Do cortisol concentrations predict short-term outcomes in extremely low birth weight infants?
Relative adrenal insufficiency in extremely low birth weight infants may contribute to significant morbidity and death. Our objective was to evaluate the relationship between cortisol concentrations and short-term outcomes. Cortisol concentrations were obtained for 350 intubated, extremely low birth weight infants at postnatal age of 12 to 48 hours and at day 5 to 7, as part of a multicenter, randomized trial of hydrocortisone treatment for prophylaxis of relative adrenal insufficiency. Death and short-term morbidity were monitored prospectively. Cortisol levels at each time point were divided into quartiles. The incidence rates of outcomes were determined for each quartile and for infants with cortisol values of <10th percentile or >90th percentile. RESULTS. Median cortisol values were 16.0 microg/dL at baseline and 13.1 microg/dL on day 5 to 7 in the placebo group. Outcomes did not differ in each quartile between treatment and placebo groups. Low cortisol values at baseline or day 5 to 7 were not associated with increased morbidity or mortality rates and were not predictive of open-label hydrocortisone use. In fact, vasopressor use was lower for infants with lower cortisol values at baseline. Severe intraventricular hemorrhage was more frequent in infants with cortisol levels in the upper quartile at baseline, and values of >90th percentile were significantly associated with higher rates of death, severe intraventricular hemorrhage, periventricular leukomalacia, gastrointestinal perforation, and severe retinopathy of prematurity. Low cortisol concentrations were not predictive of adverse short-term outcomes, but high cortisol concentrations were associated with severe intraventricular hemorrhage, and extremely elevated values were associated with morbidity and death. Low cortisol concentrations alone at these 2 time points did not identify the infants at highest risk for adverse outcomes. In contrast, high cortisol values were associated with increased morbidity and mortality rates.


The immunogenic properties of protozoan glycosylphosphatidylinositols in the mosquito Anopheles gambiae.
In contrast to humans, mosquitoes do not have an adaptive immune response to deal with pathogens, and therefore must rely on their innate immune system to deal with invaders. This facilitates the recognition of different microbes on the basis of surface components or antigens. Such antigens have been identified in various types of microbe such as bacteria and fungi, yet none has been identified in the genus protozoa, which includes pathogens such as the malaria parasite, Plasmodium falciparum and Toxoplasma gondii. This study allowed us to test the antigenic properties of protozoan glycosylphosphatidylinositol (GPI) on the mosquito immune system. We found that both P. falciparum GPI and T. gondii GPI induce the strong expression of several antimicrobial peptides following ingestion, and that as a result of the immune response against the GPIs, the number of eggs produced by the mosquito is reduced dramatically. Such effects have been associated with malaria infected mosquitoes, but never associated with a Plasmodium specific antigen. This study demonstrates that protozoan GPIs can be considered as protozoan specific immune elicitors in mosquitoes, and that P. falciparum GPI plays a critical role in the malaria parasite manipulation of the mosquito vector to facilitate its transmission.


Broad diversity of Mycobacterium tuberculosis complex strains isolated from humans and cattle in Northern Algeria suggests a zoonotic transmission cycle.
Mycobacterium tuberculosis complex (MTBC) comprises closely related species responsible for human and animal tuberculosis (TB). Efficient species determination is useful for epidemiological purposes, especially for the elucidation of the zoonotic contribution. In Algeria, data on MTBC genotypes are largely unknown. In this study, we aimed to investigate the occurrence and diversity of MTBC genotypes causing human and bovine TB in Northern Algeria. During a two-year sampling period (2017-2019) in two regions of Northern Algeria, we observed an overall prevalence of 6.5% of tuberculosis (TB) among slaughtered cattle, which is higher than previous Algerian data yet comparable to neighboring countries. A total of 296 Mycobacterium tuberculosis complex (MTBC) isolates were genotyped by spoligotyping: 181 from tissues with TB-like lesions collected from 181 cattle carcasses and 115 from TB patients. In human isolates, we identified 107 M. tuberculosis, seven M. bovis and one "M. pinnipedii-like", while for bovine samples, 174 isolates were identified as M. bovis, three as M. caprae, three as "M. pinnipedii-like" and one as "M. microti-like". The majority of isolates (89.2%) belonged to 72 different known Shared International Types (SIT) or M. bovis spoligotypes (SB), while we also identified seven new SB profiles (SB2695 to SB2701). Twenty-eight of the SB profiles were new to Algeria. Our data suggest zoonotic transmission in Sétif, where significantly more TB was observed among cattle (20%) compared to the slaughterhouses from the three other regions (5.4%-7.3%) (p < 0.0001), with the isolation of the same M. bovis genotypes from TB patients. The present study showed a high genetic diversity of MTBC isolated from human and cattle in Northern Algeria. Even though relatively small in terms of numbers, our data suggest the zoonotic transmission of TB from cattle to humans, suggesting the need for stronger eradication strategies for bovine TB.


Clinical and serological hallmarks of systemic sclerosis overlap syndromes.
To determine the prevalence of systemic sclerosis (SSc) overlap syndrome and autoantibody profile in a large single-center cohort. SSc diagnoses, subsets, and autoantibody profiles were obtained from clinical records of patients attending the Centre for Rheumatology, Royal Free Hospital, between September 1999 and February 2007. In total, 332 (20%) of 1700 patients with SSc had overlap syndrome. This comprised myositis (42.8%), rheumatoid arthritis (RA; 32%), Sjögren's syndrome (SS; 16.8%), and systemic lupus erythematosus (SLE; 8.4%). Antinuclear antibody was positive in 96.6% of patients. Anticentromere antibody (ACA) was exclusively present in limited cutaneous SSc (lcSSc) overlap cases (22%), and more common in SSc/SS overlap (44.7%), whereas no difference was found in the prevalence of Scl-70 autoantibody between lcSSc and diffuse cutaneous SSc overlap groups. U1RNP was more frequent in SSc/SLE (44%), while Ro antibody was more likely to be found in SSc/SS (29.8%). ACA was absent and anti-Scl-70 was infrequent in SSc/myositis; polymyositis-scleroderma antibody was more frequent in this group (33.1%). About 50% of patients had raised rheumatoid factor (RF), with no difference between overlap groups irrespective of RF titer. In contrast, anticyclic citrullinated peptide antibody was more frequent in patients with RA features. About one-fifth of SSc cases had overlap features. There were distinct serological features that may predict specific clinical presentation and disease course.


Influence of life-course socioeconomic position on incident heart failure in blacks and whites: the Atherosclerosis Risk in Communities Study.
The influence of early-life socioeconomic position (SEP) on incident heart failure in blacks and whites is unknown. The authors examined the relation between early-life SEP and incident, hospitalized heart failure among middle-aged US participants (2,503 black and 8,519 white) in the Atherosclerosis Risk in Communities (ARIC) Study. Early-life SEP indicators assessed included parental education, occupation, and home ownership. From 1987 to 2004, 221 and 537 incident heart failure events were identified in blacks and whites, respectively. In Cox proportional hazards regression, early-life SEP was inversely related to incident heart failure after adjustment for age, gender, and study center (for blacks, hazard ratio (HR) = 1.39, 95% confidence interval (CI): 1.00, 1.95; for whites, HR = 1.32, 95% CI: 1.06, 1.64). Additional adjustment for young and mid-to-older adulthood SEP and established heart failure risk factors attenuated this association towards the null in both blacks and whites. Of the SEP measures, mid-to-older adulthood SEP showed the strongest association with incident heart failure in both blacks (HR = 1.32, 95% CI: 0.90, 1.96) and whites (HR = 1.39, 95% CI: 1.11, 1.75). SEP over the life course is related to the risk of incident heart failure, with SEP later in adulthood having a more prominent role than earlier SEP.


Inhibition of EZH2 methyltransferase decreases immunoediting of mesothelioma cells by autologous macrophages through a PD-1-dependent mechanism.
The roles of macrophages in orchestrating innate immunity through phagocytosis and T lymphocyte activation have been extensively investigated. Much less understood is the unexpected role of macrophages in direct tumor regression. Tumoricidal macrophages can indeed manifest cancer immunoediting activity in the absence of adaptive immunity. We investigated direct macrophage cytotoxicity in malignant pleural mesothelioma, a lethal cancer that develops from mesothelial cells of the pleural cavity after occupational asbestos exposure. In particular, we analyzed the cytotoxic activity of mouse RAW264.7 macrophages upon cell-cell contact with autologous AB1/AB12 mesothelioma cells. We show that macrophages killed mesothelioma cells by oxeiptosis via a mechanism involving enhancer of zeste homolog 2 (EZH2), a histone H3 lysine 27-specific (H3K27-specific) methyltransferase of the polycomb repressive complex 2 (PRC2). A selective inhibitor of EZH2 indeed impaired RAW264.7-directed cytotoxicity and concomitantly stimulated the PD-1 immune checkpoint. In the immunocompetent BALB/c model, RAW264.7 macrophages pretreated with the EZH2 inhibitor failed to control tumor growth of AB1 and AB12 mesothelioma cells. Blockade of PD-1 engagement restored macrophage-dependent antitumor activity. We conclude that macrophages can be directly cytotoxic for mesothelioma cells independent of phagocytosis. Inhibition of the PRC2 EZH2 methyltransferase reduces this activity because of PD-1 overexpression. Combination of PD-1 blockade and EZH2 inhibition restores macrophage cytotoxicity.


Microbiology of endotracheal aspirates in intubated pediatric intensive care unit patients: correlations with radiographic findings.
We studied the utility of Gram-stained smears and semiquantitative cultures of endotracheal aspirates (ETAs) in diagnosing pneumonia in intubated patients in a pediatric intensive care unit. The chest radiographs of 35 intubated patients were independently reviewed by a pediatric radiologist and classified into probable, possible and unlikely pneumonias. Concomitant bacteriologic and radiographic information was available in 15 episodes of probable and 13 of possible pneumonia. These findings were compared with the ETAs obtained during the study from patients with no radiographic evidence of pneumonia (N = 21). There was a good correlation between ETA findings and radiographic evidence of pneumonia when ETAs were obtained within 60 minutes of initial intubation. Only a growth of greater than or equal to 3+ of a pathogen was associated with probable pneumonia when ETAs were obtained more than 60 minutes from initial intubation. There was a poor correlation between the microbiologic findings from ETAs and the results of blood cultures and postmortem examinations. Moreover 5 of 10 pairs of ETAs obtained within 18 hours of each other demonstrated discordant results. The ETAs from patients with indwelling endotracheal tubes correlated poorly with radiographic findings and are of questionable value in diagnosing the presence of pneumonia or its etiology in this group. They must be cautiously interpreted in critically ill patients.


