Intravenous versus inhalational maintenance of anaesthesia for postoperative cognitive outcomes in elderly people undergoing non-cardiac surgery.
The use of anaesthetics in the elderly surgical population (more than 60 years of age) is increasing. Postoperative delirium, an acute condition characterized by reduced awareness of the environment and a disturbance in attention, typically occurs between 24 and 72 hours after surgery and can affect up to 60% of elderly surgical patients. Postoperative cognitive dysfunction (POCD) is a new-onset of cognitive impairment which may persist for weeks or months after surgery.Traditionally, surgical anaesthesia has been maintained with inhalational agents. End-tidal concentrations require adjustment to balance the risks of accidental awareness and excessive dosing in elderly people. As an alternative, propofol-based total intravenous anaesthesia (TIVA) offers a more rapid recovery and reduces postoperative nausea and vomiting. Using TIVA with a target controlled infusion (TCI) allows plasma and effect-site concentrations to be calculated using an algorithm based on age, gender, weight and height of the patient.TIVA is a viable alternative to inhalational maintenance agents for surgical anaesthesia in elderly people. However, in terms of postoperative cognitive outcomes, the optimal technique is unknown. To compare maintenance of general anaesthesia for elderly people undergoing non-cardiac surgery using propofol-based TIVA or inhalational anaesthesia on postoperative cognitive function, mortality, risk of hypotension, length of stay in the postanaesthesia care unit (PACU), and hospital stay. We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 11), MEDLINE (1946 to November 2017), Embase (1974 to November 2017), PsycINFO (1887 to November 2017). We searched clinical trials registers for ongoing studies, and conducted backward and forward citation searching of relevant articles. We included randomized controlled trials (RCTs) with participants over 60 years of age scheduled for non-cardiac surgery under general anaesthesia. We planned to also include quasi-randomized trials. We compared maintenance of anaesthesia with propofol-based TIVA versus inhalational maintenance of anaesthesia. Two review authors independently assessed studies for inclusion, extracted data, assessed risk of bias, and synthesized findings. We included 28 RCTs with 4507 randomized participants undergoing different types of surgery (predominantly cardiovascular, laparoscopic, abdominal, orthopaedic and ophthalmic procedures). We found no quasi-randomized trials. Four studies are awaiting classification because we had insufficient information to assess eligibility.All studies compared maintenance with propofol-based TIVA versus inhalational maintenance of anaesthesia. Six studies were multi-arm and included additional TIVA groups, additional inhalational maintenance or both. Inhalational maintenance agents included sevoflurane (19 studies), isoflurane (eight studies), and desflurane (three studies), and was not specified in one study (reported as an abstract). Some studies also reported use of epidural analgesia/anaesthesia, fentanyl and remifentanil.We found insufficient reporting of randomization methods in many studies and all studies were at high risk of performance bias because it was not feasible to blind anaesthetists to study groups. Thirteen studies described blinding of outcome assessors. Three studies had a high of risk of attrition bias, and we noted differences in the use of analgesics between groups in six studies, and differences in baseline characteristics in five studies. Few studies reported clinical trials registration, which prevented assessment of risk of selective reporting bias.We found no evidence of a difference in incidences of postoperative delirium according to type of anaesthetic maintenance agents (odds ratio (OR) 0.59, 95% confidence interval (CI) 0.15 to 2.26; 321 participants; five studies; very low-certainty evidence); we noted during sensitivity analysis that using different time points in one study may influence direction of this result. Thirteen studies (3215 participants) reported POCD, and of these, six studies reported data that could not be pooled; we noted no difference in scores of POCD in four of these and in one study, data were at a time point incomparable to other studies. We excluded one large study from meta-analysis because study investigators had used non-standard anaesthetic management and this study was not methodologically comparable to other studies. We combined data for seven studies and found low-certainty evidence that TIVA may reduce POCD (OR 0.52, 95% CI 0.31 to 0.87; 869 participants).We found no evidence of a difference in mortality at 30 days (OR 1.21, 95% CI 0.33 to 4.45; 271 participants; three studies; very low-certainty evidence). Twelve studies reported intraoperative hypotension. We did not perform meta-analysis for 11 studies for this outcome. We noted visual inconsistencies in these data, which may be explained by possible variation in clinical management and medication used to manage hypotension in each study (downgraded to low-certainty evidence); one study reported data in a format that could not be combined and we noted little or no difference between groups in intraoperative hypotension for this study. Eight studies reported length of stay in the PACU, and we did not perform meta-analysis for seven studies. We noted visual inconsistencies in these data, which may be explained by possible differences in definition of time points for this outcome (downgraded to very low-certainty evidence); data were unclearly reported in one study. We found no evidence of a difference in length of hospital stay according to type of anaesthetic maintenance agent (mean difference (MD) 0 days, 95% CI -1.32 to 1.32; 175 participants; four studies; very low-certainty evidence).We used the GRADE approach to downgrade the certainty of the evidence for each outcome. Reasons for downgrading included: study limitations, because some included studies insufficiently reported randomization methods, had high attrition bias, or high risk of selective reporting bias; imprecision, because we found few studies; inconsistency, because we noted heterogeneity across studies. We are uncertain whether maintenance with propofol-based TIVA or with inhalational agents affect incidences of postoperative delirium, mortality, or length of hospital stay because certainty of the evidence was very low. We found low-certainty evidence that maintenance with propofol-based TIVA may reduce POCD. We were unable to perform meta-analysis for intraoperative hypotension or length of stay in the PACU because of heterogeneity between studies. We identified 11 ongoing studies from clinical trials register searches; inclusion of these studies in future review updates may provide more certainty for the review outcomes.


The negative impact of most relevant infections on fertility and assisted reproduction technology.
Infections may act with variable impact on the physiopathology of the reproductive organs, determining infertility or reducing the outcomes of assisted reproduction technology. The aim of this narrative review is to describe the existing evidence regarding the pathogens with a supposed or recognized role in reproductive medicine. Viral hepatitis, as well as HIV, can reduce sperm quality. Syphilis carries a risk of erectile dysfunction and increased endometrial thickness. Chlamydia is the main cause of pelvic inflammatory disease. In relation to Mycoplasma and Ureaplasma spp., only few species seem to show a correlation with infertility and poor in-vitro fertilization outcomes. There is evidence of a role for bacterial vaginosis in early pregnancy loss. HPV infection in males seems to determine infertility. Herpesviruses are more a risk for fetuses than for fertility itself. Zika virus is responsible for altered early embryo development and waiting to conceive is recommended in suspected or confirmed cases. The impact of SARS-CoV-2 is yet to be elucidated. Rubella and toxoplasmosis can provoke important congenital defects and therefore screening is mandatory before conception; a vaccine for Rubella is recommended. Further and well-designed studies are still needed to better elucidate the role of some infectious agents, to improve fertility and its treatments.


Antiviral activity of medicinal plants of Nilgiris.
Medicinal plants have been traditionally used for different kinds of ailments including infectious diseases. There is an increasing need for substances with antiviral activity since the treatment of viral infections with the available antiviral drugs often leads to the problem of viral resistance. Herpes simplex virus (HSV) causes a variety of life threatening diseases. Since the chemotherapeutic agents available for HSV infections are either low in quality or limited in efficiency, there is a need to search for new and more effective antiviral agents for HSV infections. Therefore in the present study 18 plants with ethnomedical background from different families were screened for antiviral activity against HSV-1. Different parts of the plants collected from in and around Ootacamund, Tamil Nadu were extracted with different solvents to obtain crude extracts. These extracts were screened for their cytotoxicity against Vero cell line by assay microculture tetrazolium (MTT) trypan blue dye exclusion, proteins estimation and 3H labeling. Antiviral properties of the plant extracts were determined by cytopathic effect inhibition assay and virus yield reduction assay. Three plant extracts Hypericum mysorense, Hypericum hookerianum and Usnea complanta exhibited significant antiviral activity at a concentration non toxic to the cell line used. The extracts of Melia dubia, Cryptostegia grandiflora and essential oil of Rosmarinus officinalis showed partial activity at higher concentrations. Some of the medicinal plants have shown antiviral activity. Further research is needed to elucidate the active constituents of these plants which may be useful in the development of new and effective antiviral agents.


Mutation in the ntrR gene, a member of the vap gene family, increases the symbiotic efficiency of Sinorhizobium meliloti.
In specific plant organs, namely the root nodules of alfalfa, fixed nitrogen (ammonia) produced by the symbiotic partner Sinorhizobium meliloti supports the growth of the host plant in nitrogen-depleted environment. Here, we report that a derivative of S. meliloti carrying a mutation in the chromosomal ntrR gene induced nodules with enhanced nitrogen fixation capacity, resulting in an increased dry weight and nitrogen content of alfalfa. The efficient nitrogen fixation is a result of the higher expression level of the nifH gene, encoding one of the subunits of the nitrogenase enzyme, and nifA, the transcriptional regulator of the nif operon. The ntrR gene, controlled negatively by its own product and positively by the symbiotic regulator syrM, is expressed in the same zone of nodules as the nif genes. As a result of the nitrogen-tolerant phenotype of the strain, the beneficial effect of the mutation on efficiency is not abolished in the presence of the exogenous nitrogen source. The ntrR mutant is highly competitive in nodule occupancy compared with the wild-type strain. Sequence analysis of the mutant region revealed a new cluster of genes, termed the "ntrPR operon," which is highly homologous to a group of vap-related genes of various pathogenic bacteria that are presumably implicated in bacterium-host interactions. On the basis of its favorable properties, the strain is a good candidate for future agricultural utilization.


The endocrine disruptor DEHP and the ECS: analysis of a possible crosstalk.
Studies of the last decade associated the environmental contamination by di-(2-ethylhexyl)-phthalate (DEHP) with obesity and endocrine malfunction. DEHP was found to interact with several receptors - among them are receptors of the endocannabinoid system (ECS) with high expression levels in adipose tissue. Furthermore, the correlation for BMI and body fat to the serum endocannabinoid level raises the question if the obesogenic and endocrine-disrupting DEHP effects are mediated via the ECS. We therefore characterized the ECS in a human cell model of adipogenesis using the SGBS preadipocytes to subsequently investigate if DEHP exposure affects the intrinsic ECS. The receptors of the ECS and the endocannabinoid-metabolizing enzymes were upregulated during normal adipogenesis, accompanied by an increasing secretion of the adipokines adiponectin and leptin. DEHP affected the secretion of both adipokines but not the ECS, suggesting DEHP to alter the endocrine function of adipocytes without the involvement of the intrinsic ECS.


