Toll-like receptor 2 and 4 (TLR2 and TLR4) agonists differentially regulate secretory interleukin-1 receptor antagonist gene expression in macrophages.
Treatment of macrophages with lipopolysaccharide (LPS) from Gram-negative bacteria or peptidoglycan (PGN) from Gram-positive bacteria activates multiple intracellular signaling pathways and a large, diverse group of nuclear transcription factors. The signaling receptors for PGN and LPS are now known to be the Toll-like receptors 2 and 4 (TLR2 and -4, respectively). While a large body of literature indicates that the members of the TLR family activate nearly identical cytoplasmic signaling programs, several recent reports have suggested that the functional outcomes of signaling via TLR2 or TLR4 are not equivalent. In the current studies, we compared the responses of the secretory IL-1 receptor antagonist (sIL-1Ra) gene to both LPS and PGN. Both LPS and PGN induced IL-1Ra gene expression; however, the combination of both stimuli synergistically increased sIL-1Ra mRNA expression and promoter activity, suggesting that the signals induced by PGN and LPS are not equivalent. While both LPS and PGN utilized the PU.1-binding sites in the proximal sIL-1Ra promoter region to generate a full response, additional distinct promoter elements were utilized by LPS or PGN. Activation of p38 stress-activated protein kinase was required for LPS- or PGN-induced IL-1Ra gene expression, but the p38-responsive promoter elements localized to distinct regions of the sIL-1Ra gene. Additionally, while the LPS-induced, p38-dependent response was dependent upon PU.1 binding, the PGN-induced, p38 response was not. Collectively, these data indicated that while some of the intracellular signaling events by TLR2 and TLR4 agonists are similar, there are clearly distinct differences in the responses elicited by these two bacterial products.


Evidence-based recommendations for natural bodybuilding contest preparation: nutrition and supplementation.
The popularity of natural bodybuilding is increasing; however, evidence-based recommendations for it are lacking. This paper reviewed the scientific literature relevant to competition preparation on nutrition and supplementation, resulting in the following recommendations. Caloric intake should be set at a level that results in bodyweight losses of approximately 0.5 to 1%/wk to maximize muscle retention. Within this caloric intake, most but not all bodybuilders will respond best to consuming 2.3-3.1 g/kg of lean body mass per day of protein, 15-30% of calories from fat, and the reminder of calories from carbohydrate. Eating three to six meals per day with a meal containing 0.4-0.5 g/kg bodyweight of protein prior and subsequent to resistance training likely maximizes any theoretical benefits of nutrient timing and frequency. However, alterations in nutrient timing and frequency appear to have little effect on fat loss or lean mass retention. Among popular supplements, creatine monohydrate, caffeine and beta-alanine appear to have beneficial effects relevant to contest preparation, however others do not or warrant further study. The practice of dehydration and electrolyte manipulation in the final days and hours prior to competition can be dangerous, and may not improve appearance. Increasing carbohydrate intake at the end of preparation has a theoretical rationale to improve appearance, however it is understudied. Thus, if carbohydrate loading is pursued it should be practiced prior to competition and its benefit assessed individually. Finally, competitors should be aware of the increased risk of developing eating and body image disorders in aesthetic sport and therefore should have access to the appropriate mental health professionals.


Unilateral naris closure and vascular development in the rat olfactory bulb.
The blood supply to the brain has been linked closely to nervous system function and metabolism, thereby possibly playing a direct role in brain maturation. Previously, we demonstrated that closure of an external naris early in life results in large changes within the olfactory bulb, including reductions in laminar volume and cell number and a rapid decline in metabolism and protein synthesis. To understand the role of the blood supply in the dramatic changes following naris closure, the present study examines the development of olfactory bulb vasculature in unilaterally odor-deprived and control rats. On post-partum day 1 (P1; the day after birth), littermate rat pups underwent either unilateral naris occlusion or sham surgery. On P5, P10, P15, P20, P30 and P60, animals were perfused with an india ink-gelatin mixture to assess blood vessel amount and complexity. Densitometric analyses were performed to obtain values of blood vessel area ratios (vessel area/tissue area), branch point number and branch point density. Considerable vessel development in all bulbs occurred over the first two to three weeks post-partum. By P20, large reductions in vessel area ratios were observed in all constituent laminae of deprived bulbs. While similar reductions in number of vessel branch points/tissue area were seen, few changes were noted in the number of branch points/vessel area. The effects were primarily confined to early developmental periods: bulb vasculature in animals deprived at older ages (P40) appeared normal. The results indicate that the vasculature responds to alterations in sensory stimulation early in life, therefore potentially playing an important regulative role in neural development.


Health effects of coastal storms and flooding in urban areas: a review and vulnerability assessment.
Coastal storms can take a devastating toll on the public's health. Urban areas like New York City (NYC) may be particularly at risk, given their dense population, reliance on transportation, energy infrastructure that is vulnerable to flood damage, and high-rise residential housing, which may be hard-hit by power and utility outages. Climate change will exacerbate these risks in the coming decades. Sea levels are rising due to global warming, which will intensify storm surge. These projections make preparing for the health impacts of storms even more important. We conducted a broad review of the health impacts of US coastal storms to inform climate adaptation planning efforts, with a focus on outcomes relevant to NYC and urban coastal areas, and incorporated some lessons learned from recent experience with Superstorm Sandy. Based on the literature, indicators of health vulnerability were selected and mapped within NYC neighborhoods. Preparing for the broad range of anticipated effects of coastal storms and floods may help reduce the public health burden from these events.


Frequent sugar feeding behavior by Aedes aegypti in Bamako, Mali makes them ideal candidates for control with attractive toxic sugar baits (ATSB).
Current tools and strategies are not sufficient to reliably address threats and outbreaks of arboviruses including Zika, dengue, chikungunya, and yellow fever. Hence there is a growing public health challenge to identify the best new control tools to use against the vector Aedes aegypti. In this study, we investigated Ae. aegypti sugar feeding strategies in Bamako, Mali, to determine if this species can be controlled effectively using attractive toxic sugar baits (ATSB). We determined the relative attraction of Ae. aegypti males and females to a variety of sugar sources including flowers, fruits, seedpods, and honeydew in the laboratory and using plant-baited traps in the field. Next, we observed the rhythm of blood feeding versus sugar feeding activity of Ae. aegypti in vegetation and in open areas. Finally, we studied the effectiveness of spraying vegetation with ATSB on Ae. aegypti in sugar rich (lush vegetation) and in sugar poor (sparse vegetation) urban environments. Male and female laboratory sugar feeding rates within 24 h, on 8 of 16 plants offered were over 80%. The survival rates of mosquitoes on several plant sources were nearly as long as that of controls maintained on sucrose solution. In the field, females were highly attracted to 11 of 20 sugar sources, and 8 of these were attractive to males. Peak periods of host attraction for blood-feeding and sugar feeding in open areas were nearly identical and occurred shortly after sunrise and around sunset. In shaded areas, the first sugar-seeking peak occurred between 11:30 and 12:30 while the second was from 16:30 to 17:30. In a 50-day field trial, ATSB significantly reduced mean numbers of landing / biting female Ae. aegypti in the two types of vegetation. At sugar poor sites, the mean pre-treatment catch of 20.51 females on day 14 was reduced 70-fold to 0.29 on day 50. At sugar rich sites, the mean pre-treatment catch of 32.46 females on day 14 was reduced 10-fold to a mean of 3.20 females on day 50. This is the first study to show how the vector Ae. aegypti depends on environmental resources of sugar for feeding and survival. The demonstration that Ae. aegypti populations rapidly collapsed after ATSB treatment, in both sugar rich and sugar poor environments, is strong evidence that Ae. aegypti is sugar-feeding frequently. Indeed, this study clearly demonstrates that Ae. aegypti mosquitoes depend on natural sugar resources, and a promising new method for vector control, ATSB, can be highly effective in the fight against Aedes-transmitted diseases.


Next generation sequencing has lower sequence coverage and poorer SNP-detection capability in the regulatory regions.
The rapid development of next generation sequencing (NGS) technology provides a new chance to extend the scale and resolution of genomic research. How to efficiently map millions of short reads to the reference genome and how to make accurate SNP calls are two major challenges in taking full advantage of NGS. In this article, we reviewed the current software tools for mapping and SNP calling, and evaluated their performance on samples from The Cancer Genome Atlas (TCGA) project. We found that BWA and Bowtie are better than the other alignment tools in comprehensive performance for Illumina platform, while NovoalignCS showed the best overall performance for SOLiD. Furthermore, we showed that next-generation sequencing platform has significantly lower coverage and poorer SNP-calling performance in the CpG islands, promoter and 5'-UTR regions of the genome. NGS experiments targeting for these regions should have higher sequencing depth than the normal genomic region.


First fungemia case due to environmental yeast Wickerhamomyces myanmarensis: detection by multiplex qPCR and antifungal susceptibility.
Presenting the first clinical case of Wickerhamomyces myanmarensis. Yeast cells were isolated from blood and central venous catheter of a 5.5-year-old male subject. API 20C AUX, MALDI-TOF MS, ITS and LSU rDNA sequencing, and our qPCR assay were used for identification and the MIC values were determined by CLSI M27-A3. ITS and LSU rDNA sequencing identified both isolates as W. myanmarensis, while API 20C AUX and MALDI-TOF MS did not identify them correctly. Our qPCR specifically distinguished W. myanmarensis from W. anomalus. Isolate obtained from blood showed a higher MIC value for fluconazole, voriconazole and posaconazole. Utilization of reliable identification tools might reveal the genuine spectrum of opportunistic yeast species.