Lactobionic/Folate Dual-Targeted Amphiphilic Maltodextrin-Based Micelles for Targeted Codelivery of Sulfasalazine and Resveratrol to Hepatocellular Carcinoma.
In this study, promising approaches of dual-targeted micelles and drug-polymer conjugation were combined to enable injection of poorly soluble anticancer drugs together with site-specific drug release. Ursodeoxycholic acid (UDCA) as a hepatoprotective agent was grafted to maltodextrin (MD) via carbodiimide coupling to develop amphiphilic maltodextrin-ursodeoxycholic acid (MDCA)-based micelles. Sulfasalazine (SSZ), as a novel anticancer agent, was conjugated via a tumor-cleavable ester bond to MD backbone to obtain tumor-specific release, whereas resveratrol (RSV) was physically entrapped within the hydrophobic micellar core. For maximal tumor-targeting, both folic acid (FA) and lactobionic acid (LA) were coupled to the surface of micelles to obtain dual-targeted micelles. The decrease of critical micelle concentration (CMC) from 0.012 to 0.006 mg/mL declares the significance of a dual hydrophobicized core of micelles by both UDCA and SSZ. The dual-targeted micelles showed a great hemocompatibility, as well as enhanced cytotoxicity and internalization into HepG-2 liver cancer cells via binding to overexpressed folate and asialoglycoprotein receptors. In vivo, the micelles demonstrated superior antitumor effects revealed as reduction in the liver/body weight ratio, inhibition of angiogenesis, and enhanced apoptosis. Overall, combined strategies of dual active targeted micelles with bioresponsive drug conjugation could be utilized as a promising approach for tumor-targeted drug delivery.


Developments in professional quality assurance towards quality improvement: some examples of peer review in the Netherlands and the United Kingdom.
This study will explore new developments in three clinical peer review programmes in the UK and the visitatie programme in The Netherlands and how these programmes can be linked, in the future, with other quality systems. The information about the English peer review programmes was gathered by conducting four structured interviews with the programme coordinators (see Acknowledgements). Information about the Dutch visitatie programme was gathered by the author working with different visitatie programmes at the Dutch National Institute for Quality Improvement. Comparing new developments in the models of the Institute for Standardization of Organizations and the European Foundation for Quality Management, common changes are identified which seem to reflect elements viewed internationally as necessary in quality improvement. This study will examine if and how these elements are or will be included in the clinical peer review programmes in the UK and in visitatie in The Netherlands.


Pro-Con Debate: Are Patients With a Cardiovascular Implantable Electronic Device Suitable to Receive Care in a Free-Standing Ambulatory Surgery Center?
Migration of surgical and other procedures that require anesthesia care from a hospital to a free-standing ambulatory surgery center (ASC) continues to grow. Patients with cardiac implantable electronic devices (CIED) might benefit from receiving their care in a free-standing ASC setting. However, these patients have cardiovascular comorbidities that can elevate the risk of major adverse cardiovascular events. CIEDs are also complex devices and perioperative management varies between devices marketed by various manufacturers and require consultation and ancillary services, which may not be available in a free-standing ASC. Thus, perioperative care of these patients can be challenging. Therefore, the suitability of this patient population in a free-standing ASC remains highly controversial. Although applicable advisories exist, considerable discussion continues with surgeons and other proceduralists about the concerns of anesthesiologists. In this Pro-Con commentary article, we discuss the arguments for and against scheduling a patient with a CIED in a free-standing ASC.


[Transpositions of mobile elements mdg4 (gypsy) and hobo in somatic and germ cells of a genetically unstable mutator strain of Drosophila melanogaster].
Analysis of distribution of the several families of mobile genetic elements has been performed. The analysis dealt with the X chromosomes of male progeny from the crosses of individual males of Mutator strain (MS) with attached-X females. The experimental results demonstrated different localization of the elements gypsy and hobo in the salivary gland squashes of different males-brothers. Location of other elements under study--mdg1, 412, mdg3, copia, 297, 17.6, Beagle, BS, Doc, FB, Springer--was invariant in all larvae. The analysis is equal to the study of transposition events at the level of gametes. Thus, doubtless, the capability of gypsy and hobo to transpose in germ cells of the MS individuals has been detected. Mobilization of the elements occurs at premiotic stages of gametes' development, as indicated by appearance of the clusters of transpositions. In the process of studies on coincidence of gypsy and hobo transposition acts, independent character of the elements' movement has been revealed. It has been detected in the same experiment that the distribution of the gypsy copies in different cells of the same salivary gland varies strongly. All hybridization sites were divided into two groups: "constant" sites common for all cells and "additional" ones, whose locations did not coincide in neighbouring cells of salivary gland. The existence of additional sites is major evidence of gypsy transpositions in somatic cells of MS. Transposition events have been as well discovered for hobo in somatic cells.


Reduced fatty acid uptake aggravates cardiac contractile dysfunction in streptozotocin-induced diabetic cardiomyopathy.
Diabetes is an independent risk factor for the development of heart failure. Increased fatty acid (FA) uptake and deranged utilization leads to reduced cardiac efficiency and accumulation of cardiotoxic lipids, which is suggested to facilitate diabetic cardiomyopathy. We studied whether reduced FA uptake in the heart is protective against streptozotocin (STZ)-induced diabetic cardiomyopathy by using mice doubly deficient in fatty acid binding protein 4 (FABP4) and FABP5 (DKO mice). Cardiac contractile dysfunction was aggravated 8 weeks after STZ treatment in DKO mice. Although compensatory glucose uptake was not reduced in DKO-STZ hearts, total energy supply, estimated by the pool size in the TCA cycle, was significantly reduced. Tracer analysis with 13C6-glucose revealed that accelerated glycolysis in DKO hearts was strongly suppressed by STZ treatment. Levels of ceramides, cardiotoxic lipids, were similarly elevated by STZ treatment. These findings suggest that a reduction in total energy supply by reduced FA uptake and suppressed glycolysis could account for exacerbated contractile dysfunction in DKO-STZ hearts. Thus, enhanced FA uptake in diabetic hearts seems to be a compensatory response to reduced energy supply from glucose, and therefore, limited FA use could be detrimental to cardiac contractile dysfunction due to energy insufficiency.


Sleep Apnea Cardiovascular Clinical Trials-Current Status and Steps Forward: The International Collaboration of Sleep Apnea Cardiovascular Trialists.
Sleep apnea is a common chronic disease that is associated with coronary heart disease, stroke, heart failure and mortality, although the ability of sleep apnea treatment to reduce cardiovascular morbidity and mortality has not been demonstrated. In contrast to patients seeking treatment in sleep disorders centers, as many as half of individuals with moderate to severe sleep apnea in the general population do not report excessive sleepiness; however, if treatment of sleep apnea were shown to reduce cardiovascular disease risk, this would provide a strong rationale for treatment of sleep apnea even in the absence of daytime sleepiness. This article summarizes the status of clinical trials evaluating the potential cardiovascular benefits of sleep apnea treatment and discusses the challenges of conducting such trials, and introduces the International Collaboration of Sleep Apnea Cardiovascular Trialists (INCOSACT), a clinical research collaboration formed to foster cardiovascular sleep research. Gottlieb DJ; Craig SE; Lorenzi-Filho G; Heeley E; Redline S; McEvoy RD; Durán-Cantolla J. Sleep apnea cardiovascular clinical trials- current status and steps forward: the International Collaboration of Sleep Apnea Cardiovascular Trialists. SLEEP 2013;36(7):975-980.


Growth inhibitory activity of deoxyribonucleic acid-containing factor(s) isolated from lepromatous lesions.
Deoxyribonucleic acid-containing factor(s) isolated from Mycobacterium leprae suspensions obtained from lepromas of nine patients showed growth inhibitory activity against Micrococcus and both orange-red-pigmented and coccoid mutants of mycobacteria. No growth inhibition was observed for parent mycobacterial species, Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, and Staphylococcus epidermidis.


A well-collimated quasi-continuous atom laser
Extraction of sodium atoms from a trapped Bose-Einstein condensate (BEC) by a coherent, stimulated Raman process is demonstrated. Optical Raman pulses drive transitions between trapped and untrapped magnetic sublevels, giving the output-coupled BEC fraction a well-defined momentum. The pulsed output coupling can be run at such a rate that the extracted atomic wave packets strongly overlap, forming a highly directional, quasi-continuous matter wave.


Predictors of 6-month Mortality in Patients with Non-ST Elevation Acute Coronary Syndrome: A Study in Pakistani Population.
For Southern Asian countries like Pakistan, there is inadequate evidence of risk factors associated with mortality in patients suffering from acute coronary syndrome (ACS), especially non-ST elevation ACS (NSTE-ACS) cases. Therefore, aim of this study was to evaluate predictors of 6-months mortality of patients presenting with NSTE-ACS. For this prospective observational study we recruited adult patients diagnosed with NSTE-ACS at a tertiary cardiac center. All he patients were followed-up after six months and survival status was recorded. Logistic regression analysis was performed for six-month mortality and odds ratio (OR) and 95% confidence interval (CI) were reported. Six-month follow-up was successful for 280 patients. On univariate analysis age >65 years, increased heart rate, cardiac arrest at presentation, Killip class II-IV at presentation, and diabetes were found to be associated with increased risk of 6-months mortality with OR [95% CI] of 4.27 [1.9-9.58], 1.25 [1.1-1.41], 139.44 [16.9-1150.78], 68.45 [7.88-594.41], and 2.35 [1.06-5.22] respectively. On multivariable analysis Killip class II-IV at presentation, thrombolysis in myocardial infarction (TIMI) score of >4, and global registry of acute coronary events (GRACE) score ≥150 were found to be independent predictors of mortality after six months of NSTE-ACS with adjusted OR of 32.93 [2.65-408.8], 3.42 [1.35-8.66], and 8.43 [3.33-21.38] respectively. For patients with NSTE-ACS, our study showed seven clinical parameters to be associated with an increased risk of 6-month mortality. These included increasing age, increased heart rate, cardiac arrest at presentation, Killip class II-IV, diabetes, TIMI score of >4 and GRACE score of >150. Thereby aiding clinicians to apply strategic and precise interventions in monitoring these patients accordingly.