Proteomics in early detection of cancer.
Early detection is critical in cancer control and prevention. Biomarkers help in this process by providing valuable information about a the status of a cell at any given point in time. As a cell transforms from nondiseased to neoplastic, distinct changes occur that could be potentially detected through the identification of the appropriate biomarkers. Biomarker research has benefited from advances in technology such as proteomics. We discuss here ongoing research in this field, focusing on proteomic technologies. The advances in two-dimensional electrophoresis and mass spectrometry are discussed in light of their contribution to biomarker research. Chip-based techniques, such as surface-enhanced laser desorption, and ionization and emerging methods, such as tissue and antibody arrays, are also discussed. The development of bioinformatic tools that have and are being developed in parallel to proteomics is also addressed. This report brings into focus the efforts of the Early Detection Research Network at the National Cancer Institute in harnessing scientific expertise from leading institutions to identify and validate biomarkers for early detection and risk assessment.


Antiangiogenic gene therapy of cancer: recent developments.
With the role of angiogenesis in tumor growth and progression firmly established, considerable effort has been directed to antiangiogenic therapy as a new modality to treat human cancers. Antiangiogenic agents have recently received much widespread attention but strategies for their optimal use are still being developed. Gene therapy represents an attractive alternative to recombinant protein administration for several reasons. This review evaluates the potential advantages of gene transfer for antiangiogenic cancer therapy and describes preclinical gene transfer work with endogenous angiogenesis inhibitors demonstrating the feasibility of effectively suppressing and even eradicating tumors in animal models. Additionally, we describe the advantages and disadvantages of currently available gene transfer vectors and update novel developments in this field. In conclusion, gene therapy holds great promise in advancing antiangiogenesis as an effective cancer therapy and will undoubtedly be evaluated in human clinical trials in the near future.


Evaluation of accelerometer-based fall detection algorithms on real-world falls.
Despite extensive preventive efforts, falls continue to be a major source of morbidity and mortality among elderly. Real-time detection of falls and their urgent communication to a telecare center may enable rapid medical assistance, thus increasing the sense of security of the elderly and reducing some of the negative consequences of falls. Many different approaches have been explored to automatically detect a fall using inertial sensors. Although previously published algorithms report high sensitivity (SE) and high specificity (SP), they have usually been tested on simulated falls performed by healthy volunteers. We recently collected acceleration data during a number of real-world falls among a patient population with a high-fall-risk as part of the SensAction-AAL European project. The aim of the present study is to benchmark the performance of thirteen published fall-detection algorithms when they are applied to the database of 29 real-world falls. To the best of our knowledge, this is the first systematic comparison of fall detection algorithms tested on real-world falls. We found that the SP average of the thirteen algorithms, was (mean ± std) 83.0% ± 30.3% (maximum value = 98%). The SE was considerably lower (SE = 57.0% ± 27.3%, maximum value = 82.8%), much lower than the values obtained on simulated falls. The number of false alarms generated by the algorithms during 1-day monitoring of three representative fallers ranged from 3 to 85. The factors that affect the performance of the published algorithms, when they are applied to the real-world falls, are also discussed. These findings indicate the importance of testing fall-detection algorithms in real-life conditions in order to produce more effective automated alarm systems with higher acceptance. Further, the present results support the idea that a large, shared real-world fall database could, potentially, provide an enhanced understanding of the fall process and the information needed to design and evaluate a high-performance fall detector.


Higher levels of serum uric acid influences hepatic damage in patients with non-alcoholic fatty liver disease (NAFLD).
recent evidence suggests a causal link between serum uric acid and the metabolic syndrome, diabetes mellitus, arterial hypertension, and renal and cardiac disease. Uric acid is an endogenous danger signal and activator of the inflammasome, and has been independently associated with an increased risk of cirrhosis. six hundred and thirty-four patients from the nation-wide HEPAMET registry with biopsy-proven NAFLD (53% NASH) were analyzed to determine whether hyperuricemia is related with advanced liver damage in patients with non-alcoholic fatty liver disease (NAFLD). Patients were divided into three groups according to the tertile levels of serum uric acid and gender. the cohort was composed of 50% females, with a mean age of 49 years (range 19-80). Patients in the top third of serum uric acid levels were older (p = 0.017); they had a higher body mass index (p < 0.01), arterial blood pressure (p = 0.05), triglyceridemia (p = 0.012), serum creatinine (p < 0.001) and total cholesterol (p = 0.016) and lower HDL-cholesterol (p = 0.004). According to the univariate analysis, the variables associated with patients in the top third were more advanced steatosis (p = 0.02), liver fibrosis (F2-F4 vs F0-1; p = 0.011), NASH (p = 0.002) and NAS score (p = 0.05). According to the multivariate logistic regression analysis, the top third of uric acid level was independently associated with steatosis (adjusted hazard ratio 1.7; CI 95%: 1.05-2.8) and NASH (adjusted hazard ratio 1.8; CI 95%: 1.08-3.0) but not with advanced fibrosis (F2-F4) (adjusted hazard ratio 1.09; CI 95%: 0.63-1.87). higher levels of serum uric acid were independently associated with hepatocellular steatosis and NASH in a cohort of patients with NAFLD. Serum uric acid levels warrants further evaluation as a component of the current non-invasive NAFLD scores of histopathological damage.


Microbial community succession in an unvegetated, recently deglaciated soil.
Primary succession is a fundamental process in macroecosystems; however, if and how soil development influences microbial community structure is poorly understood. Thus, we investigated changes in the bacterial community along a chronosequence of three unvegetated, early successional soils ( approximately 20-year age gradient) from a receding glacier in southeastern Peru using molecular phylogenetic techniques. We found that evenness, phylogenetic diversity, and the number of phylotypes were lowest in the youngest soils, increased in the intermediate aged soils, and plateaued in the oldest soils. This increase in diversity was commensurate with an increase in the number of sequences related to common soil bacteria in the older soils, including members of the divisions Acidobacteria, Bacteroidetes, and Verrucomicrobia. Sequences related to the Comamonadaceae clade of the Betaproteobacteria were dominant in the youngest soil, decreased in abundance in the intermediate age soil, and were not detected in the oldest soil. These sequences are closely related to culturable heterotrophs from rock and ice environments, suggesting that they originated from organisms living within or below the glacier. Sequences related to a variety of nitrogen (N)-fixing clades within the Cyanobacteria were abundant along the chronosequence, comprising 6-40% of phylotypes along the age gradient. Although there was no obvious change in the overall abundance of cyanobacterial sequences along the chronosequence, there was a dramatic shift in the abundance of specific cyanobacterial phylotypes, with the intermediate aged soils containing the greatest diversity of these sequences. Most soil biogeochemical characteristics showed little change along this approximately 20-year soil age gradient; however, soil N pools significantly increased with soil age, perhaps as a result of the activity of the N-fixing Cyanobacteria. Our results suggest that, like macrobial communities, soil microbial communities are structured by substrate age, and that they, too, undergo predictable changes through time.


Supercapacitor Performance of Nickel-Cobalt Sulfide Nanotubes Decorated Using Ni Co-Layered Double Hydroxide Nanosheets Grown in Situ on Ni Foam.
In this study, to fabricate a non-binder electrode, we grew nickel-cobalt sulfide (NCS) nanotubes (NTs) on a Ni foam substrate using a hydrothermal method through a two-step approach, namely in situ growth and an anion-exchange reaction. This was followed by the electrodeposition of double-layered nickel-cobalt hydroxide (NCOH) over a nanotube-coated substrate to fabricate NCOH core-shell nanotubes. The final product is called NCS@NCOH herein. Structural and morphological analyses of the synthesized electrode materials were conducted via SEM and XRD. Different electrodeposition times were selected, including 10, 20, 40, and 80 s. The results indicate that the NCSNTs electrodeposited with NCOH nanosheets for 40 s have the highest specific capacitance (SC), cycling stability (2105 Fg-1 at a current density of 2 Ag-1), and capacitance retention (65.1% after 3,000 cycles), in comparison with those electrodeposited for 10, 20, and 80 s. Furthermore, for practical applications, a device with negative and positive electrodes made of active carbon and NCS@NCOH was fabricated, achieving a high-energy density of 23.73 Whkg-1 at a power density of 400 Wkg-1.


Use of human microsomes and deuterated substrates: an alternative approach for the identification of novel metabolites of ketamine by mass spectrometry.
In vitro biosynthesis using pooled human liver microsomes was applied to help identify in vivo metabolites of ketamine by liquid chromatography (LC)-tandem mass spectrometry. Microsomal synthesis produced dehydronorketamine, seven structural isomers of hydroxynorketamine, and at least five structural isomers of hydroxyketamine. To aid identification, stable isotopes of the metabolites were also produced from tetra-deuterated isotopes of ketamine or norketamine as substrates. Five metabolites (three hydroxynorketamine and two hydroxyketamine isomers) gave chromatographically resolved components with product ion spectra indicating the presence of a phenolic group, with phenolic metabolites being further substantiated by selective liquid-liquid extraction after adjustments to the pH. Two glucuronide conjugates of hydroxynorketamine were also identified. Analysis by LC-coupled ion cyclotron resonance mass spectrometry gave unique masses in accordance with the predicted elemental composition. The metabolites, including the phenols, were subsequently confirmed to be present in urine of subjects after oral ketamine administration, as facilitated by the addition of deuterated metabolites generated from the in vitro biosynthesis. To our knowledge, phenolic metabolites of ketamine, including an intact glucuronide conjugate, are here reported for the first time. The use of biologically synthesized deuterated material as an internal chromatographic and mass spectrometric marker is a viable approach to aid in the identification of metabolites. Metabolites that have particular diagnostic value can be selected as candidates for chemical synthesis of standards.


