Physical Exercise as Kynurenine Pathway Modulator in Chronic Diseases: Implications for Immune and Energy Homeostasis.
Emerging evidence highlights the substantial role of the kynurenine pathway in various physiological systems and pathological conditions. Physical exercise has been shown to impact the kynurenine pathway in response to both single (acute) and multiple (chronic) exercise training stimuli. In this perspective article, we briefly outline the current knowledge concerning exercise-induced modulations of the kynurenine pathway and discuss underlying mechanisms. Furthermore, we expose the potential involvement of exercise-induced kynurenine pathway modulations on energy homeostasis (eg, through de novo synthesis of NAD+) and finally suggest how these modulations may contribute to exercise-induced benefits in the prevention and treatment of chronic diseases.


TMEM41B is a pan-flavivirus host factor.
Flaviviruses pose a constant threat to human health. These RNA viruses are transmitted by the bite of infected mosquitoes and ticks and regularly cause outbreaks. To identify host factors required for flavivirus infection we performed full-genome loss of function CRISPR-Cas9 screens. Based on these results we focused our efforts on characterizing the roles that TMEM41B and VMP1 play in the virus replication cycle. Our mechanistic studies on TMEM41B revealed that all members of the Flaviviridae family that we tested require TMEM41B. We tested 12 additional virus families and found that SARS-CoV-2 of the Coronaviridae also required TMEM41B for infection. Remarkably, single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection. Based on our mechanistic studies we hypothesize that TMEM41B is recruited to flavivirus RNA replication complexes to facilitate membrane curvature, which creates a protected environment for viral genome replication. TMEM41B and VMP1 are required for both autophagy and flavivirus infection, however, autophagy is not required for flavivirus infection.TMEM41B associates with viral proteins and likely facilitates membrane remodeling to establish viral RNA replication complexes.TMEM41B single nucleotide polymorphisms (SNPs) present at nearly twenty percent in East Asian populations reduce flavivirus infection.TMEM41B-deficient cells display an exaggerated innate immune response upon high multiplicity flavivirus infection.


Cognitive impairment in early, untreated Parkinson's disease and its relationship to motor disability.
Current knowledge of cognitive dysfunction in Parkinson's disease (PD) has largely been obtained from studies of chronically treated patients in whom effects of disease chronicity, treatment, depression and dementia are confounding factors. Studies of untreated patients have examined few cognitive domains and relationships between cognition, depression and motor disability have been incompletely explored. Accordingly, we studied 60 consecutive patients with newly diagnosed, untreated, idiopathic PD and 37 matched, healthy control subjects; no subject had clinical dementia or depression. All subjects received tests of specific processes of memory and cognition, including working memory, verbal and non-verbal short- and long-term memory, language, visuospatial capacity, set-formation and shifting and sequencing. Patients also received quantitative global clinical measures of severity of dementia, depression and motor disability. The PD group as a whole showed deficits in immediate recall of verbal material, language production and semantic fluency, set-formation, cognitive sequencing and working memory and visuomotor construction. However, this group was unimpaired in immediate memory span, long-term forgetting, naming, comprehension and visual perception. Language deficits and more severe frontal lobe impairments were confined to those PD patients scoring abnormally on a Mini Mental State examination. Motor disability correlated strongly with severity of depression but weakly with cognitive impairment. Cognitive sequencing, set-formation and set-shifting deficits tended to associate with depression, but otherwise there was no association between cognition and depression. The results indicate dissociation of cognition and motor control in early PD which suggests that cognitive dysfunction is largely independent of frontostriatal dopamine deficiency underlying motor disability. Some, but not all, of the frontal lobe deficits of chronic disease are detectable in early, untreated PD. The pathogenesis of the cognitive deficits shown here appears to involve extrastriatal dopamine systems or non-dopaminergic pathology. Longitudinal study is necessary to determine whether increasing disease duration exacerbates the early cognitive deficits and affects new cognitive domains, in addition to producing increasing motor disability.


Monosporascus eutypoides, a Cause of Root Rot and Vine Decline in Tunisia, and Evidence that M. cannonballus and M. eutypoides Are Distinct Species.
Three Monosporascus eutypoides-like isolates recovered from cucurbit plants with symptoms of Monosporascus root rot and vine decline in Tunisia were compared to 28 isolates of M. cannonballus from 12 countries for phenotypic, genomic, and pathogenicity characteristics. Morphologically, M. cannonballus and M. eutypoides-like cultures were similar, each producing fertile perithecia in culture containing globose, smooth, dark brown to black ascospores. Nevertheless, all M. cannonballus isolates had one ascospore per ascus, while M. eutypoides-like isolates had mainly two to three ascospores per ascus (rarely one). The employment of the internal transcribed spacer (ITS) of nuclear ribosomal DNA, the elongation factor 1-α (EF-1α), and the β-tubulin (β-tub) gene sequence diversity analyses and the resulting phylogenies identified a level of polymorphism that enabled separation of M. cannonballus and M. eutypoides-like isolates. All isolates of M. cannonballus had identical EF-1α and β-tub sequences irrespective of very diverse geographic origins, which were different from the EF-1α and β-tub sequences of the M. eutypoides-like isolates (96 and 97% similarity, respectively). Similar results were obtained for the ITS region of rDNA. In addition, of three M. eutypoides-like isolates tested for pathogenicity, all three were pathogenic on watermelon, two were pathogenic on muskmelon, but only one was pathogenic on cucumber. The results demonstrate that the M. eutypoides-like isolates belong to the species M. eutypoides, and that M. cannonballus and M. eutypoides are distinct species.


Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B.
Transcription factors of the NF-kappaB/Rel family are critical for inducible expression of multiple genes involved in inflammatory responses. Sulfasalazine and its salicylate moiety 5-aminosalicylic acid are among the most effective agents for treating inflammatory bowel disease and rheumatoid arthritis. However, the mode of action of these drugs remains unclear. Here we provide evidence that the transcription factor NF-kappaB is a target of sulfasalazine-mediated immunosuppression. Treatment of SW620 colon cells with sulfasalazine inhibited TNFalpha-, LPS-, or phorbol ester- induced NF-kappaB activation. NF-kappaB-dependent transcription was inhibited by sulfasalazine at micro- to millimolar concentrations. In contrast, 5-aminosalicylic acid or sulfapyridine did not block NF-kappaB activation at all doses tested. TNFalpha-induced nuclear translocation of NF-kappaB was prevented by sulfasalazine through inhibition of IkappaBalpha degradation. When blocking proteasome-mediated degradation of IkappaBalpha, we could demonstrate that sulfasalazine interfered with IkappaBalpha phosphorylation, suggesting a direct effect on an IkappaBalpha kinase or on an upstream signal. Inhibition of NF-kappaB activation seems to be specific since other DNA-binding activities such as AP1 were not affected. These results demonstrate that sulfasalazine is a potent and specific inhibitor of NF-kappaB activation, and thus may explain some of the known biological properties of sulfasalazine.


Aptamer-based nanobiosensors.
It has been more than two decades since aptamer and the systematic evolution of ligands by exponential enrichment (SELEX) method were discovered by Larry Gold and Andrew Ellington in 1990, respectively. Based on the various advantages of aptamers, they have become a potent rival of antibodies in therapeutics and bio-analysis. Especially, the recent advances in aptamer biosensor application are remarkable due to its intrinsic properties of aptamers as nucleic acids and target induced conformational changes, in addition to the introduction of graphene oxide-based easy and simple immobilization-free screening method even for dual aptamers. In addition, the incorporation of various nanomaterials such as metallic nanoparticles, carbon materials, and functional nanospheres in aptasensors has facilitated the improvement of analytical performance and commercial application of aptasensors. In this review, recent prominent reports on aptasensors utilizing nanomaterials were introduced to understand the principle of aptamer-based biosensors and provide an insight for new strategies of aptasensors and the application of various nanomaterials. The perspective on aptamer-based biosensors and diagnostics was also discussed in view of technology and market.


Degenerate optical cavities.
An optical cavity is degenerate when an arbitrary ray retraces its own path after a single round trip. The condition for degeneracy is given for ring type cavities incorporating internal lenses, using geometrical optics methods. The simplest linear configurations require a spherical mirror or a corner cube, a thin lens, and a plane mirror. Planar rings with four plane mirrors require at least three thin focusing elements. A nonplanar ring is discussed which requires only two thin lenses. The alignment of degenerate cavities is, in general, as critical as the alignment of plane Fabry-Perot.


Transmission of tuberculosis in the prison of Antananarivo (Madagascar).
The prevalence of tuberculosis in the Antananarivo prison is 16 times higher than that in the general population of Madagascar. We compared the clustering of Mycobacterium tuberculosis strains within and outside the prison and studied the transmission of strains in the prison. M. tuberculosis strains isolated in 1994 to 1995 from 146 prisoners and from 260 nonprisoner patients from Antananarivo were typed using the genetic markers IS6110 and direct repeat. We compared the strains isolated from prisoners and nonprisoners and found that the clustering rate was higher within (58.9%) than outside the prison (40%) suggesting that the transmission rate was higher in prison. Of the 146 incarcerated patients, 82 were grouped into 22 clusters. We checked for possible tuberculosis transmission between prisoners with identical strains by epidemiological investigation of the various prison clusters. We found that 9.5% of the incarcerated patients could have been sources of infection and that only 15.1% could have been infected in the prison. One hundred and twenty-seven prison patients were new cases. Epidemiological data suggested that 37% of them resulted from a reactivation of an old infection, due to poor living conditions or recent transmission from an index case outside the prison.


The effects of a low-carbohydrate, ketogenic diet on the polycystic ovary syndrome: a pilot study.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age and is associated with obesity, hyperinsulinemia, and insulin resistance. Because low carbohydrate diets have been shown to reduce insulin resistance, this pilot study investigated the six-month metabolic and endocrine effects of a low-carbohydrate, ketogenic diet (LCKD) on overweight and obese women with PCOS. Eleven women with a body mass index >27 kg/m2 and a clinical diagnosis of PCOS were recruited from the community. They were instructed to limit their carbohydrate intake to 20 grams or less per day for 24 weeks. Participants returned every two weeks to an outpatient research clinic for measurements and reinforcement of dietary instruction. In the 5 women who completed the study, there were significant reductions from baseline to 24 weeks in body weight (-12%), percent free testosterone (-22%), LH/FSH ratio (-36%), and fasting insulin (-54%). There were non-significant decreases in insulin, glucose, testosterone, HgbA1c, triglyceride, and perceived body hair. Two women became pregnant despite previous infertility problems. In this pilot study, a LCKD led to significant improvement in weight, percent free testosterone, LH/FSH ratio, and fasting insulin in women with obesity and PCOS over a 24 week period.