Maxillary sinus augmentation with leukocyte and platelet-rich fibrin and deproteinized bovine bone mineral: A split-mouth histological and histomorphometric study.
To evaluate the effect of leukocyte and platelet-rich fibrin (L-PRF) in combination with deproteinized bovine bone mineral (DBBM) on bone regeneration in maxillary sinus augmentation. Thirteen patients (nine males and four females, mean age ± SD; 49.92 ± 10.37) were enrolled to the study. 26 maxillary sinus augmentation procedures were randomly performed using DBBM and L-PRF mixture (test) or DBBM alone (control) in a split-mouth design. The same surgical procedures were performed in both groups, and bone biopsies were harvested from the implant sites 6 months postoperatively for histological and histomorphometric evaluations as the primary outcome of the study. Implants were placed and then loaded in the augmented sites after 6 months. The secondary outcomes included clinical and radiographic data and were obtained pre- and postoperatively. There was no qualitative difference in histological analyses among the groups. In all samples, a newly formed bone was in direct contact with the residual material. The percentages of newly formed bone (test; 21.38 ± 8.78% and control; 21.25 ± 5.59%), residual bone graft (test; 25.95 ± 9.54% and control; 32.79 ± 5.89%), bone graft in contact with the newly formed bone (test; 47.33 ± 12.33% and control; 54.04 ± 8.36%), and soft tissue (test; 52.67 ± 12.53% and control; 45.96 ± 8.36%) were similar among the groups (p < .05). Similar radiographic bone height in the augmented area was observed, and implant survival rate was 100% for both groups. Both techniques were effective for maxillary sinus augmentation, and after 6 months of healing, the addition of L-PRF in DBBM did not improve the amount of regenerated bone or the amount of the graft integrated into the newly formed bone under histological and histomorphometric evaluation.


Effects of age on detection of emotional information.
Age differences were examined in affective processing, in the context of a visual search task. Young and older adults were faster to detect high arousal images compared with low arousal and neutral items. Younger adults were faster to detect positive high arousal targets compared with other categories. In contrast, older adults exhibited an overall detection advantage for emotional images compared with neutral images. Together, these findings suggest that older adults do not display valence-based effects on affective processing at relatively automatic stages.


Is it time to revisit the AO classification of fractures of the distal radius? Inter- and intra-observer reliability of the AO classification.
We conducted an observational radiographic study to determine the inter- and intra-observer reliability of the AO classification of fractures of the distal radius. Plain posteroanterior and lateral radiographs of 456 patients with an acute fracture of the distal radius were classified by a consultant orthopaedic hand specialist and two specialist trainees, and the k coefficient for the inter- and intra-observer reliability of the type, group and subgroup classification was calculated. Only the type of fracture (A, B or C) was found to provide substantial intra-observer reliability (k type 0.65). The inclusion of 'group' and 'subgroup' into the classification reduced the inter-observer reliability to fair (kgroup 0.29, ksubgroup = 0.28) and the intra-observer reliability to moderate (kgroup 0.53, ksubgroup 0.49). Disagreement was found to arise between specific subgroups, which may be amenable to clarification.


[Social cognition in bipolar disorder].
Bipolar disorder is characterised by disturbed mood regulation. Recently, research has focused on cognitive deficits, including social-cognitive deficits, which have a major impact on daily functioning. To review the recent literature on social cognition in both the symptomatic and the remission phases in bipolar disorder and to discuss the link between social cognition and psychosocial functioning. We reviewed the literature systematically using the most important literature databases and cross-references. Deficits in social-cognitive domains such as emotion recognition and Theory of Mind become apparent during both the symptomatic and remission phases. These deficits are influenced by moderating variables such as medication use, clinical symptoms and neurocognitive deficits. Furthermore, in some recent studies these social-cognitive deficits have been linked to poorer functioning. In bipolar disorder, social-cognitive deficits are present in different areas and are to a large extent independent of the mood phase. There is an urgent need for more research into the various cognitive domains and into the effect that these have on daily functioning in all phases of bipolar disorder.


Heart rate and subsequent blood pressure in young adults: the CARDIA study.
The objective of the present study was to examine the hypothesis that baseline heart rate (HR) predicts subsequent blood pressure (BP) independently of baseline BP. In the multicenter longitudinal Coronary Artery Risk Development in Young Adults study of black and white men and women initially aged 18 to 30 years, we studied 4762 participants who were not current users of antihypertensive drugs and had no history of heart problems at the baseline examination (1985-1986). In each race-sex subgroup, we estimated the effect of baseline HR on BP 2, 5, 7, and 10 years later by use of repeated measures regression analysis, adjusting for baseline BP, age, education, body fatness, physical fitness, fasting insulin, parental hypertension, cigarette smoking, alcohol consumption, oral contraceptive use, and change of body mass index from baseline. The association between baseline HR and subsequent systolic BP (SBP) was explained by multivariable adjustment. However, HR was an independent predictor of subsequent diastolic BP (DBP) regardless of initial BP and other confounders in white men, white women, and black men (0.7 mm Hg increase per 10 bpm). We incorporated the part of the association that was already present at baseline by not adjusting for baseline DBP: the mean increase in subsequent DBP was 1.3 mm Hg per 10 bpm in white men, white women, and black men. A high HR may be considered a risk factor for subsequent high DBP in young persons.


Eye gaze cueing facilitates neural processing of objects in 4-month-old infants.
A major issue in developmental science is how infants use the direction of other's eye gaze to facilitate the processing of information. Four-month-old infants passively viewed images of an adult face gazing toward or away from objects. When presented with the objects a second time, infants showed differences in a slow wave event-related potential, indicating that uncued objects were perceived as less familiar than objects previously cued by the direction of gaze of another person. This result shows that the direction of eye gaze of another cannot only bias infant attention, but also lead to enhanced information processing of the objects concerned.


Modulation of the Surface Proteome through Multiple Ubiquitylation Pathways in African Trypanosomes.
Recently we identified multiple suramin-sensitivity genes with a genome wide screen in Trypanosoma brucei that includes the invariant surface glycoprotein ISG75, the adaptin-1 (AP-1) complex and two deubiquitylating enzymes (DUBs) orthologous to ScUbp15/HsHAUSP1 and pVHL-interacting DUB1 (type I), designated TbUsp7 and TbVdu1, respectively. Here we have examined the roles of these genes in trafficking of ISG75, which appears key to suramin uptake. We found that, while AP-1 does not influence ISG75 abundance, knockdown of TbUsp7 or TbVdu1 leads to reduced ISG75 abundance. Silencing TbVdu1 also reduced ISG65 abundance. TbVdu1 is a component of an evolutionarily conserved ubiquitylation switch and responsible for rapid receptor modulation, suggesting similar regulation of ISGs in T. brucei. Unexpectedly, TbUsp7 knockdown also blocked endocytosis. To integrate these observations we analysed the impact of TbUsp7 and TbVdu1 knockdown on the global proteome using SILAC. For TbVdu1, ISG65 and ISG75 are the only significantly modulated proteins, but for TbUsp7 a cohort of integral membrane proteins, including the acid phosphatase MBAP1, that is required for endocytosis, and additional ISG-related proteins are down-regulated. Furthermore, we find increased expression of the ESAG6/7 transferrin receptor and ESAG5, likely resulting from decreased endocytic activity. Therefore, multiple ubiquitylation pathways, with a complex interplay with trafficking pathways, control surface proteome expression in trypanosomes.


Genipin attenuates cisplatin-induced nephrotoxicity by counteracting oxidative stress, inflammation, and apoptosis.
Cisplatin (CP) is a potent and widely used chemotherapeutic agent. However, the clinical benefits of CP are compromised because it elicits nephrotoxicity and ototoxicity. In this study, we investigated the nephroprotective effects of the phytochemical genipin (GP) isolated from the gardenia (Gardenia jasminoides) fruit, using a murine model of CP-induced nephropathy. GP pretreatment attenuated the CP-induced renal tissue injury by diminishing the serum blood urea nitrogen, creatinine, and cystatin C levels, as well as those of kidney injury molecule-1. In addition, GP attenuated the CP-induced oxidative/nitrative stress by suppressing the activation of NADPH oxidase, augmenting the endogenous antioxidant defense system, and diminishing the accumulation of 4-hydroxynonenal and 3-nitrotyrosine in renal tissues. Furthermore, reduced levels of proinflammatory cytokines such as tumor necrosis factor-alpha and interleukin-1 beta indicated that CP-induced renal inflammation was mitigated upon the treatment with GP. GP also attenuated the CP-induced activation of mitogen-activated protein kinases, excessive activities of caspase-3/7 and poly(ADP-ribose) polymerase, DNA fragmentation, and apoptosis. When administered 12h after the onset of kidney injury, GP showed a therapeutic effect by ameliorating CP-induced nephrotoxicity. Moreover, GP synergistically enhanced the CP-induced cell death of T24 human bladder cancer cells. Collectively, our data indicate that GP attenuated the CP-induced renal tissue injury by abrogating oxidative/nitrative stress and inflammation and by blocking cell death pathways, thereby improving the renal function. Thus, our results suggest that the use of GP may be a promising new protective strategy against cisplatin-induced nephrotoxicity.


Understanding differential technologies for detection of MRD and how to incorporate into clinical practice.
Patient- and leukemia-specific factors assessed at diagnosis classify patients with acute myeloid leukemia (AML) in risk categories that are prognostic for outcome. The induction phase with intensive chemotherapy in fit patients aims to reach a complete remission (CR) of less than 5% blasts in bone marrow by morphology. To deepen and sustain the response, induction is followed by consolidation treatment. This postremission treatment of patients with AML is graduated in intensity based on this favorable, intermediate, or adverse risk group classification as defined in the European Leukemia Network (ELN) 2022 recommendations. The increment of evidence that measurable residual disease (MRD) after induction can be superimposed on risk group at diagnosis is instrumental in tailoring further treatment accordingly. Several techniques are applied to detect MRD such as multiparameter flow cytometry (MFC), quantitative (digital) polymerase chain reaction (PCR), and next-generation sequencing. The clinical implementation of MRD and the technique used differ among institutes, leading to the accumulation of a wide range of data, and therefore harmonization is warranted. Currently, evidence for MRD guidance is limited to the time point after induction using MFC or quantitative PCR for NPM1 and core binding factor abnormalities in intermediate-risk patients. The role of MRD in targeted or nonintensive therapies needs to be clarified, although some data show improved survival in patients achieving CR-MRD negativity. Potential application of MRD for selection of conditioning before stem cell transplantation, monitoring after consolidation, and use as an intermediate end point in clinical trials need further evaluation.


