of non-small cell lung cancer with myocardial and pericardial metastases obscured by physiologic F-FDG cardiac uptake but detected with the investigational PET radiotracer (4S)-4-(3-F-fluoropropyl)-L-glutamate (F-FSPG), which targets a pathway associated with glutathione biosynthesis. This case demonstrates the added value of F-FSPG PET/CT imaging.


Fatty acid compositions in local sea cucumber, Stichopus chloronotus, for wound healing.
Fatty acid profile from crude extracts of local sea cucumber Stichopus chloronotus was determined using gas chromatography (GC) technique. The extracts were prepared separately in methanol, ethanol, phosphate buffer saline (PBS), and distilled water as part of our study to look at the affinity of these solvents in extracting the lipid from sea cucumber. The PBS and distilled water extractions indicate water-soluble components, while the organic fractions are extracted in methanol and ethanol as organic solvents. Furthermore, water extraction is the conventional method practiced in Malaysia. In our analysis the C14:0 (myristic), C16:0 (palmitic), C18:0 (stearic), C18:2 (linoleic), C20:0 (arachidic), and C20:5 (eicosapentaenoic, EPA) were significantly different (p < 0.01) in the four solvent extractions. However, the PBS extraction contained a much higher percentage of EPA (25.69%) compared to 18.89% in ethanol, 7.84% in distilled water, and only 5.83% in methanol, and variances were significantly different (p < 0.01 ). On the other hand, C22:6 (docosahexaenoic acid or DHA) is much higher in water extraction (57.55%), in comparison to the others where only 3.63% in PBS and 1.20% in methanol, and this difference is significant at p < 0.01. No DHA was detected in ethanol extractions. Subsequently, C18:1 (oleic acid) was only detected in PBS (21.98%) and water extraction (7.50%). It is interesting that palmitic acid, C16:() was higher in methanol (20.82%) and ethanol (2.18%), while 12.55% was detected in PBS and only 2.20% in water extraction: and again this was significantly different at p < 0.01. Although our results have shown that all four solvents were different in terms of their ability to extract fatty acids, the major component for tissue repair was well preserved. Probably this is one of the important precocious steps when working with a delicate sea cucumber, in both experimental and/or at the preparative stages. Freshness of the sea cucumber samples is important when undertaking this type of experiment. Finally, we believe that the local sea cucumber S. chloronotus contains all the fatty acids required to play a potential active role in tissue repair.


Rheological analysis of the adhesive interactions of red blood cells parasitized by Plasmodium falciparum.
Adhesion of parasitized red blood cells (RBCs) to vascular endothelium is thought to be a key factor in the pathology of falciparum malaria. However, quantitative analyses of the intercellular forces and of the effects of flow on adhesion have been lacking. We have characterized cytoadhesion of RBCs parasitized by the strains ITO4 (which can bind to receptors ICAM-1 or CD36) and FCR3A2 (which can bind to CD36 only) using micropipette manipulation and flow chamber techniques. Target cells were unfixed or glutaraldehyde-fixed human umbilical vein endothelial cells (HUVEC, bearing ICAM-1 only) or human amelanotic melanoma cells (C32, bearing CD36 and ICAM-1). In the static, micropipette assay, 60% to 70% of parasitized cells would adhere when tested at up to three successive sites. The percentage of cells adhering and the force required for their detachment (approximately 10(-10) N) were similar for each combination of parasite strain and adhesion target (ITO4/HUVEC, ITO4/C32, FCR3A2/C32). In the flow chamber, efficiency of initial adhesion of parasitized cells was essentially constant (at about 1%) up to a stress of 0.1 Pa, and then decreased rapidly with increasing stress. Either receptor (ICAM-1 or CD36) could immobilize flowing cells at a physiologic flow stress (0.1 Pa), but the numbers of cells adhering varied for the different combinations (ITO4/C32 greater than ITO4/HUVEC greater than FCR3A2/C32). When flow was increased in steps, adhered cells were gradually washed off but many could withstand stresses at which they would not initially adhere. The force for detachment estimated in this way was similar to the pipette value, and again, was similar for the different combinations of strains and targets. Adhesion from flow depends on the affinity between surfaces being above a critical level, and once adhesion is established, the fracture energy determines resistance to disruption of adhesion. The results show that the fracture energy is greater than the affinity (ie, that adhesion becomes stabilized after it is initially established) and that the ratio of affinity to fracture energy is different for different receptor/ligand pairs, with ICAM-1 appearing to be the more efficient immobilizing receptor. Also, static and flow-based assays of adhesion clearly differ; the affinity is less critical in the static situation, so that most parasitized cells were capable of adhering in a static assay, but fewer did so under flow. Adhesiveness varied markedly from cell to cell, both for targets and parasitized cells.(ABSTRACT TRUNCATED AT 400 WORDS)


Motor Consciousness during Intention-Based and Stimulus-Based Actions: Modulating Attention Resources through Mindfulness Meditation.
Mindfulness-Based Stress Reduction meditation (MBSR) may offer optimal performance through heightened attention for increased body consciousness. To test this hypothesis, MBSR effects were assessed on the simple task of lifting an object. A dual task paradigm was included to assess the opposite effect of a limited amount of attention on motor consciousness. In a stimulus-based condition, the subjects' task was to lift an object that was hefted with weights. In an intentional-based condition, subjects were required to lift a light object while imagining that the object was virtually heavier and thus, adjust their grip voluntarily. The degree of motor consciousness was evaluated by calculating correlation factors for each participant between the grip force level used during the lift trial ("lift the object") and that used during its associated reproduce trial ("without lifting, indicate the force you think you used in the previous trial"). Under dual task condition, motor consciousness decreased for intention- and stimulus-based actions, revealing the importance of top-down attention for building the motor representation that guides action planning. For MBSR-experts, heightened attention provided stronger levels of motor consciousness; this was true for both intention and stimulus-based actions. For controls, heightened attention decreased the capacity to reproduce force levels, suggesting that voluntary top-down attention interfered with the automatic bottom-up emergence of body sensations. Our results provide strong arguments for involvement of two types of attention for the emergence of motor consciousness. Bottom-up attention would serve as an amplifier of motor-sensory afferences; top-down attention would help transfer the motor-sensory content from a preconscious to a conscious state of processing. MBSR would be a specific state for which both types of attention are optimally combined to provide experts with total experiences of their body in movement.