Efficient downregulation of immunoglobulin mu mRNA with premature translation-termination codons requires the 5'-half of the VDJ exon.
Premature translation-termination codons (PTCs) elicit rapid degradation of the mRNA by a process called nonsense-mediated mRNA decay (NMD). NMD appears to be significantly more efficient for mRNAs of genes belonging to the immunoglobulin superfamily, which frequently acquire PTCs during VDJ rearrangment, than for mRNAs of other genes. To identify determinants for efficient NMD, we developed a minigene system derived from a mouse immunoglobulin micro gene (Ig-micro) and measured the effect of PTCs at different positions on the mRNA level. This revealed that PTCs located downstream of the V-D junction in the VDJ exon of Ig-micro minigenes and of endogenous Ig-micro genes elicit very strong mRNA downregulation, whereas NMD efficiency decreases gradually further upstream in the V segment where a PTC was inserted. Interestingly, two PTCs are in positions where they usually do not trigger NMD (<50 nt from the 3'-most 5' splice site) still resulted in reduced mRNA levels. Using a set of hybrid constructs comprised of Ig-micro and an inefficient substrate for NMD, we identified a 177 nt long element in the V segment that is necessary for efficient downregulation of PTC-containing hybrid transcripts. Moreover, deletion of this NMD-promoting element from the Ig-micro minigene results in loss of strong NMD.


Monoclonal Antibodies 1G12 and 6A12 to the N-domain of human angiotensin-converting enzyme: fine epitope mapping and antibody-based detection of ACE inhibitors in human blood.
Angiotensin I-converting enzyme (ACE), a key enzyme in cardiovascular pathophysiology, consists of two homologous domains (N- and C-), each bearing a Zn-dependent active site. ACE inhibitors are among the most prescribed drugs in the treatment of hypertension and cardiac failure. Fine epitope mapping of two monoclonal antibodies (mAb), 1G12 and 6A12, against the N-domain of human ACE, was developed using the N-domain 3D-structure and 21 single and double N-domain mutants. The binding of both mAbs to their epitopes on the N-domain of ACE is significantly diminished by the presence of the C-domain in the two-domain somatic tissue ACE and further diminished by the presence of sialic acid residues on the surface of blood ACE. The binding of these mAbs to blood ACE, however, increased dramatically (5-10-fold) in the presence of ACE inhibitors or EDTA, whereas the effect of these compounds on the binding of the mAbs to somatic tissue ACE was less pronounced and even less for truncated N-domain. This implies that the binding of ACE inhibitors or removal of Zn2+ from ACE active centers causes conformational adjustments in the mutual arrangement of N- and C-domains in the two-domain ACE molecule. As a result, the regions of the epitopes for mAb 1G12 and 6A12 on the N-domain, shielded in somatic ACE by the C-domain globule and additionally shielded in blood ACE by sialic acid residues in the oligosaccharide chains localized on Asn289 and Asn416, become unmasked. Therefore, we demonstrated a possibility to employ these mAbs (1G12 or 6A12) for detection and quantification of the presence of ACE inhibitors in human blood. This method should find wide application in monitoring clinical trials with ACE inhibitors as well as in the development of the approach for personalized medicine by these effective drugs.


Corydalis yanhusuo Polysaccharides Ameliorate Chronic Stress-Induced Depression in Mice through Gut Microbiota-Derived Short-Chain Fatty Acid Activation of 5-Hydroxytryptamine Signaling.
Depression, a prevalent psychiatric disorder, presents a serious health risk to humans. Increasing evidence suggested that the gut microbiota and the 5-hydroxytryptamine (5-HT) pathway both contribute significantly to depression. This research aimed to investigate how Corydalis yanhusuo polysaccharides (CYP) could potentially alleviate depression induced by chronic unpredictable mild stress in mice, as well as its underlying mechanism. The sucrose preference test, tail suspension test, and forced swimming test were employed to evaluate the behavior of mice. Enzyme-linked immunosorbent assay and PCR techniques were utilized to measure depression-related factors (dopamine [DA], 5-HT, norepinephrine [NE], brain-derived neurotrophic factor [BDNF], tryptophan hydroxylase 2 [TPH-2], 5-hydroxytryptophan [5-HTP], and tryptophan hydroxylase [TPH-1] levels). Hematoxylin and eosin staining and Nissl staining were conducted to observe histopathological changes in the hippocampus, the differences in the diversity of gut flora between groups were analyzed using 16S rRNA sequencing, and gas chromatography-mass spectrometry metabolomics was utilized to evaluate short-chain fatty acid (SCFA) concentrations. The findings indicated that CYP treatment increased the sucrose preference index, decreased the immobility time, and improved neuropathological injury. In depressed mice, CYP improved the dysregulation of the gut microbiota, and increased the SCFA levels. In addition, CYP enhanced the DA, 5-HT, NE, BDNF, and TPH-2 levels in the brain and the expression of 5-HTP and TPH-1 in the colon, while SCFAs were positively correlated with these levels. In summary, our study suggested that CYP may mitigate depression by ameliorating gut microbiota dysregulation, promoting the generation of SCFAs, and activation of 5-HT signaling expression.


Picomole-Scale Transition Metal Electrocatalysis Screening Platform for Discovery of Mild C-C Coupling and C-H Arylation through in Situ Anodically Generated Cationic Pd.
Development of new transition-metal-catalyzed electrochemistry promises to improve overall synthetic efficiency. Here, we describe the first integrated platform for online screening of electrochemical transition-metal catalysis. It utilizes the intrinsic electrochemical capabilities of nanoelectrospray ionization mass spectrometry (nano-ESI-MS) and picomole-scale anodic corrosion of a Pd electrode to generate and evaluate highly efficient cationic catalysts for mild electrocatalysis. We demonstrate the power of the novel electrocatalysis platform by (1) identifying electrolytic Pd-catalyzed Suzuki coupling at room temperature, (2) discovering Pd-catalyzed electrochemical C-H arylation in the absence of external oxidant or additive, (3) developing electrolyzed Suzuki coupling/C-H arylation cascades, and (4) achieving late-stage functionalization of two drug molecules by the newly developed mild electrocatalytic C-H arylation. More importantly, the scale-up reactions confirm that new electrochemical pathways discovered by nano-ESI can be implemented under the conventional electrolytic reaction conditions. This approach enables in situ mechanistic studies by capturing various intermediates including transient transition metal species by MS, and thus uncovering the critical role of anodically generated cationic Pd catalyst in promoting otherwise sluggish transmetalation in C-H arylation. The anodically generated cationic Pd with superior catalytic efficiency and novel online electrochemical screening platform hold great potential for discovering mild transition-metal-catalyzed reactions.


Primitive robotic procedures: automotions for medical liquids in 12th century Asia minor.
In recent years, day by day, robotic surgery applications have increase their role in our medical life. In this article, we reported the discovery of the first primitive robotic applications as automatic machines for the sensitive calculation of liquids such as blood in the literature. Al-Jazari who wrote the book "Elcâmi 'Beyne'l - 'ilm ve'l - 'amel en-nâfi 'fi es-sınaâ 'ti'l - hiyel", lived in Anatolian territory between 1136 and 1206. In this book that was written in the twelfth century, Al-Jazari described nearly fifty graphics of robotic machines and six of them that were designed for medical purposes. We found that some of the robots mentioned in this book are related to medical applications. This book reviews approximately 50 devices, including water clocks, candle clocks, ewers, various automata used for amusement in drink assemblies, automata used for ablution, blood collection tanks, fountains, music devices, devices for water lifting, locks, a protractor, a boat-shaped water clock, and the gate of Diyarbakir City in south-east of Turkey, actually in northern Mesopotamia. We found that automata used for ablution and blood collection tanks were related with medical applications; therefore, we will describe these robots.


Trichoderma-Inoculated Miscanthus Straw Can Replace Peat in Strawberry Cultivation, with Beneficial Effects on Disease Control.
Peat based growing media are not ecologically sustainable and often fail to support biological control. Miscanthus straw was (1) tested to partially replace peat; and (2) pre-colonized with a Trichoderma strain to increase the biological control capacity of the growing media. In two strawberry pot trials (denoted as experiment I & II), extruded and non-extruded miscanthus straw, with or without pre-colonization with T. harzianum T22, was used to partially (20% v/v) replace peat. We tested the performance of each mixture by monitoring strawberry plant development, nutrient content in the leaves and growing media, sensitivity of the fruit to the fungal pathogen Botrytis cinerea, rhizosphere community and strawberry defense responses. N immobilization by miscanthus straw reduced strawberry growth and yield in experiment II but not in I. The pre-colonization of the straw with Trichoderma increased the post-harvest disease suppressiveness against B. cinerea and changed the rhizosphere fungal microbiome in both experiments. In addition, defense-related genes were induced in experiment II. The use of miscanthus straw in growing media will reduce the demand for peat and close resource loops. Successful pre-colonization of this straw with biological control fungi will optimize crop cultivation, requiring fewer pesticide applications, which will benefit the environment and human health.


A baseline study of anticoagulant management in UK hospitals.
To undertake a baseline study of the management of anticoagulants in order to allow later comparison of the impact of the National Patient Safety Agency (NPSA) patient safety alert (including a new patient held record) published in April 2007. A multimethod study comprising semistructured interviews in 20 acute trusts and a telephone/email survey of general practitioners (GPs). The authors found a high degree of consensus concerning a number of problems in the management of anticoagulation services. Consultant haematologists and chief pharmacists expressed concern about the level of competence of junior medical and nursing staff and the quality of patient discharge from general inpatient wards. Patients were regularly discharged before being stabilised on Warfarin, pre-discharge information was not always given, patient-held records were not reliably completed nor follow-up arrangements made. At the ward level, there was some confusion about the responsibility for completing the yellow book on discharge and little awareness of the role of GPs in providing a monitoring service. GPs were largely dissatisfied with the quality of discharge information. The baseline data present a significant cause for concern in the management of warfarin prior to the publication of the NPSA safety alert.


A new species of Munidopsis from a seamount of the Southwest Indian Ocean Ridge (Decapoda: Munidopsidae).
Wood and whale bone colonisation experiments were undertaken on the Southwest Indian Ocean Ridge, 18 November 2009. Later, 14 December 2011, squat lobsters were recovered from the submerged wood and assigned to Munidopsis sp. Further study indicated that the specimens belonged to the group of species having a rostrum without lateral spines, presence of two strong epigastric spines, unarmed abdominal segments, one dorsal eye-spine, and with the second pereiopod not reaching the end of the first. They were similar to M. hemingi Alcock & Anderson, 1899 but differed in that the epigastric spines are well developed (vs. tubercles in M. hemingi), the lateral margins of the carapace are straight (vs. more convex in M. hemingi), the eye has a tubercular process mediodorsally (vs. a papilliform spinule at mesial angle) and the epipods on the fourth pereiopod were absent (vs. present in M. hemingi). Consequently the Munidopsis specimens from the Southwest Indian Ocean Ridge were considered to be an undescribed species.