KOJAK encodes a cellulose synthase-like protein required for root hair cell morphogenesis in Arabidopsis.
The cell wall is an important determinant of plant cell form. Here we define a class of Arabidopsis root hair mutants with defective cell walls. Plants homozygous for kojak (kjk) mutations initiate root hairs that rupture at their tip soon after initiation. The KJK gene was isolated by positional cloning, and its identity was confirmed by the molecular complementation of the Kjk(-) phenotype and the sequence of three kjk mutant alleles. KOJAK encodes a cellulose synthase-like protein, AtCSLD3. KOJAK/AtCSLD3 is the first member of this subfamily of proteins to be shown to have a function in cell growth. Subcellular localization of the KOJAK/AtCSLD3 protein using a GFP fusion shows that KOJAK/AtCSLD3 is located on the endoplasmic reticulum, indicating that KOJAK/AtCSLD3 is required for the synthesis of a noncellulosic wall polysaccharide. Consistent with the cell specific defect in the roots of kjk mutants, KOJAK/AtCSDL3 is preferentially expressed in hair cells of the epidermis. The Kjk(-) phenotype and the pattern of KOJAK/AtCSLD3 expression suggest that this gene acts early in the process of root hair outgrowth. These results suggest that KOJAK/AtCSLD3 is involved in the biosynthesis of beta-glucan-containing polysaccharides that are required during root hair elongation.


An observational analysis of the behavioural effects of beta-phenylethylamine in isolated and grouped mice.
1. Male Swiss mice were treated systemically with beta-phenylethylamine (PEA, 25-150 mg/kg), and observed in isolation or in groups of five. The effects of PEA were scored on 13 separate components of behaviour which were produced or increased by the drug. 2. PEA at a dose of 25 mg/kg depressed activity and caused sedation, but at 50 mg/kg produced a brief stimulation of activity. At higher dose levels (75-150 mg/kg) the compound induced a biphasic stimulation of activity which was associated with the development of two distinct groups of stereotyped activities. 3. Group testing significantly antagonized early phase stereotypy (forepaw padding, headweaving, compulsive grooming) but had no effect on, or potentiated, late phase stereotypy (rearing, licking). In addition grouped mice were more active and hyperreactive than isolated mice. 4. The results are briefly discussed in the light of the possibility of a catecholamine/indoleamine interaction in the control of the hyperactivity syndrome induced by PEA in the mouse.


Alpha and beta subunits of inhibin/activin as sex cord-stromal differentiation markers.
Inhibins (alpha and beta heterodimers) and activins (beta homodimers) are related peptides with opposing biologic action on gonadotropin regulation. They serve as components of the pituitary-gonadal feedback system. Although sex-cord stromal tumors can usually be distinguished from ovarian epithelial tumors or their metastases by morphology or by using antibodies against intermediate filaments, the diagnosis remains difficult in rare situations in such cases as sarcomatoid granulosa-theca cell tumors, ovarian small cell carcinomas, or soft-tissue sarcomas. A total of 28 sex cord-stromal tumors of the ovary and 43 non-sex cord-stromal tumors were immunohistochemically evaluated for the presence of alpha and beta subunits of inhibin and activin. For comparison, 10 normal adult gonads including seven ovaries with hilar regions and three testes also were examined. Immunoreactivity for both alpha and beta subunits of inhibin/activin was identified in both non-neoplastic and neoplastic granulosa, Sertoli, Leydig, hilar and luteinized theca cells, with the strongest immunoreactivity in Leydig and hilar cells. One of three Sertoli-Leydig cell tumors that showed a sarcomatoid growth pattern and one sex-cord tumor with annular tubules also were immunoreactive for both subunits. For non-sex cord stromal-derived ovarian tumors, alpha subunit immunoreactivity was negative in all but two of five ovarian mucinous tumors. Weak immunoreactivity for beta subunit was found in most ovarian surface epithelial carcinomas, two of four colonic, and one of three pancreatic carcinomas. No immunostaining was found in nonspecialized gonadal stromal or interstitial cells, thecal cells, germ cells, ovarian small cell carcinomas, carcinoid tumors, dysgerminomas, or leiomyosarcomas. Immunostaining of alpha subunit (inhibin alpha), but not of beta subunit could serve as a sex cord-stromal differentiation marker because alpha subunit alone is largely confined to sex cord-stromal lesions with the exception of some ovarian mucinous tumors. Further studies are needed to define the usefulness of this sex cord-stromal differentiation marker in the practice of surgical pathology. Coexpression of alpha and beta subunits in sex cord-stromal elements suggests that dimeric inhibin is expressed in these cells.


Sea anemone toxin (ATX II) modulation of heart and skeletal muscle sodium channel alpha-subunits expressed in tsA201 cells.
We have expressed recombinant alpha-subunits of hH1 (human heart subtype 1), rSkM1 (rat skeletal muscle subtype 1) and hSkM1 (human skeletal muscle) sodium channels in human embryonic kidney cell line, namely the tsA201 cells and compared the effects of ATX II on these sodium channel subtypes. ATX II slows the inactivation phase of hH1 with little or no effect on activation. At intermediate concentrations of ATX II the time course of inactivation is biexponential due to the mixture of free (fast component, taufasth) and toxin-bound (slow component, tauslowh) channels. The relative amplitude of tauslowh allows an estimate of the IC50 values approximately 11 nM. The slowing of inactivation in the presence of ATX II is consistent with destabilization of the inactivated state by toxin binding. Further evidence for this conclusion is: (i) The voltage-dependence of the current decay time constants (tauh) is lost or possibly reversed (time constants plateau or increase at more positive voltages in contrast to these of untreated channels). (ii) The single channel mean open times are increased by a factor of two in the presence of ATX II. (iii) The recovery from inactivation is faster in the presence of ATX II. Similar effects of ATX II on rSkM1 channel behavior occur, but only at higher concentrations of toxin (IC50 = 51 nM). The slowing of inactivation on hSkM1 is comparable to the one seen with rSkM1. A residual or window current appears in the presence of ATX II that is similar to that observed in channels containing mutations associated with some of the familial periodic paralyses.


Human interaction moderates plasma cortisol and behavioral responses of dogs to shelter housing.
Housing in an animal shelter is a stressful experience for dogs. This study examined the effects of different forms of human interaction on concentrations of circulating cortisol and stress-related behaviors of dogs within 40 h of admittance to a county animal shelter. Blood samples were collected before and after 30-min sessions in a secluded area in which dogs received one of three forms of human interaction: exposure to a passive human, petting, or play. Controls were either exposed to the secluded area alone, or remained in the general housing area. There was a substantial and near uniform reduction in plasma cortisol concentrations from pretest to post-test in all three conditions receiving human interaction, but not in control conditions. Human interaction also reduced behavioral signs of excitation/social solicitation (vocalizing) and fear (panting). Finally, pretest cortisol levels were found to predict levels of panting and another fear-related behavior (tongue protrusions) that dogs exhibited during subsequent testing. The findings suggest practical means of reducing stress, and potentially of improving the welfare, of dogs in shelters.


First Report of Branch Dieback of Walnut Caused by Neofusicoccum parvum in Korea.
Walnut (Juglans sinensis Dode) is an economically important tree in the world, both for its wood and its fruit. Walnut fruits, as rich sources of omega-3 essential fatty acid, are valuable nutritionally. Consumer interest in Korea for walnuts has increased in recent years, and production has increased to 1,042 ha with the Kyoungbuk region consisting of 402 ha (2). In May 2012, lethal dieback disease of walnut tree was detected in two orchards in Andong, Kyoungbuk region, Korea, each with an incidence of 25 to 30%. Disease symptoms included blight and dieback of the stems, flowing resin, dark decay inside the bark of dead twigs, and defoliation. The bark of dead twigs was removed and sliced thinly using a razor blade, and water-mounted, without staining, for observation of fungal structures, if present. Pycnidia were found embedded within the bark of dead twigs and conidia were mostly characterized by fusoid, hyaline, smooth, thin-walled, unicellular and 16.25 to 21.25 μm long and 4.37 to 6.87 μm wide. These characteristics are consistent with those reported previously for Neofusicoccum parvum (Pennycook & Samuels) Crous, Slippers & A.J.L. Phillips (1). Diseased branch tissues collected from the two locations were surface sterilized with 1% NaOCl, rinsed with sterile distilled water, and plated on potato dextrose agar (PDA). The fungal isolates, recovered from the two different orchards, produced white, aerial mycelium and became light gray within a week after incubating plates at 25°C. To confirm the identities of the isolates, the complete internal transcribed spacer (ITS) rDNA of the fungi was amplified and sequenced using PCR. The sequences were compared with other DNA sequences in the GenBank database, using a BLAST search. BLAST analysis of the PCR product showed that the sequence had 99% identity with the nucleotide sequences for N. parvum (JQ411396.1 and GU997688.1). Additionally, the chitin synthase 1 gene was sequenced and analyzed using the BLAST server. The sequence of PCR product had 100% identity with the nucleotide sequences of N. parvum strain CMW9080 chitin synthase 1 gene (EU339501). Thus, both morphological and molecular characters confirmed this species as N. parvum. Pathogenecity tests were performed by inoculating 2-year-old J. sinensis trees. Inoculations consisted of inserting 5-mm-diamter agar plug bearing fresh mycelium of the fungal isolates into the wounds. Within 2 weeks, black lesions appeared on all inoculated plants accompanied by defoliation, whereas no symptoms were observed in the control plants. N. parvum has been reported a member of Botryosphaeriaceae, commonly associated with dieback and cankers of woody plants (1). To our knowledge, this study is the first report of N. parvum as a pathogen of Juglans sinensis in Korea. References: (1) P. W. Crous et al. Stud. Mycol. 55:235, 2006. (2) Statistics Korea. Forest Households by Growing Area of Walnut/Total Area. 2010.