Environmental effects on the expression of life span and aging: an extreme contrast between wild and captive cohorts of Telostylinus angusticollis (Diptera: Neriidae).
Most research on life span and aging has been based on captive populations of short-lived animals; however, we know very little about the expression of these traits in wild populations of such organisms. Because life span and aging are major components of fitness, the extent to which the results of many evolutionary studies in the laboratory can be generalized to natural settings depends on the degree to which the expression of life span and aging differ in natural environments versus laboratory environments and whether such environmental effects interact with phenotypic variation. We investigated life span and aging in Telostylinus angusticollis in the wild while simultaneously estimating these parameters under a range of conditions in a laboratory stock that was recently established from the same wild population. We found that males live less than one-fifth as long and age at least twice as rapidly in the wild as do their captive counterparts. In contrast, we found no evidence of aging in wild females. These striking sex-specific differences between captive and wild flies support the emerging view that environment exerts a profound influence on the expression of life span and aging. These findings have important implications for evolutionary gerontology and, more generally, for the interpretation of fitness estimates in captive populations.


Muscle fiber type-specific defects in insulin signal transduction to glucose transport in diabetic GK rats.
To determine whether defects in the insulin signal transduction pathway to glucose transport occur in a muscle fiber type-specific manner, post-receptor insulin-signaling events were assessed in oxidative (soleus) and glycolytic (extensor digitorum longus [EDL]) skeletal muscle from Wistar or diabetic GK rats. In soleus muscle from GK rats, maximal insulin-stimulated (120 nmol/l) glucose transport was significantly decreased, compared with that of Wistar rats. In EDL muscle from GK rats, maximal insulin-stimulated glucose transport was normal, while the submaximal response was reduced compared with that of Wistar rats. We next treated diabetic GK rats with phlorizin for 4 weeks to determine whether restoration of glycemia would lead to improved insulin signal transduction. Phlorizin treatment of GK rats resulted in full restoration of insulin-stimulated glucose transport in soleus and EDL muscle. In soleus muscle from GK rats, submaximal and maximal insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation and IRS-1-associated phosphatidylinositol (PI) 3-kinase activity were markedly reduced, compared with that of Wistar rats, but only submaximal insulin-stimulated PI 3-kinase was restored after phlorizin treatment. In EDL muscle, insulin-stimulated IRS-1 tyrosine phosphorylation and IRS-1-associated PI-3 kinase were not altered between GK and Wistar rats. Maximal insulin-stimulated Akt (protein kinase B) kinase activity is decreased in soleus muscle from GK rats and restored upon normalization of glycemia (Krook et al., Diabetes 46:2100-2114, 1997). Here, we show that in EDL muscle from GK rats, maximal insulin-stimulated Akt kinase activity is also impaired and restored to Wistar rat levels after phlorizin treatment. In conclusion, functional defects in IRS-1 and PI 3-kinase in skeletal muscle from diabetic GK rats are fiber-type-specific, with alterations observed in oxidative, but not glycolytic, muscle. Furthermore, regardless of muscle fiber type, downstream steps to PI 3-kinase (i.e., Akt and glucose transport) are sensitive to changes in the level of glycemia.


Global Foot-and-Mouth Disease Research Update and Gap Analysis: 2 - Epidemiology, Wildlife and Economics.
We assessed knowledge gaps in foot-and-mouth disease (FMD) research, and in this study, we consider (i) epidemiology, (ii) wildlife and (iii) economics. The study took the form of a literature review (2011-2015) combined with research updates collected in 2014 from 33 institutes from across the world. Findings were used to identify priority areas for future FMD research. During 2011-2015, modelling studies were dominant in the broad field of epidemiology; however, continued efforts are required to develop robust models for use during outbreaks in FMD-free countries, linking epidemiologic and economics models. More guidance is needed for both the evaluation and the setting of targets for vaccine coverage, population immunity and vaccine field efficacy. Similarly, methods for seroprevalence studies need to be improved to obtain more meaningful outputs that allow comparison across studies. To inform control programmes in endemic countries, field trials assessing the effectiveness of vaccination in extensive smallholder systems should be performed to determine whether FMD can be controlled with quality vaccines in settings where implementing effective biosecurity is challenging. Studies need to go beyond measuring only vaccine effects and should extend our knowledge of the impact of FMD and increase our understanding of how to maximize farmer participation in disease control. Where wildlife reservoirs of virus exist, particularly African Buffalo, we need to better understand when and under what circumstances transmission to domestic animals occurs in order to manage this risk appropriately, considering the impact of control measures on livelihoods and wildlife. For settings where FMD eradication is unfeasible, further ground testing of commodity-based trade is recommended. A thorough review of global FMD control programmes, covering successes and failures, would be extremely valuable and could be used to guide other control programmes.


Atlantic meridional overturning circulation during the Last Glacial Maximum.
The circulation of the deep Atlantic Ocean during the height of the last ice age appears to have been quite different from today. We review observations implying that Atlantic meridional overturning circulation during the Last Glacial Maximum was neither extremely sluggish nor an enhanced version of present-day circulation. The distribution of the decay products of uranium in sediments is consistent with a residence time for deep waters in the Atlantic only slightly greater than today. However, evidence from multiple water-mass tracers supports a different distribution of deep-water properties, including density, which is dynamically linked to circulation.


Invasive enteric infections in hospitalized patients with underlying strongyloidiasis.
Disseminated strongyloidiasis is often associated with enteric bacterial infections. This study was undertaken to determine if enteric organisms caused extraintestinal infections in patients infected with Strongyloides stercoralis but without apparent dissemination. The medical records of hospitalized patients from central Kentucky with strongyloidiasis (1993-2003) were examined to determine the occurrence of extraintestinal infections with enteric organisms. Of 30 patients with S stercoralis, 16 had invasive infections, including sepsis, meningitis, pneumonia, peritonitis, and endocarditis caused by enteric bacteria and Candida organisms. Infections were seen in 8 (62%) of 13 patients with disseminated strongyloidiasis and 8 (47%) of 17 with disease apparently limited to the gastrointestinal tract. Fifteen patients were receiving corticosteroids or other immunosuppressive therapy. Peripheral eosinophilia was seen in only 23% (7/30). Infection with S stercoralis, even without obvious dissemination, may predispose to invasive infections caused by enteric organisms. In Strongyloides-endemic areas, patients with invasive infections caused by enteric organisms should be examined for coinfection with S stercoralis.


Evaluation of immune responses of cattle as a means to identify high or low responders and use of a human microarray to differentiate gene expression.
An immune response (IR) index to identify cows with high (H) and low (L) antibody-mediated immune responses (AMIR) had been previously devised. High AMIR associated with decreased mastitis and improved response to vaccination. Measurement of cell-mediated immune response (CMIR) was not included in the index; therefore various antigen/adjuvant combinations were evaluated as inducers of DTH to be added to the IR-index. The Bacillus Calmette Guérin (BCG)-induced/purified protein derivative (PPD)-elicited tuberculin skin test is a reliable measure of DTH; however, its use to identify livestock with high CMIR may be confounded due to previous exposure to Mycobacteria tuberculosis. DTH to BCG/PPD was therefore compared with that induced by Mycobacteria phlei (saprophyte) and its derivative phlein as the test antigen. Antibody to OVA was also evaluated. The results indicated that BCG/PPD and M. phlei/phlein induced similar DTH, but cross reaction to PPD was evident following induction of DTH using M. phlei making it a less than ideal alternative for testing livestock. Nonetheless, cows could be ranked for both AMIR and CMIR. RNA from two cows with the highest and lowest IR ranks was then used to probe a human 1.7 kD microarray to determine the ability of a human array to provide information on bovine genes associated with H and L.


Hierarchical honeycomb auxetic metamaterials.
Most conventional materials expand in transverse directions when they are compressed uniaxially resulting in the familiar positive Poisson's ratio. Here we develop a new class of two dimensional (2D) metamaterials with negative Poisson's ratio that contract in transverse directions under uniaxial compressive loads leading to auxeticity. This is achieved through mechanical instabilities (i.e., buckling) introduced by structural hierarchy and retained over a wide range of applied compression. This unusual behavior is demonstrated experimentally and analyzed computationally. The work provides new insights into the role of structural organization and hierarchy in designing 2D auxetic metamaterials, and new opportunities for developing energy absorbing materials, tunable membrane filters, and acoustic dampeners.


Lifestyle factors of a five-year community-intervention program: the Hartslag Limburg intervention.
Community-based health promotion is a widely advocated strategy in public health to favorably alter lifestyle. The aim of this study was to investigate the net effect of a cardiovascular disease-prevention program (Hartslag Limburg) on lifestyle factors after 5 years of intervention (1998-2003). In a cohort study, 5-year mean changes in lifestyle factors (energy intake; fat intake; time spent on leisure-time physical activity; walking, bicycling, and sports; and smoking behavior) between subjects from the intervention area (n=2356) and the control area (n=758) were compared for men and women and for those with a low (less than intermediate secondary education) and a moderate (intermediate vocational or higher secondary education) or high (higher vocational education or university) educational level. Adjustments were made for age and the mean of the individual pre- and post-intervention measurement of the variable under study. When stratifying for gender, adjustments were made for educational level, and vice versa. In general, lifestyle factors changed unfavorably in the control group, whereas changes were less pronounced or absent in the intervention group. The adjusted difference in mean change in lifestyle factors between the intervention group and the control group was significant (p<or=0.05) for energy intake (-0.2 megajoule per day among both women and those with a low educational level); fat intake (-2.5 grams per day [g/d] among women and -3 g/d among those with a low educational level); time spent walking (+2.2 hours per week [hrs/wk] among women and +2.3 hrs/wk among those with a low educational level); time spent on total leisure-time physical activity (+2.1 hrs/wk among women); and time spent bicycling (+0.6 hrs/wk among those with a low educational level). The community intervention Hartslag Limburg succeeded in preventing age- and time-related unfavorable changes in energy intake, fat consumption, walking, and bicycling, particularly among women and those with low SES.