Diagnostic Delay in Rheumatoid Arthritis: A Qualitative Study of Symptom Interpretation Before the First Visit to the Doctor.
To prevent joint damage among patients with rheumatoid arthritis (RA), there is a need to minimize delays from the onset of symptoms until the initiation of appropriate therapy. The present study explored the factors that have an impact on the time it takes for Danish patients with RA to approach their general practitioner (GP) with joint pain, and also how GPs respond to patients' complaints. The study was based on qualitative data collected using 11 semi-structured individual interviews. When symptoms were obvious to patients, there was a shorter delay between symptom onset and contacting their GP. In cases where symptoms gradually worsened or were difficult to interpret, there was a longer delay. Participants with a high degree of body awareness appeared to be good at detecting when something was not normal, and they responded quickly to their symptoms. For those who regarded the doctor as a resource to which they were entitled and who were not worried about getting a diagnosis there was a shorter delay. Diffuse symptoms seemed to confuse GPs and can contribute to physician delay in the investigation process. Similarly, the presence of other diseases can result in a prolonged period before referral to a rheumatologist. The nature and severity of symptoms are the deciding factors in their interpretation, by both the GP and the patient. Both the patient's disease recognition and his/her subsequent interaction with the doctor is influenced by the patient's body awareness and general attitude towards going to the doctor. The results showed that the greater the patient's body awareness, the better the disease recognition, the fewer barriers to contacting the GP and the shorter the delay in doing so. Copyright © 2015 John Wiley & Sons, Ltd.


Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions.
Nitric oxide generated by the inducible form of nitric oxide synthase (iNOS) may contribute to the pathogenesis of multiple sclerosis (MS). In this report, we studied postmortem tissues of MS patients for the expression of iNOS by in situ hybridization and immunocytochemistry. Immunocytochemistry for nitrotyrosine, a putative footprint for peroxynitrite formation was also performed. In acute MS lesions, intense reactivity for iNOS mRNA and protein was detected in reactive astrocytes throughout the lesion and in adjacent normal appearing white matter. Staining of macrophages, inflammatory cell infiltrates, and endothelial cells was variable from case to case, but generally detected only in acute lesions. In chronic MS lesions reactive astrocytes at the lesion edge were positive for iNOS whereas the lesion center was nonreactive. Normal appearing white matter demonstrated little reactivity, as did tissues from noninflamed control brains. Staining for nitrotyrosine was also detected in acute but not chronic MS lesions, and displayed a diffuse parenchymal, membranous, and perivascular pattern of immunoreactivity. These results support the conclusion that iNOS is induced in multiple cell types in MS lesions and that astrocyte-derived nitric oxide could be important in orchestrating inflammatory responses in MS, particularly at the blood-brain barrier.


Hormone-dependent regulation of chicken progesterone receptor deoxyribonucleic acid binding and phosphorylation.
To further understand the structure-function relationships of the chicken oviduct progesterone receptor, the effects of in vivo and in situ progesterone treatment were studied. Immunoprecipitated receptors isolated from oviduct slices incubated in the presence of H(3)32PO4 exhibited hormone-dependent phosphorylation. This was correlated with an increase in the apparent mol wt of receptors when analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and increased DNA binding of total cytosolic receptors. Further, in vivo progesterone treatment resulted in dissociation of both the A and B receptor forms from nonhormone-binding proteins (such as heat shock protein-90) in vitro when analyzed by sucrose gradient ultracentrifugation. The 4S and 8S receptors were separated by phosphocellulose column chromatography, treated with ammonium sulfate to convert all receptors to DNA-binding forms, and analyzed for binding to DNA cellulose. The 4S receptor produced as a consequence of in vivo hormone treatment had a 3.35-fold higher affinity for DNA and bound to about a 3-fold greater extent than receptor that did not show altered interaction with other proteins. Thus, in vivo progesterone treatment results in increased receptor phosphorylation, altered interaction with heat shock protein-90, and increased DNA binding.


H-2 class I knockout, HLA-A2.1-transgenic mice: a versatile animal model for preclinical evaluation of antitumor immunotherapeutic strategies.
H-2 class I-negative, HLA-A2.1-transgenic HHD mice were used for a comparative evaluation of the immunogenicity of HLA-A2.1-restricted human tumor-associated cytotoxic T lymphocyte (CTL) epitopes. A hierarchy was established among these peptides injected into mice in incomplete Freund's adjuvant which correlates globally with their capacity to bind and stabilize HLA-A2.1 molecules. Co-injection of a helper peptide enhanced most CTL responses. In contrast, classical HLA class I-transgenic mice which still express their own class I molecules did not, in most cases, develop HLA-A2.1-restricted CTL responses under the same experimental conditions. Different monoepitope immunization strategies of acceptable clinical usage were compared in HHD mice. Recombinant Ty-virus-like particles, or DNA encoding epitopes fused to the hepatitis B virus middle envelope protein gave the best results. Using this latter approach and a melanoma-based polyepitope construct, CTL responses against five distinct epitopes could be elicited simultaneously in a single animal. Thus, HHD mice provide a versatile animal model for preclinical evaluation of peptide-based cancer immunotherapy.


Effect of electroacupuncture in patients with post-stroke motor aphasia : Neurolinguistic and neuroimaging characteristics.
In this study we investigated the neurolinguistic and neuroimaging characteristics of post-stroke motor aphasia patients. The effects of acupuncture on cortex activation by using magnetic resonance imaging (MRI) in patients with motor aphasia were also studied. In this study 43 patients with motor aphasia after stroke were assessed according to Clinical Rehabilitation Research Center aphasia examination (CRRCAE) for linguistic evaluation and MRI and computed tomography (CT) were used for the analyses of brain lesions. The MRI imaging data were also examined using statistical parametric mapping (SPM8) software. Cortex activation images during acupuncture were analyzed using generalized linear model analysis. The results of MRI and CT showed diverse brain lesion regions of post-stroke motor aphasia including the cortex, subcortex and cortex together with the subcortex. The language-related brain areas are activated by acupuncture including frontal, temporal, parietal and occipital lobes as well as insula, precuneus and other wide range of brain function areas as shown by MRI. Our study showed that the brain lesion regions in post-stroke motor aphasia were not completely consistent with the classical motor speech center. By using MRI our study results suggest that the formation of cognitive language may be involved with the cortical-subcortical functional networks. Acupuncture may be useful for treatment of motor aphasia after stroke.