Predictors of medical and mental health care use in patients with irritable bowel syndrome in the United States.
Because health care demand among IBS patients imposes a heavy economic burden, identifying high utilizers has potential for improving quality and efficiency of care. Previous research has not identified reliable predictors of utilization of IBS patients. We sought to identify factors predictive of health care utilization among severe IBS patients. 291 IBS patients completed testing whose content mapped onto the Andersen model of health care utilization. 2-stage hurdle models were used to determine predictors of health care use (probability and frequency). Separate analyses were conducted for mental health and medical services. Whether patients used any medical care was predicted by diet and insurance status. Tobacco use, education, and health insurance predicted the probability of using mental health care. The frequency of medical care was associated with alcohol use and physical health status, while frequency of mental health services was associated with marital status, tobacco use, education, distress, stress, and control beliefs over IBS symptoms. For IBS patients, the demand for health care involves a complex decision-making process influenced by many factors. Particularly strong determinants include predisposing characteristics (e.g., dietary pattern, tobacco use) and enabling factors (e.g., insurance coverage) that impede or facilitate demand. Which factors impact use depends on whether the focus is on the decision to use care or how much care is used. Decisions to use medical and mental health care are not simply influenced by symptom-specific factors but by a variety of lifestyle (e.g., dietary pattern, education, smoking) and economic (e.g., insurance coverage) factors.


The questions verbal children with autism spectrum disorder encounter in the inclusive preschool classroom.
This study investigated questions adults asked to children with autism spectrum disorder in inclusive pre-kindergarten classrooms, and whether child (e.g. autism severity) and setting (i.e. adult-to-child ratio) characteristics were related to questions asked during center-time. Videos of verbal children with autism spectrum disorder (n = 42) were coded based on the following question categories adapted from the work of Massey et al.: management, low cognitive challenging, or cognitively challenging. Results indicated that management questions (mean = 19.97, standard deviation = 12.71) were asked more than less cognitively challenging questions (mean = 14.22, standard deviation = 8.98) and less cognitively challenging questions were asked more than cognitively challenging questions (mean = 10.00, standard deviation = 6.9). Children with higher language levels had a greater likelihood of receiving cognitively challenging questions (odds ratio = 1.025; p = 0.007). Cognitively challenging questions had a greater likelihood of being asked in classrooms with more adults relative to children (odds ratio = 1.176; p = 0.037). The findings present a first step in identifying the questions directed at preschoolers with autism spectrum disorder in inclusive classrooms.


Employer-sponsored health insurance in New York: findings from the 2003 Commonwealth Fund/HRET survey.
A 2003 Commonwealth Fund/Health Research and Educational Trust survey of 576 New York State firms found that, in order to manage rising health costs, employers are increasing the share of the insurance premium that employees pay, delaying the start of benefits, and increasing cost-sharing at the point of service. This has enabled employers to preserve health benefits, but has raised costs for workers and their families. On average, workers' contributions for family coverage rose 54 percent, from $1,392 per year in 2001 to $2,148 per year in 2003. During that time period, fewer workers selected family coverage. Employers are receptive to a wide range of approaches to make coverage more available and affordable for their employees, but they have limited familiarity with public programs that could cover their lower-wage workers, such as Healthy New York, Family Health Plus, or Child Health Plus.


Diurnal variation of cerebral blood flow in rat hippocampus.
We measured local cerebral blood flow over 24 hours in 10 unanesthetized, freely moving rats to determine whether blood flow in the hippocampus fluctuated as a function of time of day. We measured hydrogen clearance at 1-hour intervals using a polyurethane-coated platinum electrode with a 1-mm bare tip implanted in the dorsal hippocampus. Individual rats displayed a wide range of local cerebral blood flow values (from 30 to 100 ml/min/100 g tissue) in a day. In seven of the 10 rats, the overall mean hippocampal blood flow for the dark cycle (7 PM-5 AM) was significantly (p less than 0.001, 0.01, or 0.05) greater than that for the light cycle (6 AM-6 PM), showing an average increase of 20%. Further, the maximum mean hippocampal blood flow at 11 PM in all 10 rats was 42% greater than the minimum at noon. Our study demonstrates for the first time that local cerebral blood flow in the hippocampus shows diurnal variation.


Is abnormal glucose tolerance in antipsychotic-naive patients with nonaffective psychosis confounded by poor health habits?
Some but not all previous studies have found abnormal glucose tolerance or fasting glucose concentrations in antipsychotic-naïve patients with nonaffective psychosis. Our finding of abnormal glucose tolerance in patients with nonaffective psychosis could not be attributed to confounding by age, ethnicity, gender, smoking, socioeconomic status (SES), hypercortisolemia, or body mass index (BMI). However, other factors merit consideration as potential confounders of this association. An extended sample of newly diagnosed, antipsychotic-naive patients with schizophrenia and related disorders and matched controls were administered an oral glucose tolerance test. Confounding factors related to diet, self-care/access to care, and drug abuse were evaluated. After accounting for the variance due to age, ethnicity, gender, smoking, SES, morning cortisol concentrations, BMI (or waist-hip ratio), our previous finding of abnormal glucose tolerance in these patients was confirmed. This difference could not be attributed to confounding by substance abuse; blood concentrations of vitamin B12, folate, or homocysteine; aerobic conditioning as measured by resting heart rate; or duration of untreated psychosis. These results provide further evidence that people with schizophrenia and related disorders have abnormal glucose tolerance and an increased risk of diabetes prior to antipsychotic treatment and independent of health habits and access to care. Other measures should also be examined.


Gadolinium-induced nephrogenic systemic fibrosis: the rise and fall of an iatrogenic disease.
BACKGROUND.: In 2006, nephrologists in Denmark unexpectedly identified chronic kidney disease (CKD) patients with a new syndrome, nephrogenic systemic fibrosis (NSF). Subsequently, 1603 NSF patients were reported to the Food and Drug Administration. Sixty hospitals in the USA account for 93% of these cases, and two hospitals in Denmark account for 4% of these reports. We review Denmark's identification and subsequent rapid eradication of NSF. METHODS.: NSF reports from clinicians, the Danish Medicines Agency (DMA) and gadolinium-based contrast agents (GBCAs) manufacturers were reviewed (2002-11). RESULTS.: In 1994, the DMA approved a non-ionic linear GBCA, gadodiamide (0.1 mmol/kg), for magnetic resonance imagings (MRIs), with a renal insufficiency contraindication. In 1996, 0.3 mmol/kg dosing received DMA approval. In 1998, the DMA removed renal contraindications. In 1997 and 2002, radiologists at Skejby Hospital and Herlev Hospital, respectively, began performing gadodiamide-enhanced magnetic resonance angiography scans (0.3 mmol/kg) of CKD patients. In 2005, Herlev clinicians requested assistance in evaluating etiological causes of NSF occurring among 10 CKD patients who had developed NSF. This investigation, focusing on infectious agents, was inconclusive. In 2006, Herlev clinicians reported that of 108 CKD patients who had received gadodiamide-enhanced MRI, 20 had developed probable NSF. Herlev radiologists voluntarily discontinued administering gadodiamide to all patients and no new NSF cases at Herlev Hospital developed subsequently. After meeting with Herlev radiologists, Skejby radiologists also discontinued administering gadodiamide to all patients. In 2007, the European Medicines Agency and the DMA contraindicated gadodiamide administration to CKD patients. In 2008, in response to these advisories, radiologists at the other 36 Danish hospitals discontinued administering gadodiamide to all patients, following on practices adopted at Skejby and Herlev Hospitals. In 2009, clinicians at Skejby Hospital reported that a look-back survey identified 33 CKD patients with NSF developing after undergoing GBCA-enhanced MRIs between 1999 and 2007. In 2010, an independent review, commissioned by the Minister of Health, concluded that the DMA had erred in rescinding gadodiamide's renal insufficiency contraindication in 1998 and that this error was a key factor in the development of NSF in Denmark. In 2011, three NSF cases associated with macrocyclic GBCA-associated NSF and three NSF patients with Stages 3 and 4 CKD disease from Skejby Hospital were reported. CONCLUSION.: A confluence of factors led to the development and eradication of NSF in Denmark.


Modeling the joint effects of adolescent and adult PrEP for sexual minority males in the United States.
Pre-exposure prophylaxis (PrEP) is an effective and safe intervention approved for use to prevent HIV transmission. PrEP scale-up strategies and clinical practice are currently being informed by modeling studies, which have estimated the impact of PrEP in adult and adolescent MSM populations separately. This partitioning may miss important effects or yield biased estimates by excluding dependencies between populations. We combined two published models of HIV transmission among adults and adolescent MSM. We simulated an HIV epidemic among MSM aged 13-39 without PrEP, with PrEP for adult MSM ages (19-39) and with the addition of PrEP for adolescents ages (16-18), comparing percent of incident infections averted (impact), the number of person-years on PrEP per infection averted (efficiency), and changes in prevalence. PrEP use among eligible 19-39 year old MSM averted 29.0% of infections and reduced HIV prevalence from 23.2% to 17.0% over ten years in the population as a whole. Despite being ineligible for PrEP in this scenario, prevalence among sexually active 18 year-olds declined from 6.0% to 4.3% due to reduced transmissions across age cohorts. The addition of PrEP for adolescents ages 16-18 had a small impact on the overall epidemic, further reducing overall prevalence from 17.0% to 16.8%; however prevalence among the sexually active 18 year-olds further declined from 4.3% to 3.8%. PrEP use among adults may significantly reduce HIV prevalence among MSM and may also have significant downstream effects on HIV incidence among adolescents; PrEP targeting adolescents remains an important intervention for HIV prevention.


Pediatric emergency research networks: a global initiative in pediatric emergency medicine.
Objectives of the Pediatric Emergency Research Network's (PERN's) meeting included (1) learn about each of the participating network's missions, goals, and infrastructure; (2) share important contributions each network has made to the creation of new knowledge; (3) discuss "best practices" to improve each network's effectiveness; and (4) explore the potential for a collaborative research project as proof of concept that would help us promote quality of care of the acutely ill and injured child/youth globally. In October 2009, a multiday meeting was attended by 18 delegates representing the following pediatric emergency medicine research networks: Pediatric Emergency Medicine Collaborative Research Committee (United States), Pediatric Emergency Care Applied Research Network (United States), Pediatric Emergency Research of Canada (Canada), Paediatric Research in Emergency Departments International Collaborative (Australia and New Zealand), and Research in European Pediatric Emergency Medicine (15 countries in Europe and the Middle East). The inaugural meeting of PERN demonstrated that there is a common desire for high-quality research and the dissemination of this research to improve health and outcomes of acutely ill and injured children and youths throughout the world. Presently, the PERN group is in the final stages of developing a protocol to assess H1N1 risk factors with the collection of retrospective data. Several members of PERN will be gathering at the International Conference on Emergency Medicine in Singapore, where the group will be presenting information about the H1N1 initiative. The PERN group is planning to bring together all 5 networks later in 2010 to discuss future global collaborations.


