The role of protein nitration in the inhibition of platelet activation by peroxynitrite.
Peroxynitrite at low concentrations (3-10 microM) inhibited agonist-induced platelet aggregation by a mechanism not dependent on the formation of cyclic guanosine monophosphate. Platelets recovered completely from peroxynitrite-induced inhibition within 30 min. Peroxynitrite induced nitration of cytosolic proteins, but this diminished to near basal levels within 60 min of exposure to the oxidant. During this period there was a reduction in tyrosine phosphorylation of specific proteins such as syk, but this was not due to direct nitration of these same proteins. The inhibition of phosphorylation was reversible with platelet proteins recovering the ability to be phosphorylated within 15 min of exposure to peroxynitrite. Conversely, peroxynitrite increased phosphorylation of other proteins, but again these events were not directly linked to nitration. Nitration may affect the phosphorylation of tyrosine residues in a number of proteins, but by an indirect route, possibly by acting on proteins upstream in the signalling cascades. We suggest that low concentrations of peroxynitrite reversibly inhibit platelet aggregation by preventing the phosphorylation of key signalling proteins.


Arrhythmogenic Biophysical Phenotype for SCN5A Mutation S1787N Depends upon Splice Variant Background and Intracellular Acidosis.
SCN5A is a susceptibility gene for type 3 long QT syndrome, Brugada syndrome, and sudden infant death syndrome. INa dysfunction from mutated SCN5A can depend upon the splice variant background in which it is expressed and also upon environmental factors such as acidosis. S1787N was reported previously as a LQT3-associated mutation and has also been observed in 1 of 295 healthy white controls. Here, we determined the in vitro biophysical phenotype of SCN5A-S1787N in an effort to further assess its possible pathogenicity. We engineered S1787N in the two most common alternatively spliced SCN5A isoforms, the major isoform lacking a glutamine at position 1077 (Q1077del) and the minor isoform containing Q1077, and expressed these two engineered constructs in HEK293 cells for electrophysiological study. Macroscopic voltage-gated INa was measured 24 hours after transfection with standard whole-cell patch clamp techniques. We applied intracellular solutions with pH7.4 or pH6.7. S1787N in the Q1077 background had WT-like INa including peak INa density, activation and inactivation parameters, and late INa amplitude in both pH 7.4 and pH 6.7. However, with S1787N in the Q1077del background, the percentages of INa late/peak were increased by 2.1 fold in pH 7.4 and by 2.9 fold in pH 6.7 when compared to WT. The LQT3-like biophysical phenotype for S1787N depends on both the SCN5A splice variant and on the intracellular pH. These findings provide further evidence that the splice variant and environmental factors affect the molecular phenotype of cardiac SCN5A-encoded sodium channel (Nav1.5), has implications for the clinical phenotype, and may provide insight into acidosis-induced arrhythmia mechanisms.


Heterotopic ossification of brachialis muscle.
A 13-year-old girl with seizure disorder presented with 90 degrees fixed flexion deformity of right elbow.


Shear stress modulates macrophage-induced urokinase plasminogen activator expression in human chondrocytes.
Synovial macrophages, which can release proinflammatory factors, are responsible for the upregulation of cartilage-breakdown proteases and play critical roles in cartilage degradation during the progression of osteoarthritis (OA). In addition, shear stress exerts multifunctional effects on chondrocytes by inducing the synthesis of catabolic or anabolic genes. However, the interplay of macrophages, chondrocytes, and shear stress during the regulation of cartilage function remains poorly understood. We investigated the mechanisms underlying the modulation of human chondrocyte urokinase plasminogen activator (uPA) expression by macrophages and shear stress. Human chondrocytes were stimulated by peripheral blood-macrophage- conditioned medium (PB-MCM), or exposure of chondrocytes cultured in PB-MCM to different levels of shear stress (2 to 20 dyn/cm2). Real-time polymerase chain reaction was used to analyze uPA gene expression. Inhibitors and small interfering RNA were used to investigate the mechanism for the effects of PB-MCM and shear stress in chondrocytes. Stimulation of human chondrocytes with PB-MCM was found to induce uPA expression. We demonstrated that activation of the JNK and Akt pathways and NF-κB are critical for PB-MCM-induced uPA expression. Blocking assays by using IL-1ra further demonstrated that IL-1β in PB-MCM is the major mediator of uPA expression in chondrocytes. PB-MCM-treated chondrocytes subjected to a lower level of shear stress showed inhibition of MCM-induced JNK and Akt phosphorylation, NF-κB activation, and uPA expression. The PB-MCM-induced uPA expression was suppressed by AMP-activated protein kinase (AMPK) agonist. The inhibitor or siRNA for AMPK abolished the shear-mediated inhibition of uPA expression. These data support the hypothesis that uPA upregulation stimulated by macrophages may play an active role in the onset of OA and in the shear-stress protection against this induction.


Simplifying the use of pharmacogenomics in clinical practice: Building the genomic prescribing system.
A barrier to the use of genomic information during prescribing is the limited number of software solutions that combine a user-friendly interface with complex medical data. We built and designed an online, secure, electronic custom interface termed the Genomic Prescribing System (GPS). Actionable pharmacogenomic (PGx) information was reviewed, collected, and stored in the back-end of GPS to enable creation of customized drug- and variant-specific clinical decision support (CDS) summaries. The database architecture utilized the star schema to store information. Patient raw genomic data underwent transformation via custom-designed algorithms to enable gene and phenotype-level associations. Multiple external data sets (PubMed, The Systematized Nomenclature of Medicine (SNOMED), National Drug File - Reference Terminology (ND-FRT), and a publically-available PGx knowledgebase) were integrated to facilitate the delivery of patient, drug, disease, and genomic information. Institutional security infrastructure was leveraged to securely store patient genomic and clinical data on a HIPAA-compliant server farm. As of May 17, 2016, the GPS back-end housed 257 CDS encompassing 112 genetic variants, 42 genes, and 46 PGx-actionable drugs. The GPS user interface presented patient-specific CDS alongside a recognizable traffic light symbol (green/yellow/red), denoting PGx risk for each genomic result. The number of traffic lights per visit increased with the corresponding increase in the number of available PGx-annotated drugs over time. An integrated drug and disease search functionality, links to primary literature sources, and potential alternative PGx drugs were indicated. The system, which was initially used as stand-alone CDS software within our clinical environment, was then integrated with the institutional electronic medical record for enhanced usability. There have been nearly 2000 logins in 43months since inception, with usage exceeding 56 logins per month and system up-times of 99.99%. For all patient-provider visits encompassing >3years of implementation, unique alert click-through rates corresponded to genomic risk: red lights clicked 100%, yellow lights 79%, green lights 43%. Successful deployment of GPS by combining complex data and recognizable iconography led to a tool that enabled point-of-care genomic delivery with high usability. Continued scalability and incorporation of additional clinical elements to be considered alongside PGx information could expand future impact.


Comorbidity of Attention-Deficit Hyperactivity Disorder and Autism Spectrum Disorders: Current Status and Promising Directions.
High rates of co-occurring Attention-Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorders (ASD) suggest common causal pathways, which await elucidation. What is well-established, however, is the negative impact of comorbid ADHD and ASD on outcomes for everyday living, particularly in social interaction and communication and on broader psychopathology. Neurocognitive approaches suggest correlates of comorbidity are rooted in functional connectivity networks associated with executive control. There is support for familial origins, with molecular-genetic studies suggesting a causal role of pleiotropic genes. Further investigation is needed to elucidate fully how genetic risk for ADHD and ASD affects neurodevelopment and to identify structural and functional neural correlates and their behavioral sequelae. Identification of intermediate phenotypes is necessary to advance understanding, which requires studies that include the full spectrum of ASD and ADHD symptom severity, use longitudinal designs and multivariate methods to probe broad constructs, such as executive and social function, and consider other sources of heterogeneity, such as age, sex, and other psychopathology. Randomized efficacy trials targeting comorbid symptomatology are needed to mitigate negative developmental outcomes.


Selection of a DTPA chelate conjugate for monoclonal antibody targeting to a human colonic tumor in nude mice.
Our previous studies with a 90Y-labelled antibody against carcinoembryonic antigen (CEA) conjugated to the cyclic anhydride-DTPA (CA-DTPA) indicated that the accretion of 90Y in the bone may limit the application of 90Y-labelled antibodies for therapy. In this report, we have compared the tumor targeting of CA-DTPA-conjugated antibody to antibody conjugated with 4 isothiocyanatobenzyl (ITC-Bz) derivatives of DTPA in nude mice bearing a human colonic tumor xenograft. In biodistribution studies using an 111In-labelled anti-CEA murine monoclonal antibody (MAb), the CA-DTPA-conjugated MAb showed lower tumor uptake, faster blood clearance, and higher accretion in the liver than any of the 4 ITC-Bz-DTPA-conjugated MAbs. There were smaller differences among the 4 ITC-Bz-DTPA conjugates. Whole-body autoradiography of animals given 90Y-MAb prepared with the CA-DTPA or the ITC-Bz-DTPA showed less radioactivity in the bone with the ITC-Bz-DTPA-MAb than the CA-DTPA-MAb. 90Y uptake in the bone corresponded with regions of low proliferative activity as defined by 3H-labelled thymidine, suggesting that the 90Y was in the cortex rather than the marrow. These studies clearly show an advantage of the ITC-Bz-DTPA derivatives for 90Y and 111In labelling of MAbs.


Cytokine production and hemofiltration in children undergoing cardiopulmonary bypass.
Multiorgan dysfunction still occurs after cardiopulmonary bypass and remains a major cause of morbidity and mortality, especially in the pediatric age group. This is consequent upon the so-called systemic inflammatory response to bypass with an increase in inflammatory mediators. Hemofiltration may be able to attenuate the effects of this response by elimination of some or all of these mediators. We undertook a prospective, randomized study to investigate the effect of hemofiltration on plasma levels of the cytokines tumor necrosis factor alpha, interleukin-8, and interleukin 6 in 18 infants and children undergoing deep hypothermic bypass. Serial plasma samples were taken before, during, and after bypass. Assay of the plasma samples revealed presence of the cytokines in a number of subjects in both groups, in some cases before operation. There were significant reductions in levels of tumor necrosis factor after hemofiltration, with no reduction noted in the group not undergoing hemofiltration. A similar difference (p < 0.05) was detected in the levels of interleukin-6 between the two groups after bypass, although this was largely due to changes in 2 subjects. Interleukin-8 was detected in a small number of subjects insufficient for statistical analysis, but with higher values in the group undergoing hemofiltration. We conclude that hemofiltration has the potential to remove cytokines from the circulation, with consequent beneficial effects.


