COVID-19: Data-Driven optimal allocation of ventilator supply under uncertainty and risk.
This study presents a new risk-averse multi-stage stochastic epidemics-ventilator-logistics compartmental model to address the resource allocation challenges of mitigating COVID-19. This epidemiological logistics model involves the uncertainty of untested asymptomatic infections and incorporates short-term human migration. Disease transmission is also forecasted through a new formulation of transmission rates that evolve over space and time with respect to various non-pharmaceutical interventions, such as wearing masks, social distancing, and lockdown. The proposed multi-stage stochastic model overviews different scenarios on the number of asymptomatic individuals while optimizing the distribution of resources, such as ventilators, to minimize the total expected number of newly infected and deceased people. The Conditional Value at Risk (CVaR) is also incorporated into the multi-stage mean-risk model to allow for a trade-off between the weighted expected loss due to the outbreak and the expected risks associated with experiencing disastrous pandemic scenarios. We apply our multi-stage mean-risk epidemics-ventilator-logistics model to the case of controlling COVID-19 in highly-impacted counties of New York and New Jersey. We calibrate, validate, and test our model using actual infection, population, and migration data. We also define a new region-based sub-problem and bounds on the problem and then show their computational benefits in terms of the optimality and relaxation gaps. The computational results indicate that short-term migration influences the transmission of the disease significantly. The optimal number of ventilators allocated to each region depends on various factors, including the number of initial infections, disease transmission rates, initial ICU capacity, the population of a geographical location, and the availability of ventilator supply. Our data-driven modeling framework can be adapted to study the disease transmission dynamics and logistics of other similar epidemics and pandemics.


Neuroprotective and neurotoxic outcomes of androgens and estrogens in an oxidative stress environment.
The role of sex hormones on cellular function is unclear. Studies show androgens and estrogens are protective in the CNS, whereas other studies found no effects or damaging effects. Furthermore, sex differences have been observed in multiple oxidative stress-associated CNS disorders, such as Alzheimer's disease, depression, and Parkinson's disease. The goal of this study is to examine the relationship between sex hormones (i.e., androgens and estrogens) and oxidative stress on cell viability. N27 and PC12 neuronal and C6 glial phenotypic cell lines were used. N27 cells are female rat derived, whereas PC12 cells and C6 cells are male rat derived. These cells express estrogen receptors and the membrane-associated androgen receptor variant, AR45, but not the full-length androgen receptor. N27, PC12, and C6 cells were exposed to sex hormones either before or after an oxidative stressor to examine neuroprotective and neurotoxic properties, respectively. Estrogen receptor and androgen receptor inhibitors were used to determine the mechanisms mediating hormone-oxidative stress interactions on cell viability. Since the presence of AR45 in the human brain tissue was unknown, we examined the postmortem brain tissue from men and women for AR45 protein expression. Neither androgens nor estrogens were protective against subsequent oxidative stress insults in glial cells. However, these hormones exhibited neuroprotective properties in neuronal N27 and PC12 cells via the estrogen receptor. Interestingly, a window of opportunity exists for sex hormone neuroprotection, wherein temporary hormone deprivation blocked neuroprotection by sex hormones. However, if sex hormones are applied following an oxidative stressor, they exacerbated oxidative stress-induced cell loss in neuronal and glial cells. Sex hormone action on cell viability is dependent on the cellular environment. In healthy neuronal cells, sex hormones are protective against oxidative stress insults via the estrogen receptor, regardless of sex chromosome complement (XX, XY). However, in unhealthy (e.g., high oxidative stress) cells, sex hormones exacerbated oxidative stress-induced cell loss, regardless of cell type or sex chromosome complement. The non-genomic AR45 receptor, which is present in humans, mediated androgen's damaging effects, but it is unknown which receptor mediated estrogen's damaging effects. These differential effects of sex hormones that are dependent on the cellular environment, receptor profile, and cell type may mediate the observed sex differences in oxidative stress-associated CNS disorders.


Clonally expanded mitochondrial DNA mutations in epileptic individuals with mutated DNA polymerase gamma.
The instability of the mitochondrial genome in individuals harboring pathogenic mutations in the catalytic subunit of mitochondrial DNA (mtDNA) polymerase gamma (POLG) is well recognized, but the underlying molecular mechanisms remain to be elucidated. In 5 pediatric patients with severe myoclonic epilepsy and valproic acid-induced liver failure, we identified 1 novel and 4 previously described pathogenic mutations in the linker region of this enzyme. Although muscle biopsies in these patients showed unremarkable histologic features, postmortem liver tissue available from 1 individual exhibited large cytochrome c oxidase-negative areas. These cytochrome c oxidase-negative areas contained 4-fold less mtDNA than cytochrome c oxidase-positive areas. Decreased copy numbers of mtDNA were observed not only in the liver, skeletal muscle, and brain but also in blood samples from all patients. There were also patient-specific patterns of multiple mtDNA deletions in different tissues, and in 2 patients, there were clonally expanded mtDNA point mutations. The low amount of deleted mtDNA molecules makes it unlikely that the deletions contribute significantly to the general biochemical defect. The clonal expansion of a few individual-specific deletions and point mutations indicates an accelerated segregation of early mtDNA mutations that likely are a consequence of low mtDNA copy numbers. Moreover, these results suggest a potential diagnostic approach for identifying mtDNA depletion in patients.


The variant forms of autoimmune hepatitis.
To review the diagnostic criteria for autoimmune hepatitis, to characterize the variant forms of autoimmune hepatitis, and to indicate appropriate therapies for this condition. A MEDLINE search (1990 to 1995) of the English-language literature, review of a personal library of journals and reprints (1975 to 1995), and review of references selected from the bibliographies of identified articles. Terms used in the MEDLINE search included the names of all autoimmune liver diseases, viral hepatitis and autoimmunity, cryptogenic hepatitis, and overlap syndromes. All articles that discussed atypical clinical features, mixed diagnostic findings, and variations in treatment response were selected. Data were selected from 548 articles. Standardized criteria permit the confident diagnosis of autoimmune hepatitis, but they exclude many patients who have features suggesting autoimmunity. Such patients have findings indicative of both autoimmune hepatitis and another disorder (overlap syndromes) or findings that are inconsistent with the classic definition of autoimmune hepatitis (outlier syndromes). Overlap syndromes include combinations of autoimmune hepatitis and primary biliary cirrhosis, primary sclerosing cholangitis, or chronic viral hepatitis. Treatment of these syndromes requires identification of the predominant disorder and selection of the most appropriate drug regimen. Outlier syndromes include autoimmune cholangitis and cryptogenic chronic hepatitis. Corticosteroids or ursodeoxycholic acid are treatment options for patients with autoimmune cholangitis; corticosteroids can also benefit patients with cryptogenic chronic hepatitis. Grading each clinical feature and developing a composite score can permit comparison of the variants and a determination of the similarity between the variants and autoimmune hepatitis. Variant forms of autoimmune hepatitis are common. Recognition of them is important in assessing common pathogenic mechanisms, developing effective treatment strategies, and refining classification schemes.


Differential Contributions of Ventral and Dorsal Striatum to Early and Late Phases of Cognitive Set Reconfiguration.
Flexible decision-making, a defining feature of human cognition, is typically thought of as a canonical pFC function. Recent work suggests that the striatum may participate as well; however, its role in this process is not well understood. We recorded activity of neurons in both the ventral (VS) and dorsal (DS) striatum while rhesus macaques performed a version of the Wisconsin Card Sorting Test, a classic test of flexibility. Our version of the task involved a trial-and-error phase before monkeys could identify the correct rule on each block. We observed changes in firing rate in both regions when monkeys switched rules. Specifically, VS neurons demonstrated switch-related activity early in the trial-and-error period when the rule needed to be updated, and a portion of these neurons signaled information about the switch context (i.e., whether the switch was intradimensional or extradimensional). Neurons in both VS and DS demonstrated switch-related activity at the end of the trial-and-error period, immediately before the rule was fully established and maintained, but these signals did not carry any information about switch context. We also observed associative learning signals (i.e., specific responses to options associated with rewards in the presentation period before choice) that followed the same pattern as switch signals (early in VS, later in DS). Taken together, these results endorse the idea that the striatum participates directly in cognitive set reconfiguration and suggest that single neurons in the striatum may contribute to a functional handoff from the VS to the DS during reconfiguration processes.


Effect of naftidrofuryl on the metabolic response to surgery.
In a randomised study of 34 patients undergoing elective operations of moderate severity naftidrofuryl infusion significantly improved postoperative nitrogen balance. The control group excreted 26.2 +/- 2.7 g nitrogen in the first three postoperative days. A group treated with naftidrofuryl excreted 18.0 +/- 1.6 g nitrogen in the same period (p less than 0.0005). The preoperative nutritional state of patients treated with naftidrofuryl did not differ from that of the controls. Though hormonal changes causing an improvement in nitrogen balance could not be excluded by this study, the results show that naftidrofuryl infusion may stimulate postoperative catabolism of endogenous carbohydrate and fat, thus sparing tissue protein.


Inappropriate shocks from a subcutaneous implantable cardioverter-defibrillator due to oversensing during periods of rate-related bundle branch block.
The subcutaneous implantable cardioverter-defibrillator (S-ICD) is a novel technology with proven efficacy in sudden cardiac death prevention; however, there is a lack of long-term safety data. We describe the case of a 55-year-old female patient implanted with an S-ICD due to idiopathic ventricular fibrillation, who subsequently presented with inappropriate shocks leading to ventricular fibrillation that was successfully terminated by another shock. Inappropriate shocks were due to intermittent T wave oversensing during periods of rate-dependent right bundle branch block. Assessment of the S-ICD electrograms during an exercise test allowed successful reprogramming of the device׳s sensing vector with no further events.