An examination of educational gaps in the diagnosis and treatment of myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) comprise a heterogeneous group of hematologic malignancies, with an incidence rate of 3.4 cases per 100,000 in the United States. MDS affects patients predominantly over 60 years of age. As these syndromes are not well understood by many medical practitioner, patients with MDS may be underrecognized or underdiagnosed. The availability of new MDS treatment options further establishes the need to more closely assess gaps in clinical practice and underscores the necessity to develop educational activities to address those gaps. A multidisciplinary panel was convened to examine current educational needs and gaps. A group consensus approach incorporating a modified nominal group technique was utilized to prioritize and review needs identified in the pre-meeting survey and to evaluate data provided by panelists prior to the meeting. The panel identified and prioritized seven educational areas of need: (1) MDS disease awareness, (2) diagnosis, (3) classification and risk stratification, (4) treatment issues, (5) referral to stem cell transplantation or new treatment protocols, (6) clinical monitoring and toxicity management, and (7) translation of new data into patient care. In-depth knowledge is critical to the timely diagnosis and optimal care of MDS patients. A number of key educational needs exist. Educational programs should be practical in orientation to integrate data into practice, and they should be tailored for the intended audience. In addition, an effective educational program must be easily applied by participants.


Does immunosuppressive property of non-steroidal anti-inflammatory drugs (NSAIDs) reduce COVID-19 vaccine-induced systemic side effects?
To help stop the coronavirus disease 2019 (COVID-19) pandemic, vaccines are currently the most critical tool. However, the COVID-19 mRNA vaccines frequently cause systemic side effects shortly after the injection, such as fever, headache and generalized fatigue. In our survey, after receiving the second dose of the COVID-19 vaccine, 80% developed fever, 62% headache and 69% generalized fatigue. Among people who required antipyretics, the average durations of fever and headache were significantly shorter in those who took non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin, loxoprofen and ibuprofen, than those who took acetaminophen. In our patch-clamp studies, NSAIDs effectively suppressed the delayed rectifier K+-channel (Kv1.3) currents in T-lymphocytes and thus exerted immunosuppressive effects. Because of this pharmacological property, the use of NSAIDs should be more effective in reducing the vaccine-induced systemic side effects that are caused primarily by the enhanced cellular immunity.


[Comparative study of the efficacy of two types of BCG vaccines administered in different doses].
In 1993, WHO and UNICEF recommended the administration of 0.05 ml doses of BCG, instead of 0.1 ml, to newborns. This recommendation was adopted by the Chilean Ministry of Health, using the Mérieux vaccine. Subsequently, different Health Services detected a high percentage of children without BCG scar at the time of their growth and development control. To assess the efficacy of BCG vaccination in a double blind randomized fashion, using two vaccine types and different doses. Newborns of two public hospitals of Santiago were randomly assigned to receive the Tokio or Mérieux BCG strains in doses of 0.05 or 0.1 ml. Ninety five to 125 days after vaccination, vaccine scar was measured and inmunogenicity was assessed using the tuberculin test. Six hundred newborns (150 in each group) were included in the protocol and results were assessed in 408. The percentage of children with a PPD reaction of 0 mm was 9.3, 3.7, 7.8 and 0% with the Mérieux vaccine in doses of 0.1 ml, Tokio vaccines in doses of 0.1 ml, Mérieux vaccine in doses of 0.05 ml and Tokio vaccine in doses of 0.05 ml, respectively. In the same groups the scar diameters were 6.4 +/- 3.4, 7.3 +/- 2.7, 5.6 +/- 2.8 and 7.3 +/- 2.9 mm. The observed differences for each group are significant, depending on the type of strain and dose, but favoring the Tokio type of vaccine. The BCG scar diameters obtained in this study are similar to those obtained in previous works in 1984 and 1986. This scar is the evidence of vaccination that nurses detect in health controls. Therefore the use of 0.1 doses for vaccination, that result in better scars and PPD response, is recommended.


Organic Fouling of Graphene Oxide Membranes and Its Implications for Membrane Fouling Control in Engineered Osmosis.
This study provides experimental evidence to mechanistically understand some contradicting effects of the characteristic properties of graphene oxide (GO), such as the high hydrophilicity, negative charge, strong adsorption capability, and large surface area, on the antifouling properties of GO membranes. Furthermore, this study demonstrates the effectiveness of forming a dense GO barrier layer on the back (i.e., porous) side of an asymmetric membrane for fouling control in pressure-retarded osmosis (PRO), an emerging engineered osmosis process whose advancement has been much hindered due to the severe irreversible fouling that occurs as foulants accumulate inside the porous membrane support. In the membrane fouling experiments, protein and alginate were used as model organic foulants. When operated in forward osmosis mode, the GO membrane exhibited fouling performance comparable with that of a polyamide (PA) membrane. Analysis of the membrane adsorption capacity showed that, likely due to the presence of hydrophobic regions in the GO basal plane, the GO membrane has an affinity toward organic foulants 4 to 5 times higher than the PA membrane. Such a high adsorption capacity along with a large surface area, however, did not noticeably aggravate the fouling problem. Our explanation for this phenomenon is that organic foulants are adsorbed mainly on the basal plane of GO nanosheets, and water enters the GO membrane primarily around the oxidized edges of GO, making foulant adsorption not create much hindrance to water flux. When operated in PRO mode, the GO membrane exhibited much better antifouling performance than the PA membrane. This is because unlike the PA membrane for which foulants can be easily trapped inside the porous support and hence cause severe irreversible fouling, the GO membrane allows the foulants to accumulate primarily on its surface due to the sealing effect of the GO layer assembled on the porous side of the asymmetric membrane support. Results from the physical cleaning experiments further showed that the water flux of GO membranes operated in PRO mode can be sufficiently restored toward its initial prefouling level.


A facile strategy for in situ core-template-functionalizing siliceous hollow nanospheres for guest species entrapment.
The shell wall-functionalized siliceous hollow nanospheres (SHNs) with functional molecules represent an important class of nanocarriers for a rich range of potential applications. Herein, a self-templated approach has been developed for the synthesis of in situ functionalized SHNs, in which the biocompatible long-chain polycarboxylates (i.e., polyacrylate, polyaspartate, gelatin) provide the framework for silica precursor deposition by simply controlling chain conformation with divalent metal ions (i.e., Ca2+, Sr2+), without the intervention of any external templates. Metal ions play crucial roles in the formation of organic vesicle templates by modulating the long chains of polymers and preventing them from separation by washing process. We also show that, by in situ functionalizing the shell wall of SHNs, it is capable of entrapping nearly an eightfold quantity of vitamin Bc in comparison to the bare bulk silica nanospheres. These results confirm the feasibility of guest species entrapment in the functionalized shell wall, and SHNs are effective carriers of guest (bio-)molecules potentially for a variety of biomedical applications. By rationally choosing the functional (self-templating) molecules, this concept may represent a general strategy for the production of functionalized silica hollow structures.


A deep-sea slant on the molecular phylogeny of the Scleractinia.
Lophelia pertusa and Madrepora oculata are azooxanthellate corals with nearly cosmopolitan distributions. They form cold-water reefs in the upper bathyal zone on continental margins and offshore banks [A.D. Rogers, Int. Rev. Hydrobiol. 84 (1999) 315]. Lophelia is classified in the family Caryophylliidae and Madrepora in the family Oculinidae, both on the basis of skeletal morphology. Recent molecular studies of the scleractinians have given a new insight into the evolutionary history of this group. This study was aimed at clarifying the phylogenetic relationships of Lophelia and Madrepora, through the analysis of partial sequences of the mitochondrial 16S rDNA. Sequences were obtained for samples of L. pertusa collected in the northeast Atlantic and off Brazil, M. oculata, four other deep-sea and eight tropical coral species from the Réunion island in the Indian Ocean. The sequences were aligned with 69 homologous sequences of Scleractinia. Maximum parsimony and Bayesian analyses support previously published molecular topologies. The two specimens of L. pertusa grouped with two caryophylliids, confirming the existing classification of the species, but the large genetic distance between the two Lophelia samples suggests that these populations are genetically isolated from one another. M. oculata did not cluster with oculinids, but formed a monotypic clade lying between the families Pocilloporidae and Caryophyliidae. Phylogenetic analysis also suggested cryptic speciation within the tropical taxa Pocillopora meandriana and possibly Acropora humilis.


Laparoscopic versus open hepatic resection for hepatocellular carcinoma: improvement in outcomes and similar cost.
To compare outcomes of laparoscopic versus open hepatic resection (OHR) exclusively for hepatocellular carcinoma in terms of morbidity and cost. Laparoscopic hepatic resection (LHR) has become more prevalent with recent improvements in instrumentation and surgeon experience. A review of multicenter, prospectively collected hepatobiliary databases from three institutions was performed from 12/1990 to 12/2009. Prospective evaluation of all patients undergoing hepatectomy for hepatocellular cancer was performed. A total of 354 patients who had resections for Hepatocellular carcinoma (HCC) were analyzed, 100 were performed laparoscopically. The two groups were similar in terms of demographics and comorbidities. Evaluation of outcomes showed significantly higher intraoperative estimated blood loss although postoperative transfusion rates were similar. The incidence of any complication (44 vs 44%, p = 0.23) and 90-day mortality (6 vs 6%, p = 0.8) were similar between the two groups, with a similar reoperation rate (4.0 vs. 2.4%; p = 0.9). Using Cox regression analysis, the laparoscopic approach had no effect on disease-free interval (OR 1.4, CI 0.31-6.3, p = 0.66) or overall survival (HR 1.2, CI 0.59-2.5 p = 0.6). Length of stay was significantly shorter in the laparoscopic group 6.2 vs. 9.3 days (p = 0.001). Adjusted operative charges ($41 vs. $39 k, p = 0.601) and adjusted total hospital charges ($71 vs. $82 k, p = 0.368) were similar in LHR versus OHR. Our study confirms previous literature showing comparable perioperative outcomes and recurrence. We further show comparable cost with laparoscopic versus open liver resection for HCC.