Acute gastric dilatation after trauma.
During a 2-year period, 248 consecutive patients were admitted with multiple trauma. Acute gastric dilatation was documented in 67 (27%) patients by review of all admission roentgenograms. There were 51 (76%) males and 16 females. Ages ranged from 2 to 80 years (mean, 29.2 years). The incidence of acute gastric dilatation in children was 44% vs. 25% for adults (p less than 0.05). The mechanism of injury was motor vehicle accident in 45 (67%), agricultural accident in 8 (12%), fall in four (6%), bicycle accident in four (6%), and miscellaneous in six (9%). There were 38 orthopedic, 35 craniocerebral, 34 abdominal, 31 thoracic, 27 maxillofacial, and 14 spinal injuries. Injury Severity Scores ranged from 4 to 66 (mean, 23.5). Thirteen (19%) patients presented in shock and there were four (6%) hospital deaths. No death was attributable to gastric dilatation. Nasogastric tubes were placed in 41 (61%) patients and 26 were managed without tube placement. Complications associated with acute gastric dilatation included pulmonary aspiration in three (4%) patients, gastric hemorrhage in three (4%), gastrointestinal perforation in one (1%), and prolonged ileus in 12 (18%). In addition, gastric dilatation rendered abdominal examination difficult and delayed peritoneal lavage. Acute gastric dilatation after trauma is frequent in our rural trauma center. Early placement of a nasogastric tube in the absence of a clear contraindication is strongly supported in the management of multiply injured patients.


Wheat germ cytoplasmic ribosomes. Structure of ribosomal subunits and localization of N6,N6-dimethyladenosine by immunoelectron microscopy.
Cytoplasmic ribosomes have been isolated from wheat germ, and the structure of ribosomal subunits has been examined by electron microscopy of negatively stained preparations. Small (40 S) subunits show structural features generally regarded as characteristic of eukaryotic particles, while large (60 S) subunits show shapes that are equally well described by models of prokaryotic 50 S particles. Small subunit 18 S RNA contains 2 residues of N6,N6-dimethyladenosine 19 and 20 residues from the 3'-end (Hagenbüchle, O., Santer, M., Steitz, J. A., and Mans, R. J. (1978) Cell 13, 551-563). Nucleoside analysis by high performance liquid chromatography shows no other residues of this component in the RNA. Anti-dimethyladenosine immunoglobulins were reacted with wheat germ 40 S subunits, and the resulting complexes were studied by electron microscopy in order to localize the nucleoside. In about 90% of the complexes observed, antibody-subunit contact was consistent with a single binding site. We place the dimethyladenosine residues at or near the end of the platform of the 40 S particle in a position nearly equivalent to that previously identified in prokaryotic and chloroplast subunits (Trempe, M. R., and Glitz, D. G. (1981) J. Biol. Chem. 256, 11873-11879).


Pharmacists' counseling protocols for minor ailments: a structure-based analysis.
Self-medication is an important component of health care. To optimize pharmacists' over-the-counter counseling, there are several guidelines and protocols used in practice. In a self-care environment, protocols should comprise items related to patients' autonomy. The structure of self-medication protocols, among other elements, should present steps to facilitate patients' participation. To analyze structural differences between existing community pharmacy minor ailment protocols, including those related to patient autonomy and empowerment in self-medication conditions. The study design followed a cross-sectional descriptive approach. Self-medication protocols were systematically collected from 3 different professional sources (Pharmaceutical Society [OF], National Pharmacies Association [ANF], and Grupo Holon [GH]). A structural-based analysis, by comparison with the general self-medication OF standard protocol, produced outcome measures such as frequencies of flowchart critical steps, active pharmaceutical substances, dosage forms, and posologies. Simple scores were computed to assess protocols' structural quality, as well as differences between protocols, produced by each professional organization. Forty-four protocols presented on average 8 counseling steps toward 10 different active substances, 7 dosages forms, and 14 posologic schemes. From a maximum of 30 critical items, 1 protocol scored 24, 7 scored 23, and 5 scored less than 15 items. Significant differences were found between protocols' structural components from different sources, particularly between GHs' protocols compared with those produced by OF and ANF. In general, all protocols matched the OF standard for ailment characterization but fell short on steps related to medicine information and selection. Steps for patient participation and agreement were absent, as was pharmacists' expected role of outcomes monitoring. It might be appropriate to redesign self-medication protocols, preferably through a consensus process that includes not only professionals' but also patients' preferences, starting from the prevalent conditions in Portuguese pharmacy practice.


Implementation of global antimicrobial resistance surveillance system (GLASS) in patients with bacteriuria.
This study aimed to evaluate the practicality and advantage of Global Antimicrobial Resistance Surveillance System (GLASS) for surveillance of urine culture samples collected from patients with bacteriuria. GLASS has been implemented at a tertiary care university hospital in Thailand by using the web application program to collect clinical data and urine culture data from patients with positive urine culture. There were 5085 urine samples from 3545 patients that were sent to our microbiology laboratory during June-December 2017. Bacteriuria was found in 1944 patients. Of those, 952 had urinary tract infection (UTI), and 1161 had colonization. Among UTI patients, hospital-acquired infection (HAI) was observed in 74.2 %, and community-acquired infection (CAI) was found in 28.7 %. E. coli and S. agalactiae were more frequently observed in CAI, but P. aeruginosa, P. mirabilis, E. faecium, and A. baumannii were more prevalent in HAI. UTI isolates demonstrated less resistance to antibiotics than colonized isolates. Non-duplicate isolates of bacteria demonstrated less resistance than duplicate isolates. E. coli, K. pneumoniae, P. aeruginosa, P. mirabilis, E. faecalis, and E. faecium causing HAI were more resistant to antibiotics than those causing CAI. GLASS is feasible to implement and more beneficial than laboratory-based surveillance. This study collects additional information beyond GLASS including causative bacteria and colonizing bacteria; types of UTI; and more specific criteria to distinguish HAI from CAI so that such data can be used for developing more valid local guidelines for selecting antibiotic therapy in UTI patients in addition to AMR surveillance in urine samples.


Serum laminin in Graves' disease.
We determined serum levels of laminin in 23 patients with Graves' disease (GD) and in 24 patients with toxic nodular goiter (TNG). Elevated levels of soluble laminin were observed in patients with GD prior to treatment (median concentration 1376 ng mL-1 [range 712-2402]), compared to patients with TNG (median 442 ng mL-1 [284-891]), and normal controls (median 492 ng mL-1 [range 235-675], n = 26), respectively. In GD patients serum laminin levels decreased during thiamazole treatment and normalized within 8 weeks of therapy. There was no correlation between serum laminin levels and serum levels of thyroid hormones and/or auto-antibodies, respectively. Whether serum laminin is a marker for alterations of extracellular matrix during GD and release of basement membrane components in the circulation and/or reflects an impaired clearance remains to be elucidated.


Effects of transient acute kidney injury, persistent acute kidney injury and acute kidney disease on the long-term renal prognosis after an initial acute kidney injury event.
To clarify the effects of the duration of acute damage and/or loss of renal function following an acute kidney injury event on the renal prognosis after recovery. We retrospectively reviewed data collected between 1995 and 2016 from the Kochi Medical School Hospital. Patients were stratified according to the time required for recovery with fluid therapy (expected to reflect the presence of renal dysfunction): ≤2 days after onset, transient injury group (n = 491); 3 to 7 days after onset, persistent injury group (n = 1076); and ≥ 8 days after onset, acute kidney disease group (n = 1046). The healthy group comprised 1000 randomly selected adult patients without acute kidney injury with at least two creatinine measurement results during the study. Survival time was defined as the time from recovery to a 30% decrease in the estimated glomerular filtration rate (primary endpoint). Kaplan-Meier and Cox proportional hazards analyses were conducted. Event incidence rates were higher for the transient injury, persistent injury and acute kidney disease groups than for the healthy group. Persistent injury and acute kidney disease presented a higher risk of renal function decline than transient injury following recovery. Transient acute kidney injury, persistent acute kidney injury and acute kidney disease resulted in functional decline and rapid chronic kidney disease progression risks despite recovery. Transient acute kidney injury recovery within 2 days could be associated with better long-term prognoses than persistent acute kidney injury and acute kidney disease persisting beyond 2 days.


Developments in resin-based composites.
With the phasing down of dental amalgam use in response to the Minamata Convention, it is likely that resin-based composite restoratives will be the dental material of choice for the direct restoration of compromised dentition in the UK, at least for the foreseeable future. The current materials have a finite lifespan, with failures predominately due to either secondary caries or fracture. Consequently, there is considerable in vitro research reported each year with the intention of producing improved materials. This review describes the recent research in materials designed to have low polymerisation shrinkage and increased mechanical properties. Also described is research into materials that are either antimicrobial or are designed to release ions into the surrounding oral environment, with the aim of stimulating remineralisation of the surrounding dental tissues. It is hoped that by describing this recent research, clinicians will be able to gain some understanding of the current research that will potentially lead to new products that they can use to improve patient treatment in the future.


Pleuroperitoneal shunts in the management of persistent chylothorax.
Between June 1981 and June 1988, we placed pleuroperitoneal shunts in 16 patients for the management of refractory chylothorax on the Pediatric Surgical Service, University of Virginia. The cause of the chylothorax was caval thrombosis from central venous catheters in 5 patients, idiopathic in 3, and mediastinal lymphangioma in 2, and in 6, it developed after a cardiac procedure. Chylothorax in each patient was unresponsive to thoracentesis, tube thoracostomy, and dietary manipulations. A Denver double-valved shunt system is currently employed and is implanted using general anesthesia. Manual pumping is required postoperatively for several months. Twelve (75%) of the 16 patients had excellent results with complete elimination of the chylothorax and resolution of symptoms. In 10 of these 12, the shunt has been removed. Four had an unsatisfactory result: 3 had inferior vena cava hypertension, and 3 were low-birth-weight premature infants. Four patients seen early in this series required revision of the position of the pleural catheter, with successful drainage in each instance. Pleuroperitoneal shunting is a safe, simple, and effective treatment of chylothorax in infants and children. In view of our success in treating chylothorax with these shunts, we recommend early shunting before the development of nutritional or immunological depletion.