In silico Evolution of Lysis-Lysogeny Strategies Reproduces Observed Lysogeny Propensities in Temperate Bacteriophages.
Bacteriophages are the most abundant organisms on the planet and both lytic and temperate phages play key roles as shapers of ecosystems and drivers of bacterial evolution. Temperate phages can choose between (i) lysis: exploiting their bacterial hosts by producing multiple phage particles and releasing them by lysing the host cell, and (ii) lysogeny: establishing a potentially mutually beneficial relationship with the host by integrating their chromosome into the host cell's genome. Temperate phages exhibit lysogeny propensities in the curiously narrow range of 5-15%. For some temperate phages, the propensity is further regulated by the multiplicity of infection, such that single infections go predominantly lytic while multiple infections go predominantly lysogenic. We ask whether these observations can be explained by selection pressures in environments where multiple phage variants compete for the same host. Our models of pairwise competition, between phage variants that differ only in their propensity to lysogenize, predict the optimal lysogeny propensity to fall within the experimentally observed range. This prediction is robust to large variation in parameters such as the phage infection rate, burst size, decision rate, as well as bacterial growth rate, and initial phage to bacteria ratio. When we compete phage variants whose lysogeny strategies are allowed to depend upon multiplicity of infection, we find that the optimal strategy is one which switches from full lysis for single infections to full lysogeny for multiple infections. Previous attempts to explain lysogeny propensity have argued for bet-hedging that optimizes the response to fluctuating environmental conditions. Our results suggest that there is an additional selection pressure for lysogeny propensity within phage populations infecting a bacterial host, independent of environmental conditions.


The effects of suplatast tosilate on acutely dissociated sensory and paratracheal ganglia neurons.
In this study, we investigated the effects of suplatast on acutely dissociated single neurons of sensory and paratracheal ganglia using a patch-clamp technique. Suplatast had little effect on various responses caused by capsaicin, acid, bradykinin, serotonin and adenosine 5'-triphosphate in rat sensory neurons. Suplatast, even at 10-3 M, also did not induce any current at various membrane potentials in rat and guinea pig paratracheal ganglia neurons. Further, acetylcholine- and bradykinin-induced depolarizations were not affected by suplatast. On the other hand, in rat paratracheal ganglia neurons, 10-5 M nicotine-induced current were inhibited by suplatast in a concentration-dependent manner with a 50% inhibitory concentration of 9.86x10-5 M. The effect was noncompetitive and voltage-dependent. Furthermore, the effect was use-independent and not affected by the pretreatment time of suplatast. The results suggested that suplatast may inhibit neurotransmission at the paratracheal ganglia via the inhibition of nicotinic current. Thus, suplatast may attenuate cough production through the improvement of pathological conditions of the lower airway via suppressed acetylcholine release from the postganglionic nerve terminal.


Endocrine Therapy Nonadherence and Discontinuation in Black and White Women.
Differential use of endocrine therapy (ET) by race may contribute to breast cancer outcome disparities, but racial differences in ET behaviors are poorly understood. Women aged 20-74 years with a first primary, stage I-III, hormone receptor-positive (HR+) breast cancer were included. At 2 years postdiagnosis, we assessed nonadherence, defined as not taking ET every day or missing more than two pills in the past 14 days, discontinuation, and a composite measure of underuse, defined as either missing pills or discontinuing completely. Using logistic regression, we evaluated the relationship between race and nonadherence, discontinuation, and overall underuse in unadjusted, clinically adjusted, and socioeconomically adjusted models. A total of 1280 women were included; 43.2% self-identified as black. Compared to white women, black women more often reported nonadherence (13.7% vs 5.2%) but not discontinuation (10.0% vs 10.7%). Black women also more often reported the following: hot flashes, night sweats, breast sensitivity, and joint pain; believing that their recurrence risk would not change if they stopped ET; forgetting to take ET; and cost-related barriers. In multivariable analysis, black race remained statistically significantly associated with nonadherence after adjusting for clinical characteristics (adjusted odds ratio = 2.72, 95% confidence interval = 1.75 to 4.24) and after adding socioeconomic to clinical characteristics (adjusted odds ratio = 2.44, 95% confidence interval = 1.50 to 3.97) but was not independently associated with discontinuation after adjustment. Low recurrence risk perception and lack of a shared decision making were strongly predictive of ET underuse across races. Our results highlight important racial differences in ET-adherence behaviors, perceptions of benefits/harms, and shared decision making that may be targeted with culturally tailored interventions.


A community based intervention program to enhance neighborhood cohesion: The Learning Families Project in Hong Kong.
Neighborhood cohesion, which refers to the extent of the connectedness and solidarity among residents in a community or neighborhood, is an important determinant of human health. To enhance neighborhood cohesion, the "Learning Families Project" was developed with a series of intervention programs in Kwun Tong in Hong Kong, a district with low neighborhood cohesion. This project, based on the social ecological model, provided a platform for neighbors to learn, communicate and interact with each other. This quasi-experimental study included two nearby government subsidized low rent housing estates separated by busy main roads. One served as the intervention (Tsui Ping (South) Estate) and one as the control (Shun Tin Estate) estate. The intervention included promotion, resident training and learning programs, embodied by a series of community activities such as talks, day camp, thematic activities and horticulture class. Baseline (before the programs) and follow-up (one year after the programs) surveys were conducted both in the intervention and control estate to assess the impact of the programs on neighborhood cohesion. The number of residents who completed both the baseline and follow-up surveys was 502 in the intervention estate and 476 in the control estate. Neighborhood cohesion significantly improved in the intervention group after the programs (Cohen effect size d: 0.15). Compared with the control group, the improvements in closeness of the neighborhood and trust in neighbors were significantly greater in the intervention group (Cohen effect size d: 0.13 and 0.14, respectively). This brief intervention program using a quasi-experimental study design increased neighborhood cohesion in a low rent housing estate. ClinicalTrials.gov NCT02851667.


Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection.
In phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3. We conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir, in a once-daily, fixed-dose combination tablet (134 patients), or sofosbuvir plus weight-based ribavirin (132 patients) for 12 weeks. In a second trial, patients with HCV genotype 3 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir for 12 weeks (277 patients) or sofosbuvir-ribavirin for 24 weeks (275 patients). The primary end point for the two trials was a sustained virologic response at 12 weeks after the end of therapy. Among patients with HCV genotype 2, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 99% (95% confidence interval [CI], 96 to 100), which was superior to the rate of 94% (95% CI, 88 to 97) in the sofosbuvir-ribavirin group (P=0.02). Among patients with HCV genotype 3, the rate of sustained virologic response in the sofosbuvir-velpatasvir group was 95% (95% CI, 92 to 98), which was superior to the rate of 80% (95% CI, 75 to 85) in the sofosbuvir-ribavirin group (P<0.001). The most common adverse events in the two studies were fatigue, headache, nausea, and insomnia. Among patients with HCV genotype 2 or 3 with or without previous treatment, including those with compensated cirrhosis, 12 weeks of treatment with sofosbuvir-velpatasvir resulted in rates of sustained virologic response that were superior to those with standard treatment with sofosbuvir-ribavirin. (Funded by Gilead Sciences; ASTRAL-2 ClinicalTrials.gov number, NCT02220998; and ASTRAL-3, NCT02201953.).


Oral Phage Therapy of Acute Bacterial Diarrhea With Two Coliphage Preparations: A Randomized Trial in Children From Bangladesh.
Antibiotic resistance is rising in important bacterial pathogens. Phage therapy (PT), the use of bacterial viruses infecting the pathogen in a species-specific way, is a potential alternative. T4-like coliphages or a commercial Russian coliphage product or placebo was orally given over 4 days to Bangladeshi children hospitalized with acute bacterial diarrhea. Safety of oral phage was assessed clinically and by functional tests; coliphage and Escherichia coli titers and enteropathogens were determined in stool and quantitative diarrhea parameters (stool output, stool frequency) were measured. Stool microbiota was studied by 16S rRNA gene sequencing; the genomes of four fecal Streptococcus isolates were sequenced. No adverse events attributable to oral phage application were observed (primary safety outcome). Fecal coliphage was increased in treated over control children, but the titers did not show substantial intestinal phage replication (secondary microbiology outcome). 60% of the children suffered from a microbiologically proven E. coli diarrhea; the most frequent diagnosis was ETEC infections. Bacterial co-pathogens were also detected. Half of the patients contained phage-susceptible E. coli colonies in the stool. E. coli represented less than 5% of fecal bacteria. Stool ETEC titers showed only a short-lived peak and were otherwise close to the replication threshold determined for T4 phage in vitro. An interim analysis after the enrollment of 120 patients showed no amelioration in quantitative diarrhea parameter by PT over standard care (tertiary clinical outcome). Stool microbiota was characterized by an overgrowth with Streptococcus belonging to the Streptococcus gallolyticus and Streptococcus salivarius species groups, their abundance correlated with quantitative diarrhea outcome, but genome sequencing did not identify virulence genes. Oral coliphages showed a safe gut transit in children, but failed to achieve intestinal amplification and to improve diarrhea outcome, possibly due to insufficient phage coverage and too low E. coli pathogen titers requiring higher oral phage doses. More knowledge is needed on in vivo phage-bacterium interaction and the role of E. coli in childhood diarrhea for successful PT. The study was supported by a grant from Nestlé Nutrition and Nestlé Health Science. The trial was registered with Identifier NCT00937274 at ClinicalTrials.gov.


Polymorphonuclear cell-mediated vascular injury in anergic surgical patients.
We examined the responses of primed polymorphonuclear neutrophils (PMNs) adhered to vascular endothelium, which can lead to endothelial cell damage as a mechanism of the capillary leak syndrome, the main cause of death in anergic patients. We tested PMNs from (1) preoperative reactive patients, (2) preoperative anergic patients, (3) anergic patients in the surgical intensive care unit, and (4) healthy controls for in vitro adherence and cytotoxicity on cultured human vein endothelial cells. Adherence of PMNs was 12.9% +/- 3.9% in preoperative anergic patients and 13.1% +/- 3.2% in anergic patients in the surgical intensive care unit compared with 9.0% +/- 2.1% in preoperative reactive patients (P < .05). Cytotoxicity was 6.0% +/- 2.8% in preoperative reactive patients, 13.7% +/- 4.1% in preoperative anergic patients, and 14.3% +/- 4.6% in anergic patients in the surgical intensive care unit. The PMNs from preoperative anergic patients were more cytotoxic against human vein endothelial cells when stimulated by Staphylococcus epidermidis or formyl-methionyleucylphenylalanine. We conclude that PMNs from anergic surgical patients adhere more to endothelial cells and can produce increased cytotoxicity that may lead to detrimental results.