Bracing has no effect on standing balance in females with adolescent idiopathic scoliosis.
Since trunk morphology and curve types were reported to affect standing in adolescent idiopathic scoliosis (AIS), it is reasonable to assume that bracing could perturb standing balance in this population. The objective here was to use time- and frequency-domain analyses to test if the Boston brace affects balance in AIS. Fifteen AIS girls were fitted with a Boston brace. At the four-month follow-up, standing balance was assessed using center of pressure (COP) displacements measured from a force plate. The subjects were tested with and without the brace. The mean position of the COP and the sway area were similar with and without the brace. Though the first peak in the power spectra was not statistically significant, the second peak was statistically smaller with the brace in the antero-posterior direction (p=0.012) and larger along the medio-lateral axis (p=0.022). In the antero-posterior direction there was a statistically significant shift towards higher mean (p=0.012) and median (p=0.003) frequencies with the brace, whereas no difference was noted in the medio-lateral direction. Time-domain parameters did not prove useful in differentiating between the in- and out-of-brace conditions in AIS individuals. The second peak in the power spectra could be associated with an inverse double-pendulum motion. The time-dependent parameters used in this study did not prove useful in differentiating between in-brace and out-of-brace conditions. Spectral analysis highlighted increased stiffness in the antero-posterior direction and less control in the medio-lateral axis in standing balance between in-brace and out-of-brace conditions in AIS.


Five-minute heart rate variability can predict obstructive angiographic coronary disease.
Obstructive coronary artery disease (CAD) is evident in only half of patients referred for diagnostic angiography. Five-minute heart rate variability (HRV) is a non-invasive marker for autonomic control of the vasculature, which this study hypothesised could risk-stratify cardiac patients and reduce unnecessary angiograms. A prospective observational study (the Alternative Risk Markers in Coronary Artery Disease (ARM-CAD) study). Three cardiac centres in Melbourne, Australia. 470 consecutive patients undergoing elective angiography (with predominantly normal cardiac rhythm), regardless of co-morbidity. The presence of obstructive CAD (≥50% stenosis) on angiography. Patients with obstructive CAD had significantly reduced HRV, particularly in the low frequency (LF) range (median 180 vs 267 ms(2) without CAD; p<0.001). There was a linear trend with the severity of CAD; median LF power (IQR) in patients with normal coronaries was 275 (612), with minor coronary irregularities 255 (400), single-vessel CAD 212 (396) and more severe disease 170 (327) ms(2); p value for trend 0.003. There was a similar reduction in LF power regardless of the anatomical location of coronary stenoses. Comparing patients with LF less than 250 and 250 ms(2) or greater, the adjusted OR for obstructive CAD using multivariate regression was 2.42, 95% CI 1.33 to 4.38 (p=0.004). No interactions were noted in subgroup analysis and HRV added to risk prediction irrespective of the baseline Framingham risk (p<0.0001). Low HRV is strongly predictive of angiographic coronary disease regardless of other co-morbidities and is clinically useful as a risk predictor in patients with sinus rhythm. http://clinicaltrials.gov/ct2/show/NCT00403351 www.armcad.com.


Occupational exposure and effects on the male reproductive system.
A significant increase in the incidence of male infertility has been described in the international literature, raising questions about its causes. Part of this effect may result from synthetic toxic substances acting on the endocrine system (endocrine disruptors), many of which are routinely used in work processes. We provide a critical review of the specialized literature on work-related chemical substances capable of causing male infertility. Pesticides such as DDT, linuron, and others, heavy metals like mercury, lead, cadmium, and copper, and substances from various industrial uses and residues such as dioxins, polychlorinated biphenyls (PCBs), ethylene dibromide (EDB), phthalates, polyvinyl chloride (PVC), and ethanol are among the main endocrine disruptors that can cause male infertility. Based on the literature, gonadal dysfunction and congenital malformation are the main alterations caused by these substances in the male reproductive system. We conclude that despite the relative lack of studies on this issue, the relevance of such risk calls for further studies as well as measures to prevent workers' exposure to the various substances.


Horizontal Bone Augmentation in the Posterior Atrophic Mandible and Dental Implant Stability Using the Tenting Screw Technique.
The aim of this study was to analyze horizontal bone augmentation using the tenting screw technique in the posterior mandible. Included subjects had a 3-mm bone width and 9-mm bone height, measured by CBCT. After the surgical approach, two to four screws were inserted, leaving 4 mm of extraosseous space; reconstruction was achieved using allogeneic biomaterial and leukocyte- and platelet-rich fibrin together with an absorbable membrane. After 4 months, a new CBCT scan was obtained to compare the bone gain and implant placement. Early and secondary stability were measured by the implant stability quotient (ISQ); prosthetic load was performed 16 weeks later. Student t test was used to compare bone gains and implant stability, with significance set at P < .05. Fourteen subjects and 27 surgical sites initially exhibited a mean bone width of 2.95 ± 0.75 mm. Four months after augmentation, the bone width was 7.15 ± 1.87 mm, confirming a significant bone gain (4.2 ± 1.26 mm). Twenty-seven implants were placed with a minimum insertion torque of 35 Ncm; the primary stability was 69.3 ± 7.16 ISQ, and the secondary stability was 75.9 ± 3.29 ISQ (P > .05). It may be concluded that the tenting screw technique is predictable in terms of bone gain and that it facilitates implant stability.


[Efficacy of atypical antipsychotics in depressive syndromes].
Depression is a frequent symptom in psychiatry, either isolated (major depression) or entangled with other psychiatric symptoms (psychotic depression, depression of bipolar disorders). Many antidepressant drugs are available with different pharmacological profiles from different classes: tricyclic antidepressants, monoamine oxydase inhibitors, selective serotonin reuptake inhibitors (SSRI). However, there are some limitations with these drugs because there is a long delay before relief for symptoms, some patients with major depression are resistant to treatment, there is a risk to induce manic symptoms in patients with bipolar disorders and these drugs have no effect on the psychotic symptoms frequently associated to major depression. The leading hypothesis for the search of more efficient new antidepressants has been the amine deficit hypothesis: noradrenaline and/or serotonin deficit and more recently dopamine deficit. Moreover, a dopamine deficit has been also hypothesized as the central mechanism explaining the negative symptoms of schizophrenia. These symptoms are the consequence of a deficit of normal behaviours and include affective flattening, alogia, apathy, avolition and social withdrawal. There is thus a great overlap between symptoms of depression and negative symptoms of schizophrenia. Atypical antipsychotics, in contrast with conventional neuroleptics, have been shown to decrease negative symptoms, most probably through the release of dopamine in prefrontal cortex, thus improving psychomotor activity, motivation, pleasure, appetite, etc. The dopamine deficit in cortical prefrontal areas was thus an unifying hypothesis to explain both some symptoms of depression and negative symptoms of schizophrenia. Studies in animal confirm this view and show that the association of an atypical antipsychotic drug and an SSRI (olanzapine plus fluoxetine) increases synergistically the release of dopamine in prefrontal areas. Moreover, most of the atypical antipsychotics have a large action spectrum, beyond the only dopamine receptors: their effects on the serotonin receptors--particularly the 5-HT2A and 5-HT2C receptors--suggest that their association to SSRI could be a promising treatment for depression. Indeed, SSRI act mainly by increasing the serotonin level in the synapse, thus leading to a non specific activation of all pre- and post-synaptic serotonin receptors. Among them, 5-HT2A/2C receptors have been involved in some of the unwanted effects of SSRI: agitation, anxiety, insomnia, sexual disorders, etc. The inhibition of these receptors could be thus beneficial for patients treated with SSRI. Amisulpride is an unique atypical antipsychotic that selectively blocks dopamine receptors presynaptically in the frontal cortex, possibly enhancing dopaminergic transmission. The antidepressant effect of amisulpride was shown in dysthymia in many clinical studies versus placebo, tricyclic antidepressants, SSRI or others. However, a shorter delay for symptom relief was not demonstrated for amisulpride as compared to comparative antidepressants. Other atypical antipsychotics (clozapine, olanzapine), which act on a large variety of receptors, have shown antidepressant effects--mainly in association with SSRI--in different psychiatric diseases: treatment-resistant major depression, major depression with psychotic symptoms and depression of bipolar disorders, with no increase of manic symptoms in this latter case. Moreover, the delay for symptom relief was greatly shortened. More comparative double-blind studies are required to confirm and to precise the antidepressant effects of atypical antipsychotics. Nevertheless, these studies suggest that atypical anti-psychotics could be of great value in depressive conditions reputed for their resistance to treatment with usual antidepressants. Particularly, new strategies emerge that combine atypical antipsychotics and antidepressants for greater efficacy and more rapid relief of depression symptoms.


Stimulation of frequency of MEPPs at the frog neuromuscular junction by extracellular EGTA.
Exposure of the frog neuromuscular junction at 17 degrees C or 23 degrees C to salines with low [Ca2+], buffered with EGTA, cause mepp frequency to fall after 4--6 min to about 20% of the control rate. Results obtained in the presence of verapamil suggest that this fall is a consequence of a lower Ca2+-influx coupled with the action of the extracellular EGTA in promoting Ca2+-efflux from the terminals. These findings confirm the suggestion that [Ca2+]i has a major role in determining mepp frequency. At 13 degrees C, the fall in mepp frequency after addition of EGTA is preceded by a transient (1--2 min) rise in mepp rate which is not present at 17 degrees C or in the presence of verapamil. This transient acceleration in spontaneous release is believed to be because EGTA promotes the emptying of a Ca2+-reservoir on or beneath the inner face of the membrane, thus causing a rapid Ca2+-efflux via the Ca2+-sensitive sites that trigger exocytosis of transmitter. The significance of the sensitivity of the response to temperature is discussed. The suppressive effect of higher temperatures can be reversed to some extent by hyperosmotic salines, an effect that may reflect the action of hypertonicity on the plasmalemma. It is concluded that the characteristics of the release system may change markedly at about 16 degrees C. Ca2+-EGTA buffers are widely used; it is suggested that extracellular EGTA can also modify [Ca2+]i in cellular systems.