Surveillance for waterborne-disease outbreaks--United States, 1993-1994.
Since 1971, CDC and the U.S. Environmental Protection Agency have maintained a collaborative surveillance system for collecting and periodically reporting data that relate to occurrences and causes of waterborne-disease outbreaks (WBDOs). This summary includes data for January 1993 through December 1994 and for previously unreported outbreaks in 1992. The surveillance system includes data about outbreaks associated with water intended for drinking (i.e., drinking water) and those associated with recreational water. State, territorial, and local public health departments are primarily responsible for detecting and investigating WBDOs and voluntarily reporting them to CDC on a standard form. For the 2-year period 1993-1994, 17 states and one territory reported a total of 30 outbreaks associated with drinking water. These outbreaks caused an estimated 405,366 persons to become ill, including 403,000 from an outbreak of cryptosporidiosis in Milwaukee, the largest WBDO ever documented in the United States, and 2,366 from the other 29 outbreaks. No etiologic agent was identified for five (16.7%) of the 30 outbreaks. The protozoan parasites Giardia lamblia and Cryptosporidium parvum caused 10 (40.0%) of the 25 outbreaks for which the etiologic agent was identified. Two outbreaks of cryptosporidiosis occurred in large metropolitan areas (i.e., Milwaukee and Las Vegas/Clark County) and were associated with deaths among immunocompromised persons. The waterborne nature of these two outbreaks was not recognized until at least 2 weeks after the onset of the Milwaukee outbreak and until after the end of the Las Vegas outbreak. Campylobacter jejuni was implicated for three outbreaks and the following pathogens for one outbreak each: Shigella sonnei, Shigella flexneri, non-O1 Vibrio cholerae (in a U.S. territory; the vehicle was commercially bottled water), and Salmonella serotype Typhimurium (the outbreak was associated with seven deaths). Eight outbreaks of chemical poisoning were reported: three were caused by lead (one case each), two by fluoride, two by nitrate and one by copper. Twenty (66.7%) of the 30 outbreaks were associated with a well-water source. Fourteen states reported a total of 26 outbreaks associated with recreational water, in which an estimated 1,714 persons became ill. Fourteen (53.8%) of these 26 were outbreaks of gastroenteritis. The etiologic agent in each of these 14 outbreaks was identified; 10 (71.4%) were caused by G. lamblia or C. parvum. Six of these 10 were associated with chlorinated, filtered pool water, and three with lake water. One of the latter was the first reported outbreak of cryptosporidiosis associated with the recreational use of lake water. Four outbreaks of lake water-associated bacterial gastroenteritis were reported, two caused by S. sonnei, one by S. flexneri, and one by Escherichia coli O157:H7. Nine outbreaks of hot tub- whirlpool-, or swimming pool-associated pseudomonas dermatitis were reported. Two outbreaks of swimming pool-associated dermatitis had a suspected chemical etiology. The child who had the one reported case of primary amebic meningoencephalitis, caused by infection with Naegleria fowleri, died. The number of WBDOs reported annually has been similar for each year during 1987-1994, except for an increase in 1992. Protozoan parasites, especially C. parvum and G. lamblia, remain important etiologic agents of WBDOs. The outbreaks of cryptosporidiosis in Milwaukee and Las Vegas demonstrate that WBDOs can occur in large metropolitan areas. Surveillance methods are needed that expedite the detection of WBDOs and the institution of preventive measures (e.g., boil-water advisories). Surveillance data that identify the types of water systems, their deficiencies, and the etiologic agents associated with outbreaks are used to evaluate the adequacy of current technologies for prov


Distribution of methylphenidate and p-hydroxymethylphenidate in rats.
Rats were administered threo-dl-methylphenidate (MPH) i.v., i.p. and p.o. A gas chromatography-mass spectrometry method incorporating deuterated internal standards was used to quantify MPH and the metabolite threo-dl-p-hydroxymethylphenidate (HOMPH). Accumulation and decay of MPH were evaluated in serum and brain to assess whether serum MPH correlated with brain content. HOMPH was quantified to appraise its contribution to the central action of MPH. MPH accumulated in the brain at a concentration of 3.75 microgram/g tissue within 1 min after i.v. injection of 1 mg/kg, and averaged 8 times the concentration in serum over the first 30 min. The steady-state volume of distribution was 1.47 liters/kg. The decay of MPH from brain and serum occurred biphasically with postdistribution (beta) T1/2 values of 20 and 50 min, respectively. After p.o. administration (1 mg/kg), brain MPH concentrations also exceeded those in serum. HOMPH was detected only in liver and kidney after 1 mg/kg MPH (i.v. and p.o.). Thirty minutes after 20 mg/kg of MPH (i.p.), MPH accumulated in kidney greater than lung greater than brain greater than heart greater than liver. Brain MPH concentration was 900 times that of HOMPH (0.02 microgram/g) after this dose. In liver, conjugated HOMPH was present (12.1 microgram/g). After i.v. administration of HOMPH, less localization occurred in brain than occurred for MPH. These data suggest that the central effects of MPH do not depend upon conversion to HOMPH.


Effectiveness of Oral Cholera Vaccine in Haiti: 37-Month Follow-Up.
The first oral cholera vaccine (OCV) campaign, since its prequalification by the World Health Organization, in response to an ongoing cholera epidemic (reactive vaccination) was successfully conducted in a poor urban slum of approximately 70,000 inhabitants in Port-au-Prince, Haiti, in 2012. Vaccine coverage was 75% of the target population. This report documents the impact of OCV in reducing the number of culture-confirmed cases of cholera admitted to the Groupe Haïtien d'Etude du Sarcome de Kaposi et des Infections Opportunistes (GHESKIO) cholera treatment center from that community in the 37 months postvaccination (April 2012-April 30, 2015). Of 1,788 patients with culture-confirmed cholera, 1,770 (99%) were either from outside the vaccine area (1,400 cases) or from the vaccinated community who had not received OCV (370 cases). Of the 388 people from the catchment area who developed culture-confirmed cholera, 370 occurred among the 17,643 people who had not been vaccinated (2.1%) and the remaining 18 occurred among the 52,357 people (0.034%) who had been vaccinated (P < 0.001), for an efficacy that approximates 97.5%. Despite not being designed as a randomized control trial, the very high efficacy is a strong evidence for the effectiveness of OCV as part of an integrated package for the control of cholera in outbreak settings.


Oncolytic viruses driven by tumor-specific promoters.
Oncolytic viruses can selectively replicate in and lead to tumor cell lysis with minimal infection/replication potential in adjoining non-neoplastic tissue. Because of paramount safety concerns, first-generation oncolytic viruses were designed to be significantly attenuated in their lytic potential. Results from recent clinical trials have revealed the safety of this approach, but have underscored the urgency for design and testing of more tumor-selective and -potent viruses to realize the full therapeutic potential of this revolutionary treatment modality. With the discovery of various molecular/genetic changes associated with neoplasia, tumor-specific transcriptional targeting of viral virulence is being tapped to generate tumor- and tissue-specific variants. This review will focus on the various strategies exploited to generate viruses whose virulence is governed by tumor-specific transcriptional events.