Testing of motor unit synchronization model for localized muscle fatigue.
Spectral compression of surface electromyogram (sEMG) is associated with onset of localized muscle fatigue. The spectral compression has been explained based on motor unit synchronization theory. According to this theory, motor units are pseudo randomly excited during muscle contraction, and with the onset of muscle fatigue the recruitment pattern changes such that motor unit firings become more synchronized. While this is widely accepted, there is little experimental proof of this phenomenon. This paper has used source dependence measures developed in research related to independent component analysis (ICA) to test this theory.


Calcite biomineralization by bacterial isolates from the recently discovered pristine karstic herrenberg cave.
Karstic caves represent one of the most important subterranean carbon storages on Earth and provide windows into the subsurface. The recent discovery of the Herrenberg Cave, Germany, gave us the opportunity to investigate the diversity and potential role of bacteria in carbonate mineral formation. Calcite was the only mineral observed by Raman spectroscopy to precipitate as stalactites from seepage water. Bacterial cells were found on the surface and interior of stalactites by confocal laser scanning microscopy. Proteobacteria dominated the microbial communities inhabiting stalactites, representing more than 70% of total 16S rRNA gene clones. Proteobacteria formed 22 to 34% of the detected communities in fluvial sediments, and a large fraction of these bacteria were also metabolically active. A total of 9 isolates, belonging to the genera Arthrobacter, Flavobacterium, Pseudomonas, Rhodococcus, Serratia, and Stenotrophomonas, grew on alkaline carbonate-precipitating medium. Two cultures with the most intense precipitate formation, Arthrobacter sulfonivorans and Rhodococcus globerulus, grew as aggregates, produced extracellular polymeric substances (EPS), and formed mixtures of calcite, vaterite, and monohydrocalcite. R. globerulus formed idiomorphous crystals with rhombohedral morphology, whereas A. sulfonivorans formed xenomorphous globular crystals, evidence for taxon-specific crystal morphologies. The results of this study highlighted the importance of combining various techniques in order to understand the geomicrobiology of karstic caves, but further studies are needed to determine whether the mineralogical biosignatures found in nutrient-rich media can also be found in oligotrophic caves.


Importance of localized skin infection in tick-borne encephalitis virus transmission.
Arboviruses are transmitted to vertebrates by the "bite" of infected arthropods. Events at the site of virus deposition are largely unknown despite increasing evidence that blood-sucking arthropods immunomodulate their skin site of feeding. This question is particularly relevant for ixodid ticks that feed for several days. To examine events under conditions mimicking tick-borne encephalitis (TBE) virus transmission in nature (i.e., infected and uninfected Ixodes ricinus ticks feeding on the same animal), infected adult and uninfected nymphal ticks were placed in one retaining chamber (skin site A) and uninfected nymphs were placed within a second chamber posteriorly (skin site B) on two natural host species, yellow-necked field mice (Apodemus flavicollis) and bank voles (Clethrionomys glareolus). Virus transmission from infected to uninfected cofeeding ticks was correlated with infection in the skin site of tick feeding. Furthermore, virus was recruited preferentially to the site in which ticks were feeding compared with uninfested skin sites. Viremia did not correspond with a generalized infection of the skin; virus was not detected in an uninfested skin site (C) of 12/13 natural hosts that had viremia levels > or = 2.0 log10 ic mouse LD50/0.02 ml blood. To characterize infected cells, laboratory mouse strains were infested with infected ticks and then explants were removed from selected skin sites and floated on culture medium. Numerous leukocytes were found to migrate from the skin explants of tick feeding sites. Two-color immunocytochemistry revealed viral antigen in both migratory Langerhans cells and neutrophils; in addition, the migratory monocyte/macrophages were shown to produce infectious virus. The results indicate that the local skin site of tick feeding is an important focus of viral replication early after TBE virus transmission by ticks. Cellular infiltration of tick feeding sites, and the migration of cells from such sites, may provide a vehicle for transmission between infected and uninfected cofeeding ticks that is independent of a patent viremia. The data support the hypothesis that viremia is a product, rather than a prerequisite, of tick-borne virus transmission.


Cutaneous anthrax in the Artibonite Valley of Haiti: 1992-2002.
More cutaneous anthrax cases were noted at Hospital Albert Schweitzer (HAS) in the Artibonite Valley of Haiti. We examine the incidence of anthrax in the Artibonite between 1992 and 2002, describe the clinical presentation of cutaneous anthrax, and determine risk factors for anthrax. In 1992 HAS reported 1 case of anthrax for an incidence of 4 cases per million persons/year. In 2002, there were 20 cases of anthrax for an incidence of 72 cases per million persons/year. This is a 17-fold increase (P = 0.0002). Causes of death from anthrax included asphyxiation from edema of the neck with tracheal compression and concurrent gastrointestinal anthrax. Butchering cattle that had died of illness was identified as a risk factor. The incidence of human anthrax has increased in the Artibonite Valley and is a cause of significant mortality. Control of anthrax in humans depends on improved animal vaccination programs.


Secretion of proteins by Bacillus subtilis 168 grown in the presence of membrane active agents (alcohols).
Sodium dodecyl sulphate-polyacrylamide gel electrophoresis was used to study the composition of proteins secreted by the Gram-positive microorganism Bacillus subtilis strain 168 when the latter was grown in the presence of primary alcohols (methanol, ethanol, 1-propanol and 1-butanol). These membrane-active agents had different effects on the pattern of proteins exported by B. subtilis. The secretion of some proteins was inhibited by the alkanols while that of others was stimulated, depending on the type of drug used. All alcohols were found to decrease the activity of extracellular enzymes such as alpha-amylase and serine protease without affecting significantly the activity of these enzymes when tested in vitro. The observed effects might be due to the ability of these agents to perturb the structure of biological membranes, thus interfering with the process of protein translocation through the lipid bilayers.


Species contributions to ecosystem process and function can be population dependent and modified by biotic and abiotic setting.
There is unequivocal evidence that altered biodiversity, through changes in the expression and distribution of functional traits, can have large impacts on ecosystem properties. However, trait-based summaries of how organisms affect ecosystem properties often assume that traits show constancy within and between populations and that species contributions to ecosystem functioning are not overly affected by the presence of other species or variations in abiotic conditions. Here, we evaluate the validity of these assumptions using an experiment in which three geographically distinct populations of intertidal sediment-dwelling invertebrates are reciprocally substituted. We find that the mediation of macronutrient generation by these species can vary between different populations and show that changes in biotic and/or abiotic conditions can further modify functionally important aspects of the behaviour of individuals within a population. Our results demonstrate the importance of knowing how, when, and why traits are expressed and suggest that these dimensions of species functionality are not sufficiently well-constrained to facilitate the accurate projection of the functional consequences of change. Information regarding the ecological role of key species and assumptions about the form of species-environment interactions needs urgent refinement.


Asthmatic airway smooth muscle CXCL10 production: mitogen-activated protein kinase JNK involvement.
CXCL10 (IP10) is involved in mast cell migration to airway smooth muscle (ASM) bundles in asthma. We aimed to investigate the role of cytokine-induced MAPK activation in CXCL10 production by ASM cells from people with and without asthma. Confluent growth-arrested ASM cells were treated with inhibitors of the MAPKs ERK, p38, and JNK and transcription factor NF-κB, or vehicle, and stimulated with IL-1β, TNF-α, or IFN-γ, alone or combined (cytomix). CXCL10 mRNA and protein, JNK, NF-κB p65 phosphorylation, and Iκ-Bα protein degradation were assessed using real-time PCR, ELISA, and immunoblotting, respectively. Cytomix, IL-1β, and TNF-α induced CXCL10 mRNA expression more rapidly in asthmatic than nonasthmatic ASM cells. IL-1β and/or TNF-α combined with IFN-γ synergistically increased asthmatic ASM cell CXCL10 release. Inhibitor effects were similar in asthmatic and nonasthmatic cells, but cytomix-induced release was least affected, with only JNK and NF-κB inhibitors halving it. Notably, JNK phosphorylation was markedly less in asthmatic compared with nonasthmatic cells. However, in both, the JNK inhibitor SP600125 reduced JNK phosphorylation and CXCL10 mRNA levels but did not affect CXCL10 mRNA stability or Iκ-Bα degradation. Together, the JNK and NF-κB inhibitors completely inhibited their CXCL10 release. We concluded that, in asthmatic compared with nonasthmatic ASM cells, JNK activation was reduced and CXCL10 gene expression was more rapid following cytomix stimulation. However, in both, JNK activation did not regulate early events leading to NF-κB activation. Thus JNK and NF-κB provide independent therapeutic targets for limiting CXCL10 production and mast cell migration to the ASM in asthma.


Mutations in Barley Row Type Genes Have Pleiotropic Effects on Shoot Branching.
Cereal crop yield is determined by different yield components such as seed weight, seed number per spike and the tiller number and spikes. Negative correlations between these traits are often attributed to resource limitation. However, recent evidence suggests that the same genes or regulatory modules can regulate both inflorescence branching and tillering. It is therefore important to explore the role of genetic correlations between different yield components in small grain cereals. In this work, we studied pleiotropic effects of row type genes on seed size, seed number per spike, thousand grain weight, and tillering in barley to better understand the genetic correlations between individual yield components. Allelic mutants of nine different row type loci (36 mutants), in the original spring barley varieties Barke, Bonus and Foma and introgressed in the spring barley cultivar Bowman, were phenotyped under greenhouse and outdoor conditions. We identified two main mutant groups characterized by their relationships between seed and tillering parameters. The first group comprises all mutants with an increased number of seeds and significant change in tiller number at early development (group 1a) or reduced tillering only at full maturity (group 1b). Mutants in the second group are characterized by a reduction in seeds per spike and tiller number, thus exhibiting positive correlations between seed and tiller number. Reduced tillering at full maturity (group 1b) is likely due to resource limitations. In contrast, altered tillering at early development (groups 1a and 2) suggests that the same genes or regulatory modules affect inflorescence and shoot branching. Understanding the genetic bases of the trade-offs between these traits is important for the genetic manipulation of individual yield components.