Minichromosome maintenance protein 2 (MCM2) is a stronger discriminator of increased proliferation in mucosa adjacent to colorectal cancer than Ki-67.
Loss of control of mucosal crypt cell proliferation resulting in a hyperproliferative field change occurs early in the adenoma-carcinoma sequence. Ki-67, the current gold-standard marker of cellular proliferation, is a cell cycle protein that may lack sensitivity in demonstrating altered mucosal crypt cell dynamics. Minichromosome maintenance protein 2 (MCM2) has a specific role in DNA replication and has been proposed as a new marker for screening for colorectal cancer. To compare the expression of Ki-67 with that of MCM2 in colorectal mucosa associated with colorectal cancer. Ki-67 and MCM2 immunostaining was performed on serial sections taken from formalin-fixed, paraffin-embedded specimens. Labelling indices were calculated by counting the proportion of positively stained nuclei in representative areas of adenocarcinoma, and in equivalent superficial, middle and basal crypt compartments of mucosa sampled 1 cm from tumour (Ca1) and 10 cm from tumour (Ca10). Specimens were obtained from 43 patients (27 adenocarcinoma, 16 no-cancer controls). Most nuclei in specimens of adenocarcinoma stained positively for MCM2 and Ki-67. In Ca1 and Ca10 samples, significantly greater staining of MCM2 than Ki-67 was seen in all crypt compartments. Receiver operator characteristic curve analysis suggested that proliferation changes (assessed by either MCM2 or Ki-67 staining) in Ca10, but not in Ca1, mucosa significantly predicted origin from a carcinoma-associated colon. MCM2 was more sensitive than Ki-67 in identifying colorectal mucosal proliferation. Increased proliferation (assessed by either MCM2 or Ki-67 staining) in mucosa at 10 cm, but not at 1 cm, from carcinoma significantly predicted origin from a carcinoma-associated colon.


Evaluation of methods for quantitating erythrocyte antibodies and description of a new method using horseradish peroxidase-labelled antiglobulin.
Concentrates of anti-D and rabbit anti-human globulin (AHG) prepared by standard elution and ammonium sulphate precipitation methods were labelled with 125I and 131I and horseradish peroxidase (HRP), respectively. The number of anti-D molecules attached per rbc ranged from 12,500 to 21,300 for the various phenotypes studied and the label of D-negative rbc never exceeded 3.4% of these values. With 131I-AHG the uptake by control D-negative cells averaged 13% of the uptake by D-positive cells. It was also found that the average ratio of AHG molecules reacting with each IgG molecule was between 2.6 and 3.3 in free solution regardless of the label but was between 3.4 and 7.5 on rbc and ghosts with 131I-AHG and 3 or lower with HRP-AHG. A colorimetric procedure for quantitating IgG antibodies on rbc ghosts is described using HRP-labelled-AHG and o-dianisidine as the hydrogen donor. The method is very sensitive and useful for the detection of coating antibodies but cannot be used for precise quantitation because about 50% of the IgG molecules on rbc are lost in preparing the ghosts. An AutoAnalyzer method for estimating the number of antibodies attached to red cells is briefly described. Direct measurements of numbers of antigens receptors with radiolabeled specific antibodies gave the most reproducible results. Labelled rabbit AHG was not as good because the ratio of AHG to IgG varied. The AutoAnalyzer method may prove useful because of its convenience.


Association of abnormal preoperative laboratory values with survival after radical nephrectomy for clinically confined clear cell renal cell carcinoma.
To determine whether preoperative laboratory values are independently associated with death from clinically confined clear cell renal cell carcinoma (RCC) after radical nephrectomy. We identified 1707 patients with clinically confined (pNx/pN0, pM0), unilateral, sporadic clear cell RCC treated with radical nephrectomy between 1970 and 2002. Associations of abnormal preoperative laboratory values including hypercalcemia, anemia, elevated erythrocyte sedimentation rate (ESR), and elevated alkaline phosphatase with death from RCC were evaluated using Cox proportional hazards regression models, both univariately and multivariately by adjusting for known prognostic features of the 2002 primary tumor classification, tumor size, nuclear grade, and coagulative tumor necrosis. At last follow-up, 1009 patients had died, including 425 who died from RCC at a median of 3.0 years after surgery (range, 0 to 26 years). Even after adjusting for known prognostic features, 9% of patients with preoperative hypercalcemia exhibited significantly increased likelihood of dying from RCC compared with patients with normal or lower levels of serum calcium (relative ration [RR] 1.64; P = 0.002). Similarly, preoperative anemia (35% of patients; RR 1.27; P = 0.026) and elevated ESR (44% of patients; RR 1.66; P = 0.003) portended an increased risk of death from RCC even after multivariate adjustment. Abnormal preoperative laboratory values including hypercalcemia, anemia, and elevated ESR are independently associated with increased risk of cancer-specific death from clinically confined clear cell RCC. Consideration of these variables in future models may improve prognostic accuracy. We believe these factors should be routinely assessed and included in prospective studies of outcome in RCC patients.


Persistent headaches sometimes concern incidental findings: A rare case of internal jugular vein agenesis in a 32-year-old man.
Absence of an internal jugular vein at birth is infrequent. These developmental anomalies affect approximately 0.05 percent to 0.25 percent of the population in the general community. Avascular abnormalities emerging from the internal jugular vein were detected during radiographic studies of chronic headache in an adult male patient. A dull headache troubled a 32-year-old man for more than 20 years. After taking most of NSAIDs and other medications for the condition, which persisted, a diagnosis of left internal jugular vein agenesis was made, which was most likely the cause of the headaches. When treating recurrent, persistent headaches in the emergency room and outdoor medical services, keep in mind that agenesis of the jugular venous system can play a role-one of the uncommon causes of headaches we have observed in our cases.


The therapeutic potential of regulatory T lymphocytes in periodontitis: A systematic review.
This systematic review aimed to: (a) generate a descriptive synthesis of preclinical studies assessing the therapeutic potential of regulatory T lymphocytes (Tregs) to arrest periodontitis, (b) evaluate the methodological heterogeneity of the reviewed animal studies and (c) assess the risk of bias (RoB) of the included studies. The electronic search for animal studies included the MEDLINE, EMBASE, Web of Science and LILACS databases. In addition, a manual search assessed the high-ranked scientific journals in "periodontics/immunology" and the references listed in the included studies. There were no language, year or publication status restrictions. Two independent reviewers selected and extracted the data, and Cohen's Kappa coefficient was calculated to determine the inter-examiner agreement. The Systematic Review Center for Laboratory Animal Experimentation's (SYRCLE) tool was used to assess the RoB. A total of 21 of the 425 studies obtained from the database search were included. Treg function was mainly described in Porphyromonas gingivalis-induced periodontitis (57.1%) in mice (76.2%), where Treg suppression was strongly related to disease progression and Treg induction was strongly related to immuno-inflammatory response reduction. Of those 21 studies, eight included eight animal experiments using three distinct therapeutic approaches, including: P. gingivalis-driven immunization (n = 3), retinoic acid inoculation (n = 2) and anti-inflammatory molecules in polymeric carriers (n = 3), which could modulate the Treg activity through cytokine production (interleukin-10 and transforming growth factor-β1), CC-chemokine- and CC-chemokine receptor-mediated chemoattraction (CCL22 and CCR4) or Th17-associated receptor activator of nuclear factor κB ligand (RANKL) downregulation. However, the studies with animal experiments did not specify the randomization sequences and housing conditions that were used, and therefore, 42.11% of the entries were rated as unclear RoB. Distinct therapeutic strategies involving Tregs could potentially suppress the immuno-inflammatory response and restore alveolar bone homeostasis during periodontitis. Nevertheless, important methodological variability, poor reporting of treatment effect estimates and unclear RoB suggest using caution when assessing the results of these studies.


The role of antimicrobial peptides in human skin and in skin infectious diseases.
Antimicrobial peptides or proteins (AMPs) represent an ancient and efficient innate defense mechanism which protects interfaces from infection with pathogenic microorganisms. In human skin AMPs are produced mainly by keratinocytes, neutrophils, sebocytes or sweat glands and are either expressed constitutively or after an inflammatory stimulus. In several human skin diseases there is an inverse correlation between severity of the disease and the level of AMP production. Skin lesions of patients with atopic dermatitis show a diminished expression of the beta-defensins and the cathelicidin LL-37. Furthermore, these patients have a reduced amount of the AMP dermcidin in their sweat which correlates with an impaired innate defense of human skin in vivo. In addition, decreased levels of AMPs are associated with burns and chronic wounds. In contrast, overexpression of AMPs can lead to increased protection against skin infections as seen in patients with psoriasis and rosacea, inflammatory skin-diseases which rarely result in superinfection. In other skin diseases, e.g. in patients with acne vulgaris, increased levels of AMPs are often found in inflamed or infected skin areas indicating a role of these peptides in the protection from infection. These data indicate that AMPs have a therapeutical potential as topical anti-infectives in several skin diseases. The broad spectrum of antimicrobial activity, the low incidence of bacterial resistance and their function as immunomodulatory agents are attractive features of AMPs for their clinical use.


Manganese induced parkinsonism: an outbreak due to an unrepaired ventilation control system in a ferromanganese smelter.
Several cases of parkinsonism were found in a ferromanganese smelter after the ventilation system had broken down and had not been repaired for eight months in 1985. To determine the aetiology and prevalence of parkinsonism, 132 workers were submitted to thorough medical examination and estimated air concentrations of carbon monoxide and manganese at different worksites. Only six of eight workers performing electrode fixation or welding during 1985 developed parkinsonism. They were exposed for 30 minutes each day, seven days a week, to high concentrations of air manganese (greater than 28.8 mg/m3). There was a consistent trend between the index of exposure to manganese and signs and symptoms exhibited by extrapyramidal systems. After repair of the ventilation system, the air concentration of manganese during electrode fixation and welding decreased to less than 4.4 mg/m3; furthermore, no new cases of parkinsonism have been observed. Workers with parkinsonism recovered partially after removal from original worksites and treatment with levodopa. It is concluded that the outbreak resulted from exposure to high concentrations of manganese fumes through the breakdown of the ventilation system.