Black tea polyphenols and polysaccharides improve body composition, increase fecal fatty acid, and regulate fat metabolism in high-fat diet-induced obese rats.
With the current changes in diet and living habits, obesity has become a global health problem. Thus, the weight-reducing function of tea has attracted considerable attention. This study investigated the anti-obesity effect and the mechanism of black tea (BT) polyphenols and polysaccharides in male Sprague-Dawley rats. The BT polyphenols and polysaccharides reduced the body weight, Lee's index, visceral fat weight, and fat cell size but improved the biochemical profile and increased the fecal fatty acid content, thereby preventing high-fat diet-induced obesity. A gene expression profile array was used to screen eight upregulated and five downregulated differentially expressed genes that affect fat metabolic pathways, such as glycerolipid and glycerophospholipid metabolism, fatty acid degradation, glycolysis and gluconeogenesis, bile and pancreatic secretion, the insulin signaling pathway, and steroid hormone secretion. The BT polyphenols and polysaccharides suppressed the formation and accumulation of fat and promoted its decomposition to prevent obesity.


Purification of angularin, a novel antifungal peptide from adzuki beans.
An antifungal peptide was isolated from the adzuki bean with a procedure involving affinity chromatography on Affi-gel blue gel and ion exchange chromatography on CM-Sepharose. The protein designated angularin was adsorbed on both types of chromatographic media and possessed a molecular weight of 8 kDa. Angularin exhibited antifungal activity against a variety of fungal species including Mycospharella arachidiocola and Botrytis cinerea. It inhibited mycelial growth in B. cinerea with an IC50 of 14.3 microM. Fusarium oxysporum and Rhizoctonia solani were not inhibited. Angularin demonstrated inhibitory activity on translation in the rabbit reticulocyte lysate system (IC50 = 8.0 microM) but did not affect proliferation of splenocytes. The activity of HIV-1 reverse transcriptase was inhibited in the presence of angularin. Its N-terminal sequence was GEPGQKE.


Myelin loss and axonal ion channel adaptations associated with gray matter neuronal hyperexcitability.
Myelination and voltage-gated ion channel clustering at the nodes of Ranvier are essential for the rapid saltatory conduction of action potentials. Whether myelination influences the structural organization of the axon initial segment (AIS) and action potential initiation is poorly understood. Using the cuprizone mouse model, we combined electrophysiological recordings with immunofluorescence of the voltage-gated Nav1.6 and Kv7.3 subunits and anchoring proteins to analyze the functional and structural properties of single demyelinated neocortical L5 axons. Whole-cell recordings demonstrated that neurons with demyelinated axons were intrinsically more excitable, characterized by increased spontaneous suprathreshold depolarizations as well as antidromically propagating action potentials ectopically generated in distal parts of the axon. Immunofluorescence examination of demyelinated axons showed that βIV-spectrin, Nav1.6, and the Kv7.3 channels in nodes of Ranvier either dissolved or extended into the paranodal domains. In contrast, while the AIS in demyelinated axons started more closely to the soma, ankyrin G, βIV-spectrin, and the ion channel expression were maintained. Structure-function analysis and computational modeling, constrained by the AIS location and realistic dendritic and axonal morphologies, confirmed that a more proximal onset of the AIS slightly reduced the efficacy of action potential generation, suggesting a compensatory role. These results suggest that oligodendroglial myelination is not only important for maximizing conduction velocity, but also for limiting hyperexcitability of pyramidal neurons.


Online or not? A comparison of students' experiences of an online and an on-campus class.
Educational discourse has long portrayed online, or e-based, learning and all non-campus-based learning options as second best to traditional face-to-face options. Critically much of the research and debate in this area of study has focused on evidence relating to student performance, attrition and retention with little consideration of the total learning experience, which values both the traditional learning outcome measures side-by-side with student-centered factors, such as students' satisfaction with their learning experience. The objective of this study was to present a synchronous head-to-head comparison between online and campus-based students' experiences of an undergraduate course. This paper reports on a qualitative comparative cross-sectional study, which used multiple data collection approaches to assess student learning and student satisfaction of 61 students who completed a semester of an undergraduate course. Of the 61 students, 34 were enrolled purely as online students, whilst the remaining 27 students studied the same material entirely through the traditional face-to-face medium. Methods included a standardised student satisfaction survey and an 'achievement of learning outcomes' measurement tool. Students on the online cohort performed better in areas where 'self-direction' in learning was indicated, for example self-directed problem-based tasks within the course. Online students gave less positive self-assessments of their perceived content mastery than their campus-based counterparts, despite performing just as well in both summative and formative assignments. A multi-factorial comparison shows online students to have comparable educational success and that, in terms of student satisfaction, online learners reported more satisfaction with their learning experience than their campus-based counterparts.


MRI of tarantulas: morphological and perfusion imaging.
This paper describes a study performed to evaluate the feasibility of using a 1.5-T whole-body magnetic resonance imaging (MRI) equipment, in combination with pharmacokinetic modeling, to obtain in vivo information about the morphology and perfusion of tarantulas (Eurypelma californicum). MRI was performed on three tarantulas using spin-echo sequences for morphological imaging and a rapid spoiled gradient-echo sequence for dynamic imaging during and after contrast medium (CM; Gd-DTPA) injection. Signal enhancement in dynamic measurements was evaluated with a pharmacokinetic two-compartment model. Spin-echo images showed morphological structures well. Dynamic images were of sufficient quality and allowed a model analysis of CM kinetics, which provides information about regional perfusion. In conclusion, morphological and dynamic contrast-enhanced MRI of tarantulas is feasible with a conventional clinical scanner. Studies of this kind are therefore possible without a dedicated high-field animal scanner.


Covalently immobilized laminin peptide Tyr-Ile-Gly-Ser-Arg (YIGSR) supports cell spreading and co-localization of the 67-kilodalton laminin receptor with alpha-actinin and vinculin.
The laminin-based nonapeptide Cys-Asp-Pro-Gly-Tyr-Ile-Gly-Ser-Arg (CDPGYIGSR) and pentapeptide Tyr-Ile-Gly-Ser-Arg (YIGSR) have been previously demonstrated to support the attachment of several cell types and to competitively bind to the 67-kDa high affinity laminin receptor. Cell attachment, but not spreading, on substrates containing adsorbed CDPGYIGSR or YIGSR was observed. In this report we describe YIGSR-mediated attachment and spreading of a wide variety of cell types. GYIGSRY promoted cell spreading and stress fiber formation when it was covalently immobilized through the amino-terminal Gly residue, used as a spacer arm. Spreading was not observed when adsorbed YIGSR peptide was used. Functionally blocking antiserum directed against the 67-kDa and related laminin-binding proteins blocked human foreskin fibroblast (HFF) spreading, but not attachment, on covalently grafted GYIGSRY substrates. However, functionally blocking antisera directed against the vitronectin receptor, integrin alpha v beta 3, and the fibronectin receptor, integrin alpha 5 beta 1, did not affect HFF spreading on these substrates. When HFFs spread on these substrates, the 67-kDa laminin receptor co-localized with the cytoplasmic proteins alpha-actinin and vinculin into discrete structures. These results suggest that the adhesion ligand YIGSR is solely sufficient for cell spreading when it is conformationally constrained by covalent attachment to a solid substrate, at least when attached via its amino terminus. Furthermore, the role of the 67-kDa laminin receptor in recognition of this ligand and mediating cell attachment is confirmed in this study. This report also provides the first evidence for direct or indirect association of this receptor with vinculin and alpha-actinin when YIGSR-mediated cell spreading occurs.


Variation in the hindgut microbial communities of the Florida manatee, Trichechus manatus latirostris over winter in Crystal River, Florida.
The Florida manatee, Trichechus manatus latirostris, is a hindgut-fermenting herbivore. In winter, manatees migrate to warm water overwintering sites where they undergo dietary shifts and may suffer from cold-induced stress. Given these seasonally induced changes in diet, the present study aimed to examine variation in the hindgut bacterial communities of wild manatees overwintering at Crystal River, west Florida. Faeces were sampled from 36 manatees of known sex and body size in early winter when manatees were newly arrived and then in mid-winter and late winter when diet had probably changed and environmental stress may have increased. Concentrations of faecal cortisol metabolite, an indicator of a stress response, were measured by enzyme immunoassay. Using 454-pyrosequencing, 2027 bacterial operational taxonomic units were identified in manatee faeces following amplicon pyrosequencing of the 16S rRNA gene V3/V4 region. Classified sequences were assigned to eight previously described bacterial phyla; only 0.36% of sequences could not be classified to phylum level. Five core phyla were identified in all samples. The majority (96.8%) of sequences were classified as Firmicutes (77.3 ± 11.1% of total sequences) or Bacteroidetes (19.5 ± 10.6%). Alpha-diversity measures trended towards higher diversity of hindgut microbiota in manatees in mid-winter compared to early and late winter. Beta-diversity measures, analysed through PERMANOVA, also indicated significant differences in bacterial communities based on the season.


Effect of AAC technology with dynamic text on the single-word recognition of adults with intellectual and developmental disabilities.
Purpose: Single-word recognition can support participation in life, including engagement in leisure activities, navigation through the community, and vocational opportunities. Given the limited reading skills of many adults with intellectual and developmental disabilities (IDD) and limited speech, the current study evaluated the effects of using an augmentative and alternative communication (AAC) app, featuring dynamic text and speech output embedded in visual scene displays, on the single-word recognition performance of six adults with IDD who demonstrated limited speech.Method: A multiple baseline across participants single-subject design was used. Ten target sight words for each participant were selected on an individual basis, based on participant interest. Intervention consisted solely of interactions between investigators and individual participants using the app.Result: In the absence of any formal instruction and solely through the use of the AAC app interaction, three of the six participants demonstrated increased accuracy in single-word recognition.Conclusion: Results from the study were mixed, but suggest that AAC apps which provide the dynamic display of text in conjunction with voice output can assist some adults with IDD in achieving gains in single-word reading.


Laws and Policies Related to the Health of US Immigrants: A Policy Scan.
We conducted a policy scan of state and local laws and policies across the United States related to social determinants of health among immigrants. We collected all state and municipal laws and policies in 10 domains that had potential to affect immigrant health from all 50 U.S. states and the 30 most populous U.S. metropolitan statistical areas. We coded these laws and policies and created an index of restrictiveness and supportiveness of immigrants. We identified 539 state and 322 municipal laws and policies. The most common restrictive state laws and policies were in the domains of identification requirements and driver's license access. The most common supportive state laws and policies were in the domains of health services and higher education access. The most common restrictive municipal laws and policies were in the domains of identification requirements and immigration policy enforcement. The most common supportive municipal laws and policies were in the domains of immigration policy enforcement and health services access. Most states had index scores reflecting policy environments that were primarily restrictive of immigrants, indicating potential negative impacts on social determinants of health. Further research examining the impact of these on health behaviors is warranted.