Spinal cord mapping as an adjunct for resection of intramedullary tumors: surgical technique with case illustrations.
Resection of intramedullary spinal cord tumors may result in transient or permanent neurological deficits. Intraoperative somatosensory evoked potentials (SSEPs) and motor evoked potentials are commonly used to limit complications. We used both antidromically elicited SSEPs for planning the myelotomy site and direct mapping of spinal cord tracts during tumor resection to reduce the risk of neurological deficits and increase the extent of tumor resection. In two patients, 3 and 12 years of age, with tumors of the thoracic and cervical spinal cord, respectively, antidromically elicited SSEPs were evoked by stimulation of the dorsal columns and were recorded with subdermal electrodes placed at the medial malleoli bilaterally. Intramedullary spinal cord mapping was performed by stimulating the resection cavity with a handheld Ojemann stimulator (Radionics, Burlington, MA). In addition to visual observation, subdermal needle electrodes inserted into the abductor pollicis brevis-flexor digiti minimi manus, tibialis anterior-gastrocnemius, and abductor halluces-abductor digiti minimi pedis muscles bilaterally recorded responses that identified motor pathways. The midline of the spinal cord was anatomically identified by visualizing branches of the dorsal medullary vein penetrating the median sulcus. Antidromic responses were obtained by stimulation at 1-mm intervals on either side of the midline, and the region where no response was elicited was selected for the myelotomy. The anatomic and electrical midlines did not precisely overlap. Stimulation of abnormal tissue within the tumor did not elicit electromyographic activity. Approaching the periphery of the tumor, stimulation at 1 mA elicited an electromyographic response before normal spinal cord was visualized. Restimulation at lower currents by use of 0.25-mA increments identified the descending motor tracts adjacent to the tumor. After tumor resection, the tracts were restimulated to confirm functional integrity. Both patients were discharged within 2 weeks of surgery with minimal neurological deficits. Antidromically elicited SSEPs were important in determining the midline of a distorted cord for placement of the myelotomy incision. Mapping spinal cord motor tracts with direct spinal cord stimulation and electromyographic recording facilitated the extent of surgical resection.


Development and psychometric evaluation of the Transdiagnostic Decision Tool: matched care for patients with a mental disorder in need of highly specialised care.
Early identification of patients with mental health problems in need of highly specialised care could enhance the timely provision of appropriate care and improve the clinical and cost-effectiveness of treatment strategies. Recent research on the development and psychometric evaluation of diagnosis-specific decision-support algorithms suggested that the treatment allocation of patients to highly specialised mental healthcare settings may be guided by a core set of transdiagnostic patient factors. To develop and psychometrically evaluate a transdiagnostic decision tool to facilitate the uniform assessment of highly specialised mental healthcare need in heterogeneous patient groups. The Transdiagnostic Decision Tool was developed based on an analysis of transdiagnostic items of earlier developed diagnosis-specific decision tools. The Transdiagnostic Decision Tool was psychometrically evaluated in 505 patients with a somatic symptom disorder or post-traumatic stress disorder. Feasibility, interrater reliability, convergent validity and criterion validity were assessed. In order to evaluate convergent validity, the five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) and the ICEpop CAPability measure for Adults (ICECAP-A) were administered. The six-item clinician-administered Transdiagnostic Decision Tool demonstrated excellent feasibility and acceptable interrater reliability. Spearman's rank correlations between the Transdiagnostic Decision Tool and ICECAP-A (-0.335), EQ-5D-5L index (-0.386) and EQ-5D-visual analogue scale (-0.348) supported convergent validity. The area under the curve was 0.81 and a cut-off value of ≥3 was found to represent the optimal cut-off value. The Transdiagnostic Decision Tool demonstrated solid psychometric properties and showed promise as a measure for the early detection of patients in need of highly specialised mental healthcare.


Genetic Investigation Into the Differential Risk of Atrial Fibrillation Among Black and White Individuals.
White persons have a higher risk of atrial fibrillation (AF) compared with black individuals despite a lower prevalence of risk factors. This difference may be due, at least in part, to genetic factors. To determine whether 9 single-nucleotide polymorphisms (SNPs) associated with AF account for this paradoxical differential racial risk for AF and to use admixture mapping to search genome-wide for loci that may account for this phenomenon. Genome-wide admixture analysis and candidate SNP study involving 3 population-based cohort studies that were initiated between 1987 and 1997, including the Cardiovascular Health Study (CHS) (n = 4173), the Atherosclerosis Risk in Communities (ARIC) (n = 12 341) study, and the Health, Aging, and Body Composition (Health ABC) (n = 1015) study. In all 3 studies, race was self-identified. Cox proportional hazards regression models and the proportion of treatment effect method were used to determine the impact of 9 AF-risk SNPs among participants from CHS and the ARIC study. The present study began July 1, 2012, and was completed in 2015. Incident AF systematically ascertained using clinic visit electrocardiograms, hospital discharge diagnosis codes, death certificates, and Medicare claims data. A single SNP, rs10824026 (chromosome 10: position 73661450), was found to significantly mediate the higher risk for AF in white participants compared with black participants in CHS (11.4%; 95% CI, 2.9%-29.9%) and ARIC (31.7%; 95% CI, 16.0%-53.0%). Admixture mapping was performed in a meta-analysis of black participants within CHS (n = 811), ARIC (n = 3112), and Health ABC (n = 1015). No loci that reached the prespecified statistical threshold for genome-wide significance were identified. The rs10824026 SNP on chromosome 10q22 mediates a modest proportion of the increased risk of AF among white individuals compared with black individuals, potentially through an effect on gene expression levels of MYOZ1. No additional genetic variants accounting for a significant portion of the differential racial risk of AF were identified with genome-wide admixture mapping, suggesting that additional genetic or environmental influences beyond single SNPs in isolation may account for the paradoxical racial risk of AF among white individuals and black individuals.


Respiratory and cardiovascular responses to walking down a traffic-polluted road compared with walking in a traffic-free area in participants aged 60 years and older with chronic lung or heart disease and age-matched healthy controls: a randomised, crossover study.
Long-term exposure to pollution can lead to an increase in the rate of decline of lung function, especially in older individuals and in those with chronic obstructive pulmonary disease (COPD), whereas shorter-term exposure at higher pollution levels has been implicated in causing excess deaths from ischaemic heart disease and exacerbations of COPD. We aimed to assess the effects on respiratory and cardiovascular responses of walking down a busy street with high levels of pollution compared with walking in a traffic-free area with lower pollution levels in older adults. In this randomised, crossover study, we recruited men and women aged 60 years and older with angiographically proven stable ischaemic heart disease or stage 2 Global initiative for Obstructive Lung Disease (GOLD) COPD who had been clinically stable for 6 months, and age-matched healthy volunteers. Individuals with ischaemic heart disease or COPD were recruited from existing databases or outpatient respiratory and cardiology clinics at the Royal Brompton & Harefield NHS Foundation Trust and age-matched healthy volunteers using advertising and existing databases. All participants had abstained from smoking for at least 12 months and medications were taken as recommended by participants' doctors during the study. Participants were randomly assigned by drawing numbered disks at random from a bag to do a 2 h walk either along a commercial street in London (Oxford Street) or in an urban park (Hyde Park). Baseline measurements of participants were taken before the walk in the hospital laboratory. During each walk session, black carbon, particulate matter (PM) concentrations, ultrafine particles, and nitrogen dioxide (NO2) concentrations were measured. Between October, 2012, and June, 2014, we screened 135 participants, of whom 40 healthy volunteers, 40 individuals with COPD, and 39 with ischaemic heart disease were recruited. Concentrations of black carbon, NO2, PM10, PM2.5, and ultrafine particles were higher on Oxford Street than in Hyde Park. Participants with COPD reported more cough (odds ratio [OR] 1·95, 95% CI 0·96-3·95; p<0·1), sputum (3·15, 1·39-7·13; p<0·05), shortness of breath (1·86, 0·97-3·57; p<0·1), and wheeze (4·00, 1·52-10·50; p<0·05) after walking down Oxford Street compared with Hyde Park. In all participants, irrespective of their disease status, walking in Hyde Park led to an increase in lung function (forced expiratory volume in the first second [FEV1] and forced vital capacity [FVC]) and a decrease in pulse wave velocity (PWV) and augmentation index up to 26 h after the walk. By contrast, these beneficial responses were attenuated after walking on Oxford Street. In participants with COPD, a reduction in FEV1 and FVC, and an increase in R5-20 were associated with an increase in during-walk exposure to NO2, ultrafine particles and PM2.5, and an increase in PWV and augmentation index with NO2 and ultrafine particles. In healthy volunteers, PWV and augmentation index were associated both with black carbon and ultrafine particles. Short-term exposure to traffic pollution prevents the beneficial cardiopulmonary effects of walking in people with COPD, ischaemic heart disease, and those free from chronic cardiopulmonary diseases. Medication use might reduce the adverse effects of air pollution in individuals with ischaemic heart disease. Policies should aim to control ambient levels of air pollution along busy streets in view of these negative health effects. British Heart Foundation.


Olanzapine versus aprepitant for the prophylaxis of chemotherapy-induced nausea and vomiting in breast cancer patients receiving doxorubicin-cyclophosphamide regimen: A prospective, nonrandomized, open-label study.
Despite the guideline-directed therapy, complete absence of nausea was noted only in 33% of breast cancer patients on anthracycline-cyclophosphamide regimen. Hence, we sought to compare the efficacy of aprepitant (APT) versus olanzapine (OLP) in preventing chemotherapy-induced nausea and vomiting (CINV) in breast cancer patients on doxorubicin-cyclophosphamide regimen. A prospective, open-label, nonrandomized study was conducted at the Department of Oncology. Eighty-three patients completed the study with 43 in the APT group and 40 in OLP group. Data about nausea and vomiting were collected using Multinational Association of Supportive Care in Cancer Antiemesis Tool (MAT). The severity of nausea and vomiting was assessed by the MAT and Common Terminology Criteria for Adverse Events (CTCAE) version 4.03, respectively. Complete response (no emesis and no rescue medication) was achieved in 81% of the patients in APT group and 85% in the OLP group in the acute period (P = 0.661); 74% of patients in APT group and 85% in OLP group had no nausea during the same period (P = 0.233). Among the OLP patients who had nausea, 67% had moderately severe and 33% had Severe grade, and in the APT group, severity was equally distributed in mild, moderate, and severe grades. Among the patients who had vomiting, severe (CTCAE) vomiting was noticed in 81% of patients who were treated with APT compared to 50% in OLP group. OLP was found to be an equally effective alternative to APT in the antiemetic prophylaxis of CINV in breast cancer patients receiving chemotherapy with doxorubicin-cyclophosphamide regimen.