Analysis of solvent induced porous PMMA-Bioglass monoliths by the phase separation method--mechanical and in vitro biocompatible studies.
Mimicking three dimensional microstructural scaffolds with their requisite mechanical properties in relation to human bone is highly needed for implant applications. Various biocompatible polymers and bioactive glasses were synthesized to achieve these properties. In the present study, we have fabricated highly porous and bioactive PMMA-Bioglass scaffolds by the phase separation method. Chloroform, acetone and an ethanol-water mixture were used as the different solvent phases in preparing the scaffolds. Large interconnecting pores of sizes ∼100 to 250 μm were observed in the scaffolds and a porosity percentage up to 54% was also achieved by this method. All samples showed a brittle fracture with the highest modulus of 91 MPa for the ethanol-water prepared scaffolds. The bioactivities of the scaffolds were further studied by immersing them in simulated body fluid for 28 days. Scanning electron microscopy, X-ray diffraction and Raman spectra confirmed the formation of bioactive hydroxyl calcium apatite on the surfaces of the scaffolds.


Voriconazole Exposure and Risk of Cutaneous Squamous Cell Carcinoma, Aspergillus Colonization, Invasive Aspergillosis and Death in Lung Transplant Recipients.
Voriconazole is a triazole antifungal used to prevent and treat invasive fungal infections after lung transplantation, but it has been associated with an increased risk of developing cutaneous squamous cell carcinoma (SCC). Despite widespread use, there are no clear guidelines for optimal prophylactic regimens that balance the competing risks and benefits. We conducted a retrospective cohort study of all lung transplant recipients at the University of California, San Francisco, who were transplanted between October 1991 and December 2012 (n = 455) to investigate whether voriconazole exposure affected development of SCC, Aspergillus colonization, invasive aspergillosis and all-cause mortality. Voriconazole exposure was associated with a 73% increased risk of developing SCC (hazard ratio [HR] 1.73; 95% confidence interval [CI]: 1.04-2.88; p = 0.03), with each additional 30-day exposure at the standard dose increasing the risk by 3.0% (HR 1.03; 95% CI: 1.02-1.04; p < 0.001). Voriconazole exposure reduced risk of Aspergillus colonization by 50% (HR 0.50; 95% CI: 0.34-0.72; p < 0.001), but we were underpowered to detect risk reduction for invasive aspergillosis. Voriconazole exposure significantly reduced all-cause mortality among subjects who developed Aspergillus colonization (HR 0.34; 95% CI: 0.13-0.91; p = 0.03) but had no significant impact on those without colonization. Physicians should consider patient-specific factors that modify the potential risks and benefits of voriconazole for the care of lung transplant recipients.


Magnetogenetics with Piezo1 Mechanosensitive Ion Channel for CRISPR Gene Editing.
Regulation of genetic activity in single cells and tissues is pivotal to determine key cellular functions in current biomedicine, yet the conventional biochemical activators lack spatiotemporal precision due to the diffusion-mediated slow kinetics and nonselectivity. Here, we describe a magnetogenetic method for target-specific activation of a clustered regularly interspaced short palindromic repeats (CRISPR) system for the regulation of intracellular proteins. We used magnetomechanical force generated by the magnetic nanostructure to activate pre-encoded Piezo1, the mechanosensitive ion channel, on the target cell. The activated Piezo1 further triggers the intracellular Ca2+ signaling pathway, inducing the pre-encoded genes to express genes of interest (GOIs), which is Cas9 protein for the CRISPR regulation of the target proteins. We demonstrated that this magnetogenetic CRISPR system successfully edits the target genome for both in vitro and pseudo-in vivo environments, providing a versatile magnetic platform for remote gene editing of animals with various size scales.


What Are the Characteristics of Primary Angle Closure With Longer Axial Length?
To compare biometric parameters between primary angle closure with longer axial length (AL) and those with medium or shorter AL. We prospectively recruited 138 primary angle-closure patients. Low-coherence interferometry and ultrasound biomicroscopy examinations were performed before laser peripheral iridotomy and pilocarpine treatment. AL was categorized as shorter (<22.5 mm), medium (≥22.5 to <23.5 mm), or longer (≥23.5 mm). Anterior chamber depth and width (ACD and ACW), lens vault (LV), anterior vault (AV), relative AV (AV/AL), relative lens position (RLP, [ACD + 1/2 lens thickness]/AL), trabecular-ciliary angle (TCA), keratometry, and other biometric parameters were compared among different AL groups. Among 138 angle-closure patients, 15 (10.9%) patients had longer ALs, of which 11 (73.3%) were male. These angle-closure eyes with longer AL had flatter cornea (P = 0.006 and 0.022 for flat and steep keratometry) and larger ACW (P = 0.006), but smaller RLP (P = 0.019) than those with medium AL; similarly, they had flatter cornea (P < 0.001 for both flat and steep keratometry), and larger ACW (P < 0.001), AV (P = 0.004), and TCA (P = 0.024), but smaller relative AV (P = 0.040) and RLP (P = 0.005) than those with shorter AL. No significant differences were found in the other parameters. Primary angle closure with longer AL was uncommon. Causes of angle closure in these atypical patients were manifold. These patients were predominantly male; they had smaller relative dimension of the anterior segment, flatter cornea, and more anterior RLP and less anteriorly rotated ciliary body compared with those angle-closure patients with relatively shorter AL.


A strategy for collecting pharmacoeconomic data during phase II/III clinical trials.
This article presents an overview of the process and organisational aspects required to support the collection of pharmacoeconomic (PE) data during phase II and phase III clinical trials of pharmaceutical products. The process described requires early involvement of the PE study team in clinical trials design and planning, as well as continuing close collaboration between the PE study team and the clinical study team as the data collection plans are implemented. Adequate resources must be made available for staffing and funding the PE component of data collection and analysis. If the suggested procedures are adequately resourced and implemented, the result should be a comprehensive, complete and accurate database that will allow the PE study team to characterise the economic value of the new drug at the same time as the clinical study team characterise its safety and efficacy. Integrated clinical and economic evaluations are essential for the appropriate use of pharmaceutical products in rapidly changing markets.


Performance of five research-domain automated WM lesion segmentation methods in a multi-center MS study.
In vivoidentification of white matter lesions plays a key-role in evaluation of patients with multiple sclerosis (MS). Automated lesion segmentation methods have been developed to substitute manual outlining, but evidence of their performance in multi-center investigations is lacking. In this work, five research-domain automated segmentation methods were evaluated using a multi-center MS dataset. 70 MS patients (median EDSS of 2.0 [range 0.0-6.5]) were included from a six-center dataset of the MAGNIMS Study Group (www.magnims.eu) which included 2D FLAIR and 3D T1 images with manual lesion segmentation as a reference. Automated lesion segmentations were produced using five algorithms: Cascade; Lesion Segmentation Toolbox (LST) with both the Lesion growth algorithm (LGA) and the Lesion prediction algorithm (LPA); Lesion-Topology preserving Anatomical Segmentation (Lesion-TOADS); and k-Nearest Neighbor with Tissue Type Priors (kNN-TTP). Main software parameters were optimized using a training set (N = 18), and formal testing was performed on the remaining patients (N = 52). To evaluate volumetric agreement with the reference segmentations, intraclass correlation coefficient (ICC) as well as mean difference in lesion volumes between the automated and reference segmentations were calculated. The Similarity Index (SI), False Positive (FP) volumes and False Negative (FN) volumes were used to examine spatial agreement. All analyses were repeated using a leave-one-center-out design to exclude the center of interest from the training phase to evaluate the performance of the method on 'unseen' center. Compared to the reference mean lesion volume (4.85 ± 7.29 mL), the methods displayed a mean difference of 1.60 ± 4.83 (Cascade), 2.31 ± 7.66 (LGA), 0.44 ± 4.68 (LPA), 1.76 ± 4.17 (Lesion-TOADS) and -1.39 ± 4.10 mL (kNN-TTP). The ICCs were 0.755, 0.713, 0.851, 0.806 and 0.723, respectively. Spatial agreement with reference segmentations was higher for LPA (SI = 0.37 ± 0.23), Lesion-TOADS (SI = 0.35 ± 0.18) and kNN-TTP (SI = 0.44 ± 0.14) than for Cascade (SI = 0.26 ± 0.17) or LGA (SI = 0.31 ± 0.23). All methods showed highly similar results when used on data from a center not used in software parameter optimization. The performance of the methods in this multi-center MS dataset was moderate, but appeared to be robust even with new datasets from centers not included in training the automated methods.


Occupation and adult gliomas in the San Francisco Bay Area.
The etiology of gliomas is not well understood. Some jobs might involve sustained and elevated exposures to carcinogens. This study compares lifetime job histories of 879 glioma cases diagnosed between August 1991 to April 1994 and May 1997 to August 1999 in the San Francisco Bay Area and 864 controls. Logistic analyses compared longest and ever held occupations of 1 year or more for all astrocytic and nonastrocytic cases and controls overall with adjustment for age, gender, and ethnicity and separately for men and women. Two-fold or higher or statistically significant elevated odds ratios were found overall and in men among those with longest held occupations, as firefighters, physicians, material moving equipment operators, and janitors; such elevated odds ratios were also observed for longest-held occupations among male motor vehicle operators and personal service workers and female messengers, legal/social service workers, electronic equipment operators, painters, and food processors. Odds ratios of 0.50 or less, but not statistically significant, were found for those with longest held jobs as writers/journalists, biological scientists, paper workers, mechanics, chemists, and photographers/photoprocessors. This study supports previously observed occupational associations and is one of the few studies with sufficient numbers to separately analyze occupations by gender.


Monitoring sexual behaviour in general populations: a synthesis of lessons of the past decade.
This supplement contains selected papers from a workshop on the measurement of sexual behaviour in the era of HIV/AIDS held at the London School of Hygiene and Tropical Medicine in September 2003. The focus was on low and middle income countries, where the majority of HIV infections occur. The motive for holding such a meeting is easy to discern. As the AIDS pandemic continues to spread and as prevention programmes are scaling up, the need to monitor trends in sexual risk behaviours becomes ever more pressing. Behavioural data are an essential complement to biological evidence of changes in HIV prevalence or incidence. Biological evidence, though indispensable, is by itself insufficient for policy and programme guidance. AIDS control programmes need to be based on monitoring of not only trends in infections but also of trends in those behaviours that underlie epidemic curtailment or further spread.