Telehealth interventions for the secondary prevention of coronary heart disease: a systematic review.
Coronary heart disease (CHD) is a leading cause of death globally. Despite proven health benefits and international recommendations, attendance at cardiac rehabilitation programs is poor. Telehealth (phone, Internet, and videoconference communication between patient and health-care provider) has emerged as an innovative way of delivering health interventions. This review aimed to determine telehealth effectiveness in CHD management. Study design includes systematic review with meta-analysis. Randomized controlled trials evaluating telehealth interventions in patients with CHD were identified by searching multiple electronic databases, reference lists, relevant conference lists, gray literature, and key-word searching of the Internet. Studies were selected if they evaluated a telephone, videoconference, or web-based intervention, provided objective measurements of mortality, changes in multiple risk factor levels or quality of life. In total, 11 trials were identified (3145 patients). Telehealth interventions were associated with nonsignificant lower all-cause mortality than controls [relative risk=0.70, 95% confidence interval (CI)=0.45-1.1; P=0.12]. These interventions showed a significantly lower weighted mean difference (WMD) at medium long-term follow-up than controls for total cholesterol (WMD=0.37 mmol/l, 95% CI=0.19-0.56, P<0.001), systolic blood pressure (WMD=4.69 mmHg, 95% CI=2.91-6.47, P<0.001), and fewer smokers (relative risk = 0.84, 95% CI=0.65-0.98, P = 0.04). Significant favorable changes at follow-up were also found in high-density lipoprotien and low-density lipoprotein. In conclusion, telehealth interventions provide effective risk factor reduction and secondary prevention. Provision of telehealth models could help increase uptake of a formal secondary prevention by those who do not access cardiac rehabilitation and narrow the current evidence-practice gap.


Zinc(II) interactions with brain-derived neurotrophic factor N-terminal peptide fragments: inorganic features and biological perspectives.
Brain-derived neurotrophic factor (BDNF) is a neurotrophin essential for neuronal differentiation, growth, and survival; it is involved in memory formation and higher cognitive functions. The N-terminal domain of BDNF is crucial for the binding selectivity and activation of its specific TrkB receptor. Zn(2+) ion binding may influence BDNF activity. Zn(2+) complexes with the peptide fragment BDNF(1-12) encompassing the sequence 1-12 of the N-terminal domain of BDNF were studied by means of potentiometry, electrospray mass spectrometry, NMR, and density functional theory (DFT) approaches. The predominant Zn(2+) complex species, at physiological pH, is [ZnL] in which the metal ion is bound to an amino, an imidazole, and two water molecules (NH2, N(Im), and 2O(water)) in a tetrahedral environment. DFT-based geometry optimization of the zinc coordination environment showed a hydrogen bond between the carboxylate and a water molecule bound to zinc in [ZnL]. The coordination features of the acetylated form [AcBDNF(1-12)] and of a single mutated peptide [BDNF(1-12)D3N] were also characterized, highlighting the role of the imidazole side chain as the first anchoring site and ruling out the direct involvement of the aspartate residue in the metal binding. Zn(2+) addition to the cell culture medium induces an increase in the proliferative activity of the BDNF(1-12) peptide and of the whole protein on the SHSY5Y neuroblastoma cell line. The effect of Zn(2+) is opposite to that previously observed for Cu(2+) addition, which determines a decrease in the proliferative activity for both peptide and protein, suggesting that these metals might discriminate and modulate differently the activity of BDNF.


EEG Signal Decomposition Evidence for a Role of Perceptual Processes during Conflict-related Behavioral Adjustments in Middle Frontal Regions.
Conflict monitoring processes are central to cope with fluctuating environmental demands. However, the efficacy of these processes depends on previous trial history/experience, which is reflected in the "congruency sequence effect" (CSE). Several theoretical accounts have been put forward to explain this effect. Some accounts stress the role of perceptual processes in the emergence of the CSE. As yet, it is elusive how these perceptual processes are implemented on a neural level. We examined this question using a newly developed moving dots flanker task. We combine decomposition methods of EEG data and source localization. We show that perceptual processes modulate the CSE and can be isolated in neurophysiological signals, especially in the N2 ERP time window. However, mechanisms relating perception to action are also coded and modulated in this time window. We show that middle frontal regions (BA 6) are associated with processes dealing with purely perceptual processes. Inferior frontal regions (BA 45) are associated with processes dealing with stimulus-response transition processes. Likely, the neurophysiological modulations reflect unbinding processes at the perceptual level, and stimulus-response translation level needed to respond correctly on the presented (changed) stimulus-response relationships. The data establish a direct relationship between psychological concepts focusing on perceptual processes during conflict monitoring and neurophysiological processes using signal decomposition.


The DNA replication and damage checkpoint pathways induce transcription by inhibition of the Crt1 repressor.
We have identified the yeast CRT1 gene as an effector of the DNA damage and replication checkpoint pathway. CRT1 encodes a DNA-binding protein that recruits the general repressors Ssn6 and Tup1 to the promoters of damage-inducible genes. Derepression of the Crt1 regulon suppresses the lethality of mec1 and rad53 null alleles and is essential for cell viability during replicative stress. In response to DNA damage and replication blocks, Crt1 becomes hyperphosphorylated and no longer binds DNA, resulting in transcriptional induction. CRT1 is autoregulated and is itself induced by DNA damage, indicating the existence of a negative feedback pathway that facilitates return to the repressed state after elimination of damage. The inhibition of an autoregulatory repressor in response to DNA damage is a strategy conserved throughout prokaryotic and eukaryotic evolution.


Out of context: clinical practice guidelines and patients with multiple chronic conditions: a systematic review.
Poor fidelity to practice guidelines in the care of people with multiple chronic conditions (MCC) may result from patients and clinicians struggling to apply recommendations that do not consider the interplay of MCC, socio-personal context, and patient preferences. The objective of the study was to assess the quality of guideline development and the extent to which guidelines take into account 3 important factors: the impact of MCC, patients' socio-personal contexts, and patients' personal values and preferences. We conducted a systematic search of clinical practice guidelines for patients with type 2 diabetes mellitus published between 2006 and 2012. Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Scopus, EBSCO CINAHL, and the National Guideline Clearinghouse were searched. Two reviewers working independently selected studies, extracted data, and evaluated the quality of the guidelines. We found 28 eligible guidelines, which, on average, had major methodological limitations (AGREE II mean score 3.8 of 7, SD=1.6). Patients or methodologists were not included in the guideline development process in 20 (71%) and 24 (86%) guidelines, respectively. There was a complete absence of incorporating the impact of MCC, socio-personal context, and patient preferences in 8 (29%), 11 (39%), and 16 (57%) of the 28 guidelines, respectively. When mentioned, MCC were considered biologically, but not as contributors of complexity or patient work or as motivation to focus on patient-centered outcomes. Extant clinical practice guidelines for one chronic disease sometimes consider the context of the patient with that disease, but only do so narrowly. Guideline panels must remove their contextual blinders if they want to practically guide the care of patients with MCC.