Ventromedial frontal lobe plays a critical role in facial emotion recognition.
The ventromedial prefrontal cortex has been implicated in a variety of emotion processes. However, findings regarding the role of this region specifically in emotion recognition have been mixed. We used a sensitive facial emotion recognition task to compare the emotion recognition performance of 7 subjects with lesions confined to ventromedial prefrontal regions, 8 subjects with lesions elsewhere in prefrontal cortex, and 16 healthy control subjects. We found that emotion recognition was impaired following ventromedial, but not dorsal or lateral, prefrontal damage. This impairment appeared to be quite general, with lower overall ratings or more confusion between all six emotions examined. We also explored the relationship between emotion recognition performance and the ability of the same patients to experience transient happiness and sadness during a laboratory mood induction. We found some support for a relationship between sadness recognition and experience. Taken together, our results indicate that the ventromedial frontal lobe plays a crucial role in facial emotion recognition, and suggest that this deficit may be related to the subjective experience of emotion.


Integral rein control in physiology II: a general model.
We generalize the principle of integral rein control to include other systems which partition in such a way that the equilibrium values of some variables are not dependent on the equations governing those variables. Instead, they are determined by the dynamics of other, "regulator" variables. We improve our earlier model for the control of glucose by insulin and glucagon by relaxing the condition necessary for it to operate. The two hormones do not have to be inhibited in the same way; they need only respond to the same combination of their concentrations. We also present a model for the control of ionized calcium by PTH and calcitonin and suggest that the role of chromogranin A may be to stabilize an otherwise unstable system.


Simplified sample preparation for the analysis of oligonucleotides by matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry.
Matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOFMS) for the analyses of oligonucleotides has generally been carried out using negative ionisation conditions, usually following ammonium ion-exchange chromatography and the addition of ammonium buffers to the MALDI matrix. The molecular ion region is complex, due to the varying degrees of ammoniation of the phosphate backbone of the oligonucleotide. This gives rise to an overall decrease in sensitivity compared with similar size peptides and can cause ambiguity of assignment of the relative molecular mass of the sample. This study describes the use of H(+) ion exchange resin in situ as the means of removing alkali metal ions from the phosphate backbone of the oligonucleotide. An increase in resolution, sensitivity and identification of the molecular species is reported, with little or no difference in sensitivity observed between positive or negative ionisation spectra. This method is now used for routine screening of synthetic oligonucleotides with a gain in sensitivity of 1-2 orders of magnitude compared with previous methods, and mass assignment errors of +/-0.1% are routinely recorded for externally calibrated data.


Collagen peptides ameliorate intestinal epithelial barrier dysfunction in immunostimulatory Caco-2 cell monolayers via enhancing tight junctions.
Dysfunction of the intestinal barrier plays a key role in the pathogenesis of inflammatory bowel disease (IBD) and multiple organ failure. The effect of Alaska pollock skin-derived collagen and its 3 tryptic hydrolytic fractions, HCP (6 kDa retentate), MCP (3 kDa retentate) and LCP (3 kDa permeate) on TNF-α induced barrier dysfunction was investigated in Caco-2 cell monolayers. TNF-α induced barrier dysfunction was significantly attenuated by the collagen and its peptide fractions, especially LCP, compared to TNF-α treated controls (P < 0.05). Compared to a negative control, 24 h pre-incubation with 2 mg mL-1 LCP significantly alleviated the TNF-α induced breakdown of the tight junction protein ZO-1 and occludin and inhibited MLC phosphorylation and MLCK expression. The activation of NFκB and Elk-1 was suppressed by LCP. Thus, collagen peptides may attenuate TNF-α induced barrier dysfunction of Caco-2 cells by inhibiting the NFκB and ERK1/2-mediated MLCK pathway with associated decreases in ZO-1 and occludin protein expression.


Involvement of Pancreatic Stellate Cells in Regeneration of Remnant Pancreas after Partial Pancreatectomy.
Mechanism of regeneration of remnant pancreas after partial pancreatectomy (PX) is still unknown. In this study, effect of siRNA against the collagen specific chaperone, HSP47, which inhibits collagen secretion from activated pancreas stellate cells (aPSCs), and induces their apoptosis, on regeneration of remnant pancreas was determined. Pancreatectomy was performed according to established methods. Proliferation of cells was assessed by BrdU incorporation. Immunostaining of HSP47 was employed to identify PSCs. Progenitor cells were identified by SOX9 staining. Acinar cells were immunostained for amylase. Co-culture of acinar cells with aPSCs were carried out in a double chamber with a cell culture insert. siRNA HSP47 encapsulated in vitamin A-coupled liposome (VA-lip siRNA HSP47) was delivered to aPSCs by iv injection. In remnant pancreas of 90% PX rat, new areas of foci were located separately from duodenal areas with normal pancreatic features. After PX, BrdU uptake of acinar cells and islet cells significantly increased, but was suppressed by treatment with VA-lip siRNA HSP47. BrdU uptake by acinar cells was augmented by co-culturing with aPSCs and the augmentation was nullified by siRNA HSP47. BrdU uptake by progenitor cells in foci area was slightly enhanced by the same treatment. New area which exhibited intermediate features between those of duodenal and area of foci, emerged after the treatment. aPSCs play a crucial role in regeneration of remnant pancreas, proliferation of acinar and islet cells after PX through the activity of secreted collagen. Characterization of new area emerged by siRNA HSP47 treatment as to its origin is a future task.


Effect of fluorosis on dentine shear bond strength of a self-etching bonding system.
The purpose of this study was to investigate the effect of dental fluorosis on shear bond strength of a composite material to dentine. Forty human premolar teeth were classified according to the severity of fluorosis using the Thylstrup and Fejerskov index and were divided into four groups (TFI scores of 0, 3, 4 and 5) of 10 teeth. Non-fluorosed teeth (TFI score of 0) served as the control group. A self-etching light-cured bonding system, Clearfil SE Bond, and a micro-hybrid light-cured composite, Clearfil AP-X were selected for the study. Buccal surfaces of mounted teeth were ground flat to expose the dentine. Composite cylinders, 4 mm diameter and 4 mm length, were bonded to the treated dentine surfaces. Shear bond strength was measured with an universal testing machine at a cross-head speed of 0.5 mm min-1. After failure, the fracture surfaces were examined under a stereo microscope. The mean bond strength was 24.37 +/- 3.54 MPa for non-fluorosed teeth and varied between 22.72 +/- 3.52 and 27.02 +/- 5.91 MPa for fluorosed teeth. The difference between the mean values for bond strength was not statistically significant (P > 0.05). Adhesive mode of failure was most prevalent in non-fluorosed teeth. It can be concluded that fluorosis does not affect the shear bond strength of composite material to human dentine.


Innominosacral dissociation: mechanism of injury as a predictor of resuscitation requirements, morbidity, and mortality.
To assess mechanism of injury as a clinical course predictor in patients with complete anterior and posterior pelvic ring disruptions [innominosacral dissociation (ISD)]. Retrospective review of radiographs and medical data. R Adams Cowley Shock Trauma Center, Baltimore, Maryland, statewide trauma center. Forty-three patients with ISD were admitted to our institution between August 1986 and October 1991. Five patients were excluded because of incomplete medical records (4) or refusal of blood transfusion (1). Injuries were grouped according to the Young classification: 18 anteroposterior compression (APC), 14 vertical shear (VS), and 6 other injuries. The mean blood replacement requirements, incidence of multiple organ system failure, mortality rate, and length of hospital stay for each injury classification were compared. The mean ISS was 34, and the mean 24-hour packed red blood cell transfusion requirement was 12.6 units. Thirteen patients (34.4%) developed multisystem organ failure. Eight patients (21%) died. Patients in the APC group were more likely to require > or = 10 units of blood (15/18, p = 0.001, and those in the VS group were more likely to receive < 10 units (11/14, p = 0.0014). Multisystem organ failure occurred more frequently (11/18 versus 2/14; p < 0.005), mortality was significantly higher (39 versus 0%, respectively; p = 0.01), and mean hospital stay for survivors was longer (48 versus 27 days; p < 0.025) in the APC than in the VS group, respectively. These findings suggest that mechanism of injury is an important determinant of clinical behavior in patients with IDS, and that ISD secondary to the APC mechanism is associated with substantially greater resuscitation requirements, morbidity, and mortality than ISD secondary to the VS mechanism.


Potential role for interleukin-10 in the immunosuppression associated with kala azar.
Patients with acute kala azar are generally nonreactive in a number of immunologic assays, including T cell proliferation and generation of macrophage-activating cytokines, principally IFN-gamma, in response to leishmania antigens in vitro. To test for potential immunosuppressive factors, a series of T cell lines and clones were established from patients with acute kala azar, from patients after chemotherapy for kala azar, and from skin test-positive adults from the same endemic region. Although CD4+ T cell lines and clones could be readily established from the skin test-positive adults, lines and clones from acute or treated patients were heavily biased in expression of CD8+. The CD8+ cells from acute patients did not themselves release cytokines in response to leishmania antigens in vitro, but markedly affected the cytokine profile of peripheral blood mononuclear cells isolated 1 yr later after recovery. Addition of the CD8+ cells caused inhibition of lymphoproliferation and IFN-gamma release, with augmentation of IL-6 and IL-10 release. The inhibitory effects of the CD8+ cells could be partially abrogated by antibodies to IL-10 but not by antibodies to IL-4. Analysis of four patients with acute kala azar demonstrated release of IL-10 that could not be demonstrated in supernatants from asymptomatic skin test-positive individuals. Generation of IL-10 may contribute to the profound suppression of IFN-gamma release that occurs during kala azar due to Leishmania chagasi.


