Functional Limitations and Physical Health in Community-Dwelling Medicare Advantage Beneficiaries: Variation by Race and Hispanic Subgroup.
Objectives: The objective is to examine racial and ethnic heterogeneity in older adults' functional limitations and physical health. Methods: Data were from 2011 to 2015 Health Outcomes Survey of Medicare Advantage beneficiaries 65 and older (N = 828,946). Outcomes were Physical Component Summary (PCS) scores and need for assistance with activities of daily living (ADLs). Six non-Hispanic racial groups and five Hispanic subgroups were analyzed. Regression models adjusted for sociodemographic and health characteristics. Results: White and Asian respondents had the lowest unadjusted ADL difficulty rates and highest PCS scores. In adjusted analyses, Cuban respondents had the highest PCS scores and lowest rates of any ADL difficulty; White respondents had the lowest rates of specific ADL difficulties. Native Hawaiian or other Pacific Islander and multiple Hispanic respondents had the highest ADL difficulty rates. Discussion: Both the healthiest and highest need subgroups of Medicare Advantage beneficiaries were Hispanic. Understanding racial and ethnic subgroup differences may help target interventions to prevent or aid with functional limitations.


Aspirin and recurrent venous thromboembolism.
While there is conclusive evidence that aspirin plays a role in reducing the risk of clinically relevant venous thromboembolism (VTE) arising in a number of surgical and non-surgical situations at risk, little is known of the potential of aspirin for the long/term prevention of recurrent VTE. In two recent multicentre, double-blind studies (WARFASA and ASPIRE), the efficacy and safety of a low dose of aspirin (100 mg per day) were assessed in patients with unprovoked VTE who had completed an initial period of conventional treatment with vitamin K antagonists. The two studies used identical aspirin regimens and had similar enrollment criteria and outcome measures. When data from these two trials were pooled, there was a 32% reduction in the rate of recurrence of VTE (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.51-0.90) and a 34% reduction in the rate of major vascular events (HR, 0.66; 95% CI, 0.51-0.86). Moreover, these benefits were achieved with a low risk of bleeding. As patients with previous symptomatic atherosclerosis were not enrolled in these two studies, whether these results apply also to this category of patients is uncertain. We recently had the opportunity to review the clinical charts of 1919 consecutive patients presented with a first episode of VTE, which was either unprovoked or triggered by transient risk factors, and were followed up for an average period of four years after discontinuing anticoagulation. The rate of recurrent VTE in the 256 patients with a history of symptomatic atherosclerosis who had been given 80-160 mg of aspirin once daily (17.2%) did not differ from that (19.9%) observed in those without atherosclerosis who were left without any antithrombotic treatments. The implication of this observation is that whenever patients with symptomatic atherosclerosis are deemed to require long-term protection against recurrent VTE, they are unlikely to benefit from (resuming) aspirin. Conversely, aspirin in low doses offers an appealing, safe and highly cost-effective option for the long-term prevention of recurrent events in patients with unprovoked VTE who are free from symptomatic atherosclerotic lesions.


Influence of the mechanical properties of biomaterials on degradability, cell behaviors and signaling pathways: current progress and challenges.
The development of suitable biomaterials with the ability to improve repair and regeneration of human tissues is continuously in progress, and mechanical properties of biomaterials play a critical role in their success in the clinical setting. Both biomaterial degradability and signaling cascades of cell interactions with biomaterials are significantly influenced by the mechanical properties of biomaterials, determining the final repair effect of bio-implants. Actually, the mechanical properties of biomaterials play a critical role in designing and developing medical material products both in research and in practice. Currently, advances in mechanics have provided new possibilities for researchers to investigate and modulate both the substrates and cell behaviors with respect to material perfection in tissue engineering. Achieving convenient and accurate approaches for producing different types of biomaterials is now possible by applying computerized methods. In this review, we have systematically clarified the influence of several selected mechanical properties of biomaterials (including stress/strain, elasticity/stiffness and certain time-dependent mechanical properties) on biomaterial degradability, cell behaviors and signaling pathways. Furthermore, the mechanical design targets and approaches for optimizing the mechanical properties of biomaterials, as well as the challenges and prospects are elaborated. This review will certainly bring up new ideas and possibilities for the field of tissue engineering and regenerative biomaterials.


Reverse-phase LbL-encapsulation of highly water soluble materials by layer-by-layer polyelectrolyte self-assembly.
We report on a novel method for the encapsulation of highly water soluble materials by using layer-by-layer (LbL) polyelectrolyte self-assembly. State of the art polyelectrolyte self-assembly LbL coating and encapsulation methods are only applicable to insoluble or poorly water soluble template materials, because the process is performed in water causing dissolution of the solid template. Our method extends the material spectrum to highly water soluble template materials by using non-ionized polyelectrolytes in an organic phase (reverse-phase) instead of polyelectrolyte salts in an aqueous environment. By using the reverse-phase layer-by-layer (RP-LbL) technique, we have demonstrated the direct encapsulation of proteins, glucose, vitamin C, and inorganic salts in the solid state. Multilayer deposition was proven, layer thickness was determined by AFM, and the advantage of the method to prepare powders of encapsulated materials was demonstrated. The method is simple, robust, and applicable to a broad range of substances with potential applications in several industries.