Cardiac abnormalities in myotonic dystrophy. Electrocardiographic and echocardiographic findings in 65 patients and 34 of their unaffected relatives. Relation with age and sex and relevance for gene detection.
Sixty-five patients with a definite diagnosis of myotonic dystrophy (MD) and 34 of their presumably unaffected relatives were examined cardiologically, including ECG in all and echocardiography in 61 and 32 persons respectively, in order to investigate the frequency of cardiac abnormalities, their clinical importance and their potential value as a preclinical marker in the diagnosis of MD. Atrioventricular conduction (AVC) abnormalities were found in 18/33 (54%) of affected males and in only 5/32 (16%) of affected females (P = 0.0025). Intraventricular (IVC) conduction abnormalities were encountered with similar frequency in both sexes: in 12/33 (36%) of affected males and 10/32 (31%) of affected females. Mitral valve prolapses (MVP) were seen more often in affected females: 9/31 (29%) of affected males vs 15/30 (50%) of affected females have MVP (P = 0.16). A previously undescribed finding was that of pericardial effusions in 5 affected and in 1 unaffected person. All affected males with MVP also had conduction abnormalities, but cardiac findings were not interrelated otherwise. None of the cardiac abnormalities mentioned were age-related. Only 8/65 (12%) of patients had cardiac symptoms, all of which were the result of conduction defects. As far as can be judged from a transversal study, the value of cardiac examination of this kind as a preclinical test for the diagnosis of MD is modest. It is argued that IVC-abnormalities, but not AVC-disturbances or MVP, in clinically unaffected relatives may indicate that they are preclinical heterozygotes. The significance of pericardial effusion for the diagnosis of MD awaits further evaluation.


The role of interferon-gamma in the increased tuberculosis risk in type 2 diabetes mellitus.
As patients with diabetes mellitus are at increased risk of developing tuberculosis, we hypothesized that this susceptibility to mycobacterial infection is due to a defective Th1-cytokine response. To explore this hypothesis, we examined four groups of subjects in Indonesia: 23 patients with tuberculosis, 34 patients with tuberculosis and diabetes, 32 patients with diabetes only and 36 healthy controls. Ex-vivo production of interferon (IFN)gamma, tumour necrosis factor-alpha and interleukin (IL)-1beta, 6, 10, -12 and -4 was measured following stimulation with Mycobacterium tuberculosis, Escherichia coli lipopolysaccharide and phytohaemagglutinin. Patients with active tuberculosis were found to have lower IFNgamma levels and a higher production of other pro-inflammatory cytokines and IL-4, both in the presence and absence of diabetes. Diabetes patients without tuberculosis, however, showed strongly reduced non-specific IFNgamma production, which is essential for inhibition of the initial growth of M. tuberculosis. Our data suggest that a defective non-specific immune response in diabetes may contribute to an increased susceptibility to develop tuberculosis.


Cattle production by intracytoplasmic sperm injection into oocytes vitrified after ovum pick-up.
Intracytoplasmic sperm injection (ICSI), oocyte vitrification after ovum pick-up (OPU), and in vitro maturation are reproductive technologies with incredible potential for efficient cattle production. However, the developmental competence of embryos produced by ICSI using vitrified OPU oocytes remains unknown. Here, we aimed to evaluate the developmental competence of these embryos from the early embryo period to full term. The cleavage rate in the ICSI embryos using vitrified OPU oocytes during in vitro culture was significantly lower than those in control in vitro fertilized (IVF) embryos using fresh OPU oocytes (30.9 ± 4.5% v.s. 65.9 ± 7.0%) (P < 0.05), but the proportion of blastocysts to cleaved embryos was significantly higher than those of IVF embryos using vitrified OPU oocytes (55.9 ± 10.8% v.s. 23.2 ± 9.3%) (P < 0.05). To further investigate the transcription levels of genes related to cell differentiation in ICSI embryos using vitrified OPU oocytes, the relative abundance of mRNAs (OCT4, NANOG, SOX2, CDX2, GATA3, and IFNT) was analyzed by quantitative reverse-transcription PCR. There were no significant differences in the expression levels between ICSI embryos using vitrified OPU oocytes and control IVF embryos. Finally, developmental competence to term in ICSI embryos using vitrified OPU oocytes was examined by embryo transfer, and two healthy calves were born. These findings confirmed that ICSI and vitrification decrease developmental rates in vitro, but both procedures can lead to full-term development of bovine embryos. These results demonstrate that ICSI embryos using vitrification OPU oocytes are viable for cattle production.


Hyperinsulinism and hyperammonaemia syndrome due to a novel missense mutation in the allosteric domain of the glutamate dehydrogenase 1 gene.
Congenital hyperinsulinism is one of the causes of persistent hypoglycaemia in neonates and infants. We describe a one-month-old boy with a rare form of congenital hyperinsulinism characterised by hypoglycaemia and hyperammonaemia.


Postgraduate training for young psychiatrists--experience of the Berlin Summer School.
Growing professional exchange between Eastern and Western European countries increases the possibilities for international postgraduate training courses and by that satisfying the need for rapid and facilitation of travel and migration in the enlarged European Union increase achieving high standards. The purpose of this study was to evaluate a summer school program that trained young Eastern European psychiatrists and to assess the impact of the program on their professional development and future activities. We evaluated the training effect of the first 3 years of the Berlin Summer School with respect to (1) the participants' satisfaction with the topics, quality and originality of the presentations, and (2) long-term effects and implications for their professional career. All participants (N=43) filled out anonymously the evaluation form at the end of each summer school. An evaluation of long-term effects was carried out 2 years later with a questionnaire that was sent via e-mail to all former participants. Participants were most satisfied with practical topics such as "how to prepare a paper", "how to evaluate a paper", or "how to participate in a congress." The appreciation of the presented topics and the appreciation of courses increased in each consecutive summer school. All summer school participants reported that the course had some influence on their future career, and one fifth of the participants felt that their professional development was influenced "a lot". Although limited to 1 week of intensive training, a summer school program can have a longer lasting positive influence on the professional development of the participants. Participants felt that particularly the training of practical skills improved their research performance. Former participants founded an independent multicentric and multinational research group and supported national courses that were organized similar to the Berlin Summer School.


Intra-anal Iferanserin 10 mg BID for hemorrhoid disease: a prospective, randomized, double-blind, placebo-controlled trial.
Despite the prevalence of internal hemorrhoid disease (HD), there are few pharmacologic options. Iferanserin, a selective serotonin receptor antagonist, is being studied for use in the treatment of HD. This Phase IIb study evaluated the efficacy and tolerability of 10-mg twice-daily iferanserin intra-anal ointment for the cessation of bleeding and other symptoms associated with internal HD. This randomized, double-blind, placebo-controlled study was conducted at 5 sites in Germany. Outpatients with Goligher grade I, II, and/or III hemorrhoids and bleeding were randomly assigned to receive iferanserin ointment 10 mg or inactive vehicle (placebo) BID for 14 days. During treatment, patients rated the severity of HD symptoms daily on a 10-point scale using a diary form. At enrollment and study end, physicians recorded the frequency and intensity of HD symptoms, adverse events, and results from blood and urine analyses on clinical-report forms. Of the 121 patients enrolled in the study, 118 were evaluable for tolerability and 111 for efficacy. The mean age of the tolerability population was 52.7 years, 78.9% were male, and all were white. The 2 groups had similar HD symptoms at baseline, but overall, patients in the placebo group had numerically higher grades of HD than did patients in the iferanserin group. Compared with placebo, iferanserin was associated with significantly lower patient-reported severity ratings of daily bleeding and itching, beginning at day 1 for bleeding and at day 2 for itching (P < 0.05), but not with reduced ratings for severity of other HD symptoms, including pain, tenderness, difficulty with defecation, fullness, throbbing, and gas. In the physician assessments, iferanserin was associated with significantly reduced bleeding frequency by day 14 compared with placebo (P < 0.05). Adverse events were mild and infrequent, with no significant differences in prevalences between the 2 treatment groups and no clinically significant changes in laboratory values in any patient. Compared with placebo, intra-anal iferanserin was associated with significantly reduced patient-reported severity of bleeding and itching and physician-assessed bleeding frequency in these patients presenting with grade I, II, and/or III internal hemorrhoids and bleeding at 5 sites in Germany. ClinicalTrials.gov identifier: 01483833.


Solar PAR and UV radiation affects the physiology and morphology of the cyanobacterium Anabaena sp. PCC 7120.
Solar UV radiation (280-400 nm) may affect morphology of cyanobacteria, however, little has been evidenced on this aspect while their physiological responses were examined. We investigated the impacts of solar PAR and UVR on the growth, photosynthetic performance and morphology of the cyanobacterium Anabaena sp. PCC7120 while it was grown under three different solar radiation treatments: exposures to (a) constant low PAR (photosynthetic active radiation, 400-700 nm), (b) natural levels of solar radiation with and (c) without UV radiation (290-400 nm). When the cells were exposed to solar PAR or PAR+UVR, the photochemical efficiency was reduced by about 40% and 90%, respectively, on day one and recovered faster under the treatment without UVR over the following days. Solar UVR inhibited the growth up to 40%, reduced trichome length by up to 49% and depressed the differentiation of heterocysts. Negligible concentrations of UV-absorbing compounds were found even in the presence of UVR. During the first 2 d of exposure to natural levels of PAR, carotenoid concentrations increased but no prolonged increase was evident. Heterocyst formation was enhanced under elevated PAR levels that stimulated quantum yield and growth after an initial inhibition. Higher concentrations of carotenoids and a twofold increase in the carotenoid to chlorophyll a ratio provided protection from the high levels of solar PAR. Under radiation treatments with UVR the relatively greater decrease in chlorophyll a concentrations compared with the increase in carotenoids was responsible for the higher carotenoid: chlorophyll a ratio. Heterocyst formation was disrupted in the presence of solar UVR. However, the longer term impact of heterocyst disruption to the survival of Anabaena sp. requires further study.


Effects of infant massage on jaundiced neonates undergoing phototherapy.
Infant massage is a natural way for caregivers to improve health, sleep patterns, and reduce colic. We aimed to investigate the effects of infant massage on neonates with jaundice who are also receiving phototherapy. Full-term neonates with jaundice, admitted for phototherapy at a regional teaching hospital, were randomly allocated to either a control group or a massage group. The medical information for each neonate, including total feeding amount, body weight, defecation frequency, and bilirubin level, was collected and compared between two groups. A total of 56 patients were enrolled in the study. This included 29 neonates in the control group and 27 in the experimental group. On the third day, the massage group showed significantly higher defecation frequency (p = 0.045) and significantly lower bilirubin levels (p = 0.03) compared with the control group. No significant differences related to feeding amount or body weight were observed between the two groups. Infant massage could help to reduce bilirubin levels and increase defecation frequency in neonates receiving phototherapy for jaundice.