Evidence-based review of the Bioenterics intragastric balloon for weight loss.
We reviewed clinical studies performed with the Bioenterics intragastric balloon (BIB) to promote weight loss. Thirty studies were included [18 prospective (5 randomized), 12 retrospective], totaling 4,877 patients. Only one of three sham-controlled trials found a significantly higher weight loss with the BIB vs the sham procedure plus exhaustive follow-up. In nonrandomized studies, weight loss with the BIB averaged 17.8 kg (range, 4.9-28.5), corresponding to BMI changes of 4.0-9.0 kg/m(2). Comorbidities resolved or improved in 52-100% of patients. Best short-term results were observed in patients devoid of binge eating disorder with a BMI in the 30.0-40.0 kg/m(2) range; the BIB also helped to prepare superobese patients for bariatric surgery. Severe complications were exceptional (gastric perforation and intestinal obstruction; 0.2% each); digestive intolerance prompted early BIB removal in 2.5% of patients. Long-term (>or=2 years) results are awaited, as well as well-designed studies to define the best indications for this therapy.


A Retrospective Cohort Study Comparing Stroke Recurrence Rate in Ischemic Stroke Patients With and Without Acupuncture Treatment.
Little was known about the effects of acupuncture on stroke recurrence. The aim of this study is to investigate whether ischemic stroke patients receiving acupuncture treatment have a decreased risk of stroke recurrence. A retrospective cohort study of 30,058 newly diagnosed cases of ischemic stroke in 2000 to 2004 was conducted based on the claims of Taiwan National Health Insurance Research Database. The use of acupuncture treatment and stroke recurrence were identified during the follow-up period from 2000 to 2009. This study compared the risk of stroke recurrence between ischemic stroke cohorts with and without acupuncture treatment by calculating adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of acupuncture associated with stroke recurrence in the Cox proportional hazard model. The stroke recurrence rate per 1000 person-years decreased from 71.4 without to 69.9 with acupuncture treatment (P < 0.001). Acupuncture treatment was associated with reduced risk of stroke recurrence (HR 0.88; 95% CI 0.84-0.91). The acupuncture effect was noted in patients with or without medical treatment for stroke prevention but its impact decreased with aging of stroke patients. Compared with stroke patients without acupuncture treatment and medication therapy, the hazard ratios of stroke recurrence for those had medication therapy only, acupuncture only, and both were 0.42 (95% CI 0.38-0.46), 0.50 (95% CI 0.43-0.57), and 0.39 (95% CI 0.35-0.43), respectively. This study raises the possibility that acupuncture might be effective in lowering stroke recurrence rate even in those on medications for stroke prevention. Results suggest the need of prospective sham-controlled and randomized trials to establish the efficacy of acupuncture in preventing stroke.


Suicidality related to first-time admissions to psychiatric hospital.
The epidemiology of suicidality shows considerable variation across sites. However, one of the strongest predictors of suicide is a suicidal attempt. Knowledge of the epidemiology of suicidal ideas and attempts in the general population as well as in the health care system is of importance for designing preventive strategies. In this study, we will explore the role of the psychiatric hospital in suicide prevention by investigating treated incidence of suicidal ideation and attempt, and further, discern whether sociodemographic, clinical and service utilization factors differ between these two groups at admission. The study was a prospective cohort study on treated incidence in a 1-year period and 12-month follow-up. The two psychiatric hospitals in northern Norway, serving a population of about 500,000 people, participated in the study. A total of 676 first-time admissions were retrospectively checked for suicidality at the time of admission. A study sample of 168 patients was found eligible for logistic regression analysis to elucidate the risk profiles of suicidal ideators versus suicidal attempters. GAF, HoNOS and SCL-90-R were used to assess symptomatology at baseline. 52.2% of all patients admitted had suicidal ideas at admission and 19.7% had attempted suicide. In the study sample, there were no differences in risk profile between the two groups with regard to sociodemographic and clinical factors. Males who had made a suicide attempt were less likely to have been in contact with an out-patient clinic before the attempt. The rating scales not measuring suicidality directly showed no differences in symptomatology. The findings provide evidence for the importance of the psychiatric hospital in suicide prevention. About half of the admissions were related to suicidality and the similar risk profiles found in suicidal ideators and suicidal attempters indicate that it is the ideators who mostly need treatment that get admitted to the hospital, and should be evaluated and treated with equal concern as those who have attempted suicide.


The energetic cost of mating in a promiscuous cephalopod.
Costs that individuals incur through mating can play an important role in understanding the evolution of life histories and senescence, particularly in promiscuous species. Copulation costs, ranging from energy expenditure to reduced longevity, are widely studied in insects but have received substantially less attention in other taxa. One cost of mating, the energetic cost, is poorly studied across all taxa despite its potential importance for the many species where copulation is physically demanding and/or frequent. Here, we investigated the energetic cost of mating in both male and female dumpling squid (Euprymna tasmanica). In this species, copulation can last up to 3 h and requires that the male physically restrains the female. We report that the act of copulation halves the swimming endurance of both sexes, and that they take up to 30 min to recover. Such a reduction in post-copulatory performance may have important implications for predator avoidance, foraging ability and energy allocation. Therefore, quantifying this cost is essential to understand the evolution of reproductive strategies and behaviours such as female receptivity and male and female mating frequency.


A Novel Scoring Based Distributed Protein Docking Application to Improve Enrichment.
Molecular docking is a computational technique which predicts the binding energy and the preferred binding mode of a ligand to a protein target. Virtual screening is a tool which uses docking to investigate large chemical libraries to identify ligands that bind favorably to a protein target. We have developed a novel scoring based distributed protein docking application to improve enrichment in virtual screening. The application addresses the issue of time and cost of screening in contrast to conventional systematic parallel virtual screening methods in two ways. Firstly, it automates the process of creating and launching multiple independent dockings on a high performance computing cluster. Secondly, it uses a Nȧi̇ve Bayes scoring function to calculate binding energy of un-docked ligands to identify and preferentially dock (Autodock predicted) better binders. The application was tested on four proteins using a library of 10,573 ligands. In all the experiments, (i). 200 of the 1,000 best binders are identified after docking only ~14 percent of the chemical library, (ii). 9 or 10 best-binders are identified after docking only ~19 percent of the chemical library, and (iii). no significant enrichment is observed after docking ~70 percent of the chemical library. The results show significant increase in enrichment of potential drug leads in early rounds of virtual screening.


Long-interval intracortical inhibition as biomarker for epilepsy: a transcranial magnetic stimulation study.
Cortical excitability, as measured by transcranial magnetic stimulation combined with electromyography, is a potential biomarker for the diagnosis and follow-up of epilepsy. We report on long-interval intracortical inhibition data measured in four different centres in healthy controls (n = 95), subjects with refractory genetic generalized epilepsy (n = 40) and with refractory focal epilepsy (n = 69). Long-interval intracortical inhibition was measured by applying two supra-threshold stimuli with an interstimulus interval of 50, 100, 150, 200 and 250 ms and calculating the ratio between the response to the second (test stimulus) and to the first (conditioning stimulus). In all subjects, the median response ratio showed inhibition at all interstimulus intervals. Using a mixed linear-effects model, we compared the long-interval intracortical inhibition response ratios between the different subject types. We conducted two analyses; one including data from the four centres and one excluding data from Centre 2, as the methods in this centre differed from the others. In the first analysis, we found no differences in long-interval intracortical inhibition between the different subject types. In all subjects, the response ratios at interstimulus intervals 100 and 150 ms showed significantly more inhibition than the response ratios at 50, 200 and 250 ms. Our second analysis showed a significant interaction between interstimulus interval and subject type (P = 0.0003). Post hoc testing showed significant differences between controls and refractory focal epilepsy at interstimulus intervals of 100 ms (P = 0.02) and 200 ms (P = 0.04). There were no significant differences between controls and refractory generalized epilepsy groups or between the refractory generalized and focal epilepsy groups. Our results do not support the body of previous work that suggests that long-interval intracortical inhibition is significantly reduced in refractory focal and genetic generalized epilepsy. Results from the second analysis are even in sharper contrast with previous work, showing inhibition in refractory focal epilepsy at 200 ms instead of facilitation previously reported. Methodological differences, especially shorter intervals between the pulse pairs, may have contributed to our inability to reproduce previous findings. Based on our results, we suggest that long-interval intracortical inhibition as measured by transcranial magnetic stimulation and electromyography is unlikely to have clinical use as a biomarker of epilepsy.


Overview of pharmacogenetics.
Pharmacogenetics is the study of relationships between genetic variation and inter-individual differences with respect to drug response. As the field has matured over the past 15 years, a remarkable diversity of pathways, variation types, and mechanisms have been found to be relevant pharmacogenetic factors. Today, pharmacogenetics is becoming more important in pharmacology for target validation, lead optimization, and understanding of idiosyncratic toxicity. This unit provides an overview of the history of pharmacogenetics and current research applications in drug discovery, as well as a discussion of research quality issues relevant for human subjects research in the pharmacogenetics laboratory.


Understanding the effect of corticosteroid pretreatment in brain-dead organ donors: new mechanistic insights for improvement of organ quality in liver transplantation.
Transplant surgeons are currently faced with the challenge to accept marginal liver transplants due to steatosis or old age. Improving organ quality by implementing a selective organ protective donor management could be the first step towards a graft of enhanced quality. However, the molecular mechanisms of such treatments are still poorly understood. Glucocorticoid medication in donor medicine has been carried out and discussed for a long time. In a recent study published in Clinical Science, Jiménez-Castro et al. [Clin. Sci. (2017) 131, 733-746] demonstrate how liver histology and transplant liver function can be improved by administration of glucocorticoids to brain-dead donor rats with steatotic livers. This work illustrates the need for further trials in order to selectively improve the quality of steatotic livers with a potential for liver transplantation.