The effect of telmisartan on glucose and lipid metabolism in nondiabetic, insulin-resistant subjects.
Intervention studies have shown that angiotensin receptor blocker therapy may reduce the incidence of type 2 diabetes mellitus. It is unknown whether short-term angiotensin receptor blocker therapy can improve glucose and lipid metabolism in insulin-resistant subjects. We evaluated the effect of telmisartan (40 mg/d, 12 weeks) in 20 subjects with insulin resistance (body mass index, 31.8 +/- 3.31 kg/m(2); triglycerides, 179 +/- 98 mg/dL; glucose, 104 +/- 9 mg/dL; homeostasis model assessment index, 3.78 +/- 1.52) in a randomized, placebo-controlled, double-blind, cross-over study. At the end of each treatment phase, oral and intravenous glucose tolerance tests including C-peptide and insulin measurements were performed, and fasting and postprandial lipids were determined. Compared to placebo, telmisartan resulted in a reduction in homeostasis model assessment index (-11%, P = .06) and glucose area under the curve during intravenous glucose tolerance (-11%, P = .04). We observed an increase (+32%, P = .05) in the insulinogenic index indicating an improved beta-cell function. Fasting and postprandial lipid parameters did not change. We observed an increase in adiponectin (6%, P = .09), whereas IL-6, high-sensitivity C-reactive protein, fibrinogen, and free fatty acid concentrations did not change. This indicates that the improvement in glucose metabolism is rather mediated by direct effects, such as activation of PPARgamma. Our data indicate that in insulin-resistant persons 12 weeks of telmisartan result in a significant improvement in glucose metabolism with a predominant improvement in beta-cell function.


Potential of Piper betle extracts on inhibition of oral pathogens.
In the present study, antimicrobial activity of Piper betle crude ethanol extract against 4 strains of oral pathogens; Candida albicans DMST 8684, C. albicans DMST 5815, Streptococcus gordonii DMST 38731 and Streptococcus mutans DMST 18777 was compared with other medicinal plants. P. betle showed the strongest antimicrobial activity against all tested strains. Fractionated extracts of P. betle using hexane, ethyl acetate, and ethanol, respectively, were subjected to antimicrobial assay. The result revealed that the fractionated extract from ethyl acetate (F-EtOAc) possessed the strongest antimicrobial activity against all tested strains. Its inhibition zones against those pathogens were 23.00 ± 0.00, 24.33 ± 0.58, 12.50 ± 0.70 and 11.00 ± 0.00 mm, respectively and its minimum inhibitory concentrations were 0.50, 1.00, 0.50 and 1.00 mg/mL, respectively. Interestingly, the minimum concentration to completely kill those pathogens was the same for all strains and found to be 2.00 mg/mL. Killing kinetic study revealed that the activity of F-EtOAc was dose dependent. HPLC chromatograms of P. betle extracts were compared with its antimicrobial activity. An obvious peak at a retention time of 4.11 min was found to be a major component of F-EtOAc whereas it was a minor compound in the other extracts. This peak was considered to be an active compound of P. betle as it was consistent with the antimicrobial activity of F-EtOAc, the most potential extract against the tested pathogens. It is suggested that F-EtOAc is a promising extract of P. betle for inhibition of oral pathogens. Separation and structure elucidation of the active compound of this extract will be further investigated.


Oxygen-Enhanced MRI Accurately Identifies, Quantifies, and Maps Tumor Hypoxia in Preclinical Cancer Models.
There is a clinical need for noninvasive biomarkers of tumor hypoxia for prognostic and predictive studies, radiotherapy planning, and therapy monitoring. Oxygen-enhanced MRI (OE-MRI) is an emerging imaging technique for quantifying the spatial distribution and extent of tumor oxygen delivery in vivo. In OE-MRI, the longitudinal relaxation rate of protons (ΔR1) changes in proportion to the concentration of molecular oxygen dissolved in plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive ΔR1. We hypothesized that the fraction of tumor tissue refractory to oxygen challenge (lack of positive ΔR1, termed "Oxy-R fraction") would be a robust biomarker of hypoxia in models with varying vascular and hypoxic features. Here, we demonstrate that OE-MRI signals are accurate, precise, and sensitive to changes in tumor pO2 in highly vascular 786-0 renal cancer xenografts. Furthermore, we show that Oxy-R fraction can quantify the hypoxic fraction in multiple models with differing hypoxic and vascular phenotypes, when used in combination with measurements of tumor perfusion. Finally, Oxy-R fraction can detect dynamic changes in hypoxia induced by the vasomodulator agent hydralazine. In contrast, more conventional biomarkers of hypoxia (derived from blood oxygenation-level dependent MRI and dynamic contrast-enhanced MRI) did not relate to tumor hypoxia consistently. Our results show that the Oxy-R fraction accurately quantifies tumor hypoxia noninvasively and is immediately translatable to the clinic.


Restoration of immediately loaded implants in a minimal number of appointments: a retrospective study of clinical effectiveness.
The purpose of this study was to assess the clinical effectiveness of an experimental technique versus the conventional method for the fabrication of implant-supported fixed complete dentures. Between January 2005 and June 2010, edentulous patients who had received rehabilitation by means of nonsegmented fixed implant-supported complete dentures were identified from the pool of individuals treated at Eastman Institute for Oral Health, University of Rochester. Data collection consisted of a chart review and recording of treatment variables in a customized database. Variables of interest included number of implants per patient, time of implant placement, number of appointments required to complete prosthesis fabrication, type of appointments, manufacturing process used for creation of the framework, and fit of the framework. The number of appointments for conventional and experimental protocols was evaluated for statistical significance using two-way analysis of variance. Presence or absence of clinically acceptable prosthesis fit with the two techniques was evaluated using the Fisher exact test and exact logistic regression analysis. Forty-two patients (48 arches) were included. When the experimental technique was used, prosthesis fabrication and delivery required an average of 4 appointments, whereas the conventional technique required an average of 7.8 appointments to deliver the definitive prosthesis. The prostheses fabricated with the experimental technique showed clinically passive fit on the implants in 17 of 18 arches. The frameworks fabricated with the conventional technique achieved clinically passive fit in 18 of 30 arches. The experimental technique significantly reduced the number of appointments required to fabricate a nonsegmented fixed implant-supported prosthesis. Moreover, this experimental technique provided clinically acceptable fit of the prosthesis in a significantly greater number of cases compared to a conventional implant elastomeric impression technique.


The Groucho ortholog UNC-37 interacts with the short Groucho-like protein LSY-22 to control developmental decisions in C. elegans.
Transcriptional co-repressors of the Groucho/TLE family are important regulators of development in many species. A subset of Groucho/TLE family members that lack the C-terminal WD40 domains have been proposed to act as dominant-negative regulators of Groucho/TLE proteins, yet such a role has not been conclusively proven. Through a mutant screen for genes controlling a left/right asymmetric cell fate decision in the nervous system of the nematode C. elegans, we have retrieved loss-of-function alleles in two distinct loci that display identical phenotypes in neuronal fate specification and in other developmental contexts. Using the novel technology of whole-genome sequencing, we find that these loci encode the C. elegans ortholog of Groucho, UNC-37, and, surprisingly, a short Groucho-like protein, LSY-22, that is similar to truncated Groucho proteins in other species. Besides their phenotypic similarities, unc-37 and lsy-22 show genetic interactions and UNC-37 and LSY-22 proteins also physically bind to each other in vivo. Our findings suggest that rather than acting as negative regulators of Groucho, small Groucho-like proteins may promote Groucho function. We propose that Groucho-mediated gene regulatory events involve heteromeric complexes of distinct Groucho-like proteins.


Evaluation of Trigonella foenum-graecum extract in combination with swimming exercise compared to glibenclamide consumption on type 2 Diabetic rodents.
The purpose of the present study was to evaluate the effect of fenugreek seed extract in combination with swimming exercise compared to glibenclamide consumption on type 2 diabetic rats. The acute toxicity test was carried out to choose the safe doses and identify the toxicity effects of the fenugreek seed extract. To investigate the hypoglycemic effect of the extract and its effect in combination with swimming training, 80 Wistar Kyoto male streptozotocin-induced diabetic rats were divided randomly into eight groups: diabetic control (C); fenugreek seed extract 0.8 g/kg (F1); fenugreek extract 1.6 g/kg (F2); swimming training (S); swimming training plus fenugreek extract 0.8 g/kg (SF1); swimming training plus fenugreek extract 1.6 g/kg (SF2); glibenclamide (G) and swimming training plus glibenclamide (SG). The rats were orally administrated with the treatments once a day with the respective treatment, and the training groups were subjected to swimming training every day for 60 min. Fasting blood samples were collected to measure fasting blood glucose, lipid profile, adiponectin, leptin, and insulin concentrations. The results obtained from acute toxicity study showed no toxicity effect of fenugreek seed extract on the tested dose. Biochemical analysis showed significant improvements in all of the groups compared to the control group (p<0.05). Plasma insulin concentration and insulin resistance (HOMA-IR) was significantly reduced in treated groups compared with the diabetic control group. Plasma leptin were significantly decreased in treated groups compared with the control group; while adiponectin had markedly increased (p<0.05). The findings suggest that fenugreek seed consuming, alongside swimming exercise, has a strong therapeutic effect on the improvement of diabetic parameters.


Mitochondrial function in human skeletal muscle is not impaired by high intensity exercise.
The hypothesis that high-intensity (HI) intermittent exercise impairs mitochondrial function was investigated with different microtechniques in human muscle samples. Ten male students performed three bouts of cycling at 130% of peak O2 consumption (V.O2,peak). Muscle biopsies were taken from the vastus lateralis muscle at rest, at fatigue and after 110 min recovery. Mitochondrial function was measured both in isolated mitochondria and in muscle fibre bundles made permeable with saponin (skinned fibres). In isolated mitochondria there was no change in maximal respiration, rate of adenosine 5'-triphosphate (ATP) production (measured with bioluminescence) and respiratory control index after exercise or after recovery. The ATP production per consumed oxygen (P/O ratio) also remained unchanged at fatigue but decreased by 4% (P<0.05) after recovery. In skinned fibres, maximal adenosine 5'-diphosphate (ADP)-stimulated respiration increased by 23% from rest to exhaustion (P<0.05) and remained elevated after recovery, whereas the respiratory rates in the absence of ADP and at 0.1 mM ADP (submaximal respiration) were unchanged. The ratio between respiration at 0.1 and 1 mM ADP (ADP sensitivity index) decreased at fatigue (P<0.05) but after the recovery period was not significantly different from that at rest. It is concluded that mitochondrial oxidative potential is maintained or improved during exhaustive HI exercise. The finding that the sensitivity of mitochondrial respiration to ADP is reversibly decreased after strenuous exercise may indicate that the control of mitochondrial respiration is altered.