Cutaneous graft-versus-host disease incidence is similar in haploidentical and matched unrelated hematopoietic transplant recipients: A retrospective cohort study.
Cutaneous graft-versus-host disease (GVHD) is common after hematopoietic cell transplants. Haploidentical transplants (Haplo) have historically higher rates of GVHD with overall outcomes improved with the use of posttransplant cyclophosphamide. Specific cutaneous outcomes have not been explored in haploidentical versus matched unrelated donor (MUD) transplants. We sought to examine the incidence of GVHD in MUD and Haplo transplants. This is a retrospective cohort study of patients' records that received MUD or Haplo transplants between 2010 and 2015 with determination of GVHD severity and features by one investigator. The Haplo cohort included more minorities (22.7% vs 6.8%; P < .001). The incidence of acute cutaneous GVHD was similar (Haplo 47.7% [95% confidence interval {CI} 37.0-58.6%] vs MUD 42.6% [95% CI 37.9-47.3%]; P = .41). Chronic GVHD was also similar (Haplo 17.1% [95% CI 9.9-26.6%] vs MUD 12.8% [95% CI 9.9-16.3%]; P = .31). The Haplo group had lower rates of sclerosis (13.3% [95% CI 1.7-4.05%] vs 50.9% [95% CI 37.3-64.4%]; P = .0095). Other secondary outcomes showed no difference. Severity of GVHD was determined retrospectively and not all patients were seen by a dermatologist. No difference was observed between rates or severity of acute or chronic GVHD. Sclerosis was less common in the Haplo group.


Biomarkers of dietary intake of flavonoids and phenolic acids for studying diet-cancer relationship in humans.
For many polyphenolic compounds found in plant-derived food, biological effects possibly relevant for cancer prevention have been shown. Since dietary intake estimates suffer from imprecision, the measurement of these compounds (or metabolites of) in biological specimens collected in epidemiological studies is expected to improve accuracy of exposure estimation. The current use of biomarkers in etiologic studies on polyphenolics and cancer risk is evaluated. In addition, available analytical methods are discussed with respect to the requirements for their integration in epidemiological studies, putting specific emphasis on the epidemiological validation of such markers. The scientific literature was screened for epidemiologic studies on the relationship of flavonoid and phenolic acid concentrations in human specimens (i.e. blood, urine) and cancer risk. In addition, original data on intra- and inter-subject variability of several flavonoids and phenolic acids are presented. Although several techniques are used in bioavailability or short-term intervention studies, their integration in epidemiological studies is very limited. An exception are phytoestrogens where validated immunoassays allow the rapid measurement of large sample numbers with small sample volume. For several polyphenols, the data on the epidemiologic validity encourages for their use in epidemiological studies. There are valid possibilities for additional biomarkers of flavonoid and phenolic acid intake that are best applied in prospective studies with more than one biological sample per subject. Currently, a combination of a single biomarker measurement with long-term dietary intake estimates will probably be the most valuable choice to decrease measurement error in exposure data.


Special issues related to the adjuvant therapy in very young women.
A small minority of breast cancer patients consists of young women (<40 years: <6%). Thus, they may not be properly represented in clinical trials. They present with unfavorable tumor characteristics, but young age is an independent negative prognosticator: age is a surrogate for biological mechanisms determining an aggressive cancer phenotype. In premenopausal patients with estrogen receptor-positive (ER+) tumors, adjuvant ovarian function suppression (OSF) was as effective as chemotherapy in ten randomized clinical trials. Chemotherapy reduces the risks of recurrence and death irrespective of endocrine responsiveness of the tumor; however, in patients with ER+ tumors this might result in chemotherapy-induced menopause. Accordingly, OFS did not prolong survival in addition to chemotherapy in meta-analyses and recent clinical trials except in subgroups of particularly young women. Adjuvant tamoxifen is efficient in premenopausal patients with ER+ tumors irrespective of age and the use of chemotherapy. Clinical trials addressing the role of OFS are underway, and future trials should be planned so that the population of young women can be properly analyzed.


Calcium-sensitive adenylyl cyclases in depression and anxiety: behavioral and biochemical consequences of isoform targeting.
Adenylyl cyclases (ACs) represent a diverse family of enzymes responsible for the generation of cyclic adenosine monophosphate (cAMP), a key intracellular second messenger. The Ca(2+)/calmodulin-stimulated AC1 and AC8 isoforms as well as the calcium-inhibited AC5 isoform are abundantly expressed within limbic regions of the central nervous system. This study examines the contribution of these AC isoforms to emotional behavior. Male and female AC1/8 double knockout mice (DKO) and AC5 knockout mice (AC5KO) were examined on a series of standard laboratory assays of emotionality. Mice were also assayed for hippocampal cell proliferation and for changes in brain-derived neurotrophic factor signaling in the nucleus accumbens, amygdala, and hippocampus, three forebrain structures involved in the regulation of mood and affect. The AC5KO mice showed striking anxiolytic and antidepressant phenotypes on standard behavioral assays. In contrast, AC1/8 DKO mice were hypoactive, exhibited diminished sucrose preference, and displayed alterations in neurotrophic signaling, generally consistent with a prodepressant phenotype. Neither line of mice displayed alterations in hippocampal cell proliferation. These data illustrate the complex manner in which Ca(2+)/calmodulin-stimulated ACs contribute to emotional behavior. In addition, they support the possibility that a selective AC5 antagonist would be of therapeutic value against depression and anxiety disorders.


Factors determining success in percutaneous revascularization of chronic total coronary occlusion: multidetector computed tomography analysis.
Percutaneous revascularization of chronic total coronary artery occlusion is a technical challenge and has a lower success rate than other angioplasty procedures. Identification of predictors of failure could lead to better selection of patients with the greatest possibility of success. In this study, we investigate the multidetector computed tomography features associated with failure of percutaneous treatment for chronic total coronary occlusion. This is a prospective, single-center study of 69 consecutive patients with chronic total occlusion in whom multidetector computed tomography study was performed before percutaneous coronary revascularization. Seventy-seven lesions were analyzed. The mean length of the occlusion was 19.9 (14.3) mm and the estimated duration of occlusion was 47 (62) months. The only angiographic factor independently predictive of failure was a severe curve between the plaque and the proximal patent vessel (odds ratio 3.8, 95% confidence interval, 1.2-12; P=.02). On multidetector computed tomography, the only factor predictive of failure was an arc of calcium affecting more than 50% of the vessel circumference in the proximal (P=.04) and middle (P=.03) third of the occlusion. Multidetector computed tomography identified a variable that cannot be measured by angiography that can predict failure in percutaneous revascularization of chronic total coronary occlusions. In selected cases, this parameter could be useful for preprocedure screening.


Genetically engineering endothelial niche in human kidney organoids enables multilineage maturation, vascularization and de novo cell types.
Vascularization plays a critical role in organ maturation and cell type development. Drug discovery, organ mimicry, and ultimately transplantation in a clinical setting thereby hinges on achieving robust vascularization of in vitro engineered organs. Here, focusing on human kidney organoids, we overcome this hurdle by combining an inducible ETS translocation variant 2 (ETV2) human induced pluripotent stem cell (iPSC) line, which directs endothelial fate, with a non-transgenic iPSC line in suspension organoid culture. The resulting human kidney organoids show extensive vascularization by endothelial cells with an identity most closely related to endogenous kidney endothelia. Vascularized organoids also show increased maturation of nephron structures including more mature podocytes with improved marker expression, foot process interdigitation, an associated fenestrated endothelium, and the presence of renin+ cells. The creation of an engineered vascular niche capable of improving kidney organoid maturation and cell type complexity is a significant step forward in the path to clinical translation. Furthermore, this approach is orthogonal to native tissue differentiation paths, hence readily adaptable to other organoid systems and thus has the potential for a broad impact on basic and translational organoid studies.


Persistence of hippocampal and striatal multivoxel patterns during awake rest after motor sequence learning.
Memory consolidation, the process by which newly encoded and fragile memories become more robust, is thought to be supported by the reactivation of brain regions - including the hippocampus - during post-learning rest. While hippocampal reactivations have been demonstrated in humans in the declarative memory domain, it remains unknown whether such a process takes place after motor learning. Using multivariate analyses of task-related and resting state fMRI data, here we show that patterns of brain activity within both the hippocampus and striatum elicited during motor learning persist into post-learning rest, indicative of the reactivation of learning-related neural activity patterns. Moreover, results indicate that hippocampal reactivation reflects the spatial representation of the learned motor sequence. These results thus provide insights into the functional significance of neural reactivation after motor sequence learning.


Bio-Filler: An Effective Facial Rejuvenation Tool-Easy on Pocket.
The Plasma Bio-Filler Facelift is an exciting aesthetic process being introduced in dermatology. The dermal filler gel is autologous and easy to obtain. It works well for fine rhytides reduction as well as to volumize, contour and rejuvenate the face, neck and hands. The consistency and autologous nature of plasma bio-filler are better accepted by patients than the high density hyaluronic acid fillers.


Age, knowledge, preferences, and risk tolerance for invasive cardiac care.
The extent to which individual knowledge, preferences, and priorities explain lower use of invasive cardiac care among older vs. younger adults presenting with acute coronary syndrome (ACS) is unknown. We directly surveyed a group of patients to ascertain their preferences and priorities for invasive cardiovascular care. We performed a prospective cohort study of adults hospitalized with ACS. We surveyed participants regarding their knowledge, preferences, goals, and concerns for cardiac care, as well as their risk tolerance for coronary artery bypass grafting (CABG). Single academic medical center. Six hundred twenty-eight participants (373 <75 years old; 255 ≥75 years old). We compared baseline characteristics, knowledge, priorities, and risk tolerance for care across age strata. We also assessed pairwise differences with 95% confidence intervals (CI) between age groups for key variables of interest. Compared with younger patients, older participants had less knowledge of invasive care; were less willing to consider cardiac catheterization (difference between 75-84 and< 65 years old: -7.8%, 95% CI: -14.4%,-1.3%; for ≥85 vs. <65: -15.7%, 95% CI: -29.8%,-1.6%), percutaneous coronary intervention (difference between 75-84 and< 65 years old: -12.8%, 95% CI: -20.8%,-4.8%; for ≥85 vs. <65: -24.8%, 95% CI: -41.2%,-8.5%), and CABG (difference between 75-84 and< 65 years old: -19.0%, 95% CI: -28.2%,-9.9%; for ≥85 vs. <65: -39.1%, 95% CI: -56.0%,-22.2%); and were more risk averse for CABG surgery (p < .001), albeit with substantial inter-individual variability and individual outliers. Many patients who stated they were not initially willing to undergo an invasive cardiovascular procedure actually ended up undergoing the procedure (49% for cardiac catheterization and 22% for PCI or CABG). Age influences treatment goals and willingness to consider invasive cardiac care, as well as risk tolerance for CABG. Individuals' willingness to undergo invasive cardiovascular procedures loosely corresponds with whether that procedure is performed after discussion with the care team.