Protective effect of curcumin against cytomegalovirus infection in Balb/c mice.
Curcumin has been found to suppress the activity of human cytomegalovirus (HCMV) in vitro, whereas its protective effects against HCMV infection in vivo remain unclear. In this study, we aimed to investigate the protective effects of curcumin against HCMV infection in Balb/c mice. Mice were randomly divided into the control, model, model+ganciclovir (positive control), and model+high-dose, model+middle-dose, and model+low-dose curcumin groups. In the model groups, each mouse was given HCMV by tail injection intravenously. Positive control animals were given ganciclovir. Animals in the curcumin treatment groups were given different concentrations of curcumin. The anti-HCMV activities of ganciclovir and curcumin were assessed by serological examination and pathology. Ganciclovir and curcumin treatment reduced the HCMV IgM level and HCMV DNA load; decreased the serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatine kinase (CK), and lactate dehydrogenase (LDH) as well as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) generation in infected mice. These treatments also suppressed malondialdehyde (MDA) content and upregulated superoxide dismutase (SOD) and glutathione (GSH) levels. In addition, both treatments prevented pathological changes of the lung, kidney, liver, and heart tissues in infected mice. Our findings indicate that curcumin protected Balb/c mice against HCMV infection possibly by its anti-inflammatory and antioxidant effects.


Treatment with EGCG in NSCLC leads to decreasing interstitial fluid pressure and hypoxia to improve chemotherapy efficacy through rebalance of Ang-1 and Ang-2.
Microvasculature and microenvironment play important roles in proliferation, invasion, metastasis and prognosis in non-small cell lung cancer (NSCLC), which might be altered by many anti-angiogenic drugs. Epigallocatechin-3-gallate (EGCG), a natural anti-angiogenesis agent refined from green tea, was defined to have multiple effects on angiogenesis factors, such as endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and angiopoietins (ANGs). Hypothesizing that EGCG might regulate microvasculature and microenvironment in NSCLC, the effects of EGCG on microvessel density (MVD), expression of Ang-1 and Ang-2, interstitial fluid pressure (IFP), tumor hypoxia, and chemotherapy sensitivity were examined. EGCG treatment of A549 cells in mice bearing xenografts in vivo led to a significant decrease of MVD detected by CD31, and of Ang-2 expression detected by quantum dots double-label immunofluorescence assessment, while Ang-1 decreased with no significance. Decreased IFP was measured by the Wink-in-needle method, while hypoxia was assessed by polarographic electrode and pimonidazole (PIMO) immunohistochemistry. Assuming that these changes would increase response to chemotherapy, tumor growth studies were p[erformed in nude mice with xenografts, which were then treated with EGCG and the chemotherapeutic agent cisplatin. EGCG therapy combined with cisplatin led to synergistic inhibition of tumor growth, compared with administration of each treatment separately (P < 0.001). According to linear regression analysis, IFP was positively correlated with PIMO staining (R(2) = 0.618, P = 0.002), Ang-2 was correlated with MVD (R(2) = 0.423, P = 0.022), IFP (R(2) = 0.663, P = 0.01) and PIMO staining (R(2) = 0.694, P = 0.01). IFP and delivery of oxygen might be improved by rebalance of Ang-1/Ang-2 under the treatment of EGCG in NSCLC, which also acts as a sensitizer of chemotherapy. These studies established a new mechanism for using EGCG as an adjuvant chemotherapy agent through modifying microvasculature and microenvironment.


Amplification of future energy demand growth due to climate change.
Future energy demand is likely to increase due to climate change, but the magnitude depends on many interacting sources of uncertainty. We combine econometrically estimated responses of energy use to income, hot and cold days with future projections of spatial population and national income under five socioeconomic scenarios and temperature increases around 2050 for two emission scenarios simulated by 21 Earth System Models (ESMs). Here we show that, across 210 realizations of socioeconomic and climate scenarios, vigorous (moderate) warming increases global climate-exposed energy demand before adaptation around 2050 by 25-58% (11-27%), on top of a factor 1.7-2.8 increase above present-day due to socioeconomic developments. We find broad agreement among ESMs that energy demand rises by more than 25% in the tropics and southern regions of the USA, Europe and China. Socioeconomic scenarios vary widely in the number of people in low-income countries exposed to increases in energy demand.


Isolation and Characterization of Exosomes from Cultures of Tissue Explants and Cell Lines.
Exosomes are specialized, nanometer-sized extracellular vesicles of endosomal origin actively secreted into the extracellular space by a variety of cells under normal and pathological conditions. Exosomes have recently emerged as important intercellular communicators and modulators of diverse mechanisms and cellular responses. Characterization of their composition and function will open possibilities for new diagnostic methods and promising therapeutic approaches based on nanobiology. This unit provides a standard isolation procedure for purification of exosomes based on density gradient ultracentrifugation with sucrose. The process of isolating exosomes relies on obtaining proper source fluids/supernatants as well as qualitative and quantitative assessment of the isolated vesicles. The methodological procedures here can be divided in three parts: (1) pre-isolation procedures aiming to obtain fluids containing exosomes, with a focus on protocols for organ explants and cell cultures; (2) a procedure for exosome isolation with several gradient alternatives; and (3) post-isolation procedures for estimating the purity and yield of the exosomal fraction. © 2016 by John Wiley & Sons, Inc.


Transpupillary thermotherapy for atypical central serous chorioretinopathy.
Central serous chorioretinopathy (CSC) has been traditionally treated with laser photocoagulation. We thought that transpupillary thermotherapy (TTT) utilizing a lower temperature than that of conventional laser photocoagulation might minimize permanent retinal and choroidal damage. Studies suggest that undesirable effects on vision due to TTT are minimal even if it is applied to foveal and/or parafoveal lesions when TTT requires a larger irradiation spot. The aim of this study was to evaluate the efficacy of TTT in the management of atypical CSC. We defined atypical CSC as bullous retinal detachment with diffuse or several leakages, severe leakage with fibrin formation under serous retinal detachment, or leakage within a pigment epithelium detachment. Eight consecutive patients with atypical CSC underwent visual acuity testing, ophthalmic examination, color photography, fluorescein angiography, and optical coherence tomography to evaluate the results of transpupillary thermotherapy. Retreatment of atypical CSC was based on ophthalmic examination, optical coherence tomography, and fluorescein angiography. TTT was performed on the leaking spots shown in fluorescein angiography, with a power of 50-250 mW, spot size of 500-1200 μm, and exposure time of 13-60 seconds to minimize retinal damage. In five of eight affected eyes, serous detachments completely resolved within 1 month after the initial TTT. One eye had persistent subretinal fluid and required a second TTT treatment. Two eyes showed no resolution of CSC and were treated by conventional photocoagulation. Initial best-corrected visual acuity (BCVA) ranged from 20/600 to 20/20 (mean, 20/40; median, 20/30). Final BCVA ranged from 20/200 to 20/20 (mean, 20/25; median, 20/20). BCVA improved in all cases. Only two eyes with persistent subretinal fibrin and existing retinal pigment epithelial alternations in macular area showed limited improvement of BCVA despite the absence of subretinal exudation. The presence of retinal attachment was confirmed by optical coherence tomography in six eyes (75%). TTT seems to be effective for the treatment of atypical CSC in the short term. Additional studies are necessary to evaluate the long-term effectiveness and safety.