Health Benefits and Cost-Effectiveness of Brief Clinician Tobacco Counseling for Youth and Adults.
To help clinicians and care systems determine the priority for tobacco counseling in busy clinic schedules, we assessed the lifetime health and economic value of annually counseling youth to discourage smoking initiation and of annually counseling adults to encourage cessation. We conducted a microsimulation analysis to estimate the health impact and cost effectiveness of both types of tobacco counseling in a US birth cohort of 4,000,000. The model used for the analysis was constructed from nationally representative data sets and structured literature reviews. Compared with no tobacco counseling, the model predicts that annual counseling for youth would reduce the average prevalence of smoking cigarettes during adult years by 2.0 percentage points, whereas annual counseling for adults will reduce prevalence by 3.8 percentage points. Youth counseling would prevent 42,686 smoking-attributable fatalities and increase quality-adjusted life years (QALYs) by 756,601 over the lifetime of the cohort. Adult counseling would prevent 69,901 smoking-attributable fatalities and increase QALYs by 1,044,392. Youth and adult counseling would yield net savings of $225 and $580 per person, respectively. If annual tobacco counseling was provided to the cohort during both youth and adult years, then adult smoking prevalence would be 5.5 percentage points lower compared with no counseling, and there would be 105,917 fewer smoking-attributable fatalities over their lifetimes. Only one-third of the potential health and economic benefits of counseling are being realized at current counseling rates. Brief tobacco counseling provides substantial health benefits while producing cost savings. Both youth and adult intervention are high-priority uses of limited clinician time.


Mandibular asymmetry in patients with the crouzon or apert syndrome.
The aim of this study was to describe directional and fluctuating mandibular asymmetry over time in children with Crouzon or Apert syndrome. Mandibular asymmetry of children between 7.5 and 14 years of age with Crouzon syndrome (n = 35) and Apert syndrome (n = 24) were compared with controls (n = 327). From panoramic radiographs, mandibular directional and fluctuating asymmetry was determined for the three groups. Multilevel statistical techniques were used to describe mandibular asymmetry changes over time. Patients with Crouzon and Apert syndromes showed statistically significant more fluctuating asymmetry for mandibular measures than did controls. Between the Crouzon and Apert syndromes groups, no statistical differences were found in directional and fluctuating asymmetry. The control group showed statistically significantly more directional asymmetry than did patients with Crouzon or Apert syndrome. The controls showed no change over time for the directional asymmetry of condylar-ramal height; however, the directional asymmetry of the gonial angle increased. Patients with Crouzon syndrome showed side dominance for only condylar-ramal height; whereas, patients with Apert syndrome did not show dominance for any of the measurements. Apert and Crouzon syndromes showed developmental instability, in contrast to the controls. No statistically significant longitudinal differences were found for either the directional or the fluctuating asymmetry between Crouzon and Apert syndromes. Findings for fluctuating and directional asymmetry for both syndromes may indicate an inability to cope with genetic and environmental stress during development and treatment, compared with untreated nonsyndromic individuals.


Exploring Psilocybe spp. mycelium and fruiting body chemistry for potential therapeutic compounds.
Psilocybe mushrooms, otherwise known as "magic" mushrooms, owe their psychedelic effect to psilocin, a serotonin subtype 2A (5-HT2A) receptor agonist and metabolite of psilocybin, the primary indole alkaloid found in Psilocybe species. Metabolomics is an advanced fingerprinting tool that can be utilized to identify the differences among fungal life stages that may otherwise be unaccounted for. In this study, by using targeted and untargeted (metabolomic) multivariate analysis, we demonstrate that the chemical composition of Psilocybe differs among mycelia, grain mycelia, and fruiting bodies. The preferential accumulation of psilocybin, baeocystin, tryptophan, ergothioneine, and phenylethylamine in fruiting bodies differentiated them from mycelia; however, the levels of alpha-glycerylphosphorylcholine (α-GPC), N-acetylglucosamine, and trimethylglycine were found to be proportionally higher in mycelia than in fruiting bodies based on Pareto-scaled data. Considering the wealth of compounds with therapeutic potential that have been isolated from various fungal genera, it would be pertinent to study the compounds found in Psilocybe mycelia as potential naturally derived therapeutic targets.


Dynamin and its role in membrane fission.
Dynamin, a 100-kDa GTPase, is an essential component of vesicle formation in receptor-mediated endocytosis, synaptic vesicle recycling, caveolae internalization, and possibly vesicle trafficking in and out of the Golgi. In addition to the GTPase domain, dynamin also contains a pleckstrin homology domain (PH) implicated in membrane binding, a GTPase effector domain (GED) shown to be essential for self-assembly and stimulated GTPase activity, and a C-terminal proline-rich domain (PRD), which contains several SH3-binding sites. Dynamin partners bind to the PRD and may either stimulate dynamin's GTPase activity or target dynamin to the plasma membrane. Purified dynamin readily self-assembles into rings or spirals. This striking structural property supports the hypothesis that dynamin wraps around the necks of budding vesicles where it plays a key role in membrane fission. The focus of this review is on the relationship between the GTPase and self-assembly properties of dynamin and its cellular function.


[A case of carcinomatous cardiac tamponade caused by breast cancer treated with instillation of paclitaxel and minocycline].
The patient was a 56-year-old woman who had undergone the Patey operation for left breast cancer when she was 45 years old. She had complained of dyspnea and shortness of breath at the time of exercise. Bilateral accumulation of pleural effusion and pericardial fluid was observed on chest radiographs and computed tomography(CT)scans. Under the diagnosis of cardiac tamponade, the patient was treated with pericardial drainage and local chemotherapy(intra-pericardial dosage of paclitaxel 45 mg and minocycline 100 mg)with the aim of preventing the accumulation of pericardial effusion. Subsequently, the pericardial effusion continued to disappear. The patient was treated with systemic chemotherapy. At the age of 58 years, she died of breast cancer. After treatment with pericardial drainage and local chemotherapy, she did not experience pericardial reaccumulation or cardiac tamponade. Thus, the method of local chemotherapy(intra-pericardial dosage of paclitaxel 45 mg and minocycline 100 mg)was considered effective.


[Fractures of upper extremities and their treatment in polytrauma].
Under study were results of treatment of 150 patients with multiple and associated injuries of the upper extremities. Shock took place in 44% of the patients. Early fixation of the fractures of the upper extremities allowed a successful treatment of other injuries as well. The primary invalidization made up 12% mainly because of the amputation of the upper extremities.


[Water-bound blood plasma components in enteral correction of posthemorrhagic hypovolemia].
In chronic experiments it was ascertained, that duodenal infusion of monomeric-electrolyte solution with respect to dogs, having undergone hemorrhage of 20-50 ml/kg, while the absorption function is remained, ensure rapid and stable increase of circulating plasma volume, mass of protein, sodium, potassium, and is an effective remedy for stable fill up of posthemorrhagic hypovolemia. Recovery of aqua-associating plasma components, revealed in experiments, testify to participation of gastro-intestinal tract in formation of basic volume substratum and in maintenance of volume homeostasis.


Across the Gap: Geochronological and Sedimentological Analyses from the Late Pleistocene-Holocene Sequence of Goda Buticha, Southeastern Ethiopia.
Goda Buticha is a cave site near Dire Dawa in southeastern Ethiopia that contains an archaeological sequence sampling the late Pleistocene and Holocene of the region. The sedimentary sequence displays complex cultural, chronological and sedimentological histories that seem incongruent with one another. A first set of radiocarbon ages suggested a long sedimentological gap from the end of Marine Isotopic Stage (MIS) 3 to the mid-Holocene. Macroscopic observations suggest that the main sedimentological change does not coincide with the chronostratigraphic hiatus. The cultural sequence shows technological continuity with a late persistence of artifacts that are usually attributed to the Middle Stone Age into the younger parts of the stratigraphic sequence, yet become increasingly associated with lithic artifacts typically related to the Later Stone Age. While not a unique case, this combination of features is unusual in the Horn of Africa. In order to evaluate the possible implications of these observations, sedimentological analyses combined with optically stimulated luminescence (OSL) were conducted. The OSL data now extend the radiocarbon chronology up to 63 ± 7 ka; they also confirm the existence of the chronological gap between 24.8 ± 2.6 ka and 7.5 ± 0.3 ka. The sedimentological analyses suggest that the origin and mode of deposition were largely similar throughout the whole sequence, although the anthropic and faunal activities increased in the younger levels. Regional climatic records are used to support the sedimentological observations and interpretations. We discuss the implications of the sedimentological and dating analyses for understanding cultural processes in the region.


Atrial fibrillation mortality trends in individuals with heart failure.
Atrial fibrillation (AF) frequently occurs concurrently with heart failure (HF). The two conditions can exacerbate each other, resulting in higher morbidity and mortality. In our analysis, we evaluated mortality trends related to AF in individuals with underlying HF. Cross-sectional analyses were performed using publicly available data from the Center for Disease Control and Prevention database to compare AF-related age-adjusted mortality rates across age, gender, racial/ethnic, and geographic subgroups. Mortality trends were evaluated by fitting log-linear regression models followed by calculation of the average annual percentage change (AAPC) using the Monte Carlo permutation test. We identified a total of 55,917 deaths within the United States from AF with comorbid HF between 1999 and 2020. Males, older adults, White populations, and non-metropolitan regions had higher age-adjusted mortality compared to females, younger adults, Black populations, and metropolitan regions, respectively. The AAPC among younger adults was significantly higher compared to older adults. Our results demonstrate existing disparities among age, gender, racial, and geographic subgroups related to AF mortality among individuals with comorbid HF. Although decreased overall mortality was observed within younger populations compared to older populations, the prominent AAPC seen in younger populations warrants further investigation. Detection of AF among younger adults with comorbid HF should prompt the intensification of preventative and treatment measures.


Taking Control: The Efficacy and Durability of a Peer-Led Uncertainty Management Intervention for People Recently Diagnosed With HIV.
HIV creates substantial uncertainty for people infected with the virus, which subsequently affects a host of psychosocial outcomes critical to successful management of the disease. This study assessed the efficacy and durability of a theoretically driven, one-on-one peer support intervention designed to facilitate uncertainty management and enhance psychosocial functioning for patients newly diagnosed with HIV. Using a pretest-posttest control group design, 98 participants received information and training in specific communication strategies (e.g., disclosing to friends and family, eliciting social support, talking to health care providers, using the Internet to gather information, and building social networks through AIDS service organizations). Participants in the experimental group attended six 1-hour sessions, whereas control participants received standard of care for 12 months (after which they received the intervention). Over time, participants in the intervention fared significantly better regarding (a) illness uncertainty, (b) depression, and (c) satisfaction with social support than did those in the control group. Given the utility and cost-effectiveness of this intervention and the uncertainty of a multitude of medical diagnoses and disease experiences, further work is indicated to determine how this program could be expanded to other illnesses and to address related factors, such as treatment adherence and clinical outcomes.