Biosynthetic incorporation of [3H]ethanolamine into protein synthesis elongation factor 1 alpha reveals a new post-translational protein modification.
Biosynthetic incorporation of [3H]ethanolamine into proteins was assessed in the human erythroleukemia cell line K562. A single predominant labeled protein of about 50 kDa was observed following electrophoresis of cell extracts on polyacrylamide gels in the presence of sodium dodecyl sulfate. Subcellular fractionation showed this protein to distribute similarly to a 46-kDa [3H]ethanolamine-labeled protein reported previously (Tisdale, E. J., and Tartakoff, A. M. (1988) J. Biol. Chem. 263, 8244-8252). In particular, the protein was enriched in cytosolic and microsomal fractions relative to plasma membrane and thus did not appear to correspond to the class of proteins with glycoinositol phospholipid anchors, the only post-translational protein modification involving ethanolamine that had been described previously. Two-dimensional polyacrylamide gel analysis involving isoelectric focusing followed by electrophoresis in sodium dodecyl sulfate indicated that the protein was very basic, and nitrocellulose blots of one- and two-dimensional gels subjected to 3H autoradiography and immunostaining with antisera to purified rabbit elongation factor (EF) 1 alpha revealed that the protein was EF-1 alpha. Copurification of rabbit EF-1 alpha and the [3H]ethanolamine-labeled protein from K562 cells further supported this identification. Analysis of tryptic fragments produced from the copurified proteins by reverse-phase high pressure liquid chromatography showed two radiolabeled peptides. Amino acid analysis demonstrated 1 residue of ethanolamine in each peptide, and peptide sequencing revealed that the ethanolamine-containing component(s) was attached to Glu301 and Glu374 in the EF-1 alpha protein sequence deduced from a human EF-1 alpha cDNA. These data confirm a new class of post-translational protein modifications involving ethanolamine.


Cosmetic results of cryosurgery versus surgical excision for primary uncomplicated basal cell carcinomas of the head and neck.
The incidence of multiple facial basal cell carcinomas (BCCs) is increasing. Comparison of cosmetic results after cryosurgery and excision for primary BCCs. Cosmetic results after cryosurgery and excision (prospective randomized study) of primary BCCs in the head/neck area were assessed by five independent professional observers and by the patients. Ninety-six BCCs were treated either with surgical excision (n = 48) or cryosurgery (n = 48). Clinical professionals evaluated the cosmetic results after surgery as significantly better. The beautician had no preference for either therapy. The patient had a significant preference for excision. Localization and size of the tumor did not modify this general preference for excision. The male dermatologist, however, had a tendency to evaluate results in the cheek, periauricular, and neck area as inferior to those in the rest of the face, regardless of which therapy was given. In general, cosmetic results after excision are better than after cryosurgery.


Novel S-Gal(®) analogs as (1)H MRI reporters for in vivo detection of β-galactosidase.
The quantitative assessment of gene expression and related enzyme activity in vivo could be important for the characterization of gene altering diseases and therapy. The development of imaging techniques, based on specific reporter molecules may enable routine non-invasive assessment of enzyme activity and gene expression in vivo. We recently reported the use of commercially available S-Gal(®) as a β-galactosidase reporter for (1)H MRI, and the synthesis of several S-Gal(®) analogs with enhanced response to β-galactosidase activity. We have now compared these analogs in vitro and have identified the optimal analog, C3-GD, based on strong T1 and T2 response to enzyme presence (ΔR1 and ΔR2~1.8 times S-Gal(®)). Moreover, application is demonstrated in vivo in human breast tumor xenografts. MRI studies in MCF7-lacZ tumors implanted subcutaneously in athymic nude mice (n=6), showed significant reduction in T1 and T2 values (each~13%) 2h after intra-tumoral injection of C3-GD, whereas the MCF7 (wild type) tumors showed slight increase. Thus, C3-GD successfully detects β-galactosidase activity in vivo and shows promise as a lacZ gene (1)H MR reporter molecule.


Antianginal efficacy of gallopamil in comparison to nifedipine.
In a randomized double-blind crossover trial 30 patients with chronic stable angina were studied to compare the antianginal actions of gallopamil (150 mg/day) and nifedipine. With the initial nifedipine dose of 60 mg/day, the trial had to be stopped because of severe exacerbation of angina in 3 patients of the nifedipine group. Twenty-one patients were entered into a second protocol with the nifedipine dose reduced to 30 mg/day. Compared to the preceding placebo period, the exercise time to onset of angina (+ 30%, P less than 0.01) and the total exercise time (+ 18%, P less than 0.01) were prolonged by gallopamil but not by nifedipine (+ 20 and 13%, respectively, not significant) with no significant difference between the test drugs. Four patients became free of angina during exercise testing with gallopamil therapy and one patient with nifedipine. Both agents significantly reduced ST depression at maximal comparable workload by 77% (gallopamil) and 52% (nifedipine) compared with placebo; the difference between the drugs reached borderline significance (P = 0.055). The increase in heart rate and the rate-pressure product at maximal comparable workload was less with gallopamil than with nifedipine (P less than 0.01). In contrast to nifedipine, very few side effects were reported with gallopamil. Thus, gallopamil is an effective antianginal agent whose therapeutic to toxic ratio appears to be superior to that of nifedipine.


Postoperative radioactive iodine-131 ablation is not necessary among patients with intermediate-risk differentiated thyroid carcinoma: a population-based study.
To assess the effectiveness of radioactive iodine (RAI) ablation among patients with intermediate-risk differentiated thyroid cancer (DTC) following surgery. This population based study obtained information from the Surveillance, Epidemiology, and End Results (SEER) Program Research Data (1973-2013). National Cancer Institute, DCCPS, Surveillance Research Programme, Surveillance Systems Branch, released April 2016, based on the November 2015 submission. A total of 93,530 patients with primary thyroid cancer were identified in the SEER database during the period of 2004-2013 and focused on patients with DTC post-operatively treated or not treated with radioactive iodine (RAI). From these 9,127 patients were selected who had intermediate-risk DTC. A total of 8,601 patients were included in this study. For the overall population, the mean age of the population was 47.3 years and the majority were female (70.5%). Kaplan-Meier analysis found the mean overall survival time (os) for subjects with no radiation therapy which was 112.9 months and 114.9 months for those who received RAI ablation treatment (P<0.001). However, thyroid cancer-specific survival was not significantly different between treatment groups (117.7 vs. 118.0 months, log-rank test P=0.164). Overall survival and thyroid cancer-specific 1 year, 5 years, and 10-years survival rates were ≥89.8% and were similar between both treated groups. Multivariate analysis found age, gender, histologic type, and degree of lymph node metastases to be associated with OS, and age, gender, degree of lymph node metastasis and extra-thyroid tumor spread were independent factors for cancer-specific survival. In DTC patients with intermediate cancer risk multivariate analysis found that RAI was associated with a reduced risk of mortality compared with no radiation therapy (HR=0.710, 95% CI: 0.562-0.897, P=0.004) but no significant difference was seen in cancer-specific survival, either based on whole study population or on tumor size category. In DTC patients with intermediate cancer risk although postoperative RAI ablation following surgery showed a benefit in overall survival, no significant difference was seen in cancer-specific survival, either based on whole study population or on tumor size category.


[Lipid aspects in subjects with glucose-6-phosphate dehydrogenase deficiency].
To control some aspects of Lipid metabolism in G-6-PD defective subjects, are evaluated the haematic levels of Cholesterol, Tri glycerides, total Lipids and Lipoproteins. There is no significative difference between enzymopathic and normal control subjects.


Assessment of the 20L SODIS bucket household water treatment technology under field conditions in rural Malawi.
Two billion people worldwide consume unsafe drinking water. The problem is particularly pronounced in Sub-Saharan Africa, where more than a quarter of the population relies on unimproved surface water sources. Based on the principles of solar water disinfection (SODIS), a new household water treatment technology, the SODIS bucket, was developed to improve the microbial quality of water from these sources based on controlled tests in a laboratory setting. This study set out to evaluate the efficacy of the technology in a field setting, in rural communities in the Chikwawa District in southern Malawi. SODIS experiments were carried out in two different vessels (1-L PET bottles and 20-L polypropylene SODIS buckets), over three months using unprotected water sources normally used by community members. Vessels were exposed to direct sunlight for 8 h per day in a village setting and were sampled at regular intervals to determine total coliforms, E. coli, turbidity, UV transmittance and UV dose. In these experiments, the SODIS bucket reached inactivation targets for E. coli (<1 CFU/100 mL) in two of seven experiments and for total coliforms in one of seven for total coliforms (<50 CFU/100 mL), despite having greater UV doses than were seen in the evaluation carried out under controlled conditions during the bucket's development. PET bottles reached inactivation targets for both E. coli and total coliforms in five of seven experiments. There was no single factor that could be identified as preventing adequate inactivation, but the role of organic matter, inconsistent nature of the water source, and vessel size, when coupled with organic matter, were identified as contributing factors. This study highlights the need for further prototyping to provide a suitable pre-treatment step for unprotected water sources, and the importance of field testing with real-life parameters to ensure new technologies are context appropriate.