Principal components analysis of protein sequence clusters.
Sequence analysis of large protein families can produce sub-clusters even within the same family. In some cases, it is of interest to know precisely which amino acid position variations are most responsible for driving separation into sub-clusters. In large protein families composed of large proteins, it can be quite challenging to assign the relative importance to specific amino acid positions. Principal components analysis (PCA) is ideal for such a task, since the problem is posed in a large variable space, i.e. the number of amino acids that make up the protein sequence, and PCA is powerful at reducing the dimensionality of complex problems by projecting the data into an eigenspace that represents the directions of greatest variation. However, PCA of aligned protein sequence families is complicated by the fact that protein sequences are traditionally represented by single letter alphabetic codes, whereas PCA of protein sequence families requires conversion of sequence information into a numerical representation. Here, we introduce a new amino acid sequence conversion algorithm optimized for PCA data input. The method is demonstrated using a small artificial dataset to illustrate the characteristics and performance of the algorithm, as well as a small protein sequence family consisting of nine members, COG2263, and finally with a large protein sequence family, Pfam04237, which contains more than 1,800 sequences that group into two sub-clusters.


Genomic Analysis of the Evolution and Global Spread of Hyper-invasive Meningococcal Lineage 5.
The predominant model for bacterial pandemics is the emergence of a virulent variant that diversifies as it spreads in human populations. We investigated a 40-year meningococcal disease pandemic caused by the hyper-invasive ET-5/ST-32 complex. A global collection of Neisseria meningitidis isolates dating from 1969 to 2008 was whole genome sequenced (WGS) and analysed using a gene-by-gene approach at http://pubmlst.org/neisseria. Analysis of WGS data identified a 'Lineage 5 pan genome' of 1940 genes, 1752 (92%) of which were present in all isolates (Lineage 5 'core genome'). Genetic diversity, which was mostly generated by horizontal gene transfer, was unevenly distributed in the genome; however, genealogical analysis of diverse and conserved core genes, accessory genes, and antigen encoding genes, robustly identified a star phylogeny with a number of sub-lineages. Most European and American isolates belonged to one of two closely related sub-lineages, which had diversified before the identification of the pandemic in the 1970s. A third, genetically more diverse sub-lineage, was associated with Asian isolates. Several isolates had acquired DNA from the related gonococcus. These data were inconsistent with a single point of origin followed by pandemic spread, rather suggesting that the sub-lineages had diversified and spread by asymptomatic transmission, with multiple distinct strains causing localised hyperendemic outbreaks.


Structure and mechanism of carbonic anhydrase.
Carbonic anhydrase (CA; carbonate hydro-lyase, EC 184.108.40.206) is a zinc-containing enzyme that catalyzes the reversible hydration of carbon dioxide: CO2+ H2O<-->HCO3(-)+H+. The enzyme is the target for drugs, such as acetazolamide, methazolamide, and dichlorphenamide, for the treatment of glaucoma. There are three evolutionarily unrelated CA families, designated alpha, beta, and gamma. All known CAs from the animal kingdom are of the alpha type. There are seven mammalian CA isozymes with different tissue distributions and intracellular locations, CA I-VII. Crystal structures of human CA I and II, bovine CA III, and murine CA V have been determined. All of them have the same tertiary fold, with a central 10-stranded beta-sheet as the dominating secondary structure element. The zinc ion is located in a cone-shaped cavity and coordinated to three histidyl residues and a solvent molecule. Inhibitors bind at or near the metal center guided by a hydrogen-bonded system comprising Glu-106 and Thr-199. The catalytic mechanism of CA II has been studied in particular detail. It involves an attack of zinc-bound OH- on a CO2 molecule loosely bound in a hydrophobic pocket. The resulting zinc-coordinated HCO3- ion is displaced from the metal ion by H2O. The rate-limiting step is an intramolecular proton transfer from the zinc-bound water molecule to His-64, which serves as a proton shuttle between the metal center and buffer molecules in the reaction medium.


Polysialic acid sustains cancer cell survival and migratory capacity in a hypoxic environment.
Polysialic acid (polySia) is a unique carbohydrate polymer expressed on the surface of NCAM (neuronal cell adhesion molecule) in a number of cancers where it modulates cell-cell and cell-matrix adhesion, migration, invasion and metastasis and is strongly associated with poor clinical prognosis. We have carried out the first investigation into the effect of polySia expression on the behaviour of cancer cells in hypoxia, a key source of chemoresistance in tumours. The role of polysialylation and associated tumour cell migration and cell adhesion were studied in hypoxia, along with effects on cell survival and the potential role of HIF-1. Our findings provide the first evidence that polySia expression sustains migratory capacity and is associated with tumour cell survival in hypoxia. Initial mechanistic studies indicate a potential role for HIF-1 in sustaining polySia-mediated migratory capacity, but not cell survival. These data add to the growing body of evidence pointing to a crucial role for the polysialyltransferases (polySTs) in neuroendocrine tumour progression and provide the first evidence to suggest that polySia is associated with an aggressive phenotype in tumour hypoxia. These results have significant potential implications for polyST inhibition as an anti-metastatic therapeutic strategy and for targeting hypoxic cancer cells.


Resource utilization and cost-effectiveness of counselor- vs. provider-based rapid point-of-care HIV screening in the emergency department.
Routine HIV screening in emergency department (ED) settings may require dedicated personnel. We evaluated the outcomes, costs and cost-effectiveness of HIV screening when offered by either a member of the ED staff or by an HIV counselor. We employed a mathematical model to extend data obtained from a randomized clinical trial of provider- vs. counselor-based HIV screening in the ED. We compared the downstream survival, costs, and cost-effectiveness of three HIV screening modalities: 1) no screening program; 2) an ED provider-based program; and 3) an HIV counselor-based program. Trial arm-specific data were used for test offer and acceptance rates (provider offer 36%, acceptance 75%; counselor offer 80%, acceptance 71%). Undiagnosed HIV prevalence (0.4%) and linkage to care rates (80%) were assumed to be equal between the screening modalities. Personnel costs were derived from trial-based resource utilization data. We examined the generalizability of results by conducting sensitivity analyses on offer and acceptance rates, undetected HIV prevalence, and costs. Estimated HIV screening costs in the provider and counselor arms averaged $8.10 and $31.00 per result received. The Provider strategy (compared to no screening) had an incremental cost-effectiveness ratio of $58,700/quality-adjusted life year (QALY) and the Counselor strategy (compared to the Provider strategy) had an incremental cost-effectiveness ratio of $64,500/QALY. Results were sensitive to the relative offer and acceptance rates by strategy and the capacity of providers to target-screen, but were robust to changes in undiagnosed HIV prevalence and programmatic costs. The cost-effectiveness of provider-based HIV screening in an emergency department setting compares favorably to other US screening programs. Despite its additional cost, counselor-based screening delivers just as much return on investment as provider based-screening. Investment in dedicated HIV screening personnel is justified in situations where ED staff resources may be insufficient to provide comprehensive, sustainable screening services.