Catheter ablation of arrhythmias.
The ability to localize the sites of origin of arrhythmias or those sites critical to their maintenance or their life-threatening consequences has provided the potential for ablating these arrhythmias by delivering shocks through catheters at these critical sites. The capability of treating various arrhythmias by the delivery of shocks through catheters placed at specific intracardiac sites is being studied. These techniques are being evaluated for the creation of atrioventricular blocks to control the ventricular response during supraventricular arrhythmias and for the ablation of bypass tracts and foci of ventricular tachycardia. Complications, including cardiac rupture, and variable success rates make it imperative that such studies only be done by well-trained electrophysiologists. As current techniques evolve, catheter ablation may prove to be a reasonable alternative to pharmacologic or surgical management of patients with disabling arrhythmias.


Carbamazepine compared with lithium in the treatment of mania.
Fifty-two hospitalized manic patients were randomized to treatment with either carbamazepine or lithium carbonate after a 2-week drug withdrawal period. All of the probands were tertiary referrals with a high proportion of failures of previous lithium and other treatment. Weekly ratings of manic, depressive, and psychotic symptoms were obtained for 8 weeks, and responders were followed up for up to 2 years. One third of patients responded favorably. Double-blind assessments revealed no statistically reliable differences between the two treatment groups. Patients receiving carbamazepine were somewhat more manageable than patients treated with lithium early in the study, whereas lithium-treated patients remained longer in the follow-up phase. However, numbers of long-term survivors were too small to be conclusive. This study adds to the growing body of evidence that acutely manic patients respond as well to carbamazepine as to lithium. However, monotherapy with either drug is not sufficient for the majority of manic patients who are referred for tertiary care.


Longitudinal evaluation of allergen and culturable fungal concentrations in inner-city households.
To characterize seasonal variation of three allergens (dust mite, cat, and cockroach) and total culturable fungi and to explore whether residential characteristics were associated with the concentrations of these agents, floor dust was collected from 47 inner-city homes in Minneapolis, Minnesota, over a 1-year period. A longitudinal analysis of allergen and fungal concentrations was carried out using mixed-effect models. Overall, relative humidity was a better predictor of allergen concentrations over time than indoor temperature. Seasonal variation of cat and cockroach allergens was negligible compared with the variability associated with residential characteristics such as race/ethnicity, family income, and the presence of cats. Fungal concentrations showed significant seasonal variation that outweighed the variability associated with residential characteristics. Less than 30% of the dust mite allergen and cockroach allergens concentrations were above limits of detection. Observed cockroach allergen concentrations were higher in Spanish- and Somali-speaking households than in English-speaking households, while English-speaking households had significantly higher cat allergen concentrations compared with the other language groups. The ratios of within-home to between-home variance for total culturable fungi, dust mite, cockroach, and cat allergen concentrations were 2.54, 1.91, 0.55, and 0.24, respectively. This ratio is used to predict the number of repeated measurements of each allergen required to robustly estimate long-term exposure estimates such that exposure misclassification bias is kept within acceptable limits. It is not clear whether repeated measurements of dust mite and cockroach allergens are required for long-term average exposure because of the large fraction of nondetects. It is concluded that a single measurement of cat allergen is a reasonable surrogate for long-term average exposure, since repeated measurements over time were highly correlated. Total culturable fungi will require greater than nine repeated measurements for robust assessment of long-term exposures because of low correlations in fungal measures over time.


Treatment of HIV/AIDS at South Africa's largest employers: myth and reality.
To determine what proportion of employees at the largest private-sector companies in South Africa have access to HIV/AIDS care and treatment, including antiretroviral therapy (ART); how many employees are enrolled in disease management programmes; how many are receiving ART; and which approach to the financing and delivery of care is proving most successful at reaching eligible employees. All 64 private-sector and parastatal companies with more than 6000 employees in South Africa were identified and contacted. Those that agreed to participate were interviewed by telephone using a structured questionnaire. Fifty-two companies agreed to participate. Among these companies, 63% of employees had access to employer-sponsored care and treatment for HIV/AIDS. However, access varied widely by sector. Approximately 27% of suspected HIV-positive employees were enrolled in disease management programmes, or 4.4% of the workforce overall. Fewer than 4000 employees in the entire sample were receiving ART. In-house (employer) disease management programmes and independent disease management programmes achieved higher uptake of services than did medical aid schemes. Publicity by large employers about their treatment programmes should be interpreted cautiously. While there is a high level of access to treatment, uptake of services is low and only a small fraction of employees medically eligible for ART are receiving it.


Exposure to a common urban pollutant affects the survival and swimming behaviour of creek chub (Semotilus atromaculatus).
Anthropogenic effects on the aquatic environment are ever present and ever increasing and while a plethora of aquatic contaminants are known to affect fishes, one ubiquitous and increasingly prevalent world-wide urban runoff pollutant is frequently disregarded, and that is pet waste. While dog waste has been identified as a significant factor contributing to bacteria and nutrient loading within receiving waters and the associated water quality changes are known to affect fishes, the impact of uncollected dog faeces on urban fish populations has never been directly investigated. In this study we exposed creek chub (Semotilus atromaculatus), a widespread tolerant stream minnow, to various realistic concentrations of dog waste as simulated urban park runoff testing both fresh and dried dog faeces in both stagnant and aerated water for 96 h to investigate the impact on fish survival and behaviour. Creek chub percentage mortality increased significantly relative to controls and across an exposure gradient and was likely caused by anoxic conditions. Survivors were initially smaller while those that died were initially larger and presented with abnormal abdominal subdermal lesions post-exposure. Additional indicators of physiological stress included significantly increased rates of aquatic surface respiration and changes in flume test derived swimming motivation metrics with increased exposure concentrations. Both mortality and behavioural responses were alleviated by aeration. Furthermore, trials with fresh and dried faeces differed only in time-to-death and swimming metrics where results from dried trials were similar to those from aerated experiments. Results demonstrated the impact that the global dog waste management problem can have on aquatic communities with effects on creek chub likely to be more severe for less pollution-tolerant species and also likely to be exacerbated under future scenarios that consider climate change and increased urbanization.


Allergy: a risk factor for suicide?
The rates of depression, anxiety, and sleep disturbance (suicide risk factors) are greater in patients with allergic rhinitis than in the general population. The rate of allergy is also greater in patients with depression. Preliminary data suggest that patients with a history of allergy may have an increased rate of suicide. Clinicians should actively inquire to diagnose allergy in patients with depression and depression in patients with allergy. Spring peaks of suicide are highly replicated, but their origin is poorly understood. Preliminary epidemiologic data suggest that seasonal spring peaks in aeroallergens are associated with seasonal spring peaks in suicide. Our research in Brown Norway rats demonstrates that sensitization and exposure to aeroallergens induces anxiety-like and aggressive behaviors as well as allergy-related helper T-cell type 2 (Th2) cytokine gene expression in the prefrontal cortex. Thus, it is possible that sensitization and exposure to aeroallergens, which peak in spring, may be conducive to seasonal exacerbation of suicide risk factors such as anxiety, depression, hostility/aggression, and sleep disturbance. Connecting allergy with suicide and suicide risk factors adds to previous neurologic literature connecting allergy with migraines and seizure disorders. Our recent report of Th2 (allergy-mediating) cytokine expression in the orbitofrontal cortex of suicide victims should lead to future studies to test the hypothesis that mediators of allergic inflammation in the nasal cavities may result in Th2 cytokine expression in the brain, influencing affect and behavioral modulation. Certain medications used to treat allergy can exacerbate suicide risk factors, potentially worsening suicide risk and even triggering suicide. Systemic (but not topical) corticosteroids have been associated with manic and depressive episodes and mixed mood states. Recently, the US Food and Drug Administration started investigating the possibility that montelukast may trigger suicide. Although this association requires further exploration and confirmation, clinicians should err on the side of caution, inquiring about past suicide attempts; hopelessness; reasons for living; and suicidal ideation, intent, or plan; and referring the patient to a mental health professional for evaluation if appropriate.


Revisiting the recent European droughts from a long-term perspective.
Early 21st-century droughts in Europe have been broadly regarded as exceptionally severe, substantially affecting a wide range of socio-economic sectors. These extreme events were linked mainly to increases in temperature and record-breaking heatwaves that have been influencing Europe since 2000, in combination with a lack of precipitation during the summer months. Drought propagated through all respective compartments of the hydrological cycle, involving low runoff and prolonged soil moisture deficits. What if these recent droughts are not as extreme as previously thought? Using reconstructed droughts over the last 250 years, we show that although the 2003 and 2015 droughts may be regarded as the most extreme droughts driven by precipitation deficits during the vegetation period, their spatial extent and severity at a long-term European scale are less uncommon. This conclusion is evident in our concurrent investigation of three major drought types - meteorological (precipitation), agricultural (soil moisture) and hydrological (grid-scale runoff) droughts. Additionally, unprecedented drying trends for soil moisture and corresponding increases in the frequency of agricultural droughts are also observed, reflecting the recurring periods of high temperatures. Since intense and extended meteorological droughts may reemerge in the future, our study highlights concerns regarding the impacts of such extreme events when combined with persistent decrease in European soil moisture.


Synthesis and anti-HIV activity of guanidinoglycosides.
The new guanidinylation reagent N,N'-diBoc-N''-triflylguanidine was used to efficiently convert multiamine-containing glycosides including kanamycin A and B, tobramycin, paromomycin, and neomycin B to the corresponding fully guanidinylated analogues (guanidinoglycosides). This transformation occurs in the presence of H(2)O under mild conditions. Guanidinotobramycin and guanidinoneomycin B were found to inhibit the replication of the HIV virus with activities approximately 100 times greater than the parent aminoglycosides.