Incidence and risk factors for symptoms from the eyes among professional computer users.
Personal computers are used by a majority of the working population in their professions. Little is known about risk-factors for incident symptoms from the eyes among professional computer users. The aim was to study the incidence and risk-factors for symptoms from the eyes among professional computer users.This study is a part of a comprehensive prospective follow-up study of factors associated with the incidence of symptoms among professional computer users. 1531 computer users of different professions at 46 companies were invited, whereof 1283 answered a baseline questionnaire (498 men; 785 women) and 1246 at least one of 10 monthly follow-up questionnaires. The computer work-station and equipment were generally of a good standard. The majority used CRT displays.During the follow-up period 329 subjects reported eye symptoms. The overall incidence rate in the whole study group was 0.38 per person-year, 0.23 in the subgroup of subjects who were symptom free at baseline and 1.06 among subjects who reported eye symptoms at baseline. In the bivariate analyses significant associations were found with all explanatory variables, except BMI. The reduced multivariate model showed significant associations with extended computer work, visual discomfort (dose-response), eye symptoms at baseline (higher risk), sex (women=higher risk) and nicotine use.The incidence of eye problems among professional computer users is high and related to both individual and work-related factors.


The Seattle appropriate level of care survey: health status and health services use in ambulatory persons with AIDS.
We surveyed 77 persons with AIDS, their physicians and their social workers during the autumn of 1987 to ascertain health status and to quantify use of health services in Seattle, Washington. Participants included the majority (59%) of persons living with AIDS in the area. Information was gathered regarding demography, health status, functional status, medical history and the use of health services. The validity of self-assessed general health was corroborated by the physician-rated Karnovsky score (kappa = 0.59), by social worker assessment (kappa = 0.41), and by correlation with functional status (r = 0.6-0.8). We found more frequent use of health services (categorized into skilled services, chore services and physician services) among AIDS patients who were dependent in basic and instrumental daily activities, had low income, had poor self-assessed general health, lived alone or lacked an available support person at home. These associations persisted in multivariate analyses, and accounted for 6-23% of the variability in service use. We conclude that health and functional status of persons with AIDS can be estimated via mailed questionnaires and accounts for a modest amount of the variability in use of health services.


Strong dispersive coupling of a high-finesse cavity to a micromechanical membrane.
Macroscopic mechanical objects and electromagnetic degrees of freedom can couple to each other through radiation pressure. Optomechanical systems in which this coupling is sufficiently strong are predicted to show quantum effects and are a topic of considerable interest. Devices in this regime would offer new types of control over the quantum state of both light and matter, and would provide a new arena in which to explore the boundary between quantum and classical physics. Experiments so far have achieved sufficient optomechanical coupling to laser-cool mechanical devices, but have not yet reached the quantum regime. The outstanding technical challenge in this field is integrating sensitive micromechanical elements (which must be small, light and flexible) into high-finesse cavities (which are typically rigid and massive) without compromising the mechanical or optical properties of either. A second, and more fundamental, challenge is to read out the mechanical element's energy eigenstate. Displacement measurements (no matter how sensitive) cannot determine an oscillator's energy eigenstate, and measurements coupling to quantities other than displacement have been difficult to realize in practice. Here we present an optomechanical system that has the potential to resolve both of these challenges. We demonstrate a cavity which is detuned by the motion of a 50-nm-thick dielectric membrane placed between two macroscopic, rigid, high-finesse mirrors. This approach segregates optical and mechanical functionality to physically distinct structures and avoids compromising either. It also allows for direct measurement of the square of the membrane's displacement, and thus in principle the membrane's energy eigenstate. We estimate that it should be practical to use this scheme to observe quantum jumps of a mechanical system, an important goal in the field of quantum measurement.


The additive effects of minoxidil and retinol on human hair growth in vitro.
Minoxidil enhances hair growth by prolonging the anagen phase and induces new hair growth in androgenetic alopecia (AGA), whereas retinol significantly improves scalp skin condition and promotes hair growth. We investigated the combined effects of minoxidil and retinol on human hair growth in vitro and on cultured human dermal papilla cells (DPCs) and epidermal keratinocytes (HaCaT). The combination of minoxidil and retinol additively promoted hair growth in hair follicle organ cultures. In addition, minoxidil plus retinol more effectively elevated phosphorylated Erk, phosphorylated Akt levels, and the Bcl-2/Bax ratio than minoxidil alone in DPCs and HaCaT. We found that the significant hair shaft elongation demonstrated after minoxidil plus retinol treatment would depend on the dual kinetics associated with the activations of Erk- and Akt-dependent pathways and the prevention of apoptosis by increasing the Bcl-2/Bax ratio.


Nanopore sequencing: An enrichment-free alternative to mitochondrial DNA sequencing.
Mitochondrial DNA sequence data are often utilized in disease studies, conservation genetics and forensic identification. The current approaches for sequencing the full mtGenome typically require several rounds of PCR enrichment during Sanger or MPS protocols followed by fairly tedious assembly and analysis. Here we describe an efficient approach to sequencing directly from genomic DNA samples without prior enrichment or extensive library preparation steps. A comparison is made between libraries sequenced directly from native DNA and the same samples sequenced from libraries generated with nine overlapping mtDNA amplicons on the Oxford Nanopore MinION™ device. The native and amplicon library preparation methods and alternative base calling strategies were assessed to establish error rates and identify trends of discordance between the two library preparation approaches. For the complete mtGenome, 16 569 nucleotides, an overall error rate of approximately 1.00% was observed. As expected with mtDNA, the majority of error was detected in homopolymeric regions. The use of a modified basecaller that corrects for ambiguous signal in homopolymeric stretches reduced the error rate for both library preparation methods to approximately 0.30%. Our study indicates that direct mtDNA sequencing from native DNA on the MinION™ device provides comparable results to those obtained from common mtDNA sequencing methods and is a reliable alternative to approaches using PCR-enriched libraries.


Stertorous breathing is a reliably identified sign that helps in the differentiation of epileptic from psychogenic non-epileptic convulsions: an audit.
Stertorous breathing may occur after epileptic convulsions, but does not typically occur after psychogenic non-epileptic convulsions. During an 18-month audit at a tertiary referral centre in the United Kingdom, we analysed 75 convulsions arising in 45 patients and found that nursing and ancillary staff can be easily trained to reliably identify the presence or absence of stertorous breathing after a convulsion. No patient with a final diagnosis of purely psychogenic non-epileptic seizures (17 out of 45 patients) was judged to have stertorous respiration. Stertorous breathing was present in 41 out of 44 interpretable video recordings from patients with epileptic convulsions proven on videotelemetry. We suggest that a history or evidence (e.g. video) of stertorous breathing may help in distinguishing epileptic from psychogenic non-epileptic convulsive seizures.


Identification of a nutrient-sensing transcriptional network in monocytes by using inbred rat models on a cafeteria diet.
Obesity has reached pandemic levels worldwide. The current models of diet-induced obesity in rodents use predominantly high-fat based diets that do not take into account the consumption of variety of highly palatable, energy-dense foods that are prevalent in Western society. We and others have shown that the cafeteria (CAF) diet is a robust and reproducible model of human metabolic syndrome with tissue inflammation in the rat. We have previously shown that inbred rat strains such as Wistar Kyoto (WKY) and Lewis (LEW) show different susceptibilities to CAF diets with distinct metabolic and morphometric profiles. Here, we show a difference in plasma MCP-1 levels and investigate the effect of the CAF diet on peripheral blood monocyte transcriptome, as powerful stress-sensing immune cells, in WKY and LEW rats. We found that 75.5% of the differentially expressed transcripts under the CAF diet were upregulated in WKY rats and were functionally related to the activation of the immune response. Using a gene co-expression network constructed from the genes differentially expressed between CAF diet-fed LEW and WKY rats, we identified acyl-CoA synthetase short-chain family member 2 (Acss2) as a hub gene for a nutrient-sensing cluster of transcripts in monocytes. The Acss2 genomic region is significantly enriched for previously established metabolism quantitative trait loci in the rat. Notably, monocyte expression levels of Acss2 significantly correlated with plasma glucose, triglyceride, leptin and non-esterified fatty acid (NEFA) levels as well as morphometric measurements such as body weight and the total fat following feeding with the CAF diet in the rat. These results show the importance of the genetic background in nutritional genomics and identify inbred rat strains as potential models for CAF-diet-induced obesity.


The Interaction between Childhood Bullying and the FKBP5 Gene on Psychotic-Like Experiences and Stress Reactivity in Real Life.
The present study employed Experience Sampling Methodology to examine whether the interaction between childhood bullying and FKBP5 variability (i) is associated with the expression of psychotic-like experiences, paranoia, and negative affect, and (ii) moderates psychotic-like, paranoid, and affective reactivity to different forms of momentary stress (situational and social) in daily life. A total of 206 nonclinical young adults were interviewed for bullying with the Childhood Experience of Care and Abuse and were prompted randomly eight times daily for one week to complete assessments of their current experiences, affect, and stress appraisals. Participants were genotyped for three FKBP5 single nucleotide polymorphisms (SNPs) (rs3800373, rs9296158, and rs1360780) that have been linked to hypothalamus-pituitary-adrenal axis reactivity. Multilevel analyses were conducted to examine the effect of the interaction between childhood bullying and the FKBP5 haplotype derived from these three SNPs. The interaction between bullying and the FKBP5 haplotype was associated with positive, but not negative, psychotic-like experiences, paranoia, and negative affect. The bullying x FKBP5 interaction also moderated the association of a social stress appraisal (specifically, being alone because people do not want to be with you) with psychotic-like experiences and negative affect in daily life. Simple slopes analyses indicated that, in all cases, the associations were significantly increased by exposure to bullying in participants with the risk haplotype, but not for those with the non-risk haplotype. The present study provides the first evidence of the interplay between childhood bullying and FKBP5 variability in the real-world expression of psychosis proneness and social stress reactivity. The findings underscore the importance of investigating how gene-environment interactions are involved in mechanistic pathways to the extended psychosis phenotype and lend further support to the increasing relevance given to socially defeating appraisals in the experience of reality distortion.