The macaque brain ONPRC18 template with combined gray and white matter labelmap for multimodal neuroimaging studies of Nonhuman Primates.
Macaques are the most common nonhuman primate (NHP) species used in neuroscience research. With the advancement of many neuroimaging techniques, new studies are beginning to apply multiple types of in vivo magnetic resonance imaging (MRI), such as structural imaging (sMRI) with T1 and T2 weighted contrasts alongside diffusion weighed (DW) imaging. In studies involving rhesus macaques, this approach can be used to better understand micro-structural changes that occur during development, in various disease states or with normative aging. However, many of the available rhesus brain atlases have been designed for only one imaging modality, making it difficult to consistently define the same brain regions across multiple imaging modalities in the same subject. To address this, we created a brain atlas from 18 adult rhesus macaques that includes co-registered templates constructed from images frequently used to characterize macroscopic brain structure (T2/SPACE and T1/MP-RAGE), and a diffusion tensor imaging (DTI) template. The DTI template was up-sampled from 1 mm isotropic resolution to resolution match to the T1 and T2-weighted images (0.5 mm isotropic), and the parameter maps were derived for FA, AD, RD and MD.The labelmap volumes delineate 57 gray matter regions of interest (ROIs; 36 cortical regions and 21 subcortical structures), as well as 74 white matter tracts. Importantly, the labelmap overlays both the structural and diffusion templates, enabling the same regions to be consistently identified across imaging modalities. A specialized condensed version of the labelmap ROIs are also included to further extend the usefulness of this tool for imaging data with lower spatial resolution, such as functional MRI (fMRI) or positron emission tomography (PET).


Heterotopic heart transplantation in the rat receiving FK-506 alone or with cyclosporine.
In rats, FK significantly prolonged heterotopic heart graft survival over a wide dose range when given for 2 weeks starting on the day of the operation. Brief courses of FK for one to four days preoperatively, and especially beginning four days postoperatively, allowed long subsequent survival of heart grafts in otherwise untreated recipients. The seeming acceptance of the grafts with postoperative FK treatment was largely but not exclusively donor specific when tested eight days after the last FK dose by second grafts from the same donor v third-party donor grafts. FK in minimally therapeutic doses was synergistic with suboptimal doses of CyA.


Sex differences in line bisection as a function of hand.
If subjects are asked to indicate the midpoint of a horizontal line, they tend to bisect it left of the center, a phenomenon called 'pseudoneglect'. Assuming that this task evokes visuospatial processes, the left bias is generally considered to arise from a right-hemispheric activation. Numerous factors affect pseudoneglect. Although, only few studies have examined the influence of sex in visual line bisection, most of theses studies reported no significant main effect of sex. Possible interactions between sex and other performance factors that are linked to the motor component of this task, e.g. hand use, are rarely examined. We studied the interaction of these two variables using right-handed females and males in a line bisection task. The results clearly indicate that hand use and sex interact, with females showing the left bias to a similar extent with both hands while males show the bias predominantly with the left hand. Moreover, the position of the lines (left, middle and right) significantly affect left bias in visual line bisection and interact with hand use. It is hypothesized that the larger cross-section of the posterior corpus callosum in females enables a stronger interhemispheric connectivity of visuospatial cortical areas resulting in a strong left-sided bias in hand motor cortical areas of both hemispheres. In males, motor cortical activation would accordingly be mainly restricted to the right hemisphere.


3-dimensional characterization of thick grating formation in PVA/AA based photopolymer.
Large thickness is required in holographic recording materials to be used as holographic memories. Photopolymers have proved to be a good alternative to construct holographic memories. Nevertheless, modeling the behavior of thick layers poses some problems due to high absorption of the dye, as discussed in previous papers. In this study, the gratings stored in photopolymers based on PVA/AA are analyzed considering the attenuation of light in depth. This is done by fitting the theoretical results, predicted by a model that considers this effect, to the experimental results obtained using diffraction gratings recorded in PVA/AA based photopolymer. In order to determine the diffraction efficiency at the first Bragg angle, an algorithm based on the rigorous coupled wave theory is used. Also, the characteristics of the gratings obtained using different recording intensities are analyzed, and the effective optical thickness is seen to increase as the intensity is increased.


Radiological changes five years after unicompartmental knee replacement.
Failure of a unicompartmental knee replacement (UKR) may be caused by progressive osteoarthritis of the knee and/or failure of the prosthesis. Limb alignment can influence both of these factors. We have examined the fate of the other compartments and measured changes in leg alignment after UKR. A total of 50 UKRs was carried out on 45 carefully selected patients between 1989 and 1992. At operation, deliberate attempts were made to avoid overcorrection of the deformity. Four patients died, one patient was lost to follow-up and two knees were revised before review which was at a minimum of five years. Standard long-leg weight-bearing anteroposterior views of the knee and skyline views of the patellofemoral joint were taken before and at eight months and five years after operation. The radiographs of the remaining 43 knees were reviewed twice by blind and randomised assessment to measure the progression of osteoarthritis within the joints. Overcorrection of the deformity in the coronal plane was avoided in all but two knees. Only one showed evidence of progression of osteoarthritis within the patellofemoral joint, and this was only identified in one of the four assessments. Deterioration in the state of the opposite tibiofemoral compartment was not seen. Varus deformity tended to recur. Recurrent varus of 2 degrees was observed between eight months and five years after operation. There was no correlation between the postoperative tibiofemoral angle and the extent of recurrent varus recorded at five years. Changes in alignment may be indicative of minor polyethylene wear or of subsidence of the tibial component. The incidence of progressive osteoarthritis within the knee was very low after UKR. Patients should be carefully selected and overcorrection of the deformity be avoided.


Calculations of and evidence for chain packing stress in inverse lyotropic bicontinuous cubic phases.
Inverse bicontinuous cubic lyotropic phases are a complex solution to the dilemma faced by all self-assembled water-amphiphile systems: how to satisfy the incompatible requirements for uniform interfacial curvature and uniform molecular packing. The solution reached in this case is for the water-amphiphile interfaces to deform hyperbolically onto triply periodic minimal surfaces. We have previously suggested that although the molecular packing in these structures is rather uniform the relative phase behavior of the gyroid, double diamond, and primitive inverse bicontinuous cubic phases can be understood in terms of subtle differences in packing frustration. In this work, we have calculated the packing frustration for these cubics under the constraint that their interfaces have constant mean curvature. We find that the relative packing stress does indeed differ between phases. The gyroid cubic has the least packing stress, and at low water volume fraction, the primitive cubic has the greatest packing stress. However, at very high water volume fraction, the double diamond cubic becomes the structure with the greatest packing stress. We have tested the model in two ways. For a system with a double diamond cubic phase in excess water, the addition of a hydrophobe may release packing frustration and preferentially stabilize the primitive cubic, since this has previously been shown to have lower curvature elastic energy. We have confirmed this prediction by adding the long chain alkane tricosane to 1-monoolein in excess water. The model also predicts that if one were able to hydrate the double diamond cubic to high water volume fractions, one should destabilize the phase with respect to the primitive cubic. We have found that such highly swollen metastable bicontinuous cubic phases can be formed within onion vesicles. Data from monoelaidin in excess water display a well-defined transition, with the primitive cubic appearing above a water volume fraction of 0.75. Both of these results lend support to the proposition that differences in the packing frustration between inverse bicontinuous cubic phases play a pivotal role in their relative phase stability.


Adrenal collision tumors and their mimics: multimodality imaging findings.
Adrenal collision tumors (ACTs) refer to coexistence of two adjacent, but histologically distinct neoplasms involving the adrenal gland without histologic admixture at interface. ACTs include adenoma with myelolipoma, adenoma with metastases, hemangioma with adenoma, and adrenocortical carcinoma with myelolipoma. In addition, hemorrhage into a pre-existing adrenal mass can mimic an ACT, and it is important to differentiate these two pathologies. Accurate characterization of ACTs is difficult, but critical, for correct staging of patients with malignancies and to guide percutaneous biopsy. Magnetic resonance imaging (MRI) and multidetector computed tomography imaging techniques may depict different tumor components separately; however, biopsy may be required in selected patients for confirmation. [(18)F]Fluorodeoxyglucose-positron emission tomography (PET) shows increased uptake in the malignant component of ACTs, and guides percutaneous biopsy. Even in patients requiring percutaneous biopsy for a definite diagnosis, imaging findings can help in guiding the appropriate component to be biopsied. Knowledge of imaging findings of different ACTs and their mimics on MRI, computed tomography, and PET help in optimal patient management.


Probability density of the orbital angular momentum mode of Hankel-Bessel beams in an atmospheric turbulence.
We develop a novel model of the probability density of the orbital angular momentum (OAM) modes for Hankel-Bessel beams in paraxial turbulence channel based on the Rytov approximation. The results show that there are multi-peaks of the mode probability density along the radial direction. The peak position of the mode probability density moves to beam center with the increasing of non-Kolmogorov turbulence-parameters and the generalized refractive-index structure parameters and with the decreasing of OAM quantum number, propagation distance and wavelength of the beams. Additionally, larger OAM quantum number and smaller non-Kolmogorov turbulence-parameter can be selected in order to obtain larger mode probability density. The probability density of the OAM mode crosstalk is increasing with the decreasing of the quantum number deviation and the wavelength. Because of the focusing properties of Hankel-Bessel beams in turbulence channel, compared with the Laguerre-Gaussian beams, Hankel-Bessel beams are a good light source for weakening turbulence spreading of the beams and mitigating the effects of turbulence on the probability density of the OAM mode.


Polyparasitism with Schistosoma haematobium and soil-transmitted helminth infections among school children in Loum, Cameroon.
Prevalence and abundance of Schistosoma haematobium and soil-transmitted helminths (STH) were assessed among a total of 1600 pupils (urine, n = 1190; faecal samples, n = 1454) attending five schools in Loum, Littoral Province, Cameroon, with the specific aim of assessing the extent of polyparasitism and the extent to which infections were focused in particular subsets of the study group. Prevalence of S. haematobium was 62.8% with an abundance (arithmetic mean of egg counts) of 54 eggs/10 ml urine. For the STH these were 47.7% and 619 eggs per gram of faeces (EPG) for Trichuris trichiura, 65.5% and 3636 EPG for Ascaris lumbricoides, and 1.4% and <0.1 EPG for hookworms. Most children (90.3%) were infected with at least one of these four species, the largest proportion (34.3%) carrying two species; 27.4% carried three and 1.1% carried concurrently all four species of parasites. The average number of species harboured increased with age, as did the prevalences of S. haematobium and T. trichiura but not that of A. lumbricoides. All STH showed marked differences in prevalence between the five schools but only T. trichiura varied significantly between sexes. Mean abundance of infection varied significantly between age classes, among schools and between the sexes, with females showing heavier mean EPGs for A. lumbricoides and T. trichiura and males higher mean eggs/10 ml urine for S. haematobium infections. A highly significant association was detected between A. lumbricoides and T. trichiura, that was not context-dependent. This was confirmed in quantitative analyses after controlling for differences in abundance between schools, sexes and age classes. A weaker context-dependent association (prevalence data) was detected between S. haematobium and A. lumbricoides (sex- and age-dependent) but quantitative associations between these two species, as well as between S. haematobium and T. trichiura, were not convincing.