The 4G/5G sequence polymorphism in the promoter of plasminogen activator inhibitor-1 (PAI-1) gene: relationship to plasma PAI-1 level in venous thromboembolism.
Impaired fibrinolysis due to increased plasminogen activator inhibitor-1 (PAI-1) is observed in up to 40% of patients with venous thromboembolism and might be causally related to the disease. There is evidence that genetic variations in the promoter of the PAI-1 gene and metabolic factors contribute to increased plasma PAI-1 levels. A single nucleotide insertion/deletion (4G/5G) polymorphism in the promoter region of the PAI-1 gene and metabolic factors were studied in 158 unrelated patients below the age of 61 years (43 +/- 11 years, mean +/- standard deviation) with history of objectively confirmed venous thromboembolism and in 145 apparently healthy controls. Patients had on average two times higher PAI activity (11.9 vs. 6.1 IU/ml) and by 40% higher PAI-1 antigen (14.8 vs. 10.7 ng/ml) than healthy controls, and also higher body mass index, lipid levels, fasting glucose and insulin. Patients differed significantly from healthy controls neither in the frequency of the 4G and 5G alleles (0.57/0.43 in patients and 0.52/0.48 in controls) nor in the distribution of the 4G/5G genotypes. Possession of the 4G/4G or the 4G/5G genotype did not increase relative risk for venous thromboembolic disease and the distribution of the 4G/5G genotypes was neither associated with recurrent nor with spontaneous disease. In patients association between the 4G/5G genotypes and PAI activity (adjusted for body mass index, triglyceride and glucose level) was observed, with the highest PAI activity values in the 4G/4G genotype (14.6 IU/ml), intermediate in the 4G/5G genotype (13.3 IU/ml) and the lowest in the 5G/5G genotype (5.2 IU/ml, all values means). Association between PAI activity and triglyceride level was the strongest in the 4G/4G genotype (correlation coefficient r = 0.47, p < 0.01) and the weakest in the 5G/5G genotype (r = -0.04, not significant). In conclusion, the present case-control study shows an association between the 4G/5G polymorphism in the promoter of the PAI-1 gene and plasma PAI-1 levels in patients with venous thromboembolism. Similar distribution of the 4G/5G genotypes in patients and healthy controls suggests that this genetic variation by itself is not a major risk factor for venous thromboembolism.


Postsynaptic Density-95 Isoform Abnormalities in Schizophrenia.
Postsynaptic density-95 (PSD-95) protein expression is dysregulated in schizophrenia in a variety of brain regions. We have designed experiments to examine PSD-95 mRNA splice variant expression in the dorsolateral prefrontal cortex from subjects with schizophrenia. We performed quantitative PCR and western blot analysis to measure PSD-95 expression in schizophrenia vs control subjects, rodent haloperidol treatment studies, rodent postmortem interval studies, and GluN1 knockdown (KD) mice vs controls. We found decreased mRNA expression of beta (t = 4.506, df = 383, P < .0001) and truncated (t = 3.378, df = 383, P = .0008) isoforms of PSD-95, whereas alpha was unchanged. Additionally, we found decreased PSD-95 protein expression in schizophrenia (t = 2.746, df = 71, P = .0076). We found no correlation between PSD-95 protein and alpha, beta, or truncated mRNA isoforms in schizophrenia. PSD-95 beta transcript was increased (t = 3.346, df = 14, P < .05) in the GluN1 KD mouse model of schizophrenia. There was an increase in PSD-95 alpha mRNA expression (t = 2.905, df = 16, P < .05) in rats following long-term haloperidol administration. Our findings describe a unique pathophysiology of specific PSD-95 isoform dysregulation in schizophrenia, chronic neuroleptic treatment, and a genetic lesion mouse model of drastically reduced N-methyl-d-aspartate receptor (NMDAR) complex expression. These data indicate that regulation of PSD-95 is multifaceted, may be isoform specific, and biologically relevant for synaptic signaling function. Specifically, NMDAR-mediated synaptic remodeling, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking and interaction may be impaired in schizophrenia by decreased PSD-95 beta and truncated expression (respectively). Further, increased PSD-95 beta transcript in the GluN1 KD mouse model poses a potential compensatory rescue of NMDAR-mediated function via increased postsynaptic throughput of the severely reduced GluN1 signal. Together, these data propose that disruption of excitatory signaling complexes through genetic (GluN1 KD), pharmacologic (antipsychotics), or disease (schizophrenia) mechanisms specifically dysregulates PSD-95 expression.


In their own words: assessment of satisfaction with residential location among migrants in Nairobi slums.
Using qualitative data collected from a sample of rural-urban migrants over the age of 15 in two Nairobi slums interviewed in 2008, this paper discusses the migrants' extent of satisfaction with their residential location and decision to migrate. The study sheds light on why people continue to migrate to, and stay in, the rapidly growing slum settlements despite the high levels of poverty and poor health conditions in these areas. Tenure status is related to satisfaction for all ages. Environmental factors were frequently mentioned as a source of dissatisfaction. Life cycle and 'age-cohort effects' may also affect satisfaction for different age groups in terms of who is satisfied as well as the issues that are considered for satisfaction. High levels of dissatisfaction with slum life may be responsible for high out-migration in slum areas, although it does not mean that those who remain do so because they are satisfied. At the same time, challenges associated with slum life do not automatically signify dissatisfaction. Perceived success, as well as conditions in the area of origin can be used to explain and understand satisfaction/dissatisfaction with slum life. Satisfaction with migration and residential location may be related not only to the destination place, but also to events in the area of origin.


Zoonotic Chlamydiae as rare causes of severe pneumonia.
Zoonotic species of the Chlamydiaceae family should be considered as rare pathogenic agents of severe atypical pneumonia. A fatal case of a severe pneumonia due to Chlamydia psittaci was traced back to pet birds, and pneumonia in a pregnant woman was attributed to abortions in a sheep and goat flock, being the source of Chlamydia abortus. The two SARS‑CoV‑2-negative pneumonia cases presented here were investigated in an inter-disciplinary approach involving physicians and veterinarians. State-of-art molecular methods allowed the identification and genotyping of zoonotic Chlamydiae.