New strategies for targeting the hypoxic tumour microenvironment in breast cancer.
Radiation and drug resistance remain major challenges and causes of mortality in the treatment of locally advanced, recurrent and metastatic breast cancer. Metabolic reprogramming is a recently recognised hallmark of cancer with the hypoxic acidic extracellular environment as a major driver of invasion and metastases. Nearly 40% of all breast cancers and 50% of locally advanced breast cancers are hypoxic and their altered metabolism is strongly linked to resistance to radiotherapy and systemic therapy. The dependence of metabolically adapted breast cancer cells on alterations in cell function presents a wide range of new therapeutic targets such as carbonic anhydrase IX (CAIX). This review highlights preclinical approaches to evaluating an array of targets against tumour metabolism in breast cancer and early phase clinical studies on efficacy.


Phage Phenomics: Physiological Approaches to Characterize Novel Viral Proteins.
Current investigations into phage-host interactions are dependent on extrapolating knowledge from (meta)genomes. Interestingly, 60 - 95% of all phage sequences share no homology to current annotated proteins. As a result, a large proportion of phage genes are annotated as hypothetical. This reality heavily affects the annotation of both structural and auxiliary metabolic genes. Here we present phenomic methods designed to capture the physiological response(s) of a selected host during expression of one of these unknown phage genes. Multi-phenotype Assay Plates (MAPs) are used to monitor the diversity of host substrate utilization and subsequent biomass formation, while metabolomics provides bi-product analysis by monitoring metabolite abundance and diversity. Both tools are used simultaneously to provide a phenotypic profile associated with expression of a single putative phage open reading frame (ORF). Representative results for both methods are compared, highlighting the phenotypic profile differences of a host carrying either putative structural or metabolic phage genes. In addition, the visualization techniques and high throughput computational pipelines that facilitated experimental analysis are presented.


The Relationship Between Gray Matter Morphometry and Neuropsychological Performance in a Large Sample of Cognitively Healthy Adults.
Voxel-based morphometry (VBM) was used to examine the relationship between gray matter (GM) volume and performance on two commonly used clinical neuropsychological measures of frontal lobe or executive function, the Trail Making Test part B (TrailsB) and the Controlled Oral Word Association Test (COWAT) in 221 cognitively healthy adults between the ages of 18 and 84. We hypothesized that these measures would be associated with GM volume in the dorsolateral frontal lobes. Voxel-based multiple regression was used to correlate cognitive function with modulated GM probability maps while controlling for age, education, gender, and total intracranial volume. A relationship with TrailsB was found in bilateral lateral inferior frontal gyri and left basal ganglia. A relationship with COWAT was found in the left lateral inferior and middle frontal gyri. Lesion studies have long implicated the importance of these regions for executive function. The present results confirm and extend those prior findings to healthy adults.


Elements of dialysis nursing practice associated with successful cannulation: result of an international survey.
Vascular access (VA) cannulation is an essential skill for dialysis nurses: failure to correctly repeat this operation daily may result in serious complications for the patients. This study investigates if different aspects of arteriovenous fistula and graft cannulation have an effect on the development of acute access complications, which may affect the VA survival. In April 2009 a cross-sectional survey was conducted in 171 dialysis units located in Europe, the Middle East and Africa to collect details on VA cannulation practices. Information on cannulation retrieved from the survey comprised fistula type and location, cannulation technique, needle size, use of disinfectants and of local anaesthetics, application of arm compression at the time of cannulation, needle and bevel direction, needle rotation, and needle fixation. Five categories of complications were investigated: multiple-cannulation, infiltration, haematoma, haemorrhage and unknown. There were 10,807 cannulation procedures evaluated in the same number of patients. Of these, 367 showed some kind of complication, the most frequent (33.8%) being the need for multiple-cannulation. The following were associated with a significantly higher odds ratio for occurrence of an acute complication: prescription of back-eye needles, use of rope-ladder cannulation technique, insertion of venous needle as first needle, and rotation of the arterial needle. Use of 16-17-gauge needles was also significantly associated with complications, but this possibly reflects poor quality of the VA. The risk of an acute VA complication could be reduced with appropriate training of nurses, physicians and patients. This could potentially prolong the VA life.


Clinical Overlap Between Myopericarditis and Stress Induced Cardiomyopathy: A Diagnostic and Therapeutic Challenge.
BACKGROUND Stress induced cardiomyopathy (SIC) is characterized by non-obstructive coronary arteries and characteristic ventricular apical ballooning. The exact pathogenesis of SIC is not well recognized. We present an unusual case of SIC that mimicked acute myopericarditis and discuss the effect of this masquerading presentation of SIC in recognizing pathophysiological association between myopericarditis and SIC and limitations of current diagnostic criteria. CASE REPORT A 47-year-old female presented with flu-like illness and pleuritic chest pain. An electrocardiogram (ECG) showed diffuse PR depressions and ST elevations, troponin 5 ng/mL, hemoglobin 14.2 mg/dL, leukocytosis (white blood cell count of 15.1×103/uL) and erythrocyte sedimentation rate (ESR) of 22.4 mm/hour. Echocardiogram showed reduced ejection fraction (EF) with apical ballooning. Catheterization showed non-obstructive coronary disease. The patient was given colchicine and ibuprofen for 1 day with symptom resolution over the next 2 days and repeat echocardiogram with preserved EF. Troponin trended down to 3.24 ng/mL and 0.44 ng/mL, 6 hours apart. ECG showed resolution of PR depressions and subsequent T wave inversions in 1, AVl, V1-V6 by day 3. The diagnosis of myopericarditis was favored by viral prodrome, fever, pleuritic pain, pericardial rub, ECG findings, and elevated ESR. History of emotional stress, characteristic ballooning of left ventricle apex with rapid resolution favored SIC. CONCLUSIONS This case showed that SIC and myocarditis need not be mutually exclusive and differentiating clinically between these 2 entities can be difficult. Alternatively, SIC can accompany other cardiac conditions like myocardial infarction, pericarditis, and myocarditis making diagnosis and management challenging. Clinicians need to be cautious while making this differentiation as duration and type of therapy may be significantly different. SIC can be considered a variant of regional inflammatory myocarditis wherein pericarditis may result secondary to extension of myocardial inflammation to overlying pericardium. The current Mayo Clinic criteria for diagnosis of SIC appears to be outdated, not accounting for such atypical presentations, and therefore needs to be revised.


Role of nutrition on anemia in elderly.
Anemia in elderly population have a great incidence and is related to increased mortality risk. The incidence of nutrition in anemia is about one third of the total. Caloric and protein restriction, iron, vitamin B12, folic deficiency are the causes of nutritional anemia. Protein and energy malnutrition stimulate an increased cytokines production with induction of inflammation, immunodeficiency and anemia. Anorexia and obesity can be associated with anemia due to increased cytokines and hepdicin serum level. Macrophages activity is inhibited and a decrease in red blood cells (RBC), hemoglobin (Hb) concentration due to ineffective erythropoiesis is observed. An adequate energy and protein diet is necessary to reduce inflammation and increase iron absorption. A minimum of 1700 kcal/day and 1.7 gr/kg/day of protein intake are necessary to maintain anabolism in chronic patients to prevent and treat anemia. Iron supplementation by intravenous injection is safe and effective to correct severe iron deficiency. The supplementation of vitamins and oligomineral are useful to reduce oxidative stress and improve RBC longevity. Anemia in elderly could be prevented by an adequate nutrition, a simple and not expensive intervention, and associated to physical exercise reduce the incidence of mortality rate.


SU-E-I-102: Independent Implementation of AAPM TG-150 Draft Image Receptor Test Recommendations.
To determine whether a proposed suite of generic tests for digital radiography (DR) detectors could be reduced to practice. MATLAB software was developed to analyze images according to descriptions in a document drafted by the TG150 Detector Subgroup. Forprocessing images were acquired directly from the acquisition stations of three DR and one Computed Radiography system. Images included flat-field exposures at the manufacturer's calibration condition, twice the exposure, ½ the exposure, and a low exposure, plus three images of a lead bar pattern in different orientations, also at the calibration condition. The flat field images were analyzed to determine Detector Response; Gain Correction; Signal, Noise, and Signal-to-noise (SNR) Uniformity; SNR Magnitude; and Anomalous Detector Element (del) Identification. The program also allowed visual inspection for evaluation of collimation and non-uniformity. Bar pattern images were analyzed to evaluate spatial resolution by a variance method. Acquisition revealed a number of pitfalls. Some manufacturers have multiple calibration points. For-processing images are not directly available from all systems, and PACS may modify them from their original state. The orientation of the flat field with respect to the anodecathode axis may not be defined by the manufacturer. Care must be taken to ensure collimation outside the edges of detectors, or the software must exclude collimator shadows. The matrix size of images differs among manufacturers, so the size of the region of interest (ROI) for analysis varies from the default size of 100×100 dels, as does the number of ROIs. The approach for dealing with edges and ROIs may affect the numerical results. The detector response function may also affect the interpretation of results. The software successfully implements most of the detector tests recommended by TG150. Comparison of these results with those of the parallel effort will validate the draft test definition.


Risk factors by molecular subtypes of breast cancer across a population-based study of women 56 years or younger.
Differences in incidence, prognosis, and treatment response suggest gene expression patterns may discern breast cancer subtypes with unique risk factor profiles; however, previous results were based predominantly on older women. In this study, we examined similar relationships in women ≤ 56 years, classified by immunohistochemical staining for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 for 890 breast cancer cases and 3,432 frequency-matched population-based controls. Odds ratios (OR) and 95% confidence intervals (CI) for tumor subtypes were calculated using multivariate polytomous regression models. A total of 455 (51.1%) tumors were considered luminal A, 72 (8.1%) luminal B, 117 (13.1%) non-luminal HER-2/neu+, and 246 (27.6%) triple negative. Triple negative tumors were associated with breast feeding duration (per 6 months: OR = 0.76, 95% CI 0.64-0.90). Among premenopausal women, increasing body size was more strongly associated with luminal B (OR = 1.73, 95% CI 1.07-2.77) and triple negative tumors (OR = 1.67, 95% CI 1.22-2.28). A history of benign breast disease was associated only with increased risk of luminal A tumors (OR = 1.89, 95% CI 1.43-2.50). A family history of breast cancer was a risk factor for luminal A tumors (OR = 1.93, 95% CI 1.38-2.70) regardless of age, and triple negative tumors with higher risks for women <45 (OR = 5.02, 95% CI 2.82-8.92; P for age interaction = 0.005). We found that little-to-no breastfeeding and high BMI were associated with increased risk of triple negative breast cancer. That some risk factors differ by molecular subtypes suggests etiologic heterogeneity in breast carcinogenesis among young women.