Chemical composition, antiproliferative and antioxidant properties of lipid classes in ordinary and dark muscles from chub mackerel (Scomber japonicus).
This study investigated to compare lipid profiles in ordinary and dark muscles from chub mackerel and to examine antiproliferative and antioxidative properties of lipid classes. The average levels of neutral lipids (NL), glycolipids (GL), and phospholipids (PL) in ordinary muscle were 92.32±0.19%, 5.10±0.48%, and 2.58±0.46%; in dark muscle were 96.88±0.15%, 2.59±0.36%, and 0.54±0.29%, respectively. The fatty acid composition indicated that PL had a higher percentage of PUFA (especially 22:6n-3) with lower percentages of SFA and MUFA compared to NL and GL (p<0.05). The main ion peaks of GL in ordinary and dark muscles showed that monocharged and bischarged molecular ion were presented at m/z 876.9 and 438.8, respectively. In MTT assay, inhibition of AGS and HT-29 cell proliferation was greatest with the 0.5 and 1.0 mg mL(-1) GL treatments. The GL of ordinary muscle with 0.05 mg mL(-1) concentrations markedly decreased the levels of reactive oxygen species (ROS) induced by H2O2 compared to the control (p<0.05). From our results, GL might have antiproliferative and antioxidant properties based on protective effect against the production of intracellular ROS.


Potential impacts of global elevated CO(2) concentrations on plants.
Early experiments investigating the effects of CO(2) enrichment on plants frequently showed photosynthetic stimulation and reduced stomatal aperture over short time periods. Work on the effects of elevated CO(2) has advanced in two major areas: by the extension of long-term and field experiments, and through investigations on the wide range of negative feedbacks affecting plant responses to CO(2). Downward photosynthetic acclimation in response to CO(2) enrichment is frequently observed over the short and long term, and indicates the activity of diverse feedback mechanisms. CO(2) is generally viewed as a limiting photosynthetic resource. However, recent work on stomatal development has shown that this view is simplistic: long- and short-distance signalling of CO(2) concentration are necessary components of normal plant development.


Untargeted metabolomics coupled with chemometric analysis reveals species-specific steroidal alkaloids for the authentication of medicinal Fritillariae Bulbus and relevant products.
Authentication of original species is embedded in the quality control system of herbal medicines. In this work, ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry-based untargeted metabolomics coupled with chemometric analysis was utilized for the precise authentication of the Fritillaria species for both raw materials and commercial products. First, a stepwise difference-enlarging chemometric analysis strategy was proposed to analyze eight medicinal Fritillaria species. Subsequently, 21 species-specific markers were discovered and the specificity was investigated under different sample preparation methods. Finally, the obtained species-specific markers were successfully utilized to identify the Fritillaria species in commercially relevant products. This work is the first to report robust and specific markers for authentication of Fritillaria products, showing promise for tracking the supply chain of herbal suppliers.


Consumption of fruits, vegetables, soft drinks, and high-fat-containing snacks among Mexican children on the Mexico-U.S. border.
The recommended diet for children would promote health, support growth, and prevent risk of disease. Diets high in fruits and vegetables demonstrate a strong and consistent pattern for decreasing the risk for many cancers and providing benefits against cardiovascular disease, diabetes, obesity, and stroke. The purpose of this study was to assess fruit, vegetable, soft drink, and high-fat-containing snack consumption among fifth- and ninth-grade children attending public schools in the northeastern Mexican state of Baja California. A randomized design was used to select 20 schools with fifth-grade students and 20 schools with ninth-grade students in each of the five Baja California counties. A randomized sample of 20 classes of fifth- and ninth-grade students was then selected. The food frequency questionnaire used contained 36 items. Foods were grouped in the five main food categories, plus soft drinks, sweets, and high-fat-containing snacks. Means, standard deviations (SDs), and frequencies were calculated using SPSS, while chi square was employed to test the association between food consumption and selected variables. Mean daily intake of fruits was 1.5 by children from both grades, while daily mean intake of vegetables was 2.5 for fifth-grade students. The percentage of children with intakes lower than the standard (Apple of Health) was 77 and 80% for fifth and ninth graders for fruits and 62 and 53% for vegetables, respectively. At least 92% of fifth graders reported consuming one soft drink, and 85% consumed one portion of high-fat-containing snacks daily. Our results demonstrated overall low intake of fruits and vegetables and excessive consumption of soft drinks and high-fat-containing snacks, leading to the possibility of costly health complications later in life.


Changes of lipid peroxidation and superoxide dismutase activity in the human placenta.
The oxygen radical may induce peroxidation of unsaturated fatty acids in vivo. We studied changes in superoxide dismutase (SOD) activity and lipid peroxidation using human placental tissue. Lipid peroxidation was marked in early stages (2 to 4 months) of gestation but decreased with growth and was very small by the end of pregnancy. The SOD activity of placental tissue in early gestation was approximately 250 to 500 U per gram of wet weight. The activity increased with growth of the placenta and reached a level of 400 to 1,500 U per gram of wet weight by the end of gestation. These results for SOD activity suggest that the oxygen requirement in the placenta at early stages of gestation is low compared with that at the end of gestation.


Neural Interface: Frontiers and Applications : Cochlear Implants.
The theory and implementation of modern cochlear implant are presented in this chapter. Major signal processing strategies of cochlear implants are discussed in detail. Hardware implementation including wireless signal transmission circuit, integrated circuit design of implant circuit, and neural response measurement circuit are provided in the latter part of the chapter. Finally, new technologies that are likely to improve the performance of current cochlear implants are introduced.


Metal export by CusCFBA, the periplasmic Cu(I)/Ag(I) transport system of Escherichia coli.
High levels of metal ions have the potential to cause cellular toxicity through a variety of mechanisms; therefore, cells have developed numerous systems that regulate their intracellular concentrations. The Cus resistance system aids in protection of Escherichia coli from high levels of Cu(I) and Ag(I) by actively transporting these metal ions to the extracellular environment. The Cus system forms a continuous complex, CusCBA, that spans the inner membrane, periplasm, and outer membrane of Gram-negative bacteria, together with a novel fourth component, the periplasmic metallochaperone, CusF. The metal-binding sites of CusA, CusB, and CusF are exquisitely tuned for Cu(I) and Ag(I), and thus effectively discriminate these ions for transport from other metals that may be required in the cell. Furthermore, direct transfer of metal from protein to protein within the Cus system during the transport process is likely to reduce the potential toxicity posed by the free metal ions. Here we review the wealth of structural, biochemical, and genetic information on the Cus system, which demonstrates the many intriguing aspects of function for metal-transporting efflux systems.


Chasing genes in Alzheimer's and Parkinson's disease.
Alzheimer's disease (AD), the most common type of dementia, and Parkinson's disease (PD), the most common movement disorder, are both neurodegenerative adult-onset diseases characterized by the progressive loss of specific neuronal populations and the accumulation of intraneuronal inclusions. The search for genetic and environmental factors that determine the fate of neurons during the ageing process has been a widespread approach in the battle against neurodegenerative disorders. Genetic studies of AD and PD initially focused on the search for genes involved in the aetiological mechanisms of monogenic forms of these diseases. They later expanded to study hundreds of patients, affected relative-pairs and population-based studies, sometimes performed on "special" isolated populations. A growing number of genes (and pathogenic mutations) is being identified that cause or increase susceptibility to AD and PD. This review discusses the way in which strategies of "gene hunting" have evolved during the last few years and the significance of finding genes such as the presenilins, alpha- synuclein, parkin and DJ- 1. In addition, we discuss possible links between these two neurodegenerative disorders. The clinical, pathological and genetic presentation of AD and PD suggests the involvement of a few overlapping interrelated pathways. Their imbricate features point to a spectrum of neurodegeneration (tauopathies, synucleinopathies, amyloidopathies) that need further intense investigation to find the missing links.


Intra-operative electroencephalogram frontal alpha-band spectral analysis and postoperative delirium in cardiac surgery: A prospective cohort study.
Postoperative delirium (POD) remains a frequent complication after cardiac surgery, with pre-operative cognitive status being one of the main predisposing factors. However, performing complete pre-operative neuropsychological testing is challenging. The magnitude of frontal electroencephalographic (EEG) α oscillations during general anaesthesia has been related to pre-operative cognition and could constitute a functional marker for brain vulnerability. We hypothesised that features of intra-operative α-band activity could predict the occurrence of POD. Single-centre prospective observational study. University hospital, from 15 May 2019 to 15 December 2021. Adult patients undergoing elective cardiac surgery. Pre-operative cognitive status was assessed by neuropsychological tests and scored as a global z score. A 5-min EEG recording was obtained 30 min after induction of anaesthesia. Anaesthesia was maintained with sevoflurane. Power and peak frequency in the α-band were extracted from the frequency spectra. POD was assessed using the Confusion Assessment Method for Intensive Care Unit, the Confusion Assessment Method and a chart review. Sixty-five (29.5%) of 220 patients developed POD. Delirious patients were significantly older with median [IQR] ages of 74 [64 to 79] years vs. 67 [59 to 74] years; P < 0.001) and had lower pre-operative cognitive z scores (-0.52 ± 1.14 vs. 0.21 ± 0.84; P < 0.001). Mean α power (-14.03 ± 4.61 dB vs. -11.59 ± 3.37 dB; P < 0.001) and maximum α power (-11.36 ± 5.28 dB vs. -8.85 ± 3.90 dB; P < 0.001) were significantly lower in delirious patients. Intra-operative mean α power was significantly associated with the probability of developing POD (adjusted odds ratio, 0.88; 95% confidence interval (CI), 0.81 to 0.96; P = 0.007), independently of age and only whenever cognitive status was not considered. A lower intra-operative frontal α-band power is associated with a higher incidence of POD after cardiac surgery. Intra-operative measures of α power could constitute a means of identifying patients at risk of this complication. NCT03706989.


Temperature and mortality in nine US cities.
Extreme temperatures have been associated with increased mortality worldwide. The extent to which air pollutants may confound or modify this association remains unclear. We examined the association between mean apparent temperature and total mortality in 9 cities across the United States during the warm season (May to September) from 1999 to 2002. We applied case-crossover and time-series analyses, adjusting for day of the week and season in time-series analysis. City-specific estimates were then combined using a meta-analysis. A total of 213,438 deaths for all causes occurred in these cities during the study period. We found that mortality increased with apparent temperature. A 5.5 degrees C (10 degrees F) increase in apparent temperature was associated with an increase in mortality of 1.8% (95% confidence interval = 1.09% to 2.5%) when using case-crossover analysis and with an increase of 2.7% (2.0% to 3.5%) using the time-series analysis. This study provides evidence of increased mortality due to elevated apparent temperature exposure, with no confounding or effect modification due to air pollution.