Transcranial magnetic resonance-guided focused ultrasound surgery at 1.5T: a technical note.
Magnetic resonance-guided focused ultrasound is one of the emerging non-invasive technologies offering both image guidance and thermal monitoring. In recent years transcranial application of this technology is starting to impact heavily the neuroscience field. We present here the imaging protocol and the technological methods successfully used with a transcranial magnetic resonance-guided focused ultrasound system certified for clinical treatments of functional neurological disorders, integrated for the first time with a 1.5T magnetic resonance scanner. Compared to the body radiofrequency coil (the one commonly used with transcranial magnetic resonance-guided focused ultrasound system integrated with 3T magnetic resonance scanners), the use of a dedicated two channel coil enabled a signal-to-noise ratio gain up to five times higher.


Comparison between two methods of asthma control evaluation based on individual perception.
To compare the subjective perception of asthma control reported by the patient with that measured by the score obtained on the Asthma Control Questionnaire 6-item version (ACQ-6) in patients with severe asthma and to determine whether asthma control is associated with the number of emergency room visits in the previous month. This was a cross-sectional study involving 528 patients treated at the Bahia State Asthma and Allergic Rhinitis Control Program Central Referral Clinic between August of 2008 and March of 2010, in the city of Salvador, Brazil. The patients completed the ACQ-6 and answered a specific additional question in order to evaluate their own perception of asthma control in the previous week. We evaluated 423 patients who met the inclusion criteria. The sample was predominantly female (81.3%), and 64.3% had an income lower than two times the national minimum wage. The mean age was 49.85 ± 13.71 years, and the duration of asthma symptoms was 32.11 ± 16.35 years. The patients had been regularly treated via the program for 36.65 ± 18.10 months. Based on the subjective perception of asthma control, only 8% of the patients considered their asthma to be uncontrolled, whereas 38.8% had an ACQ-6 score > 1.5, which indicates poor control. The kappa statistic revealed poor concordance between the two methods. There was a direct association between uncontrolled asthma and the number of emergency room visits in the previous month (p < 0.001). In this sample of patients, the subjective perception of asthma control differed from that measured by the ACQ-6 score, and the patients overestimated their own level of asthma control, which puts them at risk of being undertreated.


Colonization of Bordetella pertussis clinical isolates that differ by pulsed field gel electrophoresis types in the lungs of naïve mice or mice immunized with the whole-cell pertussis vaccine used in Poland.
The goal of our study was to compare the elimination of Bordetella pertussis clinical isolates that differ according to pulsed field gel electrophoresis (PFGE), serotypes and genes encoding virulence factors from the lungs of naïve mice or mice immunized with commercial diphtheria-tetanus-whole-cell pertussis vaccine used in Poland. When a mixture of four isolates, given in equal proportions and harboring different PFGE profiles, serotypes, and alleles encoding virulence factors, was used to infect non-immunized mice, a single isolate, characterized by PFGE type IVγ, Fim2 phenotype and ptxA1-prn2-tcfA2-fim2-1-ptxP1-ptxC1-fim3-1 alleles, was found to be significantly predominant compared to the others. This PFGE profile is commonly found in B. pertussis isolates circulating in some European countries since the late 1990s, confirming its high fitness. The Polish commercial whole-cell pertussis vaccine induced an immunity effective at eliminating the B. pertussis isolates from the lungs. However, the elimination of the isolate harboring PFGE type C profile, Fim2,3 phenotype and ptxA1-prn1-tcfA2-fim2-1-ptxP1-ptxC1-fim3-1 alleles was delayed as compared to the others, suggesting phenotypic differences with the other isolates and vaccine strains. Nevertheless, the same isolate, when challenged into mice in the defined mixture of strains, lost the competition with the others, as measured by lung colonization efficiency. This PFGE profile represents 15 % of the isolates circulating in Poland between 2001 and 2012.


Effects of ionising radiation exposure on plants, fish and mammals: relevant data for environmental radiation protection.
In order to develop a framework for the assessment of the environmental impact of radiation, it is necessary to establish the relationship between exposure (dose rate, accumulated dose) and the effects that may be induced in plants and animals. With this purpose in mind, the data available on effects induced by ionising radiation in various wildlife groups have been reviewed as part of the FASSET project. This paper has highlighted that the available information on the effects of low dose rate, continuous irradiation (< 10(3) microGy h(-1)) is reasonable for plants, fish and mammals, but is scarce or non-existent for other wildlife groups. Thus, the effects induced in plants, fish and mammals after chronic exposure to radiation are presented in this paper. The fragmentary nature of the available, relevant information has made it very difficult to characterise the desired dose rate-response relationships in any detail. However, it can be broadly concluded that, although minor effects may be seen at lower dose rates in the most sensitive species and systems, the threshold for statistically significant effects in most studies is about 10(2) microGy h(-1). The responses then increase progressively with increasing dose rate and usually become very clear at dose rates > 10(3) microGy h(-1) sustained for a large fraction of the lifespan.


Effect of body orientation on regional lung expansion: a computed tomographic approach.
The Dynamic Spatial Reconstructor (DSR) was used to study in vivo lung geometry and function. By replacing the lungs of three dogs with potato flakes and ping-pong balls of known air content and scanning these realistic phantoms in the DSR we have estimated accuracy of lung density to be within 7% and have demonstrated a high (+/- 3%) internal consistency (relative density within dogs). Change in total lung air content (y) as calculated from DSR volume imaging of anesthetized dogs matched the known inflation steps (x) to within 7% [range was 1-7% with a mean of 3 +/- 0.5% (SE)]. A gradient of decreasing percent lung air content was measured in the ventral-dorsal direction at functional residual capacity (FRC) in the supine body posture (y = 3.29% air content/cm lung height + 46.48% air content; r = 0.90). Regional lung air content change with lung inflation was greatest in the dependent lung regions. In contrast, regional lung air content at FRC was approximately uniform along the ventral-dorsal direction with the dog in the prone posture and was 66 +/- 0.6% (SE). Ventral-dorsal gradients in lung air content measured within an isogravimetric plane of the dogs in the left or right lateral body posture suggest that regional differences in lung air content cannot be explained solely on the basis of a direct gravitational effect on the lung. Evidence is presented to suggest a possible major role of the intrathoracic position of the mediastinal contents in determining these lung air content distributions.