Interprofessional learning.
Effective care in hospitals and in the community requires doctors, nurses and other healthcare professionals to work together to achieve the best possible outcomes for patients. In the UK, a shift in emphasis towards a primary care led service and recent changes to the ways in which healthcare is funded and organised, are profoundly affecting traditional patterns of working. Boundaries which define the roles and responsibilities of individual professions are becoming less clear and there is increasing overlap of knowledge and skills. The provision of effective patient care now depends much more on the individual practitioner's understanding of the need to collaborate within and between healthcare teams in community settings and the care provided in hospitals. This paper describes some of the ways in which those providing education and training for the professions are seeking to create opportunities for learners which will not only help them to understand the complexities of working in a multiprofessional healthcare environment, but also enable them to develop the skills and attitudes they need for interprofessional working. However, it is not yet established whether 'learning together' during basic training will result in better 'working together' in practice. Higher education institutions are understandably cautious about adopting new learning methods which make extra demands on decreasing resources. More studies are therefore needed to show whether interprofessional learning during basic education has an impact on future working practice.


The words of the regulatory code are arranged in a variable manner in highly conserved enhancers.
The cis-regulatory regions of many developmental regulators and transcription factors are believed to be highly conserved in the genomes of vertebrate species, suggesting specific regulatory mechanisms for these gene classes. We functionally characterized five notochord enhancers, whose sequence is highly conserved, and systematically mutated two of them. Two subregions were identified to be essential for expression in the notochord of the zebrafish embryo. Synthetic enhancers containing the two essential regions in front of a TATA-box drive expression in the notochord while concatemerization of the subregions alone is not sufficient, indicating that the combination of the two sequence elements is required for notochord expression. Both regions are present in the five functionally characterized notochord enhancers. However, the position, the distance and relative orientation of the two sequence motifs can vary substantially within the enhancer sequences. This suggests that the regulatory grammar itself does not dictate the high evolutionary conservation between these orthologous cis-regulatory sequences. Rather, it represents a less well-conserved layer of sequence organization within these sequences.


Do dual tasks have an added value over single tasks for balance assessment in fall prevention programs? A mini-review.
The Prevention of Falls Network Europe (ProFaNE) aims to bring together European researchers and clinicians to focus on the development of effective falls prevention programs for older people. One of the objectives is to identify suitable balance assessment tools. Assessment procedures that combine a balance task with a cognitive task may be relevant since part of all falls occurs during dual-task performance of walking or other balance activities. To evaluate whether dual-task balance assessments are more sensitive than single balance tasks in predicting falls and detecting changes in balance performance after fall interventions. A systematic literature search was performed in the databases PubMed, EMBASE, CINAHL, AMED, PsycINFO and Cochrane. Articles were selected according to the following inclusion criteria: (1) population: older adults (mean age > or =65 years), (2) assessment tool: dual task combining gait or other balance task with a cognitive task, (3) design: prospective or retrospective data collection of falls, or intervention study. Analysis of papers focused on measures of predictive ability or sensitivity-to-change for both tasks during dual-task performance as well as for the single balance and cognitive task. Out of 114 dual-task studies in older people, 19 articles matched the inclusion criteria. Fourteen studies had sample sizes of 60 subjects or less; the studied populations, task combinations as well as other methodological aspects varied. None of the articles reported the same statistical measures for both tasks during dual-task performance as well as single balance and cognitive task. In two studies with prospective data collection of falls, higher odds ratios were found for the dual compared to the single balance task. Upon the available literature, conclusions for an added value of dual balance tasks for fall prediction or assessing fall intervention effects cannot be made due to incomplete comparisons of single and dual balance tasks. Nevertheless, two studies do provide an indication that dual balance tasks may have added value for fall prediction.


Head-out immersion in natural thermal mineral water for the management of hypertension: a review of randomized controlled trials.
Hypertension is a major public health problem in the world, and the management of hypertension has always been a research of interest. Balneotherapy, with its recreational aspect, is more acceptable than medication intake and lifestyle change for the management of hypertension. The aim of this review was to summarize the current available data on the clinical effects of head-out immersion in natural thermal mineral water (HINTMW) as the most common method of balneotherapy used in the management of hypertension. We screened the PubMed, EMBASE, Cochrane Library, China Science and Technology Journal, China National Knowledge Infrastructure, WANFANG, and China Biology Medicine disc databases and selected 12 randomized controlled trials involving a total of 1122 participants. Among 12 trials, HINTMW was taken as the only intervention in only one study, HINTMW was taken in addition to basic antihypertensive drugs in three studies, and HINTMW was taken in combination with advice to follow nonpharmacological methods in one study involving participants who partly used antihypertensive drugs, while HINTMW combined with other interventions, such as natural convalescent factor therapy, psychotherapy, exercises, nutrition therapy, and integrated care, was taken in addition to basic antihypertensive drugs in the other 7 studies. Our results showed that natural thermal mineral water immersion alone or natural thermal mineral water immersion as an adjuvant therapy to medication or natural thermal mineral water immersion combined with other interventions had no adverse effects on hypertensive patients, and most even had positive effects. However, more high-quality evidences on therapeutic effectiveness of natural thermal mineral water immersion on hypertension are needed from additional randomized controlled trials with high methodological quality.


Percutaneous superficial femoral artery interventions for claudication--does runoff matter?
Endoluminal therapy for superficial femoral artery (SFA) occlusive disease for claudication is commonplace, but the implications of tibial vessel runoff on long-term outcomes of these interventions in patients with claudication are unclear. Runoff is known to negatively affect graft patency, but no data are available on the impact of runoff on percutaneous SFA interventions and their implications during follow-up. We examined the impact of distal popliteal and tibial runoff on long-term outcomes of SFA interventions for claudication. A prospective database of patients undergoing endovascular treatment of the SFA between 1986 and 2007 was queried. Patients with Rutherford symptom classifications 1, 2, and 3 were selected; those with concomitant tibial interventions were excluded. Angiograms were reviewed preoperatively in all cases to assess distal popliteal and tibial runoff and scored according to modified Society for Vascular Surgery criteria for both vessels such that a higher score implies worse runoff (minimum 1, maximum 19). Three run-off score groups were identified: <5 (good), 5-10 (compromised), and >10 (poor). Kaplan-Meier survival analyses were performed to assess time-dependent outcomes. Multivariate and factor analyses were performed. There were 481 limbs in 347 patients (70% male, average age 66 years) that underwent endovascular SFA treatment for claudication: 87% had hypertension, 51% had diabetes mellitus, 67% had hyperlipidemia, and 16% had chronic renal insufficiency (1% on hemodialysis). Technical success was 92%, with 63% SFA undergoing angioplasty, 26% SFA undergoing primary stenting, and 3% SFA undergoing atherectomy. Overall mortality was 1.1% and overall morbidity was 17% at 90 days after the procedure. At 5 years, vessels with compromised and poor runoff had significantly lower freedom from recurrent symptoms and lower freedom from restenosis. Primary and assisted primary patency rates were significantly worse in patients with poor runoff. However, secondary patency was equivalent between the groups. Compromised or poor runoff was associated with incremental lower limb salvage. Following SFA percutaneous interventions for claudication, runoff can identify patients more likely to develop restenosis and recurrent symptoms and, more importantly, those at higher risk of limb loss. Defining such subgroups allows a clear risk stratification of patients with claudication and can guide the intensity of surveillance in the outpatient setting.


Superparamagnetic gamma-Fe(2)O(3) nanoparticles with tailored functionality for protein separation.
Polymer coated superparamagnetic gamma-Fe(2)O(3) nanoparticles were derivatized with a synthetic double-stranded RNA [poly(IC)], a known allosteric activator of the latent (2-5)A synthetase, to separate a single 35 kDa protein from a crude extract which cross reacted with antibodies raised against the sponge enzyme.


The ABC of tDCS: Effects of Anodal, Bilateral and Cathodal Montages of Transcranial Direct Current Stimulation in Patients with Stroke-A Pilot Study.
Transcranial direct current stimulation (tDCS) is a noninvasive technique that is emerging as a prospective therapy for different neurologic disorders. Previous studies have demonstrated that anodal and cathodal stimulation can improve motor performance in terms of dexterity and manual force. The objective of this study was to determine whether different electrodes' setups (anodal, cathodal, and simultaneous bilateral tDCS) provide different motor performance and which montage was more effective. As secondary outcome, we have asked to the patients about their satisfaction, and to determine if the bilateral tDCS was more uncomfortable than unilateral tDCS. Nine patients with stroke in subacute phase were enrolled in this study and randomly divided in three groups. Our results showed that tDCS was an effective treatment if compared to Sham stimulation (P = 0.022). In particular, anodal stimulation provided the higher improvement in terms of manual dexterity. Cathodal stimulation seemed to have a little effect in terms of force improvement, not observed with other setups. Bipolar stimulation seemed to be the less effective. No significant differences have been noted for the different set-ups for patients' judgment. These results highlight the potential efficacy of tDCS for patients with stroke in subacute phase.


New insights into lipid and fatty acid metabolism via stable isotopes.
Dynamic processes are of great interest in the study of lipid and fatty acid metabolism. Their in vivo investigation is now possible with the use of stable isotope tracers and the available sensitive analytical technology. We present some examples demonstrating the assessment of lipid oxidation as well as modulating factors by analysis of the tracer appearance in breath CO2 by isotope ratio mass spectrometry (IRMS). In a child with severe hypertriglycendaemia due to decreased cleavage of chylomicrons, medium-chain triglycerides were oxidised normally, whereas utilisation of long-chain triglycerides was severely disturbed. In another patient with primary carnitine deficiency, the beneficial effect of carnitine supplementation on fat oxidation could be demonstrated. In combination with gas chromatography, the high sensitivity of IRMS may be used for the detection of tracer materials in various plasma metabolites. In a pilot study, we applied C-13C labelled linoleic and alpha-linolenic acids to infants aged 2 weeks and 11 months, respectively. In these subjects, we could show a relative decrease of the conversion of these essential fatty acids to their longer chain polyunsaturated derivatives with age. The ability of term infants aged 19 days to convert linoleic into arachidonic acid was evaluated by using small natural differences in 13C abundance between different foods. Stable isotopes are also suitable for elucidation of new metabolic pathways. As an example, we could show in rats that linoleic and alpha-linolenic acids, which are usually considered to be essential substrates, can be synthesized endogenously from C16 precursors. IRMS is well suitable for the clinical investigation of lipid metabolism with stable isotopes in children. With different sample preparation devices, breath CO2 as well as specific plasma components can be analysed. While breath tests are already applied in clinical routing testing, GC-C-IRMS is a promising tool for research.