The efficacy of psychological interventions for the prevention and treatment of mental health disorders in university students: A systematic review and meta-analysis.
Mental health problems are becoming increasingly prevalent among students and adequate support should be provided to prevent and treat mental health disorders in those at risk. This systematic review and meta-analysis examined the efficacy of psychological interventions for students, with consideration of how adaptions to intervention content and delivery could improve outcomes. We searched for randomised controlled trials (RCTs) of interventions in students with or at risk of mental health problems and extracted data for study characteristics, symptom severity, wellbeing, educational outcomes, and attrition. Eighty-four studies were included. Promising effects were found for indicated and selective interventions to treat anxiety disorders, depression and eating disorders. PTSD and self-harm data was limited, and did not demonstrate significant effects. Relatively few trials adapted intervention delivery to student-specific concerns, and overall adapted interventions showed no benefit over non-adapted interventions. There was some suggestion that adaptions based on empirical evidence and provision of additional sessions, and transdiagnostic models may yield some benefits. The review is limited by the often poor quality of the literature and exclusion of non-published data. Interventions for students show benefit though uncertainty remains around how best to optimise treatment delivery and content for students. Additional research into content targeting specific underlying mechanisms of problems and transdiagnostic approaches to provision could be promising avenues for further research.


Use of adjunct cardiovascular therapy in patients hospitalised for acute exacerbations of COPD.
In real-life practice, acute exacerbation of COPD is often treated as a cardiopulmonary syndrome http://ow.ly/uAnk30luMYz.


Hepatitis B reactivation and immune check point inhibitors.
Liver toxicity during immune checkpoint inhibitor treatment is mostly due to immune mediated hepatitis. Viral hepatitis, as well as auto-immune or metabolic hepatitis, are considered as exclusion criteria for ICI induced immune hepatitis diagnosis. However, considering the high prevalence of viral hepatitis B infection and the increasing prescription of immune checkpoint inhibitors, their use in patients with HBV chronic viral infection may be common, even more if patients are treated for hepatocellular carcinoma. Few clinical studies directly deal with the risk of HBV reactivation during ICI therapy and real-life data is currently based on five reported cases of HBV reactivation, one with fatal outcome. In this review, we summarize the current available clinical information about HBV reactivation risk during ICI treatment, its hypothetic mechanism, and propose practical recommendations about verifying and monitoring HBV status throughout the treatment.


How to avoid intraoperative and postoperative complications in maxillary sinus elevation.
Maxillary sinus floor elevation, via the lateral approach, is one of the most predictable bone augmentation procedures performed in implant dentistry. but both intra- and postoperative complications can occur, and some of them are severe. Our aim is as follows: To review the pertinent literature on the topic, especially assessing the risk factors related to complications. To give clinical recommendations to minimize intra- and postoperative complications with the ultimate scope of improving the standard of clinical care and patient safety.


TanshinoneIIA Alleviates Inflammatory Response and Directs Macrophage Polarization in Lipopolysaccharide-Stimulated RAW264.7 Cells.
TanshinoneIIA (TanIIA) has been demonstrated to possess numerous biological effects. However, the specific effect of TanIIA on macrophage polarization has not been reported. In this study, it was revealed that TanIIA might play a pivotal role in macrophage polarization. As our results indicated, cell morphology was changed in RAW264.7 cells which were treated with LPS or LPS/TanIIA (0.1 μM, 1 μM, 10 μM). Subsequently, pro-inflammatory cytokine TNF-α and anti-inflammatory cytokine IL-10 were measured by ELISA kits. Furthermore, TanIIA enhanced the expression of M2 macrophage markers (Arg1 and FIZZ1) and decreased the expression of markers associated with M1 macrophage polarization (iNOS and IL-1β). Increased expression of CD206 was also detected by flow cytometry in TanIIA-treated groups. Mechanistically, it was revealed that TanIIA modulated macrophage polarization by ameliorating mitochondrial function and regulating TLR4-HMGB1/CEBP-β pathway. In addition, increased expression of miR-155 was observed in RAW264.7 cells incubated with LPS and were effectively inhibited by TanIIA. Taken together, it was suggested that TanIIA inhibits inflammatory response and promotes macrophage polarization toward an M2 phenotype, which provides new evidence for the anti-inflammation activity of TanIIA.


T-cell receptor gamma/delta: comparison of gene configurations and function between humans and chimpanzees.
The human and chimpanzee T-cell receptor gamma-delta (TCR gamma delta) bearing cells represent a minor subset (3-8%) of T lymphocytes. In the periphery, the TCR gamma delta population has a restricted combinatorial repertoire. The TCRD-V1 and -V2 gene products are expressed in a mutually exclusive fashion, whereas, the TCRD-V2 and the TCRG-V9 encoded proteins show, in general, a coordinated expression. Restriction fragment length polymorphism analysis showed conservation of the restriction sites that identify the TCRG-V9 and TCRD-V2 rearrangements. The human TCRG-V9 locus has two alleles, TCRG-V9A1 and TCRG-V9A2 differing at codon position 31. The chimpanzee TCRG-V9 gene product differs from the products of the human TCRG-V9A1 and TCRG-V9A2 allele by two and three amino acid replacements, respectively. The human and the chimpanzee TCRG-V9-TCRD-V2 lymphocytes show a similar specific proliferative and cytolytic response to human Daudi Burkitt's lymphoma cells. Therefore, the amino acid replacements found in the chimpanzee TCRG-V9 gene product do not change the superantigen specificity across this species barrier.


Occlusion of the thoracic duct using ultrasonically activated shears in six dogs.
To assess the feasibility of sealing the thoracic duct (TD) in dogs using ultrasonically activated shears via thoracoscopy. In vivo experimental study. Mature dogs (n = 6). Dogs were anesthetized without pulmonary exclusion and positioned in left lateral recumbency. Lymphangiography was performed to identify TD anatomy. Methylene blue was injected into the lymphatic catheter to identify the TD and its branches. Under thoracoscopic guidance (right dorsal 8-10th intercostal spaces), the TD was sealed with an ultrasonic device and lymphangiography was repeated. If the flow of contrast continued beyond the occlusion site, additional attempts to seal the duct were made. Dogs were euthanatized, the TD was excised and fixed in formalin for histopathology. Thoracoscopic identification of the TD was possible in 5 dogs. Three dogs required conversion to a thoracoscopic-assisted approach and 3 dogs required resealing of the TD closer to the diaphragm. Thoracic duct occlusion (TDO) was ultimately achieved in all 6 dogs based on follow-up lymphangiography. TDO by tissue coagulation was confirmed by histopathology. Thoracoscopic identification and occlusion of the TD using ultrasonically activated shears with bilateral lung ventilation is technically feasible in normal dogs and provides a less invasive alternative to open thoracotomy procedures.


Development of CuMnxOy (x = 2, and y = 4)-GO heterostructure for the synthesis of pyranoquinoline derivatives.
The pyranoquinoline derivatives are synthetically important due to their biological properties. In this research, these derivatives were produced through an environmentally friendly method. This method includes the use of CuMnxOy (x = 2, and y = 4)-GO as a nanocatalyst, which is easy to produce, has excellent performance, cost-effectiveness, and recyclability among its features, and also the use of water as a green solvent. Pyranoquinolines through the one-pot, the multi-component reaction between different derivatives of aryl glyoxal, ethyl cyanoacetate, and 4-hydroxyquinoline-2(1H)-one were synthesized using nanocatalyst, K2CO3, and H2O. Also, the structure of the CuMnxOy-GO nanocatalyst was evaluated and confirmed via different analyses. The distinguishing features of this work compared to previous works are easy workup, recyclability of nanocatalyst, facile synthesis process, and provide high yields of products.


Antimicrobial, Antitumor and Side Effects Assessment of a Newly Synthesized Tamoxifen Analog.
Tamoxifen citrate is a very prevalent drug marketed under several trade names like Apo-Tamox, Nolvadex, Tamec, Tamizam, and Tamoplex. This molecule is approved by the FDA for breast cancer treatment. Some studies have shown that tamoxifen has anti-tuberculosis and antiparasitic activities. Like any drug, tamoxifen possesses side effects, more or less dangerous. Basically, this work is a comparative study that aims to: primarily compare the antimicrobial and antitumor activities of tamoxifen and a newly synthesized tamoxifen analog; and to determine the molecule with lesser side effects. Three groups of mice were injected with tamoxifen citrate and compound 2(1,1-bis[4-(3- dimethylaminopropoxy)phenyl]-2-phenyl-but-1-ene dihydrochloride) at doses corresponding to C1 (1/10), C2 (1/50), and C3 (1/100) to compound 2 lethal dose (LD50 = 75 mg/kg) administered to adult mice. A group of noninjected mice served as a study control. Experimental results suggest that compound 2 has better antitumor and antimicrobial activity than tamoxifen citrate besides its lower toxicity effects. The results obtained from the present study confirmed the antitumor and antimicrobial effect of tamoxifen citrate and its hematological side effects. Compound 2 seems to be more effective than tamoxifen citrate for antitumor and antimicrobial treatment while having less hematological side effects and less disruption of the blood biochemical parameters. These findings encourage us to perform further studies on compound 2 and test it for other therapeutic uses for which tamoxifen was found effective.


Below-knee physiologic cryoanesthesia in the critically ill patient.
Controversy has surrounded the role of local hypothermia as a preoperative treatment in amputations of the lower extremity. A study was undertaken to determine the effectiveness of amputation under cryoanesthesia in decreasing postoperative morbidity and mortality in below-knee (BK) amputations. Of 154 BK amputations, only 91 with unreconstructable vascular disease, gangrene, or both, were included in this study. Group I consisted of 48 patients (mean age 63.9 years) who had undergone a routine BK amputation; group II consisted of 43 patients (mean age 65.7 years) who were acutely ill and too unstable to undergo a major surgical procedure. Group II patients were treated by amputation while under cryoanesthesia before any definitive operative intervention. The patients in group II were significantly (p less than 0.05) more ill preoperatively than those in group I. Group II patients had a higher prevalence of previous myocardial infarction, previous stroke, diabetes mellitus, osteomyelitis, and wet gangrene. Seventy percent of the patients in group II had three or more risk factors vs. 46% in group I. Early postoperative mortality rates did not differ significantly between groups (group I, 8%; group II, 9%); the average length of hospital stay for group I patients was 24.2 days compared with 17.7 days in group II. Group II patients sustained slightly more postoperative complications. Amputation under cryoanesthesia appears to be of value in reducing postoperative morbidity and mortality and length of hospital stay in the acutely ill patient with unreconstructable vascular disease, gangrene, or both.