IL-17RA promotes pathologic epithelial inflammation in a mouse model of upper respiratory influenza infection.
The upper respiratory tract (nasopharynx or NP) is the first site of influenza replication, allowing the virus to disseminate to the lower respiratory tract or promoting community transmission. The host response in the NP regulates an intricate balance between viral control and tissue pathology. The hyper-inflammatory responses promote epithelial injury, allowing for increased viral dissemination and susceptibility to secondary bacterial infections. However, the pathologic contributors to influenza upper respiratory tissue pathology are incompletely understood. In this study, we investigated the role of interleukin IL-17 recetor A (IL-17RA) as a modulator of influenza host response and inflammation in the upper respiratory tract. We used a combined experimental approach involving IL-17RA-/- mice and an air-liquid interface (ALI) epithelial culture model to investigate the role of IL-17 response in epithelial inflammation, barrier function, and tissue pathology. Our data show that IL-17RA-/- mice exhibited significantly reduced neutrophilia, epithelial injury, and viral load. The reduced NP inflammation and epithelial injury in IL-17RA-/- mice correlated with increased resistance against co-infection by Streptococcus pneumoniae (Spn). IL-17A treatment, while potentiating the apoptosis of IAV-infected epithelial cells, caused bystander cell death and disrupted the barrier function in ALI epithelial model, supporting the in vivo findings.


Kinetic adaptation during locomotion on a split-belt treadmill.
It has been suggested that a feedforward control mechanism drives the adaptation of the spatial and temporal interlimb locomotion variables. However, the internal representation of limb kinetics during split-belt locomotion has not yet been studied. In hand movements, it has been suggested that kinetic and kinematic parameters are controlled by separate neural processes; therefore, it is possible that separate neural processes are responsible for kinetic and kinematic locomotion parameters. In the present study, we assessed the adaptation of the limb kinetics by analyzing the ground reaction forces (GRFs) as well as the center of pressure (COP) during adaptation to speed perturbation, using a split-belt treadmill with an integrated force plate. We found that both the GRF of each leg at initial contact and the COP changed gradually and showed motor aftereffects during early postadaptation, suggesting the use of a feedforward predictive mechanism. However, the GRF of each leg in the single-support period used a feedback control mechanism. It changed rapidly during the adaptation phase and showed no motor aftereffect when the speed perturbation was removed. Finally, we found that the motor adaptation of the GRF and the COP are mediated by a dual-rate process. Our results suggest two important contributions to neural control of locomotion. First, different control mechanisms are responsible for forces at single- and double-support periods, as previously reported for kinematic variables. Second, our results suggest that motor adaptation during split-belt locomotion is mediated by fast and slow adaptation processes.


Towards identifying dyslexia in Standard Indonesian: the development of a reading assessment battery.
With its transparent orthography, Standard Indonesian is spoken by over 160 million inhabitants and is the primary language of instruction in education and the government in Indonesia. An assessment battery of reading and reading-related skills was developed as a starting point for the diagnosis of dyslexia in beginner learners. Founded on the International Dyslexia Association's definition of dyslexia, the test battery comprises nine empirically motivated reading and reading-related tasks assessing word reading, pseudoword reading, arithmetic, rapid automatized naming, phoneme deletion, forward and backward digit span, verbal fluency, orthographic choice (spelling), and writing. The test was validated by computing the relationships between the outcomes on the reading-skills and reading-related measures by means of correlation and factor analyses. External variables, i.e., school grades and teacher ratings of the reading and learning abilities of individual students, were also utilized to provide evidence of its construct validity. Four variables were found to be significantly related with reading-skill measures: phonological awareness, rapid naming, spelling, and digit span. The current study on reading development in Standard Indonesian confirms findings from other languages with transparent orthographies and suggests a test battery including preliminary norm scores for screening and assessment of elementary school children learning to read Standard Indonesian.


Two monoclonal antibodies against glycoprotein Gn protect mice from Rift Valley Fever challenge by cooperative effects.
Rift Valley fever virus (RVFV) is a zoonotic arbovirus that causes severe disease in humans and ruminants. The infection is characterized by abortions in pregnant animals, high mortality in neonates as well as febrile illness in humans that develop in 1% of cases encephalitis or hemorrhagic fever. There is presently no specific antiviral treatment for RVFV infection available. In this study, two monoclonal antibodies (mAbs), raised against glycoprotein Gn, were applied in a therapeutic study. Treatment of RVFV infected mice with neutralizing mAb Gn3 alone at two different time points (30 minutes before or 30 minutes after virus challenge) showed only moderate efficacy of about 58.3% survival in both applications. However, a combination therapy together with non-neutralizing mAb Gn32 demonstrated complete protection (100% survival) when applied 30 minutes after the lethal challenge dose. The increase of mAb efficacy is probably based on cooperative neutralization effects. These data suggest that a combination therapy with mAbs Gn3 and Gn32 could be an effective treatment option against RVFV infection.


Are adolescents who were breast-fed less likely to be overweight? Analyses of sibling pairs to reduce confounding.
Cohort analyses suggesting that breast-feeding protects against being overweight have been criticized for inadequately controlling for confounding associated with the self-selection of feeding practices. Using nationally representative U.S. data from the National Longitudinal Study of Adolescent Health (1994-1996), we performed traditional cohort analyses (n = 11,998) using logistic regression to estimate the relation between breast-feeding and adolescent overweight (body mass index > or =85 percentile, based on year 2000 CDC growth charts), controlling for known potential confounders. Breast-feeding also was assessed in a subsample of 850 sibling pairs to account for unmeasured genetic and environmental factors. Among girls in the full cohort, the odds of being overweight declined among those who had been breast-fed at least 9 months; odds ratios ranged from 0.90 (95% confidence interval = 0.74-1.09) for <3 months of breast-feeding to 0.78 (0.64-0.96) for > or =9 months. A similar effect was seen in boys, although these trends were less consistent. In contrast, an analysis of sibling pairs provided no evidence of breast-feeding effects on weight within discordant trends. Cohort data indicate that odds of being overweight decrease as breast-feeding duration increases, at least among girls. However, sibling analyses suggest that this relationship may not be causal but rather attributable to unmeasured confounding related to mothers' choice to breast-feed, or to other childhood risk factors for overweight. Our results illustrate the utility of sibling analyses in understanding the true effect of early life exposures (such as breast-feeding) on health outcomes over time, independent of confounding factors that may not be satisfactorily controlled using traditional prospective cohort methods.