Fluorescein angiography of the iris in anterior segment pigment dispersal syndrome.
The results are presented of fluorescein angiography of the iris in 11 patients with anterior segment pigment dispersal syndrome. These show a general hypovascularity of the iris with fine neovascularisation at the pupil margin and the peripupillary area. Hypoplasia of the iris stroma was also present in many cases. When the condition was virtually unilateral, the vascular changes were present though less marked in the relatively unaffected eye. It is postulated that the anterior segment pigment dispersal syndrome is secondary to a congenital mesodermal deficiency of the iris stroma with hypovascularity of the iris, which forms a poor support tissue for the pigment epithelium of the iris, resulting in shedding of pigment granules particularly in the region of the attachment of the dilator muscle to the pigment epithelium. The condition may be hereditary. Because of the hypovascularity the mesodermal hypoplasia may be progressive, but pigment release may diminish in later life with treatment, with consequent diminution of pupil activity.


Formation of glaciers on Mars by atmospheric precipitation at high obliquity.
Surface conditions on Mars are currently cold and dry, with water ice unstable on the surface except near the poles. However, geologically recent glacierlike landforms have been identified in the tropics and the midlatitudes of Mars. The ice has been proposed to originate from either a subsurface reservoir or the atmosphere. We present high-resolution climate simulations performed with a model designed to simulate the present-day Mars water cycle but assuming a 45 degrees obliquity as experienced by Mars a few million years ago. The model predicts ice accumulation in regions where glacier landforms are observed, on the western flanks of the great volcanoes and in the eastern Hellas region. This agreement points to an atmospheric origin for the ice and reveals how precipitation could have formed glaciers on Mars.


Methane Activation on H-ZSM-5 Zeolite with Low Copper Loading. The Nature of Active Sites and Intermediates Identified with the Combination of Spectroscopic Methods.
Cu-modified zeolites have enormous potential as the catalysts facilitating the conversion of methane to methanol. It becomes important to investigate the active sites and the reaction mechanisms involved. In this paper, several spectroscopic methods such as UV-vis diffuse reflectance spectroscopy (UV-vis DRS), pulse electron paramagnetic resonance (EPR), diffuse reflectance Fourier transform infrared spectroscopy, and solid-state (13C MAS) NMR have been employed to characterize the state of the Cu sites and the intermediates formed during the catalyst activation and methane-to-methanol transformation on Cu/H-ZSM-5 zeolite with low (0.10 wt %) Cu content. UV-vis DRS and EPR data imply the presence of two types of Cu2+ cations bound to the zeolite framework Si-O--Al sites (Z). One of them is a species of the type Z[Cu(II)O] or Z[Cu(II)(OH)] with extra-framework O- or OH- ligands. The other one refers to Z2Cu(II) species without extra-framework O-containing ligands. CW EPR studies reveal that the Z2Cu(II) species are the major part of the Cu(II) sites present in the zeolite. 1H HYSCORE and DRIFTS data are supportive of the formation of a molecular complex of methane and Z2Cu(II) species, with a strongly polarized C-H bond and a 3.3 Å separation between the hydrogen atom of methane and Cu. 13C MAS NMR provides evidence for the formation of both the surface methoxy intermediate and physisorbed methanol. It is suggested that experimentally identified Z[Cu(II)O] or Z[Cu(II)(OH)] are those sites that provide a homolytic cleavage of the methane C-H bond to yield surface bound methoxy species and/or methanol molecule, the possibility that has been recently justified with density functional theory ( Kulkarni et al. Catal. Sci. Technol. 2018 , 8 , 114 ). The comparison of the amount of the surface methoxy intermediates formed and the number of different Cu(II) sites present in the zeolite allowed us to conclude the involvement of Z2Cu(II) sites in methane C-H bond activation. The mechanism of methane activation on Z2Cu(II) sites has been proposed. It includes two steps: (1) the formation of the molecular complex of methane with Z2Cu(II); (2) heterolytic dissociation of the polarized C-H bond affording surface copper(II) hydride and methoxy species, both bound to zeolite framework Si-O--Al sites.


Effectiveness and cost-effectiveness of a very brief physical activity intervention delivered in NHS Health Checks (VBI Trial): study protocol for a randomised controlled trial.
Physical activity interventions that are targeted at individuals can be effective in encouraging people to be more physically active. However, most such interventions are too long or complex and not scalable to the general population. This trial will test the effectiveness and cost-effectiveness of a very brief physical activity intervention when delivered as part of preventative health checks in primary care (National Health Service (NHS) Health Check). The Very Brief Intervention (VBI) Trial is a two parallel-group, randomised, controlled trial with 1:1 individual allocation and follow-up at 3 months. A total of 1,140 participants will be recruited from 23 primary care practices in the east of England. Participants eligible for an NHS Health Check and who are considered suitable to take part by their doctor and able to provide written informed consent are eligible for the trial. Participants are randomly assigned at the beginning of the NHS Health Check to either 1) the control arm, in which they receive only the NHS Health Check, or 2) the intervention arm, in which they receive the NHS Health Check plus 'Step It Up' (a very brief intervention that can be delivered in 5 minutes by nurses and/or healthcare assistants at the end of the Health Check). 'Step It Up' includes (1) a face-to-face discussion, including feedback on current activity level, recommendations for physical activity, and information on how to use a pedometer, set step goals, and monitor progress; (2) written material supporting the discussion and tips and links to further resources to help increase physical activity; and (3) a pedometer to wear and a step chart for monitoring progress. The primary outcome is accelerometer counts per minute at 3-month follow-up. Secondary outcomes include the time spent in the different levels of physical activity, self-reported physical activity and economic measures. Trial recruitment is underway. The VBI trial will provide evidence on the effectiveness and cost-effectiveness of the Step It Up intervention delivered during NHS Health Checks and will inform policy decisions about introducing very brief interventions into routine primary care practice. ISRCTN Registry, ISRCTN72691150 . Registered on 17 July 2014.


Usefulness of immunomodulators for maturation of dendritic cells.
Biological response modifiers (BRMs) augment the cytotoxic activity of various effector cells by the induction of multiple cytokines and suppression of immunosuppressive factors. BRMs are used extensively in adjuvant therapy for gastric cancer in Japan. In dendritic cell (DC)-based vaccine therapy, the quality of DCs is important in inducing strong antitumor immunity. A good manufacturing practice (GMP) grade agent for DCs maturation is desirable for safety. Here we report the effects of two BRMs, OK432 and PSK, which are GMP grade agents for the functional maturation of DCs. OK432 and PSK were examined in vitro, and compared with lipopolysaccharide (LPS) and a cytokine cocktail (IL-1beta, TNF-alpha, IL-6 and PGE2). In the immunophenotypical analysis, the expression of CD80 and CD83 of DCs stimulated with OK-432 increased significantly compared with PSK and medium, and this up-regulation was the same as levels of DCs stimulated with cytokine cocktail. DCs stimulated with OK-432 showed significantly higher production of IL-12 and Th1-type cytokines (IL-2 and IFN-gamma) compared with DCs stimulated with LPS or cytokine cocktail. OK-432 stimulated DCs could induce the significantly high level of cytotoxic T cell activity compared with PSK-stimulated or unstimulated DCs. These results suggest that OK432 is a GMP-grade reagent that promotes functional maturation of DCs and could be applied in DC-based vaccinations.


Concise diastereoselective synthesis of calcaripeptide C via asymmetric transfer hydrogenation/Pd-induced chiral allenylzinc as a key reaction.
Synthesis of the natural product calcaripeptide C derived from the fungal metabolite mycelium KF525 of Calcarisporium sp. has been achieved. This complementary approach avoids the use of a stoichiometric amount of chiral auxiliary reagents as commonly used to generate enantioenriched advanced precursors. The enantioselective synthesis of calcaripeptide C is remarkable in that using catalytic reactions sets the two stereogenic centers efficiently with good levels of enantioselectivity. Further diversification of the calcaripeptide C structures is possible by employing a complementary catalytic enantioenriched Ru-catalyst.


Characterizing an ERP correlate of intentions understanding using a sequential comic strips paradigm.
Chronometric properties of theory of mind and intentions understanding more specifically are well documented. Notably, it was demonstrated using magnetoencephalography that the brain regions involved were recruited as soon as 200 ms post-stimulus. We used event-related potentials (ERPs) to characterize an electrophysiological marker of attribution of intentions. We also explored the robustness of this ERP signature under two conditions corresponding to either explicit instructions to focus on others' intentions or implicit instructions with no reference to mental states. Two matched groups of 16 healthy volunteers each received either explicit or no instructions about intentions and performed a nonverbal attribution of intentions task based on sequential four-image comic strips depicting either intentional or physical causality. A bilateral posterior positive component, ranging from 250 to 650 ms post-stimulus, showed greater amplitude in intentional than in physical condition (the intention ERP effect). This effect occurs during the third image only, suggesting that it reflects the integration of information depicted in the third image to the contextual cues given by the first two. The intention effect was similar in the two groups of subjects. Overall, our results identify a clear ERP marker of the first hundreds of milliseconds of intentions processing probably related to a contextual integrative mechanism and suggest its robustness by showing its blindness to task demands manipulation.


Assessing the effects of multiple infections and long latency in the dynamics of tuberculosis.
In order to achieve a better understanding of multiple infections and long latency in the dynamics of Mycobacterium tuberculosis infection, we analyze a simple model. Since backward bifurcation is well documented in the literature with respect to the model we are considering, our aim is to illustrate this behavior in terms of the range of variations of the model's parameters. We show that backward bifurcation disappears (and forward bifurcation occurs) if: (a) the latent period is shortened below a critical value; and (b) the rates of super-infection and re-infection are decreased. This result shows that among immunosuppressed individuals, super-infection and/or changes in the latent period could act to facilitate the onset of tuberculosis. When we decrease the incubation period below the critical value, we obtain the curve of the incidence of tuberculosis following forward bifurcation; however, this curve envelops that obtained from the backward bifurcation diagram.