Risk factors for postoperative ileus after diverting loop ileostomy closure.
Postoperative ileus is one of the most common complications after diverting loop ileostomy closure. Some reports have investigated the risk factors for postoperative complications or ileus after ileostomy closure; however, these studies did not evaluate the index surgery sufficiently. In this study, we evaluated the risk factors, including the details of the index surgery, for ileus after diverting ileostomy closure. This was a retrospective study of patients who underwent ileostomy closure following index surgery for rectal cancer. Patients who developed postoperative ileus [POI (+)] and patients who did not [POI (-)] after ileostomy closure were compared. Sixty-eight patients were evaluated and were divided into two groups: POI (+) (n = 11) and POI (-) (n = 57), and the groups were compared. There were no significant differences in the details of the index surgery, operative procedure, transanal total mesorectal excision, lateral lymph node dissection, operating time, or blood loss. The incidence of Clavien-Dindo grade ≥ III complications and adjuvant chemotherapy after index surgery were significantly higher in the POI (+) group. The incidence of Clavien-Dindo grade ≥ III complications and adjuvant chemotherapy after index surgery may increase the risk of postoperative ileus after ileostomy closure.


The risk of infection from Giardia lamblia due to drinking water supply, use of water, and latrines among preschool children in rural Lesotho.
Stool samples were collected from 267 rural, preschool children in four districts in Lesotho during October-November, 1984. Sixty-three children (23.6%) were tested positive for Giardia lamblia, the most commonly recovered parasite from stool samples. The use of low amounts of water for personal hygiene was associated significantly with having G. lamblia (OR = 2.42), but the use of traditional, non-improved drinking water sources (OR = 1.38) or lack of latrines (OR = 0.94) was not. Although G. lamblia may be primarily waterborne in developed countries, the amount of water that is used for personal and domestic hygiene may be more important than the quality of drinking water in developing countries. Other risk factors that were identified to be associated significantly with having or not having Giardia were child older than 24 months (OR = 6.79), mother less than 20 years of age (OR = 5.18), residing in Mohales Hoek district (OR = 2.33), and possessing several agricultural tools (OR = 0.70).


The Kindlin Outside Connection.
Transmembrane integrin bridges the extracellular and intracellular environments and is activated by focal adhesion proteins, talin and kindlin. Activated integrin engages ligands from the extracellular matrix and controls intracellular responses. In this issue of Structure, Zhu et al. (2019) describe an initial step involving recruitment of paxillin by ubiquitin-like kindlin-2 domain.


Correlation of the detection rate of upper GI cancer with artificial intelligence score: results from a multicenter trial (with video).
The quality of EGD is a prerequisite for a high detection rate of upper GI lesions, especially early gastric cancer. Our previous study showed that an artificial intelligence system, named intelligent detection endoscopic assistant (IDEA), could help to monitor blind spots and provide an operation score during EGD. Here, we verified the effectiveness of IDEA to help evaluate the quality of EGD in a large-scale multicenter trial. Patients undergoing EGD in 12 hospitals were consecutively enrolled. All hospitals were equipped with IDEA developed using deep convolutional neural networks and long short-term memory. Patients were examined by EGD, and the results were recorded by IDEA. The primary outcome was the detection rate of upper GI cancer. Secondary outcomes were part scores, total scores, and endoscopic procedure time, which were analyzed by IDEA. A total of 17,787 patients were recruited. The total detection rate of cancer-positive cases was 1.50%, ranging from .60% to 3.94% in each hospital. The total detection rate of early cancer-positive cases was .36%, ranging from .00% to 1.58% in each hospital. The average total score analyzed by IDEA ranged from 64.87 ± 16.87 to 83.50 ± 9.57 in each hospital. The cancer detection rate in each hospital was positively correlated with total score (r = .775, P = .003). Similarly, the early cancer detection rate was positively correlated with total score (r = .756, P = .004). This multicenter trial confirmed that the quality of the EGD result is positively correlated with the detection rate of cancer, which can be monitored by IDEA. (Clinical trial registration number: ChiCTR2000029001.).


Is a minor clinical anastomotic leak clinically significant after resection of colorectal cancer?
There are few reports comparing the variety and frequency of postoperative complications between patients with a major clinical leak requiring emergency abdominal reoperation and those with a minor leak diagnosed from clinical signs and managed expectantly without reoperation. This study examined the association between severity of leakage and 18 other postoperative complications, postoperative mortality, and length of postoperative hospital stay. Data were drawn from a comprehensive, prospective hospital registry of 1,507 colorectal cancer resections involving an anastomosis from January 1995 to December 2006. Differences were evaluated by two-tailed Fisher's exact test, Student's t-test, or Mann-Whitney U test. Leaks occurred in 54 patients (3.6%; 95% CI, 2.7% to 4.7%), comprising 21 major (1.4%; 95% CI, 0.9% to 2.1%) and 33 minor leaks (2.2%; 95% CI, 1.5% to 3.2%). Patients with a leak were significantly (p < 0.01) more likely than those without to have 11 of 18 other surgical and medical complications considered, although with few differences in complication rates between those with major and minor leaks. As compared with patients without leak, those with a leak (major or minor) had several of these complications rather than just one (p < 0.001) and greatly prolonged hospital stay (p < 0.001). Postoperative mortality was higher after major leaks than after minor leaks (4 of 21 and 0 of 33, respectively, p = 0.019). A minor leak is not trivial. Apart from the fact that major clinical leakage necessitates urgent reoperation, there were few other differences between major and minor clinical leaks in the frequency of other complications.


Neuromodulation of fast-spiking and non-fast-spiking hippocampal CA1 interneurons by human cerebrospinal fluid.
How the brain extracellular fluid influences the activity of GABAergic interneurons in vivo is not known. This issue is examined in the hippocampal brain slice by comparing GABAergic interneuron activity in human versus artificial cerebrospinal fluid. Human cerebrospinal fluid (hCSF) substantially increases the excitability of fast-spiking and non-fast-spiking CA1 interneurons. CA1 pyramidal cells are even more strongly excited by hCSF. The tonic excitation of pyramidal cells, in combination with an increased responsiveness of interneurons to excitatory input, is likely to promote the generation of synchronized network activity in the hippocampus. GABAergic interneurons intricately regulate the activity of hippocampal and neocortical networks. Their function in vivo is likely to be tuned by neuromodulatory substances in the brain extracellular fluid. However, in vitro investigations of GABAergic interneuron function do not account for such effects, as neurons are kept in artificial extracellular fluid. To examine the neuromodulatory influence of brain extracellular fluid on GABAergic activity, we recorded from fast-spiking and non-fast-spiking CA1 interneurons, as well as from pyramidal cells, in the presence of human cerebrospinal fluid (hCSF), using a matched artificial cerebrospinal fluid (aCSF) as control. We found that hCSF increased the frequency of spontaneous firing more than twofold in the two groups of interneurons, and more than fourfold in CA1 pyramidal cells. hCSF did not affect the resting membrane potential of CA1 interneurons but caused depolarization in pyramidal cells. The increased excitability of interneurons and pyramidal cells was accompanied by reductions in after-hyperpolarization amplitudes and a left-shift in the frequency-current relationships. Our results suggest that ambient concentrations of neuromodulators in the brain extracellular fluid powerfully influence the excitability of neuronal networks.


Unveiling the dynamics of antibiotic resistome, bacterial communities, and metals from the feces of patients in a typical hospital wastewater treatment system.
Bacterial pathogens and antibiotic resistance genes (ARGs) are extensively disseminated into the environment via hospital wastewater (HWW), as it contains large quantities of feces from resident patients. However, studies on the antibiotic resistome and pathogenic bacteria from the gut of resident patients within the hospital wastewater treatment plant (hWWTP) are limited. Here, we examined and compared the occurrence and abundance of ARGs, mobile genetic elements (MGEs), metals, and bacterial communities from the feces of patients in a typical hWWTP system and determined the pathogenic hosts responsible for transferring ARGs. There were 176 ARGs and 43 MGEs detected in the feces of hospitalized patients, 129 genes were persistent, and 88 genes were enriched after HWW treatment, particularly for the blaVEB, blaNDM, and class 1 integron (intI1), with an average of 659-fold, 202-fold, and seven-fold enrichment, respectively. MGEs, especially Is613, in the feces of hospitalized patients were exceptionally abundant and even surpassed the abundance of total ARGs, which explained the persistence of ARGs in hWWTPs due to possible gene mobilization events. Bacteroidetes and Firmicutes were the most abundant phyla in these feces, accounting for 81 % of the total gut microbiota, while Epsilonbacteraeota and Proteobacteria dominated the hWWTPs. Additionally, 54 possible bacterial pathogens were found in the hospital environment, including four "ESKAPE" pathogens and 14 cancer-related pathogens. Many of them were strongly associated with different types of ARGs. Notably, Bacteroides was the major potential ARG-harboring pathogenic genus, as determined by the network analysis, and was highly abundant after the treatment. The altered microbial community was the major contributing factor shaping antibiotic resistome. This study might provide a comprehensive insight into the distribution profiles of ARGs and pathogens from the gut of inpatients throughout the HWW treatment system, which could be used as a reference for optimizing HWW treatment and monitoring public risk.


Use of laparoscopy in trauma at a level II trauma center.
Enthusiasm for the use of laparoscopy in trauma has not rivaled that for general surgery. The purpose of this study was to evaluate our experience with laparoscopy at a level II trauma center. A retrospective review of all trauma patients undergoing diagnostic or therapeutic laparoscopy was performed from January 2004 to July 2010. Laparoscopy was performed in 16 patients during the study period. The average age was 35 years. Injuries included left diaphragm in 4 patients, mesenteric injury in 2, and vaginal laceration, liver laceration, small bowel injury, renal laceration, urethral/pelvic, and colon injury in 1 patient each. Diagnostic laparoscopy was performed in 11 patients (69%) with 3 patients requiring conversion to an open procedure. Successful therapeutic laparoscopy was performed in 5 patients for repair of isolated diaphragm injuries (2), a small bowel injury, a colon injury, and placement of a suprapubic bladder catheter. Average length of stay was 5.6 days (range, 0 to 23), and 75% of patients were discharged home. Morbidity rate was 13% with no mortalities or missed injuries. Laparoscopy is a seldom-used modality at our trauma center; however, it may play a role in a select subset of patients.