Laser pulses into bullets: tabletop shock experiments.
This article discusses tabletop high-throughput laser experiments on shock waves in solids and liquids, where the more usual laser pump pulse is replaced by a 0.5 mm diameter laser-launched bullet, a thin metal disk called a flyer plate. The hypervelocity flyer (up to 6 km s-1 or Mach 18) can have kinetic energy (∼1 J) to briefly produce extreme conditions of temperature and pressure, thousands of K and tens of GPa (1 GPa = 10 000 bar) in a small volume with a rise time <2 ns. The experiments are performed using a "shock compression microscope", a microscope fitted with the laser flyer launcher plus an optical velocimeter, a high-speed laser interferometer that measures the motion of the flyer plate or the sample material after impact. This makes it possible to generate extreme conditions at the push of a button in an intrinsically safe environment, and probe with any of the diagnostics used in microscope experiments, such as high-speed video, optical emission, nonlinear coherent spectroscopies and so on. The barrier to entering this field is relatively low since many laser laboratories already possess much of the needed instrumentation. A brief introduction to shock waves and instrumentation is presented. Then several examples of recent applications are described, including shocked water, the photophysics of fluorescent molecules under extreme conditions, shocked protein solutions, shocked metal-organic frameworks (MOFs), shocked explosives, chemical catalysis in a shocked liquid, and molecules at shocked interfaces. Since one can shoot a bullet at practically anything, there are many emerging opportunities in chemistry, biophysics, materials science, physics and hypervelocity aerodynamics.


Local delivery of bupivacaine in the wound reduces opioid requirements after intraabdominal surgery in children.
Local anaesthetic infusions into the surgical wound have been shown to reduce postoperative pain and the need for opioids in adults. In children, it was found to be safe and efficacious following sternotomy and orthopaedic surgery. The aim of this study was to evaluate the need for opioids postoperatively in children receiving wound catheters delivering either bupivacaine or saline following one of three defined abdominal or bladder procedures. Prospective, randomized, double-blind, placebo controlled study. Thirty-three children, 6 months of age to 13 years of age, undergoing elective surgery for enterostomy closure, open gastrostomy or ureteral reimplantation were randomized to receive bupivacaine or saline wound infusions for 72 h postoperatively. All patients received acetaminophen orally or rectally for every 6 h. Breakthrough pain was treated with morphine bolus doses of 0.05 mg/kg or infusions if more than three morphine doses were required. Pain scores were assessed every 3 h. Outcome measures were morphine dosages, return to full oral intake and length of hospital stay. On the first postoperative day, patients with bupivacaine infusions had significantly less need for morphine (1.3 ± 1.3 SD doses) compared to those receiving saline infusions (3.1+/2.5 SD doses, p < 0.05). No difference was seen during postoperative day two or three. There was no significant difference between the groups regarding time to full oral intake and time to discharge. Continuous infusion of bupivacaine in the abdominal wound was effective in reducing postoperative pain in children. It significantly reduced the need for additional opioids and can be considered for postoperative pain management in children.


Regulation of SREBP during hypoxia requires Ofd1-mediated control of both DNA binding and degradation.
Cells adapt to changes in ambient oxygen by changing their gene expression patterns. In fission yeast, the sterol regulatory element-binding protein Sre1 is proteolytically cleaved under low oxygen, and its N-terminal segment (Sre1N) serves as a hypoxic transcription factor. When oxygen is present, the prolyl hydroxylase Ofd1 down-regulates Sre1N activity in two ways: first, by inhibiting its binding to DNA, and second, by accelerating its degradation. Here we use a mathematical model to assess what each of these two regulatory functions contributes to the hypoxic response of the cell. By disabling individual regulatory functions in the model, which would be difficult in vivo, we found that the Ofd1 function of inhibiting Sre1N binding to DNA is essential for oxygen-dependent Sre1N regulation. The other Ofd1 function of accelerating Sre1N degradation is necessary for the yeast to quickly turn off its hypoxic response when oxygen is restored. In addition, the model predicts that increased Ofd1 production at low oxygen plays an important role in the hypoxic response, and the model indicates that the Ofd1 binding partner Nro1 tunes the response to oxygen. This model quantifies our understanding of a novel oxygen-sensing mechanism that is widely conserved.


Current role of autologous and allogeneic stem cell transplantation for relapsed and refractory hodgkin lymphoma.
Classical Hodgkin lymphoma (cHL) is a relatively rare disease, with approximately 9,200 estimated new cases and 1,200 estimated deaths per year in the United States. First-line chemo-radiotherapy leads to cure rates approaching 80% in patients with advanced-stage disease. However, 25 to 30% of these patients are not cured with chemotherapy alone (i.e., the ABVD regimen) and show either primary refractoriness to chemotherapy, early disease relapse or late disease relapse. Second-line salvage high-dose chemotherapy (HDC) and autologous stem cell transplantation (SCT) have an established role in the management of refractory/relapsed cHL, leading to durable responses in approximately 50% of relapsed patients and a minority of refractory patients. However, due to the poor responses to second-line salvage chemotherapy and dismal long-term disease control of primary refractory and early relapsed patients, their treatment represents an unmet medical need. Allogeneic SCT represents, by far, the only strategy with a curative potential for these patients; however, as discussed in this review, it's role in cHL remains controversial. Despite a general consensus that early relapsed and primary refractory patients represent a clinical challenge requiring effective treatments to achieve long-term disease control, there has been no consensus on the optimal therapy that should be offered to these patients. This review will briefly discuss the clinical results and the main issues regarding autologous SCT as well as the current role of allogeneic SCT.