Clinical chemistry profiles in injection heroin users from Coastal Region, Kenya.
Although the co-burden of injection drug use and HIV is increasing in Africa, little is known about the laboratory markers of injection drug use and anti-retroviral treatment (ART) in Kenyan injection drug users. This study, therefore, aimed at determining the clinical chemistry profiles and identifying the key laboratory markers of HIV infection during ART in injection heroin users (IHUs). Clinical chemistry measurements were performed on serum samples collected from HIV-1 infected ART-experienced (n = 22), naive (n = 16) and HIV-1 negative (n = 23) IHUs, and healthy controls (n = 15) from Mombasa, coastal Kenya. HIV uninfected IHUs had lower alanine aminotransferase (ALT) levels (P = 0.023) as ART-exposed IHUs exhibited lower albumin (P = 0.014) and higher AST to platelet index (APRI) (P < 0.0001). All IHUs presented with lower aspartate aminotransferase to ALT values (P = 0.001) and higher C-reactive protein (CRP) levels (P = 0.002). ART-naive IHUs had higher globulin levels (P = 0.013) while ART-experienced and naive IHUs had higher albumin to total protein (P < 0.0001) and albumin to globulin (P < 0.0001) values. In addition, CD4+ T cells correlated with ALT (ρ = -0.522, P = 0.011) and CRP (rho, ρ = 0.529, P = 0.011) in HIV negative and ART-experienced IHUs, respectively. HIV-1 viral load correlated with albumin to globulin index in ART-experienced (ρ = -0.468, P = 0.037) and naive (ρ = -0.554, P = 0.040) IHUs; and with albumin to total protein index (ρ = -0.554, P = 0.040) and globulin (ρ = 0.570, P = 0.033) in ART-naive IHUs. Absolute ALT, albumin, globulin, and CRP measurements in combination with APRI, AST to ALT, albumin to total protein and albumin to globulin indices may be useful laboratory markers for screening IHUs for initiating and monitoring treatment.


Mismatch repair deficiency does not enhance ENU mutagenesis in the zebrafish germ line.
S(N)1-type alkylating agents such as N-ethyl-N-nitrosourea (ENU) are very potent mutagens. They act by transferring their alkyl group to DNA bases, which, upon mispairing during replication, can cause single base pair mutations in the next replication cycle. As DNA mismatch repair (MMR) proteins are involved in the recognition of alkylation damage, we hypothesized that ENU-induced mutation rates could be increased in a MMR-deficient background, which would be beneficial for mutagenesis approaches. We applied a standard ENU mutagenesis protocol to adult zebrafish deficient in the MMR gene msh6 and heterozygous controls to study the effect of MMR on ENU-induced DNA damage. Dose-dependent lethality was found to be similar for homozygous and heterozygous mutants, indicating that there is no difference in ENU resistance. Mutation discovery by high-throughput dideoxy resequencing of genomic targets in outcrossed progeny of the mutagenized fish did also not reveal any differences in germ line mutation frequency. These results may indicate that the maximum mutation load for zebrafish has been reached with the currently used, highly optimized ENU mutagenesis protocol. Alternatively, the MMR system in the zebrafish germ line may be saturated very rapidly, thereby having a limited effect on high-dose ENU mutagenesis.


Advancing school-based interventions through economic analysis.
Commentators interested in school-based prevention programs point to the importance of economic issues for the future of prevention efforts. Many of the processes and aims of prevention science are dependent upon prevention resources. Although economic analysis is an essential tool for assessing resource use, the attention given economic analysis within school-based prevention remains cursory. Largely, economic analyses of school-based prevention efforts are undertaken as secondary research. This limits these efforts to data that have been collected previously as part of epidemiological and outcomes research. Therefore, economic analyses suffer from gaps in the knowledge generated by these studies. This chapter addresses the importance of economic analysis for the future of school-based substance abuse prevention programs and highlights the role of prevention research in the development of knowledge that can be used for economic analysis.


The effect of methylphenidate on anxiety and depression symptoms in patients with Asperger syndrome and comorbid attention deficit/hyperactivity disorder.
The objective of this study was to assess the response of anxiety and depression symptoms to methylphenidate (MPH) treatment in patients with Asperger syndrome (AS) combined with attention deficit/hyperactivity disorder (ADHD). A group of 12 patients with AS/ADHD, aged 8-18 years, received 12 weeks of MPH treatment. The severities of ADHD, anxiety, and depression symptoms were assessed by means of the ADHD Rating Scale (ADHD-RS), Screen for Child Anxiety Related Emotional Disorders, and the Children's Depression Inventory. The severity of ADHD and depression symptoms was reduced significantly (P<0.0003 and P=0.046, respectively). No improvement in total anxiety symptoms was found, but a significant reduction was obtained in the school-related subscale of the Screen for Child Anxiety Related Emotional Disorders (P=0.0054). A positive correlation was found between the reductions in ADHD-RS and Children's Depression Inventory scores (r=0.59, P=0.039). MPH treatment may be safe, tolerable, and effective in alleviating depression and school-related anxiety symptoms in patients with AS and ADHD.


Genomic removal of a therapeutic mini-dystrophin gene from adult mice elicits a Duchenne muscular dystrophy-like phenotype.
Duchenne muscular dystrophy (DMD) is caused by dystrophin deficiency. A fundamental question in DMD pathogenesis and dystrophin gene therapy is whether muscle health depends on continuous dystrophin expression throughout the life. Published data suggest that transient dystrophin expression in early life might offer permanent protection. To study the consequences of adulthood dystrophin loss, we generated two strains of floxed mini-dystrophin transgenic mice on the dystrophin-null background. Muscle diseases were prevented in skeletal muscle of the YL238 strain and the heart of the SJ13 strain by selective expression of a therapeutic mini-dystrophin gene in skeletal muscle and heart, respectively. The mini-dystrophin gene was removed from the tibialis anterior (TA) muscle of 8-month-old YL238 mice and the heart of 7-month-old SJ13 mice using an adeno-associated virus serotype-9 Cre recombinase vector (AAV.CBA.Cre). At 12 and 15 months after AAV.CBA.Cre injection, mini-dystrophin expression was reduced by ∼87% in the TA muscle of YL238 mice and ∼64% in the heart of SJ13 mice. Mini-dystrophin reduction caused muscle atrophy, degeneration and force loss in the TA muscle of YL238 mice and significantly compromised left ventricular hemodynamics in SJ13 mice. Our results suggest that persistent dystrophin expression is essential for continuous muscle and heart protection.


Aging, trends in CD4+/CD8+ cell ratio, and clinical outcomes with persistent HIV suppression in a dynamic cohort of ambulatory HIV patients.
Age blunts CD4+ lymphocyte cell count/μl (CD4+) improvements observed with antiretroviral therapy (ART)-induced viral suppression among people with HIV (PWH). Prolonged viral suppression reduces immune dysregulation, reflected by rising CD4+/CD8+ ratios (CD4+/CD8+). We studied CD4+/CD8+ over time to determine whether it predicts risk for select comorbidities and mortality among aging PWH with viral suppression. We studied HIV Outpatient Study (HOPS) participants prescribed ART during 2000-2018 who achieved a viral load less than 200 copies/ml on or after 1 January 2000, and remained virally suppressed at least 1 year thereafter. We modeled associations of CD4+/CD8+ with select incident comorbidities and all-cause mortality using Cox regression and controlling for demographic and clinical factors. Of 2480 eligible participants,1145 (46%) were aged less than 40 years, 835 (34%) 40-49 years, and 500 (20%) ≥ 50 years. At baseline, median CD4+/CD8+ was 0.53 (interquartile range: 0.30-0.84) and similar among all age groups (P = 0.18). CD4+/CD8+ values and percentage of participants with CD4+/CD8+ at least 0.70 increased within each age group (P < 0.001 for all). CD4+/CD8+ increase was greatest for PWH aged less than 40 years at baseline. In adjusted models, most recent CD4+/CD8+less than 1.00 and less than 0.70 were independently associated with higher risk of non-AIDS cancer and mortality, respectively. Pretreatment immune dysregulation may persist as indicated by CD4+/CD8+ less than 0.70. Persistent viral suppression can improve immune dysregulation over time, reducing comorbidity, and mortality risk. Monitoring CD4+/CD8+ among ART-treated PWH with lower values provide a means to assess for mortality and comorbidity risk.


Intracellular localization of the p35 subunit of murine IL-12.
Production of interleukin-12 (IL-12), a heterodimer of p35 and p40 subunits, is limited by p35 expression. A long and a short murine p35 mRNA potentially encoding proteins differing in pre-sequence size are produced. Increased pre-sequence size could convert a cleaved signal peptide to an uncleaved signal peptide, raising the possibility that a membrane-bound form of p35 is produced. The intracellular localization of the p35 encoded by each mRNA isoform was determined by constructing cDNAs containing the long or short p35 cDNA isoform fused in-frame to a cDNA encoding green fluorescent protein (GFP). After transfection of a CV-1 African green monkey kidney cell line with the constructs, confocal microscopy and immunoblotting of extracted microsomal membranes demonstrated that the p35-GFP fusion protein encoded by the long or short mRNA accumulates in the Golgi apparatus as an endoglycosidase H-sensitive glycosylated integral membrane protein. In contrast, a p40-GFP fusion protein accumulates in the Golgi apparatus as a soluble protein. Since assembly of the p35 and p40 subunits to form bioactive IL-12 occurs in the ER, release of membrane-tethered IL-12 by proteolytic cleavage in a late Golgi or post-Golgi compartment may represent an as yet unidentified level at which bioactive IL-12 secretion is regulated.


Stabilization of F-actin prevents cAMP-elicited Cl- secretion in T84 cells.
T84 cells, a human intestinal epithelial cell line, serve as a model of electrogenic Cl- secretion. We find that cAMP-elicited Cl- secretion in T84 cells is accompanied by a marked redistribution of F-actin in the basolateral portion of the cell. To prevent this F-actin redistribution and thereby assess its importance to Cl- secretion, we have defined simple conditions under which this model epithelium can be loaded with nitrobenzoxadiazole (NBD)-phallicidin. This reagent binds F-actin with high affinity thus stabilizing the F-actin cytoskeleton by preventing depolymerization, an event necessary for dynamic reordering of actin microfilaments. NBD-phallicidin loading is not cytotoxic as assessed by lactic dehydrogenase release, protein synthesis, transepithelial resistance, and the ability of the loaded cells to pump Na+ in an absorptive direction in response to the apical addition of a Na+ ionophore. However, cAMP-elicited redistribution of F-actin and the cAMP-elicited Cl- secretory response are both markedly impaired in NBD-phallicidin preloaded T84 cells. In contrast, the carbachol-elicited Cl- secretory response (Ca++ mediated) is not attenuated by NBD-phallicidin preloading nor is it accompanied by redistribution of F-actin. These findings suggest that the cAMP-elicited cytoskeletal redistribution we describe is an integral part of cAMP-elicited Cl- secretion in T84 cells.