Differential stabilities and sequence-dependent base pair opening dynamics of Watson-Crick base pairs with 5-hydroxymethylcytosine, 5-formylcytosine, or 5-carboxylcytosine.
5-Hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC) form during active demethylation of 5-methylcytosine (5mC) and are implicated in epigenetic regulation of the genome. They are differentially processed by thymine DNA glycosylase (TDG), an enzyme involved in active demethylation of 5mC. Three modified Dickerson-Drew dodecamer (DDD) sequences, amenable to crystallographic and spectroscopic analyses and containing the 5'-CG-3' sequence associated with genomic cytosine methylation, containing 5hmC, 5fC, or 5caC placed site-specifically into the 5'-T(8)X(9)G(10)-3' sequence of the DDD, were compared. The presence of 5caC at the X(9) base increased the stability of the DDD, whereas 5hmC or 5fC did not. Both 5hmC and 5fC increased imino proton exchange rates and calculated rate constants for base pair opening at the neighboring base pair A(5):T(8), whereas 5caC did not. At the oxidized base pair G(4):X(9), 5fC exhibited an increase in the imino proton exchange rate and the calculated kop. In all cases, minimal effects to imino proton exchange rates occurred at the neighboring base pair C(3):G(10). No evidence was observed for imino tautomerization, accompanied by wobble base pairing, for 5hmC, 5fC, or 5caC when positioned at base pair G(4):X(9); each favored Watson-Crick base pairing. However, both 5fC and 5caC exhibited intranucleobase hydrogen bonding between their formyl or carboxyl oxygens, respectively, and the adjacent cytosine N(4) exocyclic amines. The lesion-specific differences observed in the DDD may be implicated in recognition of 5hmC, 5fC, or 5caC in DNA by TDG. However, they do not correlate with differential excision of 5hmC, 5fC, or 5caC by TDG, which may be mediated by differences in transition states of the enzyme-bound complexes.


Expression of Toll-like receptor 3 in the human cerebellar cortex in rabies, herpes simplex encephalitis, and other neurological diseases.
There is recent in vitro evidence that human neurons express the innate immune response receptor, Toll-like receptor-3 (TLR-3), and that expression is enhanced in viral infections. The authors examined the immunohistochemical expression of TLR-3 in the cerebellar cortex of postmortem human brains. Purkinje cells were found to express TLR-3 in all cases of rabies (4 of 4) and herpes simplex encephalitis (2 of 2) as well as in cases of amyotrophic lateral sclerosis (1 of 2), stroke (1 of 2), and Alzheimer's disease (3 of 3). In cases of viral infection, direct viral infection was not necessary for enhanced neuronal TLR-3 expression, suggesting that soluble factors likely play an important role in inducing TLR-3 expression. In addition to neurons, occasional Bergmann glia expressed TLR-3 in some cases. This study has provided evidence that human brain neurons can express TLR-3 in vivo and suggests that neurons may play an important role in initiating an inflammatory reaction in a variety of neurological diseases.


The critical protein interactions and structures that elicit growth deregulation in cancer and viral replication.
One of the greatest challenges in biomedicine is to define the critical targets and network interactions that are subverted to elicit growth deregulation in human cells. Understanding and developing rational treatments for cancer requires a definition of the key molecular targets and how they interact to elicit the complex growth deregulation phenotype. Viral proteins provide discerning and powerful probes to understand both how cells work and how they can be manipulated using a minimal number of components. The small DNA viruses have evolved to target inherent weaknesses in cellular protein interaction networks to hijack the cellular DNA and protein replication machinery. In the battle to escape the inevitability of senescence and programmed cell death, cancers have converged on similar mechanisms, through the acquisition and selection of somatic mutations that drive unchecked cellular replication in tumors. Understanding the dynamic mechanisms through which a minimal number of viral proteins promote host cells to undergo unscheduled and pathological replication is a powerful strategy to identify critical targets that are also disrupted in cancer. Viruses can therefore be used as tools to probe the system-wide protein-protein interactions and structures that drive growth deregulation in human cells. Ultimately this can provide a path for developing system context-dependent therapeutics. This review will describe ongoing experimental approaches using viruses to study pathways deregulated in cancer, with a particular focus on viral cellular protein-protein interactions and structures.


Antimicrobial-resistant pathogens associated with healthcare-associated infections: summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-2010.
To describe antimicrobial resistance patterns for healthcare-associated infections (HAIs) reported to the National Healthcare Safety Network (NHSN) during 2009-2010. Central line-associated bloodstream infections, catheter-associated urinary tract infections, ventilator-associated pneumonia, and surgical site infections were included. Pooled mean proportions of isolates interpreted as resistant (or, in some cases, nonsusceptible) to selected antimicrobial agents were calculated by type of HAI and compared to historical data. Overall, 2,039 hospitals reported 1 or more HAIs; 1,749 (86%) were general acute care hospitals, and 1,143 (56%) had fewer than 200 beds. There were 69,475 HAIs and 81,139 pathogens reported. Eight pathogen groups accounted for about 80% of reported pathogens: Staphylococcus aureus (16%), Enterococcus spp. (14%), Escherichia coli (12%), coagulase-negative staphylococci (11%), Candida spp. (9%), Klebsiella pneumoniae (and Klebsiella oxytoca; 8%), Pseudomonas aeruginosa (8%), and Enterobacter spp. (5%). The percentage of resistance was similar to that reported in the previous 2-year period, with a slight decrease in the percentage of S. aureus resistant to oxacillins (MRSA). Nearly 20% of pathogens reported from all HAIs were the following multidrug-resistant phenotypes: MRSA (8.5%); vancomycin-resistant Enterococcus (3%); extended-spectrum cephalosporin-resistant K. pneumoniae and K. oxytoca (2%), E. coli (2%), and Enterobacter spp. (2%); and carbapenem-resistant P. aeruginosa (2%), K. pneumoniae/oxytoca (<1%), E. coli (<1%), and Enterobacter spp. (<1%). Among facilities reporting HAIs with 1 of the above gram-negative bacteria, 20%-40% reported at least 1 with the resistant phenotype. While the proportion of resistant isolates did not substantially change from that in the previous 2 years, multidrug-resistant gram-negative phenotypes were reported from a moderate proportion of facilities.


Extragenital gonorrhea and chlamydia testing and infection among men who have sex with men--STD Surveillance Network, United States, 2010-2012.
Gonorrhea (GC) and chlamydia (CT) are the most commonly reported notifiable diseases in the United States. The Centers for Disease Control and Prevention recommends that men who have sex with men (MSM) be screened for urogenital GC/CT, rectal GC/CT, and pharyngeal GC. We describe extragenital GC/CT testing and infections among MSM attending sexually transmitted disease (STD) clinics. The STD Surveillance Network collects patient data from 42 STD clinics. We assessed the proportion of MSM attending these clinics during July 2011-June 2012 who were tested and positive for extragenital GC/CT at their most recent visit or in the preceding 12 months and the number of extragenital infections that would have remained undetected with urethral screening alone. Of 21 994 MSM, 83.9% were tested for urogenital GC, 65.9% for pharyngeal GC, 50.4% for rectal GC, 81.4% for urogenital CT, 31.7% for pharyngeal CT, and 45.9% for rectal CT. Of MSM tested, 11.1% tested positive for urogenital GC, 7.9% for pharyngeal GC, 10.2% for rectal GC, 8.4% for urogenital CT, 2.9% for pharyngeal CT, and 14.1% for rectal CT. More than 70% of extragenital GC infections and 85% of extragenital CT infections were associated with negative urethral tests at the same visit and would not have been detected with urethral screening alone. Extragenital GC/CT was common among MSM attending STD clinics, but many MSM were not tested. Most extragenital infections would not have been identified, and likely would have remained untreated, with urethral screening alone. Efforts are needed to facilitate implementation of extragenital GC/CT screening recommendations for MSM.


A Waterborne Pursuit-Deterrent Signal Deployed by a Sea Urchin.
Selection by consumers has led to the evolution of a vast array of defenses in animals and plants. These defenses include physical structures, behaviors, and chemical signals that mediate interactions with predators. Some of the strangest defensive structures in nature are the globiferous pedicellariae of the echinoderms. These are small venomous appendages with jaws and teeth that cover the test of many sea urchins and sea stars. In this study, we report a unique use of these defensive structures by the collector sea urchin Tripneustes gratilla. In both the laboratory and the field, globiferous pedicellariae were unpalatable to fish consumers. When subject to simulated predator attack, sea urchins released a cloud of pedicellaria heads into the water column. Flume experiments established the presence of a waterborne cue associated with this release of pedicellariae that is deterrent to predatory fish. These novel results add to our understanding of how the ecosystem-shaping sea urchin T. gratilla is able to reach high densities in many reef habitats, with subsequent impacts on algal cover.


Class of solitary wave solutions of the one-dimensional Gross-Pitaevskii equation.
We present a large family of exact solitary wave solutions of the one-dimensional Gross-Pitaevskii equation, with time-varying scattering length and gain or loss, in both expulsive and regular parabolic confinement regimes. The consistency condition governing the soliton profiles is shown to map onto a linear Schrödinger eigenvalue problem, thereby enabling one to find analytically the effect of a wide variety of temporal variations in the control parameters, which are experimentally realizable. Corresponding to each solvable quantum mechanical system, one can identify a soliton configuration. These include soliton trains in close analogy to experimental observations of Streckeret al. [Nature (London) 417, 150 (2002)], spatiotemporal dynamics, solitons undergoing rapid amplification, collapse and revival of condensates, and analytical expression of two-soliton bound states, to name a few.


New developments in planar array infrared spectroscopy.
A planar array infrared (PA-IR) spectrograph offers several advantages over other infrared approaches, including high acquisition rate and sensitivity. However, it suffers from some important drawbacks, such as a limited spectral range and a significant curvature of the recorded spectral images, which still need to be addressed. In this article, we present new developments in PA-IR spectroscopy that overcome these drawbacks. First, a data processing method for the correction of the curvature observed in the spectral images has been developed and refined. In addition, a dual-beam instrument that allows the simultaneous recording of two independent spectral images has been developed. These two improvements have been combined to demonstrate the real-time background correction capability of PA-IR instruments. Finally, the accessible spectral range of the PA-IR spectrograph has been extended to cover simultaneously the methylene stretching (3200-2800 cm(-1)) and the finger-print (2000-1000 cm(-1)) spectral regions.