Microcrystalline hexagonal tungsten bronze. 1. Basis of ion exchange selectivity for cesium and strontium.
The structural basis of selectivity for cesium and strontium of microcrystalline hexagonal tungsten bronze (HTB) phase Na(x)WO(3+x/2).zH(2)O has been studied using X-ray and neutron diffraction techniques, 1D and 2D (23)Na magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy, and radiochemical ion exchange investigations. For the HTB system, this study has shown that scattering techniques alone provide an incomplete description of the disorder and rapid exchange of water (with tunnel cations) occurring in this system. However, 1D and 2D (23)Na MAS NMR has identified three sodium species within the HTB tunnels-species A, which is located at the center of the hexagonal window and is devoid of coordinated water, and species B and C, which are the di- and monohydrated variants, respectively, of species A. Although species B accords with the traditional crystallographic model of the HTB phase, this work is the first to propose and identify the anhydrous species A and monohydrate species C. The population (total) of species B and C decreases in comparison to that of species A with increasing exchange of either cesium or strontium; that is, species B and C appear more exchangeable than species A. Moreover, a significant proportion of tunnel water is redistributed by these cations. Multiple ion exchange investigations with radiotracers (137)Cs and (85)Sr have shown that for strontium there is a definite advantage in ensuring that any easily exchanged sodium is removed from the HTB tunnels prior to exchange. The decrease in selectivity (wrt cesium) is most probably due to the slightly smaller effective size of Sr(2+); namely, it is less of a good fit for the hexagonal window, ion exchange site. The selectivity of the HTB framework for cesium has been shown unequivocally to be defined by the structure of the hexagonal window, ion exchange site. Compromising the geometry of this window even in the slightest way by either (1) varying the cell volume through changes to hydration or sodium content or (2) introducing disorder in the a-b plane through isomorphous substitution of molybdenum is sufficient to reduce the selectivity. Indeed, it is our hypothesis that this applies for all cations which are strongly bound by the HTB framework.


Both Maintenance and Avoidance of RNA-Binding Protein Interactions Constrain Coding Sequence Evolution.
While the principal force directing coding sequence (CDS) evolution is selection on protein function, to ensure correct gene expression CDSs must also maintain interactions with RNA-binding proteins (RBPs). Understanding how our genes are shaped by these RNA-level pressures is necessary for diagnostics and for improving transgenes. However, the evolutionary impact of the need to maintain RBP interactions remains unresolved. Are coding sequences constrained by the need to specify RBP binding motifs? If so, what proportion of mutations are affected? Might sequence evolution also be constrained by the need not to specify motifs that might attract unwanted binding, for instance because it would interfere with exon definition? Here, we have scanned human CDSs for motifs that have been experimentally determined to be recognized by RBPs. We observe two sets of motifs-those that are enriched over nucleotide-controlled null and those that are depleted. Importantly, the depleted set is enriched for motifs recognized by non-CDS binding RBPs. Supporting the functional relevance of our observations, we find that motifs that are more enriched are also slower-evolving. The net effect of this selection to preserve is a reduction in the over-all rate of synonymous evolution of 2-3% in both primates and rodents. Stronger motif depletion, on the other hand, is associated with stronger selection against motif gain in evolution. The challenge faced by our CDSs is therefore not only one of attracting the right RBPs but also of avoiding the wrong ones, all while also evolving under selection pressures related to protein structure.


Epidemiological cutoffs and cross-resistance to azole drugs in Aspergillus fumigatus.
Antifungal susceptibility testing of molds has been standardized in Europe and in the United States. Aspergillus fumigatus strains with resistance to azole drugs have recently been detected and the underlying molecular mechanisms of resistance characterized. Three hundred and ninety-three isolates, including 32 itraconazole-resistant strains, were used to define wild-type populations, epidemiological cutoffs, and cross-resistance between azole drugs. The epidemiological cutoff for itraconazole, voriconazole, and ravuconazole for the wild-type populations of A. fumigatus was < or =1 mg/liter. For posaconazole, the epidemiological cutoff was < or =0.25 mg/liter. Up till now, isolates susceptible to itraconazole have not yet displayed resistance to other azole drugs. Cross-resistance between azole drugs depends on specific mutations in cyp51A. Thus, a substitution of glycine in position 54 of Cyp51A confers cross-resistance between itraconazole and posaconazole. A substitution of methionine at position 220 or a duplication in tandem of a 34-bp fragment in the cyp51A promoter combined with a substitution of leucine at position 98 for histidine confers cross-resistance to all azole drugs tested. The results obtained in this study will help to develop clinical breakpoints for azole drugs and A. fumigatus.


Universal van der Waals Force between Heavy Polarons in Superfluids.
We investigate the long-range behavior of the induced Casimir interaction between two spinless heavy impurities, or polarons, in superfluid cold atomic gases. With the help of effective field theory (EFT) of a Galilean invariant superfluid, we show that the induced impurity-impurity potential at long distance universally shows a relativistic van der Waals-like attraction (∼1/r^{7}) resulting from the exchange of two superfluid phonons. We also clarify finite temperature effects from the same two-phonon exchange process. The temperature T introduces the additional length scale c_{s}/T with the speed of sound c_{s}. Leading corrections at finite temperature scale as T^{6}/r for distances r≪c_{s}/T smaller than the thermal length. For larger distances the potential shows a nonrelativistic van der Waals behavior (∼T/r^{6}) instead of the relativistic one. Our EFT formulation applies not only to weakly coupled Bose or Fermi superfluids but also to those composed of strongly correlated unitary fermions with a weakly coupled impurity. The sound velocity controls the magnitude of the van der Waals potential, which we evaluate for the fermionic superfluid in the BCS-BEC crossover.