Introduction to the newborn screening fact sheets.
Newborn screening fact sheets were last revised in 1996 by the Committee on Genetics of the American Academy of Pediatrics. These fact sheets have been revised again because of advances in the field, including technologic innovations such as tandem mass spectrometry, as well as greater appreciation of ethical issues such as informed consent. The fact sheets provide information to assist pediatricians and other professionals who care for children in performing their essential role within the newborn screening public health system. The newborn screening system consists of 5 parts: (1) newborn testing; (2) follow-up of abnormal screening results to facilitate timely diagnostic testing and management; (3) diagnostic testing; (4) disease management, which requires coordination with the medical home and genetic counseling; and (5) continuous evaluation and improvement of the newborn screening system. The following disorders are reviewed in the newborn screening fact sheets (which are available at www.pediatrics.org/cgi/content/full/118/3/e934): biotinidase deficiency, congenital adrenal hyperplasia, congenital hearing loss, congenital hypothyroidism, cystic fibrosis, galactosemia,homocystinuria, maple syrup urine disease, medium-chain acyl-coenzyme A dehydrogenase deficiency, phenylketonuria, sickle cell disease and other hemoglobinopathies,and tyrosinemia.


Ethyl 4-hy-droxy-1-methyl-5-oxo-2-phenyl-pyrrolidine-3-carboxyl-ate 1.25-hydrate.
The asymmetric unit of the title compound, C(14)H(17)NO(4)·1.25H(2)O, consists of four substituted pyrrolidone mol-ecules (two pairs of enanti-omers) and five water mol-ecules. The five-membered rings each have an envelope conformation, with the C atom bonded to the ester group as the flap. The mean planes of the five-membered rings of the four pyrrolidone mol-ecules make dihedral angles of 60.87 (5), 64.45 (5), 62.03 (5) and 65.79 (5)° with respect to the phenyl rings. In the crystal, the pyrrolidone and water mol-ecules are connected through O-H⋯O hydrogen bonds, forming a layer parallel to the ab plane. The two-dimensional network is further stabilized by inter-molecular C-H⋯O hydrogen bonds.


Nitric oxide modulation mediates the protective effect of trazodone in a mouse model of chronic fatigue syndrome.
The present study was conducted with the aim of elucidating the possible role of nitric oxide (NO) in the neuroprotective effects of trazodone used to treat chronic fatigue syndrome (CFS) in mice. Male albino mice were forced to swim for a six minute session each day for 7 days and the immobility period was recorded every other day. Trazodone (5 mg/kg and 10 mg/kg) was administered each day 30 min before the forced swim test. In addition, L-arginine (100 mg/kg) and L-NAME (5 mg/kg) were administered 15 min before administration of trazodone (5 mg/kg). Various behavioral tests, including locomotor (actophotometer) and anxiety (mirror chamber and plus maze) tests, as well as biochemical parameters (lipid peroxidation, reduced glutathione, catalase, and nitrites) were evaluated on the 8th day. Forced swimming for 7 days caused a chronic fatigue-like condition, anxiety-like behavior, impairments in locomotor activity, and oxidative damage (increased lipid peroxidation and nitrite levels, and depletions in the reduced forms of glutathione and catalase activity) in animals. Pretreatment with L-NAME (5 mg/kg) potentiated the antioxidant effect of trazodone (5 mg/kg). However, L-arginine (100 mg/kg) pretreatment reversed the protective effect of trazodone (5 mg/kg) (p<0.05). The present study suggests the possible involvement of NO signaling in the protective effect of trazodone.


2D-IR Spectroscopy of an AHA Labeled Photoswitchable PDZ2 Domain.
We explore the capability of the non-natural amino acid azidohomoalanine (AHA) as an IR label to sense relatively small structural changes in proteins with the help of 2D IR difference spectroscopy. To that end, we AHA-labeled an allosteric protein (the PDZ2 domain from human tyrosine-phosphatase 1E) and furthermore covalently linked it to an azobenzene-derived photoswitch as to mimic its conformational transition upon ligand binding. To determine the strengths and limitations of the AHA label, in total six mutants have been investigated with the label at sites with varying properties. Only one mutant revealed a measurable 2D IR difference signal. In contrast to the commonly observed frequency shifts that report on the degree of solvation, in this case we observe an intensity change. To understand this spectral response, we performed classical MD simulations, evaluating local contacts of the AHA labels to water molecules and protein side chains and calculating the vibrational frequency on the basis of an electrostatic model. Although these simulations revealed in part significant and complex changes of the number of intraprotein and water contacts upon trans-cis photoisomerization, they could not provide a clear explanation of why this one label would stick out. Subsequent quantum-chemistry calculations suggest that the response is the result of an electronic interaction involving charge transfer of the azido group with sulfonate groups from the photoswitch. To the best of our knowledge, such an effect has not been described before.


Tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPα.
Variants near the gene TRIB1 are significantly associated with several plasma lipid traits, circulating liver enzymes, and the development of coronary artery disease in humans; however, it is not clear how its protein product tribbles-1 regulates lipid metabolism. Here, we evaluated mice harboring a liver-specific deletion of Trib1 (Trib1_LSKO) to elucidate the role of tribbles-1 in mammalian hepatic lipid metabolism. These mice exhibited increased hepatic triglyceride (TG) content, lipogenic gene transcription, and de novo lipogenesis. Microarray analysis revealed altered transcription of genes that are downstream of the transcription factor C/EBPα, and Trib1_LSKO mice had increased hepatic C/EBPα protein. Hepatic overexpression of C/EBPα in WT mice phenocopied Trib1_LSKO livers, and hepatic knockout of Cebpa in Trib1_LSKO mice revealed that C/EBPα is required for the increased lipogenesis. Using ChIP-Seq, we found that Trib1_LSKO mice had increased DNA-bound C/EBPα near lipogenic genes and the Trib1 gene, which itself was transcriptionally upregulated by C/EBPα overexpression. Together, our results reveal that tribbles-1 regulates hepatic lipogenesis through posttranscriptional regulation of C/EBPα, which in turn transcriptionally upregulates Trib1. These data suggest an important role for C/EBPα in mediating the lipogenic effects of hepatic Trib1 deletion and provide insight into the association between TRIB1 and plasma lipids, and liver traits in humans.


Association of wild bird density and farm management factors with the prevalence of E. coli O157 in dairy herds in Ohio (2007-2009).
Our objective was to determine the role that European starlings (Sturnus vulgaris) play in the epidemiology of Escherichia coli O157:H7 in dairy cattle. We visited 150 dairy farms in Ohio twice during summer and fall months from 2007 to 2009. Fresh faecal pats from 30 lactating cows were collected during each visit. Information on farm management and environmental variables was gathered through a questionnaire administered to the farm owner. The number of starlings observed on the farm was also recorded. Approximately 1% of dairy cattle and 24% of farms were positive for E. coli O157. Risk factors associated with the presence of E. coli O157 in faecal pats included contact between adult cattle and calves, types or number of ventilation and manure management systems and number of birds per milking cow.


Distinguishing between poor/dysfunctional parenting and child emotional maltreatment.
This paper was intended to distinguish between poor parenting and child emotional maltreatment (CEM), to inform child welfare and public health policymakers of the need for differentiated responses. Scientific literature was integrated with current practice and assumptions relating to poor/dysfunctional parenting and child emotional maltreatment, with a primary focus on the parent-child relationship context (rather than abnormal parent behavior alone). Numerous factors that impinge on the distinction between these acts were considered, such as the child's age, the frequency, and severity of behavior shown by caregivers, cultural norms, and parental beliefs and goals in childrearing. The literature on child emotional maltreatment has advanced beyond the descriptive phase of scientific understanding, and principles and practical criteria for distinguishing such behavior from poor parenting are presented. Recommendations focus on practical guidelines for assessing risk and activating appropriate prevention and intervention: (1) parental actions and relative risk of harm to the child are both important ingredients in defining and distinguishing child emotional maltreatment from other forms of poor parenting; (2) poor parenting methods fall along a broad continuum and fit within a population health mandate aimed at reducing incidence of all forms of negative parenting methods; (3) child emotional maltreatment can be defined categorically based on qualitatively more extreme and potentially more harmful behaviors (than poor parenting), which requires a focused intervention response. Additional recommendations for training, research, and community-based public health initiatives are presented.


Using a novel ambulatory monitoring system to support patient safety on an acute infectious disease ward during an unfolding pandemic.
To gain staff feedback on the implementation and impact of a novel ambulatory monitoring system to support coronavirus patient management on an isolation ward. Qualitative service evaluation. Semi-structured interviews were conducted with 15 multidisciplinary isolation ward staff in the United Kingdom between July 2020 and May 2021. Interviews were audio-recorded, transcribed and analysed using thematic analysis. Adopting Innovation to Assist Patient Safety was identified as the overriding theme. Three interlinked sub-themes represent facets of how the system supported patient safety. Patient Selection was developed throughout the pandemic, as clinical staff became more confident in choosing which patients would benefit most. Trust In the System described how nurses coped with discrepancies between the ambulatory system and ward observation machines. Finally, Resource Management examined how, once trust was built, staff perceived the ambulatory system assisted with caseload management. This supported efficient personal protective equipment resource use by reducing the number of isolation room entries. Despite these reported benefits, face-to-face contact was still highly valued, despite the risk of coronavirus exposure. Hospital wards should consider using ambulatory monitoring systems to support caseload management and patient safety. Patients in isolation rooms or at high risk of deterioration may particularly benefit from this additional monitoring. However, these systems should be seen as an adjunct to nursing care, not a replacement. Nurses valued ambulatory monitoring as a means of ensuring the safety of patients at risk of deterioration and prioritizing their workload. The findings of this research will be useful to all those developing or considering implementation of ambulatory monitoring systems in hospital wards. This manuscript follows the Consolidated criteria for Reporting Qualitative Research (COREQ) guidelines with inclusion of relevant SQUIRE guidelines for reporting quality improvement. No Patient or Public Contribution.


Cerebellar network plasticity: from genes to fast oscillation.
The role of the cerebellum has been increasingly recognized not only in motor control but in sensory, cognitive and emotional learning and regulation. Purkinje cells, being the sole output from the cerebellar cortex, occupy an integrative position in this network. Plasticity at this level is known to critically involve calcium signaling. In the last few years, electrophysiological study of genetically engineered mice has demonstrated the topical role of several genes encoding calcium-binding proteins (calretinin, calbindin, parvalbumin). Specific inactivation of these genes results in the emergence of a fast network oscillation (ca. 160 Hz) throughout the cerebellar cortex in alert animals, associated with ataxia. This oscillation is produced by synchronization of Purkinje cells along the parallel fiber beam. It behaves as an electrophysiological arrest rhythm, being blocked by sensorimotor stimulation. Pharmacological manipulations showed that the oscillation is blocked by GABA(A) and NMDA antagonists as well as gap junction blockers. This cerebellar network oscillation has also been documented in mouse models of human conditions with complex developmental cerebellar dysfunction, such as Angelman syndrome and fetal alcohol syndrome. Recent evidence suggests a relationship between fast oscillation and cerebellar long term depression (LTD). This may have major implications for future therapeutic targeting.