Hypothyroidism in utero stimulates pancreatic beta cell proliferation and hyperinsulinaemia in the ovine fetus during late gestation.
Thyroid hormones are important regulators of growth and maturation before birth, although the extent to which their actions are mediated by insulin and the development of pancreatic beta cell mass is unknown. Hypothyroidism in fetal sheep induced by removal of the thyroid gland caused asymmetric organ growth, increased pancreatic beta cell mass and proliferation, and was associated with increased circulating concentrations of insulin and leptin. In isolated fetal sheep islets studied in vitro, thyroid hormones inhibited beta cell proliferation in a dose-dependent manner, while high concentrations of insulin and leptin stimulated proliferation. The developing pancreatic beta cell is therefore sensitive to thyroid hormone, insulin and leptin before birth, with possible consequences for pancreatic function in fetal and later life. The findings of this study highlight the importance of thyroid hormones during pregnancy for normal development of the fetal pancreas. Development of pancreatic beta cell mass before birth is essential for normal growth of the fetus and for long-term control of carbohydrate metabolism in postnatal life. Thyroid hormones are also important regulators of fetal growth, and the present study tested the hypotheses that thyroid hormones promote beta cell proliferation in the fetal ovine pancreatic islets, and that growth retardation in hypothyroid fetal sheep is associated with reductions in pancreatic beta cell mass and circulating insulin concentration in utero. Organ growth and pancreatic islet cell proliferation and mass were examined in sheep fetuses following removal of the thyroid gland in utero. The effects of triiodothyronine (T3 ), insulin and leptin on beta cell proliferation rates were determined in isolated fetal ovine pancreatic islets in vitro. Hypothyroidism in the sheep fetus resulted in an asymmetric pattern of organ growth, pancreatic beta cell hyperplasia, and elevated plasma insulin and leptin concentrations. In pancreatic islets isolated from intact fetal sheep, beta cell proliferation in vitro was reduced by T3 in a dose-dependent manner and increased by insulin at high concentrations only. Leptin induced a bimodal response whereby beta cell proliferation was suppressed at the lowest, and increased at the highest, concentrations. Therefore, proliferation of beta cells isolated from the ovine fetal pancreas is sensitive to physiological concentrations of T3 , insulin and leptin. Alterations in these hormones may be responsible for the increased beta cell proliferation and mass observed in the hypothyroid sheep fetus and may have consequences for pancreatic function in later life.


Vitamin D for the treatment of chronic painful conditions in adults.
Vitamin D is produced in the skin after sun-light exposure and can also be obtained through food. Vitamin D deficiency has recently been linked with a range of diseases including chronic pain. Observational and circumstantial evidence suggests that there may be a role for vitamin D deficiency in the aetiology of chronic pain conditions. To assess the efficacy and adverse events of vitamin D supplementation in chronic painful conditions. We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to September 2009. This was supplemented by searching the reference lists of retrieved articles, textbooks and reviews. Studies were included if they were randomised double blind trials of vitamin D supplementation compared with placebo or with active comparators for the treatment of chronic pain conditions in adults. Two review authors independently selected the studies for inclusion, assessed methodological quality, and extracted data. Pooled analysis was not undertaken due to paucity and heterogeneity of data. Four studies, with a total of 294 participants, were included. The studies were heterogeneous with regard to study quality, the chronic painful conditions that were investigated, and the outcome measures reported. Only one study reported a beneficial effect, the others found no benefit of vitamin D over placebo in treating chronic pain. The evidence base for the use of vitamin D for chronic pain in adults is poor at present. This is due to low quality and insufficient randomised controlled trials in this area of research.


Dielectric shell isolated and graphene shell isolated nanoparticle enhanced Raman spectroscopies and their applications.
Surface-enhanced Raman scattering (SERS) is a powerful technique that provides fingerprint vibrational information with ultrahigh sensitivity. However, only a few metals (gold, silver and copper) yield a large SERS effect, and they must be rough at the nanoscale. Shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS) was developed to overcome the long-standing materials and morphological limitations of SERS. It has already been applied in a variety of fields such as materials science, electrochemistry, surface science, catalysis, food safety and the life sciences. Here, the principles and applications of SHINERS are highlighted. To provide an understanding of the plasmonics involved, finite-difference time-domain (FDTD) calculations and single nanoparticle SHINERS experiments are reviewed. Next, various shell-isolated nanoparticle (SHIN) types are described. Then a number of applications are discussed. In the first application, SHINERS is used to characterize the adsorption processes of pyridine on Au(hkl) single-crystal electrode surfaces. Then, SHINERS' applicability to food inspection and cultural heritage science is demonstrated by the detection of parathion and fenthion pesticides, and Lauth's violet (thionine dye). Finally, graphene-isolated Au nanoparticles (GIANs) are shown to be effective for multimodal cell imaging, photothermal cancer therapy and photothermally-enhanced chemotherapy. SHINERS is a fast, simple and reliable method, suitable for application to many areas of science and technology. The concept of shell-isolation can also be applied to other surface-enhanced spectroscopies such as fluorescence, infrared absorption and sum frequency generation.


Why did this happen to me? Religious believers' and non-believers' teleological reasoning about life events.
People often believe that significant life events happen for a reason. In three studies, we examined evidence for the view that teleological beliefs reflect a general cognitive bias to view the world in terms of agency, purpose, and design. Consistent with this hypothesis, we found that individual differences in mentalizing ability predicted both the tendency to believe in fate (Study 1) and to infer purposeful causes of one's own life events (Study 2). In addition, people's perception of purpose in life events was correlated with their teleological beliefs about nature, but this relationship was driven primarily by individuals' explicit religious and paranormal beliefs (Study 3). Across all three studies, we found that while people who believe in God hold stronger teleological beliefs than those who do not, there is nonetheless evidence of teleological beliefs among non-believers, confirming that the perception of purpose in life events does not rely on theistic belief. These findings suggest that the tendency to perceive design and purpose in life events-while moderated by theistic belief-is not solely a consequence of culturally transmitted religious ideas. Rather, this teleological bias has its roots in certain more general social propensities.


SYNGAP1 encephalopathy: A distinctive generalized developmental and epileptic encephalopathy.
To delineate the epileptology, a key part of the SYNGAP1 phenotypic spectrum, in a large patient cohort. Patients were recruited via investigators' practices or social media. We included patients with (likely) pathogenic SYNGAP1 variants or chromosome 6p21.32 microdeletions incorporating SYNGAP1. We analyzed patients' phenotypes using a standardized epilepsy questionnaire, medical records, EEG, MRI, and seizure videos. We included 57 patients (53% male, median age 8 years) with SYNGAP1 mutations (n = 53) or microdeletions (n = 4). Of the 57 patients, 56 had epilepsy: generalized in 55, with focal seizures in 7 and infantile spasms in 1. Median seizure onset age was 2 years. A novel type of drop attack was identified comprising eyelid myoclonia evolving to a myoclonic-atonic (n = 5) or atonic (n = 8) seizure. Seizure types included eyelid myoclonia with absences (65%), myoclonic seizures (34%), atypical (20%) and typical (18%) absences, and atonic seizures (14%), triggered by eating in 25%. Developmental delay preceded seizure onset in 54 of 56 (96%) patients for whom early developmental history was available. Developmental plateauing or regression occurred with seizures in 56 in the context of a developmental and epileptic encephalopathy (DEE). Fifty-five of 57 patients had intellectual disability, which was moderate to severe in 50. Other common features included behavioral problems (73%); high pain threshold (72%); eating problems, including oral aversion (68%); hypotonia (67%); sleeping problems (62%); autism spectrum disorder (54%); and ataxia or gait abnormalities (51%). SYNGAP1 mutations cause a generalized DEE with a distinctive syndrome combining epilepsy with eyelid myoclonia with absences and myoclonic-atonic seizures, as well as a predilection to seizures triggered by eating.


Stereo matching with linear superposition of layers.
In this paper, we address stereo matching in the presence of a class of non-Lambertian effects, where image formation can be modeled as the additive superposition of layers at different depths. The presence of such effects makes it impossible for traditional stereo vision algorithms to recover depths using direct color matching-based methods. We develop several techniques to estimate both depths and colors of the component layers. Depth hypotheses are enumerated in pairs, one from each layer, in a nested plane sweep. For each pair of depth hypotheses, matching is accomplished using spatial-temporal differencing. We then use graph cut optimization to solve for the depths of both layers. This is followed by an iterative color update algorithm which we proved to be convergent. Our algorithm recovers depth and color estimates for both synthetic and real image sequences.


Discovery and identification of a male-killing agent in the Japanese ladybird Propylea japonica (Coleoptera: Coccinellidae).
Endosymbionts that manipulate the reproduction of their hosts have been reported widely in invertebrates. One such group of endosymbionts is the male-killers. To date all male-killers reported are bacterial in nature, but comprise a diverse group. Ladybirds have been described as a model system for the study of male-killing, which has been reported in multiple species from widespread geographic locations. Whilst criteria of low egg hatch-rate and female-biased progenic sex ratio have been used to identify female hosts of male-killers, variation in vertical transmission efficiency and host genetic factors may result in variation in these phenotypic indicators of male-killer presence. Molecular identification of bacteria and screening for bacterial presence provide us with a more accurate method than breeding data alone to link the presence of the bacteria to the male-killing phenotype. In addition, by identifying the bacteria responsible we may find evidence for horizontal transfer between endosymbiont hosts and can gain insight into the evolutionary origins of male-killing. Phylogenetic placement of male-killing bacteria will allow us to address the question of whether male-killing is a potential strategy for only some, or all, maternally inherited bacteria. Together, phenotypic and molecular characterisation of male-killers will allow a deeper insight into the interactions between host and endosymbiont, which ultimately may lead to an understanding of how male-killers identify and kill male-hosts. A male-killer was detected in the Japanese coccinellid, Propylea japonica (Thunberg) a species not previously known to harbour male-killers. Families produced by female P. japonica showed significantly female-biased sex ratios. One female produced only daughters. This male-killer trait was maternally inherited and antibiotic treatment produced a full, heritable cure. Molecular analysis identified Rickettsia to be associated with the trait in this species of ladybird. We conclude that P. japonica is host to a bacterial male-killer that is vertically inherited with variable transmission efficiency. Rickettsia presence correlates with the male-killing trait, but there is some variation in the phenotypic expression of the trait due to interaction with host factors. Phylogenetic analysis using the 16S rRNA and 17 kDa antigen genes suggests there may have been horizontal transfer of Rickettsial male-killers between different ladybird hosts.