The impact of training in problem-based interviewing on the detection and management of psychological problems presenting in primary care.
The vast majority of mental health problems present to primary care teams. However, rates of under-diagnosis remain worryingly high. This study explores a GP-centred approach to these issues. To examine the impact of training in problem-based interviewing (BPI) on the detection and management of psychological problems in primary care. The detection and management of psychological problems by 10 general practitioners (GPs) who had received PBI training 12 months earlier was compared with that of 10 control GPs matched for age, sex, clinical experience, and practice setting; and had originally applied for, but had not been able to attend, BPI training. Consecutive attendees at one randomly selected surgery undertaken by each GP were invited to participate in the study. Two hundred and eighty patients living in Newcastle upon Tyne met inclusion criteria and gave informed consent. The presence or absence of psychological problems was assessed using patient self-ratings on the 28-item version of the General Health Questionnaire (GHQ) and blind independent observer ratings of the brief Present State Examination (PSE). Patient satisfaction with interviews was rated using the Medical Interview Satisfaction Scale (MISS). After each consultation, the GPs (blind to subjective and observer ratings) recorded their assessment and management of the patients' problems on a Practice Activity Card (PAC). In comparison with control GPs, index GPs demonstrated significantly greater sensitivity in the detection of psychological problems in the GHQ-PAC ratings. The absolute decrease in misdiagnosis of GHQ cases was 9% and of PSE cases was 15%. Patients meeting GHQ criteria for caseness were more likely to be prescribed psychotropic medication by an index GP than compared with a control GP. Length of interview did not differ between the groups and mean scores on the MISS suggested that patients attending PBI-trained GPs, compared with control GPs, were as satisfied or slightly more satisfied with their consultation. In comparison with control GPs, PBI-trained GPs were better at recognizing and managing psychological disorders. The potential benefits of BPI training are discussed in light of other attempts to improve mental health skills in primary care.


Fine needle aspiration biopsy of pulmonary lesions: a 2-year experience in a district general hospital with a literature review.
During the 2 years of 1987 and 1988, 74 patients with suspected malignant lung lesions underwent fine needle aspiration biopsy at the Bradford Royal Infirmary. Using a 20Fr needle, sufficient specimen (smear and clot) was obtained in 70 (95%) patients for histological examination. The indications for the procedure were: failure to make a diagnosis at bronchoscopy and bronchial lavage in 32 (43%) patients, peripherally located lesion in 28 (38%) patients, poor anaesthetic risk in 20 (27%) patients, negative bronchoscopy and mediastinostomy in five (7%) patients and three (4%) patients refused operative intervention. There were no deaths and complications were few. Seven patients developed pneumothorax, three of whom required intercostal drainage. Transient haemorrhage as shown by haemoptysis occurred in one patient and one patient complained of pleuritic chest pain. Of the 60 patients with malignant disease eventually proven, 50 were diagnosed correctly. The overall sensitivity and specificity of the test were 81 and 100% respectively based on histological and/or clinical outcome of the lung lesion. The test was cost-effective, diagnostic yield was high and complications were few. The use of fine needle aspiration biopsy as part of the management policy in peripheral lung lesions is realistic in a district general hospital.


Efficient assays to quantify the life history traits of algal viruses.
Viruses play a crucial role in microbial ecosystems by liberating nutrients and regulating the growth of their hosts. These effects are governed by viral life history traits, i.e., by the traits determining viral reproduction and survival. Understanding these traits is essential to predicting viral effects, but measuring them is generally labor intensive. In this study, we present efficient methods to quantify the full life cycle of lytic viruses. We developed these methods for viruses infecting unicellular Chlorella algae but expect them to be applicable to other lytic viruses that can be quantified by flow cytometry. By making viral phenotypes accessible, our methods will support research into the diversity and ecological effects of microbial viruses.


The alphabet soup of pneumonia: CAP, HAP, HCAP, NHAP, and VAP.
The classification of pneumonia is increasingly complex as the patient population becomes more diverse. More and more patients are identified with pneumonia attributed to multidrug-resistant (MDR) bacteria, occurring both in the hospital setting and outside of the hospital. This is likely related to the expanding pool of patients at risk for colonization with MDR bacteria. These expanding patient populations include individuals residing in nonhospital health care facilities (e.g., long-term nursing facilities, assisted living environments, rehabilitation centers), patients undergoing outpatient procedures or therapies (hemodialysis, wound care, infusion therapy), patients who have been recently discharged from the hospital setting, and those with significant underlying immunosuppression. Patients exposed to these nonhospital risks who develop pneumonia have traditionally been categorized as having community-acquired pneumonia (CAP). However, the new designation for pneumonia acquired in these environments is healthcare-associated pneumonia (HCAP). Additionally, some authors have categorized patients in nursing homes as developing nursing home-acquired pneumonia (NHAP) because there may be distinct epidemiological associations with this infection. Although HCAP is currently treated with the same protocols as CAP in many hospitals, recent evidence indicates that HCAP differs from CAP with respect to pathogens and prognosis, and in fact, more closely resembles hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) requiring broader empirical antimicrobial therapy than CAP.