Role of Bacterial Exopolysaccharides (EPS) in the Fate of the Oil Released during the Deepwater Horizon Oil Spill.
Halomonas species are recognized for producing exopolysaccharides (EPS) exhibiting amphiphilic properties that allow these macromolecules to interface with hydrophobic substrates, such as hydrocarbons. There remains a paucity of knowledge, however, on the potential of Halomonas EPS to influence the biodegradation of hydrocarbons. In this study, the well-characterized amphiphilic EPS produced by Halomonas species strain TG39 was shown to effectively increase the solubilization of aromatic hydrocarbons and enhance their biodegradation by an indigenous microbial community from oil-contaminated surface waters collected during the active phase of the Deepwater Horizon oil spill. Three Halomonas strains were isolated from the Deepwater Horizon site, all of which produced EPS with excellent emulsifying qualities and shared high (97-100%) 16S rRNA sequence identity with strain TG39 and other EPS-producing Halomonas strains. Analysis of pyrosequence data from surface water samples collected during the spill revealed several distinct Halomonas phylotypes, of which some shared a high sequence identity (≥97%) to strain TG39 and the Gulf spill isolates. Other bacterial groups comprising members with well-characterized EPS-producing qualities, such as Alteromonas, Colwellia and Pseudoalteromonas, were also found enriched in surface waters, suggesting that the total pool of EPS in the Gulf during the spill may have been supplemented by these organisms. Roller bottle incubations with one of the Halomonas isolates from the Deepwater Horizon spill site demonstrated its ability to effectively produce oil aggregates and emulsify the oil. The enrichment of EPS-producing bacteria during the spill coupled with their capacity to produce amphiphilic EPS is likely to have contributed to the ultimate removal of the oil and to the formation of oil aggregates, which were a dominant feature observed in contaminated surface waters.


Stochastic Turing patterns in the Brusselator model.
A stochastic version of the Brusselator model is proposed and studied via the system size expansion. The mean-field equations are derived and shown to yield to organized Turing patterns within a specific parameters region. When determining the Turing condition for instability, we pay particular attention to the role of cross-diffusive terms, often neglected in the heuristic derivation of reaction-diffusion schemes. Stochastic fluctuations are shown to give rise to spatially ordered solutions, sharing the same quantitative characteristic of the mean-field based Turing scenario, in term of excited wavelengths. Interestingly, the region of parameter yielding to the stochastic self-organization is wider than that determined via the conventional Turing approach, suggesting that the condition for spatial order to appear can be less stringent than customarily believed.


Fin development in a cartilaginous fish and the origin of vertebrate limbs.
Recent fossil finds and experimental analysis of chick and mouse embryos highlighted the lateral fin fold theory, which suggests that two pairs of limbs in tetrapods evolved by subdivision of an elongated single fin. Here we examine fin development in embryos of the primitive cartilaginous fish, Scyliorhinus canicula (dogfish) using scanning electron microscopy and investigate expression of genes known to be involved in limb positioning, identity and patterning in higher vertebrates. Although we did not detect lateral fin folds in dogfish embryos, Engrailed-1 expression suggests that the body is compartmentalized dorso-ventrally. Furthermore, specification of limb identity occurs through the Tbx4 and Tbx5 genes, as in higher vertebrates. In contrast, unlike higher vertebrates, we did not detect Shh transcripts in dogfish fin-buds, although dHand (a gene involved in establishing Shh) is expressed. In S. canicula, the main fin axis seems to lie parallel to the body axis. 'Freeing' fins from the body axis and establishing a separate 'limb' axis has been proposed to be a crucial step in evolution of tetrapod limbs. We suggest that Shh plays a critical role in this process.


Correlation of maternal A1c with glucose infusion rate requirements in the newborn.
Fetal hyperinsulinemia and neonatal hyperglycemia are complications of poor maternal glycemic control and may result in increased glucose infusion rate (GIR) requirements in infants of diabetic mothers (IDMs). The objectives of this study were to correlate maternal A1c levels with GIR requirements in IDMs, establish an A1c threshold predictive for GIR requirements, and identify associations between A1c levels and complications in IDMs. A retrospective review of paired maternal A1c values and GIR requirements of IDMs were compared via logistic regression analysis. A likelihood ratio was calculated to correlate A1c levels with GIR requirements, and identify a maternal A1c threshold. Increasing A1c values were significantly correlated with GIR≥5 mg/kg/min (OR, 1.37; 95% CI 1.04-1.79, p = 0.021). Macrosomia was the most frequent complication (OR, 1.31; 95% CI 1.04-1.67, p = 0.022) and A1c > 6.8% was predictive for increased GIR requirements. Increased A1c values were significantly associated with GIR requirements≥5 mg/kg/min. Increased maternal A1c is significantly associated with complications in newborns, specifically macrosomia. A maternal A1c of 6.8% was identified as a threshold predictive of increased GIR requirements.


A preliminary categorization of end-of-life electrical and electronic equipment as secondary metal resources.
End-of-life electrical and electronic equipment (EEE) has recently received attention as a secondary source of metals. This study examined characteristics of end-of-life EEE as secondary metal resources to consider efficient collection and metal recovery systems according to the specific metals and types of EEE. We constructed an analogy between natural resource development and metal recovery from end-of-life EEE and found that metal content and total annual amount of metal contained in each type of end-of-life EEE should be considered in secondary resource development, as well as the collectability of the end-of-life products. We then categorized 21 EEE types into five groups and discussed their potential as secondary metal resources. Refrigerators, washing machines, air conditioners, and CRT TVs were evaluated as the most important sources of common metals, and personal computers, mobile phones, and video games were evaluated as the most important sources of precious metals. Several types of small digital equipment were also identified as important sources of precious metals; however, mid-size information and communication technology (ICT) equipment (e.g., printers and fax machines) and audio/video equipment were shown to be more important as a source of a variety of less common metals. The physical collectability of each type of EEE was roughly characterized by unit size and number of end-of-life products generated annually. Current collection systems in Japan were examined and potentially appropriate collection methods were suggested for equipment types that currently have no specific collection systems in Japan, particularly for video games, notebook computers, and mid-size ICT and audio/video equipment.


The feasibility of axiomatically-based expert systems.
We distinguish axiomatically-based expert systems, whose design and implementation are guided by one or more axiomatically-based theories of decision-making (e.g., decision theory, Bayesian probability theory, maximum entropy theory), from traditional expert systems. An analysis of the knowledge acquisition and computational needs of axiomatically-based expert systems is presented. An explicit quantitative comparison is made between the actual knowledge acquisition effort required to build an existing expert system, and the effort that would be required to build an analogous axiomatically-based advice system. The costs and benefits of the axiomatic approach are discussed. The analysis suggests that the small additional cost of knowledge acquisition for the axiomatic approach are outweighed by the long-term benefits this approach provides.


Picking ChIP-seq peak detectors for analyzing chromatin modification experiments.
Numerous algorithms have been developed to analyze ChIP-Seq data. However, the complexity of analyzing diverse patterns of ChIP-Seq signals, especially for epigenetic marks, still calls for the development of new algorithms and objective comparisons of existing methods. We developed Qeseq, an algorithm to detect regions of increased ChIP read density relative to background. Qeseq employs critical novel elements, such as iterative recalibration and neighbor joining of reads to identify enriched regions of any length. To objectively assess its performance relative to other 14 ChIP-Seq peak finders, we designed a novel protocol based on Validation Discriminant Analysis (VDA) to optimally select validation sites and generated two validation datasets, which are the most comprehensive to date for algorithmic benchmarking of key epigenetic marks. In addition, we systematically explored a total of 315 diverse parameter configurations from these algorithms and found that typically optimal parameters in one dataset do not generalize to other datasets. Nevertheless, default parameters show the most stable performance, suggesting that they should be used. This study also provides a reproducible and generalizable methodology for unbiased comparative analysis of high-throughput sequencing tools that can facilitate future algorithmic development.


Endovascular perforation subarachnoid hemorrhage fails to cause Morris water maze deficits in the mouse.
Cognitive dysfunction is the primary driver of poor long-term outcome in aneurysmal subarachnoid hemorrhage (SAH) survivors; modeling such deficits preclinically is thus key for mechanistic and translational investigation. Although rat SAH causes long-term deficits in learning and memory, it remains unknown whether similar deficits are seen in the mouse, a species particularly amenable to powerful, targeted genetic manipulation. We thus subjected mice to endovascular perforation SAH and assessed long-term cognitive outcome via the Morris water maze (MWM), the most commonly used metric for rodent neurocognition. No significant differences in MWM performance (by either of two protocols) were seen in SAH versus sham mice. Moreover, SAH caused negligible hippocampal CA1 injury. These results undercut the potential of commonly used methods (of SAH induction and assessment of long-term neurocognitive outcome) for use in targeted molecular studies of SAH-induced cognitive deficits in the mouse.


The Safe Motherhood Initiative: why has it stalled?
Complications of pregnancy and childbirth are still the leading cause of death and disability among women of reproductive age in developing countries. After decades of neglect, the founding of the Safe Motherhood Initiative in 1987 promised action on this problem. A dozen years later, there is no evidence that maternal mortality has declined and there are still few sizeable programs. A major reason for this disappointing record is that the initiative lacks a clear, concise, feasible strategy. This article reviews the available options and proposes a strategy based on improving the availability and quality of medical treatment of obstetric complications. Once district hospitals and health centers provide such needed care, community mobilization to improve prove utilization may be beneficial. Substantial reductions in maternal deaths would be possible in a relatively short period of time if this strategy were embraced.