Bi-specific tenascin-C and fibronectin targeted peptide for solid tumor delivery.
Oncofetal fibronectin (FN-EDB) and tenascin-C C domain (TNC-C) are nearly absent in extracellular matrix of normal adult tissues but upregulated in malignant tissues. Both FN-EDB and TNC-C are developed as targets of antibody-based therapies. Here we used peptide phage biopanning to identify a novel targeting peptide (PL1, sequence: PPRRGLIKLKTS) that interacts with both FN-EDB and TNC-C. Systemic PL1-functionalized model nanoscale payloads [iron oxide nanoworms (NWs) and metallic silver nanoparticles] homed to glioblastoma (GBM) and prostate carcinoma xenografts, and to non-malignant angiogenic neovessels induced by VEGF-overexpression. Antibody blockage experiments demonstrated that PL1 tumor homing involved interactions with both receptor proteins. Treatment of GBM mice with PL1-targeted model therapeutic nanocarrier (NWs loaded with a proapoptotic peptide) resulted in reduced tumor growth and increased survival, whereas treatment with untargeted particles had no effect. PL1 peptide may have applications as an affinity ligand for delivery of diagnostic and therapeutic compounds to microenvironment of solid tumors.


Asian strain of Batrachochytrium dendrobatidis is widespread in the Western Ghats, India.
We investigated the distribution of Batrachochytrium dendrobatidis (Bd) fungal infections in amphibians of the Western Ghats mountain range in India, based on data from 497 samples. Eight individuals were positive, with genomic equivalents ranging from 2 to 785 zoospores. A single widespread Bd strain identical to the haplotype endemic to Asia was isolated. Our findings suggest that chytridiomycosis is widespread among the endemic and threatened amphibians of the entire stretch of the Western Ghats. An ecological niche-based prediction model based on all Bd-positive reports from the Western Ghats to date suggested a higher probability of infection in the central Western Ghats of Karnataka and northern Kerala states, which host a rich diversity of endemic and threatened amphibians.


Familial amyloidotic polyneuropathy in Sweden: a pedigree analysis.
Extended genealogical studies were performed on the heredity patterns in Swedish patients with familial amyloidotic polyneuropathy (FAP) using Swedish historical archives. The population studied included 239 patients: 109 patients were linked to five large pedigrees and 80 patients belonged to 30 smaller pedigrees or nuclear families. In the remaining 50 cases, no genealogical links were found. Differences in mean ages of onset between the different pedigrees were found, although a considerable variation within the pedigrees was also present. There was a tendency for later ages of onset among older generations than younger ones: descendants of affected mothers seem to be more prone to anticipation in age of onset than descendants of affected fathers. Furthermore, there seems to be a tendency for earlier ages of onset among patients with a carrier mother than a carrier father. Some extended pedigrees, from the Skellefteå and Piteå areas, are presented in detail. The former go back into the middle of the 17th century. One important conclusion is that the mutational event may have occurred in late mediaeval times.


Rewarding effects of the optical isomers of 3,4-methylenedioxy-methylamphetamine ('Ecstasy') and 3,4-methylenedioxy-ethylamphetamine ('Eve') measured by conditioned place preference in rats.
3,4-methylenedioxy-methylamphetamine (MDMA) ('Ecstasy') and its analogue 3,4-methylenedioxy-methylamphetamine (MDE) ('Eve') are well known illicit street drugs mainly abused by young people. In spite of the actual research going on, the classification of their abuse potential remains unclear. Since secondary reinforcers are the main factors responsible for craving and relapse, the aim of our study was to assess the potency of MDMA and MDE in a second order reinforcement paradigm, i.e. conditioned place preference (CPP). For the general assessment of our study conditions, we compared MDMA with amphetamine. Unexpectedly, no significant CPP for MDMA was found in contrast to amphetamine. Detailed analysis of current literature led us to the working hypothesis that social environment is crucial for the development of CPP. In a subsequent experiment we tested the influence of housing conditions on CPP using MDMA and demonstrated that isolated animals show significant CPP compared to group-housed ones. In order to better understand the rewarding mechanisms of Ecstasy-derivatives, we tested both the racemic drugs and the pure isomers in the CPP paradigm. Both MDMA's optical isomers and racemic MDMA showed significant CPP without notable differences, while MDE and its isomers completely failed to show any significant CPP. In conclusion, the mechanism by which MDMA induces addiction is much more complicated than assumed so far and more pronounced in isolated animals. The fact that both optical isomers of MDMA led to CPP implies that at least two pathways by which MDMA induces craving behaviour exist.


[The EMECAM project: a discussion of the results in the participating cities. Estudio Multicéntrico Español sobre la Relación entre la Contaminación Atmosférica y la Mortalidad].
This article draws a comparison and provides a discussion of the findings resulting from the local analyses of the 14 cities participating in the EMECAM Project. An analysis is made of the time series related to mortality, pollutants (particles in suspension, SO2, NO2, O3 and CO), temperature and other factors taken from records of public institutions. By using Poisson autoregressive regression, an estimate has been made of the short-term relationship between the number of deaths and the air pollution indicators in each one of the following cities: Barcelona, metropolitan area of Bilbao, Cartagena, Castellón, Gijón, Huelva, Madrid, Pamplona, Seville, Oviedo, Valencia, Vigo, Vitoria and Saragossa. The findings reveal the air pollution figures in our country to be similar to those of other European cities. The levels of the different pollutants point toward road traffic as being the main source of most of this pollution. A relationship has been found between the mortality and different pollutants in most cities, although the results are not homogeneous among the cities and show variability in the different causes under study. In some cities, especially in those having smaller populations, there have been no findings providing any evidence of a relationship, or the findings themselves are not highly consistent. The meta-analysis will provide estimates for all of the cities as a whole and will allow the possibility of making a more clear-cut assessment of the time lag impact of air pollution on the mortality. Worthy of special mention is the participation in this project of public health officers as actively involved researchers.


Unveiling a novel serpinB2-tripeptidyl peptidase II signaling axis during senescence.
Tripeptidyl peptidase II (TPPII or TPP2) degrades N-terminal tripeptides from proteins and peptides. Studies in both humans and mice have shown that TPPII deficiency is linked to cellular immune-senescence, lifespan regulation and the aging process. However, the mechanism of how TPPII participates in these processes is less clear. In this study, we established a chemical probe-based assay and found that although the mRNA and protein levels of TPPII were not altered during senescence, its enzymatic activity was reduced in senescent human fibroblasts. We also showed that elevation of the levels of the serine protease inhibitor serpinB2 reduced TPPII activity in senescent cells. Moreover, suppression of TPPII led to elevation in the amount of lysosomal contents as in well as TPPI (TPP1) and β-galactosidase activities, suggesting that lysosome biogenesis is induced to compensate for the reduction of TPPII activity in senescent cells. Together, this study discloses a critical role of the serpinB2-TPPII signaling pathway in proteostasis during senescence. Since serpinB2 levels can be increased by a variety of cellular stresses, reduction of TPPII activity through activation of serpinB2 might represent a common pathway for cells to respond to different stress conditions. This article has an associated First Person interview with the first author of the paper.