Bisthiazolidines: A Substrate-Mimicking Scaffold as an Inhibitor of the NDM-1 Carbapenemase.
Pathogenic Gram-negative bacteria resistant to almost all β-lactam antibiotics are a major public health threat. Zn(II)-dependent or metallo-β-lactamases (MBLs) produced by these bacteria inactivate most β-lactam antibiotics, including the carbapenems, which are "last line therapies" for life-threatening Gram-negative infections. NDM-1 is a carbapenemase belonging to the MBL family that is rapidly spreading worldwide. Regrettably, inhibitors of MBLs are not yet developed. Here we present the bisthiazolidine (BTZ) scaffold as a structure with some features of β-lactam substrates, which can be modified with metal-binding groups to target the MBL active site. Inspired by known interactions of MBLs with β-lactams, we designed four BTZs that behave as in vitro NDM-1 inhibitors with Ki values in the low micromolar range (from 7 ± 1 to 19 ± 3 μM). NMR spectroscopy demonstrated that they inhibit hydrolysis of imipenem in NDM-1-producing Escherichia coli. In vitro time kill cell-based assays against a variety of bacterial strains harboring blaNDM-1 including Acinetobacter baumannii show that the compounds restore the antibacterial activity of imipenem. A crystal structure of the most potent heterocycle (L-CS319) in complex with NDM-1 at 1.9 Å resolution identified both structural determinants for inhibitor binding and opportunities for further improvements in potency.


Analysis of the prevalence of and risk factors for atopic dermatitis using an ISAAC questionnaire in 8,750 Korean children.
Since 1995, epidemiologic studies of atopic disorders using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire have been performed in many countries, including the Republic of Korea. The prevalence, burden and risk factors of atopic dermatitis were surveyed in these studies, which helped to enhance their comparability among different areas and age groups, as well as to clarify the nature of atopic dermatitis and other atopic disorders. From 21 facilities, 8,750 children were enrolled in this cross-sectional study. The data were collected via the Internet using a questionnaire based on the Korean-language version of the ISAAC study format. The prevalence of atopic dermatitis over the previous 12 months was 14.4%. The prevalence in preschool children was significantly higher than in elementary school children. Family history of atopic diseases, diagnosis of allergic conjunctivitis and diagnosis of food allergy were positively associated with atopic dermatitis in both preschool and elementary school children. In addition, raising pets was positively associated with atopic dermatitis in preschool children. In elementary school children, female gender, secondhand smoking, breastfeeding, changing the parents' house to a newly built one during the first year of life, diagnosis of asthma and diagnosis of allergic rhinitis were positively associated with atopic dermatitis. The prevalence of atopic dermatitis in preschool and elementary school children in Korea is similar to that of children in other developing countries. The risk factors for atopic dermatitis are different in preschool and elementary school children. More detailed strategies will be necessary to reduce atopic dermatitis in both age groups.


Isolation and characterization of brush border membrane vesicles from bovine small intestine.
Intestinal brush border membrane vesicles were prepared from 21-wk-old Holstein bulls. The method of preparation included magnesium precipitation, differential centrifugation and sucrose density gradient centrifugation. Purification of brush border membranes was indicated by sevenfold enrichment of alkaline phosphatase activity. Uptake of D-[U-14C]glucose was sodium-stimulated and exhibited characteristic "overshoot" phenomenon. Sodium-dependent and sodium-independent D-glucose uptake was into an osmotically active space. Phloridzin (100 mM) completely inhibited sodium-dependent, but did not affect sodium-independent transport. Sodium-dependent D-glucose transport was inhibited more by D-glucose than by D-galactose, which inhibited more than D-xylose did. The sodium-dependent D-glucose transport was not inhibited by D-fructose, D-ribose or D-arabinose. Sodium-independent D-glucose transport was unaffected by the sugars tested. Glucose transport in bovine intestinal brush border is similar to that in monogastric species and is composed of two pathways: a sodium-dependent inhibitable system and a diffusional system.


Topical use of tranexamic acid can effectively decrease hidden blood loss during posterior lumbar spinal fusion surgery: A retrospective study.
In spinal fusion surgery, total blood loss (TBL) is composed of visible blood loss from the surgical field and wound drainage, and hidden blood loss (HBL). Until now, no published studies exist reporting the effect of topical use of tranexamic acid (tTXA) on HBL in patients undergoing posterior lumbar spinal fusion surgery. This study aimed to explore the effect of tTXA on HBL during primary posterior lumbar spinal fusion surgery. Between September 2014 and September 2016, 100 adult patients (age > 18 years) with lumbar disc herniation or lumbar spinal stenosis undergoing primary posterior lumbar instrumented spinal fusions at 1 institution were divided into tTXA and control groups. The primary outcome was HBL. Secondary outcomes include TBL, intraoperative blood loss (IBL), postoperative blood loss (PBL), hemoglobin (HGB) levels on preoperative (Pre-op) and postoperatively (days 1-3, POD1, POD2, POD3, respectively), and amount of allogeneic blood transfusion. Complications occurring perioperatively until hospitalization discharge were also collected. In the tTXA group (n = 50 patients), wound surface was soaked with TXA (1 g in 100 mL saline solution) for 5 minutes before wound closure. For the control group (n = 50 patients), wound surface was soaked with the same volume of normal saline. There were no significant differences in demographics, surgical traits between the 2 groups. There were no significant differences in IBL or perioperative blood transfusion requirements between the 2 groups. However, in the tTXA group, TBL, PBL, and HBL were significantly lower than those in the control group (550 ± 268 vs 833 ± 298 mL, 53.5 ± 43.9 vs 136.7 ± 87.9 mL, 356.7 ± 254.8 vs 501.1 ± 216.9 mL, P < .001, respectively). HGB levels were significantly higher in the tTXA group (P < .001) on POD1 and had a slower decline on POD2 and POD3 than the control group. No complications associated with TXA were observed. From these data, we conclude that tTXA can effectively reduce HBL, without significant complications in adult patients undergoing posterior lumbar spinal fusion surgery.


Characterization of productive and sterile transcripts from the immunoglobulin heavy-chain locus: processing of micron and muS mRNA.
An analysis of the sizes and sequence content of nuclear RNA transcripts of the heavy-chain locus in two B-cell lymphomas, 70Z/3 and 38C-13, and in selected hybridoma derivatives of 38C has led to the identification of two distinct precursors of the mRNAs encoding the membrane and secretory forms of mu chain. These precursors, termed Pm1 and Ps1, extend from a common 5' terminus (presumably the cap site) to alternative polyadenylation sites located 3' of the membrane and secretory tailpieces, Pm1 and Ps1 are present in similar amounts in lymphomas, indicating roughly equivalent usage of the two polyadenylation sites, whereas Ps1 much greater than Pm1 in hybridomas, indicating that mature plasma cells produce a trans-acting factor which enhances cleavage at the proximal (muS) site. The lymphomas also synthesize several nonproductive or sterile mu (Smu) transcripts from the second H allele. One class of sterile mu transcripts appears to be initiated about 1 kilobase downstream from the JH4 element. In 70Z, in which the nonproductive H allele has undergone a D1J2 fusion, another initiation site was located about 0.3 kilobase upstream of the D1 element. The sterile mu transcripts exhibit the same regulated termination at alternative polyadenylation sites as the mu mRNA precursors, although their rate of production is not necessarily coupled to that of the productive allele. This analysis has also defined probable processing pathways for productive and sterile components in which there is a 5' leads to 3' order for the excision of the large introns.


Can changes in 3D genome architecture create new regulatory landscapes that contribute to phenotypic evolution?
Animal genomes are compartmentalized into insulated regulatory units named topology-associated domains (TADs). TADs insulate gene promoters from enhancers that occupy neighboring TADs. Chromosomal rearrangements that disrupt TAD structure can generate new regulatory interactions between enhancers and promoters that were once separated into different TADs, which might lead to new gene expression patterns. On the one hand, TAD rearrangements are known to cause deleterious phenotypes, but, on the other hand, rearrangements can also create novel expression patterns that may be selected during evolution because they generate advantageous phenotypes. Here, we review recent studies that explore the effects of chromosomal rearrangements and genetic perturbations on TAD structure and gene regulation in the context of development and evolution. We discuss the possible contribution of evolutionary breakpoints (EBRs) that affect TAD structure to the evolution of gene regulation and the phenotype.


An implantable bi-directional brain-machine interface system for chronic neuroprosthesis research.
An implantable bi-directional brain-machine interface (BMI) prototype is presented. With sensing, algorithm, wireless telemetry, and stimulation therapy capabilities, the system is designed for chronic studies exploring closed-loop and diagnostic opportunities for neuroprosthetics. In particular, we hope to enable fundamental chronic research into the physiology of neurological disorders, define key electrical biomarkers related to disease, and apply this learning to patient-specific algorithms for therapeutic stimulation and diagnostics. The ultimate goal is to provide practical neuroprosthetics with adaptive therapy for improved efficiency and efficacy.


Periodic solitons in nonlocal nonlinear media.
We identify periodic solitons in nonlocal nonlinear media: multi-hump soliton solutions propagating in a fully periodic fashion. We also demonstrate recurrences and breathers whose evolution is statistically periodic and discuss why some systems support periodic solitons while others do not.


Understanding epigenetic changes in aging stem cells--a computational model approach.
During aging, a decline in stem cell function is observed in many tissues. This decline is accompanied by complex changes of the chromatin structure among them changes in histone modifications and DNA methylation which both affect transcription of a tissue-specific subset of genes. A mechanistic understanding of these age-associated processes, their interrelations and environmental dependence is currently lacking. Here, we discuss related questions on the molecular, cellular, and population level. We combine an individual cell-based model of stem cell populations with a model of epigenetic regulation of transcription. The novel model enables to simulate age-related changes of trimethylation of lysine 4 at histone H3 and of DNA methylation. These changes entail expression changes of genes that induce age-related phenotypes (ARPs) of cells. We compare age-related changes of regulatory states in quiescent stem cells occupying a niche with those observed in proliferating cells. Moreover, we analyze the impact of the activity of the involved epigenetic modifiers on these changes. We find that epigenetic aging strongly affects stem cell heterogeneity and that homing at stem cell niches retards epigenetic aging. Our model provides a mechanistic explanation how increased stem cell proliferation can lead to progeroid phenotypes. Adapting our model to properties observed for aged hematopoietic stem cell (HSC) clones, we predict that the hematopoietic ARP activates young HSCs and thereby retards aging of the entire HSC population. In addition, our model suggests that the experimentally observed high interindividual variance in HSC numbers originates in a variance of histone methyltransferase activity.