CNOT3 is a modifier of PRPF31 mutations in retinitis pigmentosa with incomplete penetrance.
Heterozygous mutations in the PRPF31 gene cause autosomal dominant retinitis pigmentosa (adRP), a hereditary disorder leading to progressive blindness. In some cases, such mutations display incomplete penetrance, implying that certain carriers develop retinal degeneration while others have no symptoms at all. Asymptomatic carriers are protected from the disease by a higher than average expression of the PRPF31 allele that is not mutated, mainly through the action of an unknown modifier gene mapping to chromosome 19q13.4. We investigated a large family with adRP segregating an 11-bp deletion in PRPF31. The analysis of cell lines derived from asymptomatic and affected individuals revealed that the expression of only one gene among a number of candidates within the 19q13.4 interval significantly correlated with that of PRPF31, both at the mRNA and protein levels, and according to an inverse relationship. This gene was CNOT3, encoding a subunit of the Ccr4-not transcription complex. In cultured cells, siRNA-mediated silencing of CNOT3 provoked an increase in PRPF31 expression, confirming a repressive nature of CNOT3 on PRPF31. Furthermore, chromatin immunoprecipitation revealed that CNOT3 directly binds to a specific PRPF31 promoter sequence, while next-generation sequencing of the CNOT3 genomic region indicated that its variable expression is associated with a common intronic SNP. In conclusion, we identify CNOT3 as the main modifier gene determining penetrance of PRPF31 mutations, via a mechanism of transcriptional repression. In asymptomatic carriers CNOT3 is expressed at low levels, allowing higher amounts of wild-type PRPF31 transcripts to be produced and preventing manifestation of retinal degeneration.


Extending Vulnerability Assessment to Include Life Stages Considerations.
Species are experiencing a suite of novel stressors from anthropogenic activities that have impacts at multiple scales. Vulnerability assessment is one tool to evaluate the likely impacts that these stressors pose to species so that high-vulnerability cases can be identified and prioritized for monitoring, protection, or mitigation. Commonly used semi-quantitative methods lack a framework to explicitly account for differences in exposure to stressors and organism responses across life stages. Here we propose a modification to commonly used spatial vulnerability assessment methods that includes such an approach, using ocean acidification in the California Current as an illustrative case study. Life stage considerations were included by assessing vulnerability of each life stage to ocean acidification and were used to estimate population vulnerability in two ways. We set population vulnerability equal to: (1) the maximum stage vulnerability and (2) a weighted mean across all stages, with weights calculated using Lefkovitch matrix models. Vulnerability was found to vary across life stages for the six species explored in this case study: two krill-Euphausia pacifica and Thysanoessa spinifera, pteropod-Limacina helicina, pink shrimp-Pandalus jordani, Dungeness crab-Metacarcinus magister and Pacific hake-Merluccius productus. The maximum vulnerability estimates ranged from larval to subadult and adult stages with no consistent stage having maximum vulnerability across species. Similarly, integrated vulnerability metrics varied greatly across species. A comparison showed that some species had vulnerabilities that were similar between the two metrics, while other species' vulnerabilities varied substantially between the two metrics. These differences primarily resulted from cases where the most vulnerable stage had a low relative weight. We compare these methods and explore circumstances where each method may be appropriate.


Simple parameter determination for twisted nematic liquid-crystal display.
A simple and accurate measurement method for determining the cell parameters of a twisted nematic liquid-crystal display (TN-LCD) is proposed. Based on the measurement of the maximum reflectance and the maximum transmittance of a TN-LCD by rotating the polarizer at a particular angle, between the front director of the liquid crystals and the transmission axis of the polarizer, the cell gap and the twist angle can be determined according to the Jones matrix theory, and the twist sense can also be determined easily by applying an external small voltage to slightly change the effective refractive index of the liquid crystal.


Nutrient oxidation patterns and protein metabolism in lean and obese subjects.
The immediate metabolic response to eating has been compared in a group of grossly obese subjects (W/H2 = 45) with that in lean controls (W/H2 = 22). Dietary intake of energy for obese subjects was based on their estimated basal energy expenditure for ideal body weight (given at an hourly rate of 3 X BMR over a 4-h period). Lean subjects were measured twice: control 1 with the same intake of energy as the obese in terms of ideal body weight and control 2 with the same energy intake in relation to each subject's measured resting energy expenditure (2.2 X REE). The changes in energy expenditure and nutrient disposal with the onset of eating have been assessed by a method of combined respiratory gas analysis and intravenous infusion of 13C-labelled leucine. Leucine kinetics were used to quantitate rapid changes in protein oxidation and to assess protein synthesis and degradation. 1) Total energy expenditure was 20-30 per cent greater in obese subjects than lean subjects in fasting and feeding. Energy expenditure expressed per kg fat-free mass, from D2O dilution, was similar in obese and lean subjects in both fasting (5.8 v. 5.5 kJ/kg FFM/h) and feeding [6.7 v. 6.3 (Control 2) kJ/kg FFM/h]. 2) The onset of eating was associated with increased carbohydrate and protein oxidation with decreased fat oxidation in both lean and obese individuals. In obese subjects, however, both the decrease in fat oxidation and the increase in protein oxidation were significantly smaller (P less than 0.05) than the corresponding increments in lean subjects (Control 2). 3) The rate of protein synthesis was significantly (P less than 0.05) higher in obese subjects both in the fasting state (99 v. 84 mumols leucine/kg FFM/h) and in the fed state [94 v. 67 (Control 2) mumols leucine/kg FFM/h]. The rate of protein degradation was also higher in obese individuals in fasting (117 +/- 6 v. 106 +/- 4 mumol leucine/kg FFM/h) and feeding [65 +/- 4 v. 54 +/- 6 (Control 2) mumol leucine/kg FFM/h] though these differences are not statistically significant (P greater than 0.05). 4) The observed differences between obese and lean individuals in protein and energy metabolism in the fasted state and in the immediate response to eating do not support a hypothesis of greater metabolic efficiency in obesity.


Effects of Reducing Suppressors of Cytokine Signaling-3 (SOCS3) Expression on Dendritic Outgrowth and Demyelination after Spinal Cord Injury.
Suppressors of cytokine signaling-3 (SOCS3) is associated with limitations of nerve growth capacity after injury to the central nervous system. Although genetic manipulations of SOCS3 can enhance axonal regeneration after optic injury, the role of SOCS3 in dendritic outgrowth after spinal cord injury (SCI) is still unclear. The present study investigated the endogenous expression of SOCS3 and its role in regulating neurite outgrowth in vitro. Interleukin-6 (IL-6) induces SOCS3 expression at the mRNA and protein levels in neuroscreen-1 (NS-1) cells. In parallel to SOCS3 expression, IL-6 induced tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3) in NS-1 cells. Lentiviral delivery of short hairpin RNA (shSOCS3) (Lenti-shSOCS3) to decrease SOCS3 expression into NS-1 cells enhanced IL-6-induced tyrosine phosphorylation of STAT3 (P-STAT3 Tyr705) and promoted neurite outgrowth. In addition, we determined if reduction of SOCS3 expression by microinjection of Lenti-shSOCS3 into spinal cord enhances dendrite outgrowth in spinal cord neurons after SCI. Knocking down of SOCS3 in spinal cord neurons with Lenti-shSOCS3 increased complete SCI-induced P-STAT3 Tyr705. Immunohistochemical analysis showed that complete SCI induced a significant reduction of microtubule association protein 2-positive (MAP-2+) dendrites in the gray and white matter at 1 and 4 weeks after injury. The SCI-induced reduction of MAP-2+ dendrites was inhibited by infection with Lenti-shSOCS3 in areas both rostral and caudal to the lesion at 1 and 4 weeks after complete SCI. Furthermore, shSOCS3 treatment enhanced up-regulation of growth associated protein-43 (GAP-43) expression, which co-localized with MAP-2+ dendrites in white matter and with MAP-2+ cell bodies in gray matter, indicating Lenti-shSOCS3 may induce dendritic regeneration after SCI. Moreover, we demonstrated that Lenti-shSOCS3 decreased SCI-induced demyelination in white matter of spinal cord both rostral and caudal to the injury site 1 week post-injury, but not rostral to the injury at 4 weeks post-injury. Importantly, similar effects as Lenti-shSOCS3 on increasing MAP-2+ intensity and dendrite length, and preventing demyelination were observed when a second shSOCS3 (Lenti-shSOCS3 #2) was applied to rule out the possibilities of off target effects of shRNA. Collectively, these results suggest that knocking down of SOCS3 enhances dendritic regeneration and prevents demyelination after SCI.


V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations.
Severe combined immunodeficiency (SCID) comprises a heterogeneous group of primary immunodeficiencies, a proportion of which are due to mutations in either of the 2 recombination activating genes (RAG)-1 and -2, which mediate the process of V(D)J recombination leading to the assembly of antigen receptor genes. It is reported here that the clinical and immunologic phenotypes of patients bearing mutations in RAGs are more diverse than previously thought and that this variability is related, in part, to the specific type of RAG mutation. By analyzing 44 such patients from 41 families, the following conclusions were reached: (1) null mutations on both alleles lead to the T-B-SCID phenotype; (2) patients manifesting classic Omenn syndrome (OS) have missense mutations on at least one allele and maintain partial V(D)J recombination activity, which accounts for the generation of residual, oligoclonal T-lymphocytes; (3) in a third group of patients, findings were only partially compatible with OS, and these patients, who also carried at least one missense mutation, may be considered to have atypical SCID/OS; (4) patients with engraftment of maternal T cells as a complication of a transplacental transfusion represented a fourth group, and these patients, who often presented with a clinical phenotype mimicking OS, may be observed regardless of the type of RAG gene mutation. Analysis of the RAG genes by direct sequencing is an effective way to provide accurate diagnosis of RAG-deficient as opposed to RAG-independent V(D)J recombination defects, a distinction that cannot be made based on clinical and immunologic phenotype alone.