Kettle test--a brief measure of cognitive functional performance. Reliability and valdity in stroke rehabilitation.
We examined the reliability and validity of the Kettle Test, a brief performance measure based on a complex everyday task designed to tap into basic and higher level cognitive processes. Participants included 21 people attending stroke rehabilitation and 4 occupational therapists for the reliability analysis, 36 people at discharge from stroke rehabilitation, and 36 age-matched healthy control participants for the validity analyses. Instruments included a battery of conventional cognitive measures and functional outcomes. Interrater reliability was found to be high. Stroke survivors at discharge from rehabilitation were found to require significantly more assistance on the Kettle Test than control participants (p < .000); their scores on the Kettle Test were significantly and moderately correlated with the conventional cognitive and functional outcome measures. The results support the reliability and validity of the Kettle Test as a top-down measure of cognition-in-function in people at discharge from stroke rehabilitation.


Superoxide dismutase ameliorates neuronal death from hypoxia in culture.
Studies showing efficacy with free radical scavengers have been conflicting, and when protection was demonstrated it was attributed to action at the level of the vascular endothelium. The purpose of this study was to test the hypotheses that neuronal free radical formation plays a role in the ischemic cascade and occurs intracellularly and that free radical scavengers, if taken up intracellularly, will protect against hypoxic damage. A tissue culture model of hypoxia followed by restoration of oxygen was employed, using both superior cervical ganglia and hippocampal neurons. Cells were exposed to an anoxic atmosphere of 95% N2 and 5% CO2 and examined 2 to 24 hours later after restoration of oxygen. Determination of survival was measured by trypan blue exclusion. Nitroblue tetrazolium stain was used to assess free radical formation. Pretreatment with free superoxide dismutase did not decrease cell death after hypoxia as measured by trypan blue exclusion. However, when superoxide dismutase was taken up intracellularly under depolarizing conditions (55 mmol/L KCl in the medium), cell death was decreased significantly compared with hypoxic controls (28.7 +/- 4.34 versus 40.3 +/- 4.33; P < .03). During hypoxia neurons reduced nitroblue tetrazolium to form the blue precipitate formazan, and the color change was blocked in neurons pretreated with superoxide dismutase in depolarizing medium. Similar findings occurred in both superior cervical ganglia and hippocampal neurons. These findings provide evidence to support the role of neuronal free radical formation in cell death secondary to hypoxia. In addition, free radical scavengers, if taken up intracellularly, may partially ameliorate their deleterious effect.


Identifying migrant remains in South Texas: policy and practice.
In 2012, Texas surpassed Arizona in migrant deaths. The majority of deaths occurred in the Rio Grande Valley, specifically in Brooks County, Texas. Brooks County is one of the poorest in the state and was overwhelmed with deaths, without appropriate resources to follow the state laws pertaining to the investigation of unidentified human remains. Until 2013, most remains that were not immediately identified were buried without collecting DNA samples and the location of burials was not recorded. Our paper outlines the difficulties searching for these burials, the struggles of the families of the missing, and the collaborative approaches to facilitating identifications in South Texas. Community outreach combined with geophysical surveys guide which cemeteries are in need of exhumations. Once cemeteries are surveyed, archaeological methods are employed to exhume remains and document burials. Remains are taken to the Forensic Anthropology Center at Texas State for processing, analysis, and identification efforts. Undergraduate and graduate students clean remains and wash clothing and personal effects. After skeletal analysis, all information regarding the remains, including photographs of personal effects, are uploaded to the National Missing and Unidentified Persons System (NamUs) and a DNA sample is submitted to the University of North Texas for inclusion in the Combined DNA Index System (CODIS) DNA database. However, CODIS lacks DNA family reference samples from many families of the missing due to families living outside the US or because they do not feel comfortable providing a DNA sample in the presence of law enforcement. Therefore, it is necessary to work with non-governmental organizations who specialize in collecting missing persons reports and DNA samples from the families of the missing. Working collaboratively with multiple agencies, identification of migrant remains is possible.


Acute hydrodynamic damage induced by SPLITT fractionation and centrifugation in red blood cells.
Though blood bank processing traditionally employs centrifugation, new separation techniques may be appealing for large scale processes. Split-flow fractionation (SPLITT) is a family of techniques that separates in absence of labelling and uses very low flow rates and force fields, and is therefore expected to minimize cell damage. However, the hydrodynamic stress and possible consequent damaging effects of SPLITT fractionation have not been yet examined. The aim of this study was to investigate the hydrodynamic damage of SPLITT fractionation to human red blood cells, and to compare these effects with those induced by centrifugation. Peripheral whole blood samples were collected from healthy volunteers. Samples were diluted in a buffered saline solution, and were exposed to SPLITT fractionation (flow rates 1-10 ml/min) or centrifugation (100-1500 g) for 10 min. Cell viability, shape, diameter, mean corpuscular hemoglobin, and membrane potential were measured. Under the operating conditions employed, both SPLITT and centrifugation maintained cell viability above 98%, but resulted in significant sublethal damage, including echinocyte formation, decreased cell diameter, decreased mean corpuscular hemoglobin, and membrane hyperpolarization which was inhibited by EGTA. Wall shear stress and maximum energy dissipation rate showed significant correlation with lethal and sublethal damage. Our data do not support the assumption that SPLITT fractionation induces very low shear stress and is innocuous to cell function. Some changes in SPLITT channel design are suggested to minimize cell damage. Measurement of membrane potential and cell diameter could provide a new, reliable and convenient basis for evaluation of hydrodynamic effects on different cell models, allowing identification of optimal operating conditions on different scales.


Effect of titanium surface roughness on proliferation, differentiation, and protein synthesis of human osteoblast-like cells (MG63).
The effect of surface roughness on osteoblast proliferation, differentiation, and protein synthesis was examined. Human osteoblast-like cells (MG63) were cultured on titanium (Ti) disks that had been prepared by one of five different treatment regimens. All disks were pretreated with hydrofluroic acid-nitric acid and washed (PT). PT disks were also: washed, and then electropolished (EP); fine sandblasted, etched with HCl and H2SO4, and washed (FA); coarse sandblasted, etched with HCl and H2SO4, and washed (CA); or Ti plasma-sprayed (TPS). Standard tissue culture plastic was used as a control. Surface topography and profile were evaluated by brightfield and darkfield microscopy, cold field emission scanning electron microscopy, and laser confocal microscopy, while chemical composition was mapped using energy dispersion X-ray analysis and elemental distribution determined using Auger electron spectroscopy. The effect of surface roughness on the cells was evaluated by measuring cell number, [3H]thymidine incorporation into DNA, alkaline phosphatase specific activity, [3H]uridine incorporation into RNA, [3H]proline incorporation into collagenase digestible protein (CDP) and noncollagenase-digestible protein (NCP), and [35S]sulfate incorporation into proteoglycan. Based on surface analysis, the five different Ti surfaces were ranked in order of smoothest to roughest: EP, PT, FA, CA, and TPS. A TiO2 layer was found on all surfaces that ranged in thickness from 100 A in the smoothest group to 300 A in the roughest. When compared to confluent cultures of cells on plastic, the number of cells was reduced on the TPS surfaces and increased on the EP surfaces, while the number of cells on the other surfaces was equivalent to plastic. [3H]Thymidine incorporation was inversely related to surface roughness. Alkaline phosphatase specific activity in isolated cells was found to decrease with increasing surface roughness, except for those cells cultured on CA. In contrast, enzyme activity in the cell layer was only decreased in cultures grown on FA- and TPS-treated surfaces. A direct correlation between surface roughness and RNA and CDP production was found. Surface roughness had no apparent effect on NCP production. Proteoglycan synthesis by the cells was inhibited on all the surfaces studied, with the largest inhibition observed in the CA and EP groups. These results demonstrate that surface roughness alters osteoblast proliferation, differentiation, and matrix production in vitro. The results also suggest that implant surface roughness may play a role in determining phenotypic expression of cells in vivo.


Dopaminergic modulation of receptive fields in rat sensorimotor cortex.
Dopaminergic projections to primary sensorimotor cortex (SMC) have been described anatomically, but their functional role is unknown. The objective here was to characterize how dopamine modulates the somatosensory evoked potential (SEP) and its receptive field in SMC. SEPs were evoked by median and tibial nerve stimulation and recorded using thin-film multielectrode arrays implanted epidurally over the caudal sensorimotor cortex of rats. SEP amplitudes and receptive fields were measured before and after intracortical injection of a D1- (SCH 23390) or a D2-receptor antagonist (raclopride). Both increased maximum SEP amplitudes by 107.5% and 82.1%, respectively (p<0.01), while vehicle application had no effect (5.9% change). SEP latencies and receptive fields remained unchanged. Dopamine antagonists increase the excitability of sensorimotor cortex to afferent signals. Dopamine, therefore, expectedly reduces SMC excitability thereby improving sensory signal-to-noise ratio. Dopaminergic modulation may render SMC circuitry more effective in processing sensory information from different sources.


Genome-wide association analysis in sarcoidosis and Crohn's disease unravels a common susceptibility locus on 10p12.2.
Crohn's disease (CD) and sarcoidosis (SA) are chronic inflammatory barrier diseases that share several clinical and immunological features, including the occurrence of granulomas. A 100k genome-wide association study with 83,360 single-nucleotide polymorphisms (SNPs) was performed on 382 CD patients, 398 SA patients, and 394 control individuals. The 24 SNPs that were most strongly associated in the combined CD/SA phenotype were selected for verification in an independent sample of 1,317 patients (660 CD and 657 SA) and 1,091 controls. The most significant association (Bonferroni corrected P = .036) was obtained at SNP rs1398024 on chromosome 10p12.2, with an odds ratio (OR) for both diseases of 0.81 (95% confidence interval [CI], 0.69-0.96) for carriership of the rarer allele A. The P value in the overall combined sample was 4.24 x 10(-6). During further follow-up, a moderate association (OR, 0.83; 95% CI, 0.72-0.96; P = .015) was observed between rs1398024 and ulcerative colitis (1,080 patients vs 1,091 controls), the second main subphenotype of inflammatory bowel disease in addition to CD. Extensive fine mapping of the 10p12.2 locus points to yet unidentified variants in the C10ORF67 gene region as the most likely underlying risk factors. Our study demonstrates that the combined analysis of different, albeit clinically related, phenotypes can lead to the identification of common susceptibility loci.