Confocal total-internal-reflection fluorescence microscopy with a high-aperture parabolic mirror lens.
We present a theoretical study of a new total-internal-reflection fluorescence microscope for the detection of fluorescence at a water-glass interface. The system is designed for confocal imaging and spectroscopy of nanoparticles and single molecules. Focusing and fluorescence collection through standard glass coverslips is accomplished by a parabolic mirror lens. The large aperture of the element is used to excite fluorescence within the evanescent field of a diffraction-limited focus and to collect focal emission with high efficiency. Tight focusing and supercritical excitation reduce the detection volume for fluorescent analyte molecules well below that of an attoliter (10(-18) L), which can be advantageous for monitoring surface binding of single molecules without interference from fluorescence of the unbound bulk. Calculations of the electric fields in the focus region and simulated confocal imaging demonstrate the performance of the system.


Defective proliferation and regulatory function of CD4+ T cells bearing Leu-8 homing receptor in primary biliary cirrhosis. Phorbol myristate acetate enhances T-cell function.
The majority of circulating CD4+ T cells express the Leu-8 peripheral lymph node homing receptor, and these cells have previously been shown to have suppressor-inducer and suppressor function. In the present study, it was found that CD4+, Leu-8+ T cells from patients with primary biliary cirrhosis (PBC) have a significantly (P < 0.01) lower proliferative response when stimulated with phytohemagglutinin (PHA), concanavalin A (Con A), or pokeweed mitogen (PWM) compared to normal controls. The proliferative response of CD4+, Leu-8- T cells was similar in patients and controls. However, the proliferative responses of CD4+, Leu-8+ from patients with PBC was normal when cells were stimulated with PHA, Con A, anti-CD3 monoclonal antibody, or ionomycin in combination with phorbol myristate acetate (PMA). CD4+ T cells from patients with PBC mediated normal helper function for PWM-stimulated immunoglobulin synthesis at high T/B ratios and their regulatory function was similar to that of normal CD4+ T cells that had been irradiated to inactivate their suppressor activity. When CD4+ T cells from patients with PBC were precultured with the combination of Con A and PMA, they mediated potent inhibitory activity similar to that of normal CD4+ T cells. Thus, CD4+, Leu-8+ T cells from patients with PBC have a defect of proliferation and suppressor function that is reversed by coculture with PMA. This finding suggests that impairment of a PMA-inducible lymphocyte activation pathway contributes to abnormal lymphocyte function in PBC.


Effects of exercise training on glucose homeostasis: the HERITAGE Family Study.
To determine the effect of a 20-week endurance training program in healthy, previously sedentary participants on measures derived from an intravenous glucose tolerance test (i.v.GTT). An i.v.GTT was performed before and after a standardized training program in 316 women and 280 men (173 blacks and 423 whites). Participants exercised on cycle ergometers 3 days per week for 60 sessions. The exercise intensity was progressively increased from 55% VO2max for 30 min per session to 75% VO2max for 50 min per session. Mean insulin sensitivity increased by 10% (P < 0.001) following the intervention, but the variability in the changes was high. Men had larger improvements than women (P = 0.02). Improvements in fasting insulin were transitory, disappearing 72 h after the last bout of exercise. There were also significant mean increases in the glucose disappearance index (3%, P = 0.02) and in glucose effectiveness (11%, P < 0.001), measures of glucose tolerance and of the capacity of glucose to mediate its own disposal, respectively. The acute insulin response to glucose, a measure of insulin secretion, increased by 7% in the quartile with the lowest baseline glucose tolerance and decreased by 14% in the quartile with the highest baseline glucose tolerance (P < 0.001). The glucose area below fasting levels during the i.v.GTT was reduced by 7% (P = 0.02). Although the effects of structured regular exercise were highly variable, there were improvements in virtually all i.v.GTT-derived variables. In the absence of substantial weight loss, regular exercise is required for sustained improvements in glucose homeostasis.


Control of large chromosomal duplications in Escherichia coli by the mismatch repair system.
Excessive recombination between repeated, interspersed, and diverged DNA sequences is a potential source of genomic instability. We have investigated the possibility that a mechanism exists to suppress genetic exchange between these quasi-homologous (homeologous) sequences. We examined the role of the general mismatch repair system of Escherichia coli because previous work has shown that the mismatch repair pathway functions as a barrier to interspecies recombination between E. coli and Salmonella typhimurium. The formation of large duplications by homeologous recombination in E. coli was increased some tenfold by mutations in the mutL and mutS genes that encode the mismatch recognition proteins. These findings indicate that the mismatch recognition proteins act to prevent excessive intrachromosomal exchanges. We conclude that mismatch repair proteins serve as general controllers of the fidelity of genetic inheritance, acting to suppress chromosomal rearrangements as well as point mutations.


How do psychological treatments work? Investigating mediators of change.
Little is known about how psychological treatments work. Research on treatment-induced mediators of change may be of help in identifying potential causal mechanisms through which they operate. Outcome-focused randomised controlled trials provide an excellent opportunity for such work. However, certain conceptual and practical difficulties arise when studying psychological treatments, most especially deciding how best to conceptualise the treatment concerned and how to accommodate the fact that most psychological treatments are implemented flexibly. In this paper, these difficulties are discussed, and strategies and procedures for overcoming them are described.


Immune responses and pathogenesis of SARS-CoV-2 during an outbreak in Iran: Comparison with SARS and MERS.
The beginning of 2020 has seen the emergence of COVID-19, an outbreak caused by a novel coronavirus, SARS-CoV-2, an important pathogen for humans. There is an urgent need to better understand this new virus and to develop ways to control its spread. In Iran, the first case of the COVID-19 was reported after spread from China and other countries. Fever, cough, and fatigue were the most common symptoms of this virus. In worldwide, the incubation period of COVID-19 was 3 to 7 days and approximately 80% of infections are mild or asymptomatic, 15% are severe, requiring oxygen, and 5% are critical infections, requiring ventilation. To mount an antiviral response, the innate immune system recognizes molecular structures that are produced by the invasion of the virus. COVID-19 infection induces IgG antibodies against N protein that can be detected by serum as early as day 4 after the onset of disease and with most patients seroconverting by day 14. Laboratory evidence of clinical patients showed that a specific T-cell response against SARS-CoV-2 is important for the recognition and killing of infected cells, particularly in the lungs of infected individuals. At present, there is no specific antiviral therapy for COVID-19 and the main treatments are supportive. In this review, we investigated the innate and acquired immune responses in patients who recovered from COVID-19, which could inform the design of prophylactic vaccines and immunotherapy for the future.