Target site search and effective inhibition of leukaemic cell growth by a covalently closed multiple anti-sense oligonucleotide to c-myb.
Systematic secondary structure simulation of a target mRNA sequence is shown to be effective for locating a good anti-sense target site. Multiple selected anti-sense sequences were placed in a single molecule. The anti-sense oligonucleotide (oligo) was covalently closed to avoid exonuclease activities and was designated CMAS (covalently closed multiple anti-sense)-oligo. CMAS-oligo was found to be stable, largely preserving its structural integrity after 24 h of incubation in the presence of either exonuclease III or serum. When human c-myb mRNA was targeted by the c-myb CMAS-oligo, expression of the gene was completely abolished. Further, tumour cell growth was inhibited by 82+/-3% as determined by an MTT [3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide] assay and by 90+/-1% by [(3)H]thymidine incorporation. When a leukaemic cell line K562 was treated with CMAS-oligo, colony formation on soft agarose was also decreased by 93%. In contrast, treatment with a scrambled control oligo did not significantly inhibit leukaemic cell growth. These results suggest that a rational target site search is possible for an anti-sense oligo and that CMAS-oligo can be employed as an effective anti-sense agent with enhanced stability.


Unbiased quantitation of Escherichia coli membrane proteome using phase transfer surfactants.
We developed a sample preparation protocol for rapid and unbiased analysis of the membrane proteome using an alimentary canal-mimicking system in which proteases are activated in the presence of bile salts. In this rapid and unbiased protocol, immobilized trypsin is used in the presence of deoxycholate and lauroylsarcosine to increase digestion efficiency as well as to increase the solubility of the membrane proteins. Using 22.5 microg of Escherichia coli whole cell lysate, we quantitatively demonstrated that membrane proteins were extracted and digested at the same level as soluble proteins without any solubility-related bias. The recovery of membrane proteins was independent of the number of transmembrane domains per protein. In the analysis of the membrane-enriched fraction from 22.5 microg of E. coli cell lysate, the abundance distribution of the membrane proteins was in agreement with that of the membrane protein-coding genes when this protocol, coupled with strong cation exchange prefractionation prior to nano-LC-MS/MS analysis, was used. Because this protocol allows unbiased sample preparation, protein abundance estimation based on the number of observed peptides per protein was applied to both soluble and membrane proteins simultaneously, and the copy numbers per cell for 1,453 E. coli proteins, including 545 membrane proteins, were successfully obtained. Finally, this protocol was applied to quantitative analysis of guanosine tetra- and pentaphosphate-dependent signaling in E. coli wild-type and relA knock-out strains.


Predictors of NOAC versus VKA use for stroke prevention in patients with newly diagnosed atrial fibrillation: Results from GARFIELD-AF.
A principal aim of the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF) was to document changes in treatment practice for patients with newly diagnosed atrial fibrillation during an era when non-vitamin K antagonist oral anticoagulants (NOACs) were becoming more widely adopted. In these analyses, the key factors which determined the choice between NOACs and vitamin K antagonists (VKAs) are explored. Logistic least absolute shrinkage and selection operator regression determined predictors of NOAC and VKA use. Data were collected from 24,137 patients who were initiated on AC ± antiplatelet (AP) therapy (NOAC [51.4%] or VKA [48.6%]) between April 2013 and August 2016. The most significant predictors of AC therapy were country, enrolment year, care setting at diagnosis, AF type, concomitant AP, and kidney disease. Patients enrolled in emergency care or in the outpatient setting were more likely to receive a NOAC than those enrolled in hospital (OR 1.16 [95% CI: 1.04-1.30], OR: 1.15 [95% CI: 1.05-1.25], respectively). NOAC prescribing seemed to be favored in lower-risk groups, namely, patients with paroxysmal AF, normotensive patients, and those with moderate alcohol consumption, but also the elderly and patients with acute coronary syndrome. By contrast, VKAs were preferentially used in patients with permanent AF, moderate to severe kidney disease, heart failure, vascular disease, and diabetes and with concomitant AP. GARFIELD-AF data highlight marked heterogeneity in stroke prevention strategies globally. Physicians are adopting an individualized approach to stroke prevention where NOACs are favored in patients with a lower stroke risk but also in the elderly and patients with acute coronary syndrome.


Comparative whole genome transcriptome analysis of three Plasmodium falciparum strains.
Gene expression patterns have been demonstrated to be highly variable between similar cell types, for example lab strains and wild strains of Saccharomyces cerevisiae cultured under identical growth conditions exhibit a wide range of expression differences. We have used a genome-wide approach to characterize transcriptional differences between strains of Plasmodium falciparum by characterizing the transcriptome of the 48 h intraerythrocytic developmental cycle (IDC) for two strains, 3D7 and Dd2 and compared these results to our prior work using the HB3 strain. These three strains originate from geographically diverse locations and possess distinct drug sensitivity phenotypes. Our goal was to identify transcriptional differences related to phenotypic properties of these strains including immune evasion and drug sensitivity. We find that the highly streamlined transcriptome is remarkably well conserved among all three strains, and differences in gene expression occur mainly in genes coding for surface antigens involved in parasite-host interactions. Our analysis also detects several transcripts that are unique to individual strains as well as identifying large chromosomal deletions and highly polymorphic regions across strains. The majority of these genes are uncharacterized and have no homology to other species. These tractable transcriptional differences provide important phenotypes for these otherwise highly related strains of Plasmodium.


Prevalent serum antibody is not a marker of immune protection against acquisition of oncogenic HPV16 in men.
In women, naturally induced anti-human papilloma virus (HPV) serum antibodies are a likely marker of host immune protection against subsequent HPV acquisition and progression to precancerous lesions and cancers. However, it is unclear whether the same is the case in men. In this study, we assessed the risk of incident genital infection and 6-month persistent genital infection with HPV16 in relation to baseline serostatus in a cohort of 2,187 men over a 48-month period. Genital swabs were collected every 6 months and tested for HPV presence. Incidence proportions by serostatus were calculated at each study visit to examine whether potential immune protection attenuated over time. Overall, incidence proportions did not differ statistically between baseline seropositive and seronegative men at any study visit or over the follow-up period. The risk of incident and 6-month persistent infection was not associated with baseline serostatus or baseline serum antibody levels in the cohort. Our findings suggest that baseline HPV seropositivity in men is not associated with reduced risk of subsequent HPV16 acquisition. Thus, prevalent serum antibodies induced by prior infection may not be a suitable marker for subsequent immune protection against genital HPV16 acquisition in men.


How do tiger moths jam bat sonar?
The tiger moth Bertholdia trigona is the only animal in nature known to defend itself by jamming the sonar of its predators - bats. In this study we analyzed the three-dimensional flight paths and echolocation behavior of big brown bats (Eptesicus fuscus) attacking B. trigona in a flight room over seven consecutive nights to determine the acoustic mechanism of the sonar-jamming defense. Three mechanisms have been proposed: (1) the phantom echo hypothesis, which states that bats misinterpret moth clicks as echoes; (2) the ranging interference hypothesis, which states that moth clicks degrade the bats' precision in determining target distance; and (3) the masking hypothesis, which states that moth clicks mask the moth echoes entirely, making the moth temporarily invisible. On nights one and two of the experiment, the bats appeared startled by the clicks; however, on nights three through seven, the bats frequently missed their prey by a distance predicted by the ranging interference hypothesis (∼15-20 cm). Three-dimensional simulations show that bats did not avoid phantom targets, and the bats' ability to track clicking prey contradicts the predictions of the masking hypothesis. The moth clicks also forced the bats to reverse their stereotyped pattern of echolocation emissions during attack, even while bats continued pursuit of the moths. This likely further hinders the bats' ability to track prey. These results have implications for the evolution of sonar jamming in tiger moths, and we suggest evolutionary pathways by which sonar jamming may have evolved from other tiger moth defense mechanisms.


Better assessment of physical function: item improvement is neglected but essential.
Physical function is a key component of patient-reported outcome (PRO) assessment in rheumatology. Modern psychometric methods, such as Item Response Theory (IRT) and Computerized Adaptive Testing, can materially improve measurement precision at the item level. We present the qualitative and quantitative item-evaluation process for developing the Patient Reported Outcomes Measurement Information System (PROMIS) Physical Function item bank. The process was stepwise: we searched extensively to identify extant Physical Function items and then classified and selectively reduced the item pool. We evaluated retained items for content, clarity, relevance and comprehension, reading level, and translation ease by experts and patient surveys, focus groups, and cognitive interviews. We then assessed items by using classic test theory and IRT, used confirmatory factor analyses to estimate item parameters, and graded response modeling for parameter estimation. We retained the 20 Legacy (original) Health Assessment Questionnaire Disability Index (HAQ-DI) and the 10 SF-36's PF-10 items for comparison. Subjects were from rheumatoid arthritis, osteoarthritis, and healthy aging cohorts (n = 1,100) and a national Internet sample of 21,133 subjects. We identified 1,860 items. After qualitative and quantitative evaluation, 124 newly developed PROMIS items composed the PROMIS item bank, which included revised Legacy items with good fit that met IRT model assumptions. Results showed that the clearest and best-understood items were simple, in the present tense, and straightforward. Basic tasks (like dressing) were more relevant and important versus complex ones (like dancing). Revised HAQ-DI and PF-10 items with five response options had higher item-information content than did comparable original Legacy items with fewer response options. IRT analyses showed that the Physical Function domain satisfied general criteria for unidimensionality with one-, two-, three-, and four-factor models having comparable model fits. Correlations between factors in the test data sets were > 0.90. Item improvement must underlie attempts to improve outcome assessment. The clear, personally important and relevant, ability-framed items in the PROMIS Physical Function item bank perform well in PRO assessment. They will benefit from further study and application in a wider variety of rheumatic diseases in diverse clinical groups, including those at the extremes of physical functioning, and in different administration modes.


Environmental genomics reveals a single-species ecosystem deep within Earth.
DNA from low-biodiversity fracture water collected at 2.8-kilometer depth in a South African gold mine was sequenced and assembled into a single, complete genome. This bacterium, Candidatus Desulforudis audaxviator, composes >99.9% of the microorganisms inhabiting the fluid phase of this particular fracture. Its genome indicates a motile, sporulating, sulfate-reducing, chemoautotrophic thermophile that can fix its own nitrogen and carbon by using machinery shared with archaea. Candidatus Desulforudis audaxviator is capable of an independent life-style well suited to long-term isolation from the photosphere deep within Earth's crust and offers an example of a natural ecosystem that appears to have its biological component entirely encoded within a single genome.