Anticancer activity of grape and grape skin extracts alone and combined with green tea infusions.
Grapes and grape extracts were compared for inhibition of a growth-related and cancer-specific form of cell surface NADH oxidase with protein disulfide-thiol interchange activity designated tNOX from human cervical carcinoma (HeLa) cells and growth of HeLa and mouse mammary 4T1 cells in culture and transplanted tumors in mice. Grapes and grape extracts of several varieties had activity. With an extracted grape preparation provided by the California Table Grape Commission, an active fraction was eluted with methanol from a Diaion HP-20 column after removal of inactive water-soluble materials. Grape skins were a much more potent source than either grape pulp, juice or seeds. Ethanol extracts of the ground freeze-dried pomace was an excellent source. The grape extracts interacted, often synergistically, with decaffeinated green tea extracts both in the inhibition of tNOX activity and in the inhibition of cancer cell growth. Intratumoral injections of a 25:1 mixture of a green tea extract plus ground freeze-dried pomace was nearly as effective as standard synergistic green tea-Capsicum mixtures in inhibiting growth of 4T1 mammary tumors in situ in mice.


Longitudinal diffusion changes following postoperative delirium in older people without dementia.
To investigate the effect of postoperative delirium on longitudinal brain microstructural changes, as measured by diffusion tensor imaging. We studied a subset of the larger Successful Aging after Elective Surgery (SAGES) study cohort of older adults (≥70 years) without dementia undergoing elective surgery: 113 participants who had diffusion tensor imaging before and 1 year after surgery. Postoperative delirium severity and occurrence were assessed during the hospital stay using the Confusion Assessment Method and a validated chart review method. We investigated the association of delirium severity and occurrence with longitudinal diffusion changes across 1 year, adjusting for age, sex, vascular comorbidity, and baseline cognitive performance. We also assessed the association between changes in diffusion and cognitive performance across the 1-year follow-up period, adjusting for age, sex, education, and baseline cognitive performance. Postoperative delirium occurred in 25 participants (22%). Delirium severity and occurrence were associated with longitudinal diffusion changes in the periventricular, frontal, and temporal white matter. Diffusion changes were also associated with changes in cognitive performance across 1 year, although the cognitive changes did not show significant association with delirium severity or occurrence. Our study raises the possibility that delirium has an effect on the development of brain microstructural abnormalities, which may reflect brain changes underlying cognitive trajectories. Future studies are warranted to clarify whether delirium is the driving factor of the observed changes or rather a correlate of a vulnerable brain that is at high risk for neurodegenerative processes.


Cancer associated with obstetric delivery: results of linkage with the California cancer registry.
This study provides revised population-based measurements for the occurrence rates of cancer associated with obstetric delivery and examines perinatal and cancer-related outcomes within the group of women with 4,846,505 obstetric deliveries in California, inclusive of the years 1991 through 1999. This observational study used a population-based retrospective review of cases identified as a result of computer linkage of maternal/neonatal hospital discharge and birth/death records with case files in the California Cancer Registry (CCR). The effect of timing of cancer diagnosis on clinical outcomes was studied by dividing the cases into three groups as follows: "prenatal" for cancer diagnosis within 9 months before delivery, "at delivery" for cancer diagnosis during delivery hospitalization, and "post partum" for cancer diagnosis within 12 months after delivery. Computerized records for 4,846,505 obstetric patients and 4,906,920 newborn infants comprising the linked vital statistics birth/patient discharge database (VS/PDD) were used to identity-match cases within the CCR case files. Cases of malignant disease were categorized into 22 anatomic or histologic subgroups. Perinatal clinical outcomes including preterm delivery, prolonged neonatal hospital stay, stillbirth, neonatal death, frequency of first trimester prenatal care, and cesarean delivery were analyzed by use of International Classification of Diseases, 9th Revision, Clinical Modification codes from the VS/PDD. Clinical cancer outcomes including cancer stage and vital status on follow-up were drawn from CCR records. Statistical comparisons for trends were performed with the Cochran-Armitage test, outcomes comparisons with the Fisher exact test, and survival comparisons were performed with the Cox proportional hazard model. Among 4,846,505 obstetric deliveries, 4,539 cases of invasive malignancy were identified for an observed occurrence rate of 0.94 per 1000 births. Sixty-four percent of the cases occurred post partum; cancers of the breast, thyroid, cervix, along with malignant melanoma, and Hodgkin's disease accounted for 64% of the cases. The timing of cancer diagnosis affected clinical outcomes: for all cancer cases as a group, the most favorable perinatal and cancer outcomes occurred in women whose cancer diagnosis was made 6 to 9 months before delivery (6% of cases). The most unfavorable perinatal and cancer outcomes were associated with cancer diagnosis made 0 to 3 months before delivery (14% of cases). For women whose cancer was diagnosed post partum, perinatal outcomes were minimally affected by the presumed existence of occult cancer at the time of obstetric delivery. The use of computer-linkage to the CCR files enhanced identification of cases of maternal malignancy associated with obstetric delivery. Cancer diagnosis was associated with approximately 1 in 1000 deliveries. Most cases were diagnosed after delivery and were comprised predominantly of cancers of the breast, thyroid, cervix, malignant melanoma, and Hodgkin's disease. A small group of women (approximately 1 per 5000 deliveries) are seen within a few months before delivery or at delivery with malignant disease, many of whom have rapidly progressing disease and may require high-risk perinatal and oncology services.


Nuclear magnetic resonance study of the thermal denaturation of ribonuclease A: implications for multistate behavior at low pH.
The thermal denaturation of ribonuclease A has been studied by use of Fourier transform nuclear magnetic resonance by monitoring the imidazole C-2 proton resonances of the histidine residues as a function of temperature at pH 1.3. As the temperature is raised, a slow chemical exchange process results in the disappearance of the peaks corresponding to the native conformation and the appearance of a single peak corresponding to histidine in the denatured state. The disappearance of the native peaks is not simultaneous, implying that at least two regions of the molecule denature at different temperatures. Also, fast chemical exchange processes result in small chemical shifts that appear to be related to local conformational changes. The observed phenomena have been shown to be reversible by the measurement of absorbance at 278 nm, enzyme activity, and nuclear magnetic resonance spectroscopy. The results of this equilibrium study support a multistate denaturation mechanism for ribonuclease A at pH 1.3.


Gender-related behavior in women exposed prenatally to diethylstilbestrol.
Accumulating evidence in experimental animals over the past three decades suggests that mammalian brain development and differentiation of the central nervous system are influenced by perinatal exposure to sex hormones. Hence, changes in human behavioral patterns may be associated with prenatal exposure to estrogenic substances such as diethylstilbestrol (DES). This paper reviews relevant studies from a series of laboratories and finds that no clear-cut differences can be demonstrated to date between unexposed and DES-exposed women in gender-related behavior, although the physical and psychological impact of the problems associated with exposure to DES are well documented. If both prenatal and postnatal influences such as social, economic, and environmental factors are taken into consideration, individual variation is more apparent than differences in gender-related behavior between unexposed and DES-exposed women. In summary, gender-related behavior is determined by a complex array of interacting factors, and prenatal influences are only one of many developmental events. More studies are needed using larger populations with carefully controlled selection criteria to suggest a direct role of prenatal DES exposure on subsequent gender-related behavior.


Classification of proteomic data with multiclass Logistic Partial Least Squares algorithm.
Early detection of cancer is crucial for successful treatments. In this paper, we propose a multiclass Logistic Partial Least Squares (LPLS) algorithm for classification of normal vs. cancer using Mass Spectrometry (MS). LPLS combines the multiclass logistic regression with Partial Least Squares (PLS) algorithm. Wavelet decomposition is also proposed for pre-processing of original data. Wavelet decomposition and the proposed LPLS are applied to real life cancer data. Experimental comparisons show that LPLS with wavelet decomposition outperforms other methods in the analysis of MS data.


Parallel evolution controlled by adaptation and covariation in ammonoid cephalopods.
A major goal in evolutionary biology is to understand the processes that shape the evolutionary trajectory of clades. The repeated and similar large-scale morphological evolutionary trends of distinct lineages suggest that adaptation by means of natural selection (functional constraints) is the major cause of parallel evolution, a very common phenomenon in extinct and extant lineages. However, parallel evolution can result from other processes, which are usually ignored or difficult to identify, such as developmental constraints. Hence, understanding the underlying processes of parallel evolution still requires further research. Herein, we present a possible case of parallel evolution between two ammonoid lineages (Auguritidae and Pinacitidae) of Early-Middle Devonian age (405-395 Ma), which are extinct cephalopods with an external, chambered shell. In time and through phylogenetic order of appearance, both lineages display a morphological shift toward more involute coiling (i.e. more tightly coiled whorls), larger adult body size, more complex suture line (the folded walls separating the gas-filled buoyancy-chambers), and the development of an umbilical lid (a very peculiar extension of the lateral shell wall covering the umbilicus) in the most derived taxa. Increased involution toward shells with closed umbilicus has been demonstrated to reflect improved hydrodynamic properties of the shell and thus likely results from similar natural selection pressures. The peculiar umbilical lid might have also added to the improvement of the hydrodynamic properties of the shell. Finally, increasing complexity of suture lines likely results from covariation induced by trends of increasing adult size and whorl overlap given the morphogenetic properties of the suture. The morphological evolution of these two Devonian ammonoid lineages follows a near parallel evolutionary path for some important shell characters during several million years and through their phylogeny. Evolution of some traits (involution, umbilical lid) appears to be mainly driven by adaptation to improve the hydrodynamic properties of the shell, whereas other characters (sutural complexity) evolved due to covariation with features that play a central role in the morphogenesis of mollusc shells. This example provides evidence that parallel evolution can be driven simultaneously by different factors such as covariation (constructional constraints) and adaptation (natural selection).