Multiple linked mouse chromosome 7 loci influence body fat mass.
Congenic mouse strains contain donor mouse strain DNA in genomes otherwise identical to a background strain. They can be used to identify defined chromosomal regions containing obesity genes with small effects. : The objective of this study was to discover congenic strains containing genes that influence body fat in mice and to examine interactions between these genes. A survey of congenic strains showed that the B6.C-Tyr(c) H1(b) Hbb(d)/By (B6.C-H1) congenic strain, with a 24 centiMorgan (cM) donor region from strain BALB/cBy on chromosome 7, had 50% less fat than background C57BL/6By (B6By) mice. The congenic donor region was then divided into 11 smaller overlapping subcongenic regions. Genotype effects on obesity traits in the subcongenics were determined by breeding heterozygotes for each line and comparing phenotypes of littermates with different donor genotypes. At least three subcongenic strains, two with overlapping donor regions and one with a nonoverlapping donor strain region, were found to exhibit significant influences of donor region genotype on obesity. A cross of the two overlapping subcongenics demonstrated that a single gene in the overlap region could not account for the observed obesity effects. We also observed significant obesity differences between genetically identical progeny that were contingent on the genotype of their subcongenic mothers. These results demonstrate the existence of at least three genes influencing obesity in three subcongenic strains with donor strain chromosomal regions whose size ranges from 0.5 to 5 cM. A maternal effect gene influencing obesity may be present in some subcongenic strains.


DFT study of caesium ion complexation by cucurbit[n]urils (n = 5-7).
Using density functional theory (DFT) calculations and the available crystallographic data we have investigated the binding of hydrated Cs(+) ions to the pumpkin-shaped cucurbituril macrocycles, CB[n] with n = 5-7. The calculations indicate that besides the interactions between caesium ions and the carbonyl-laced portals, also the hydrogen bonds established between the coordinated water molecules and the macrocycle do contribute to the overall binding affinity. Although the other alkali metal ions compete for binding with caesium, the partial dehydration of the caesium aqua ions is likely favoured by the relatively small interaction energy associated with the water-Cs(+) bond. The inclusion inside the macrocycle's cavity of either one water molecule or one chloride anion enhances the binding of Cs(+) due to the additional ion-dipole or ion-ion interactions, respectively, established within the complexes. An advantage in using cucurbituril macrocycles for the sequestration of caesium ions from an aqueous solution is the possibility of binding two hydrated metal ions by the carbonyl-laced portals thereby forming 1 : 2 complexes.


A patient with bilateral facial palsy associated with hypertension and chickenpox: learning points.
Bilateral facial nerve paralysis is an uncommon presentation and even more so in children. There are reports of different causes of bilateral facial nerve palsy. It is well-established that hypertension and chickenpox causes unilateral facial paralysis and the importance of checking the blood pressure in children with facial nerve paralysis cannot be stressed enough. The authors report a boy with bilateral facial nerve paralysis in association with hypertension and having recently recovered from chickenpox. The authors review aspects of bilateral facial nerve paralysis as well as hypertension and chickenpox causing facial nerve paralysis.


High-throughput DNA analysis shows the importance of methylation in the control of immune inflammatory gene transcription in chronic periodontitis.
Chronic periodontitis represents a complex disease that is hard to control and is not completely understood. Evidence from past studies suggests that there is a key role for DNA methylation in the pathogenesis of periodontitis. However, all reports have applied technologies that investigate genes in a low throughput. In order to advance in the knowledge of the disease, we analyzed DNA methylation variations associated with gene transcription using a high-throughput assay. Infinium® HumanMethylation450 (Illumina) was performed on gingival samples from 12 periodontitis cases and 11 age-matched healthy individuals. Methylation data of 1,284 immune-related genes and 1,038 cell cycle-related genes from Gene Ontology (GO) and 575 genes from a dataset of stably expressed genes (genes with consistent expression in different physiological states and tissues) were extracted from a microarray dataset and analyzed using bioinformatics tools. DNA methylation variations ranging from -2,000 to +2,000 bp from the transcription start site (TSS) were analyzed, and the results were tested against a differential expression microarray dataset between healthy and periodontitis gingival tissues. Differences were evaluated using tests from the R Statistical Project. The comparison of probes between periodontitis and normal gingival tissues showed that the mean methylation scores and the frequency of methylated probes were significantly lower in genes related to the immune process. In the immune group, these parameters were negatively correlated with gene expression (Mann-Whitney test, p < 2.2e - 16). Our results show that variations in DNA methylation between healthy and periodontitis cases are higher in genes related to the immune-inflammatory process. Thus, DNA methylation must be modulating chromatin regions and, consequently, modulating the mRNA transcription of immune-inflammatory genes related with periodontitis, impacting the prognosis of disease.


Targeting pancreatic cancer by TAK-981: a SUMOylation inhibitor that activates the immune system and blocks cancer cell cycle progression in a preclinical model.
Pancreatic ductal adenocarcinoma (PDAC) has the characteristics of high-density desmoplastic stroma, a distinctive immunosuppressive microenvironment and is profoundly resistant to all forms of chemotherapy and immunotherapy, leading to a 5-year survival rate of 9%. Our study aims to add novel small molecule therapeutics for the treatment of PDAC. We have studied whether TAK-981, a novel highly selective and potent small molecule inhibitor of the small ubiquitin like modifier (SUMO) activating enzyme E1 could be used to treat a preclinical syngeneic PDAC mouse model and we have studied the mode of action of TAK-981. We found that SUMOylation, a reversible post-translational modification required for cell cycle progression, is increased in PDAC patient samples compared with normal pancreatic tissue. TAK-981 decreased SUMOylation in PDAC cells at the nanomolar range, thereby causing a G2/M cell cycle arrest, mitotic failure and chromosomal segregation defects. TAK-981 efficiently limited tumour burden in the KPC3 syngeneic mouse model without evidence of systemic toxicity. In vivo treatment with TAK-981 enhanced the proportions of activated CD8 T cells and natural killer (NK) cells but transiently decreased B cell numbers in tumour, peripheral blood, spleen and lymph nodes. Single cell RNA sequencing revealed activation of the interferon response on TAK-981 treatment in lymphocytes including T, B and NK cells. TAK-981 treatment of CD8 T cells ex vivo induced activation of STAT1 and interferon target genes. Our findings indicate that pharmacological inhibition of the SUMO pathway represents a potential strategy to target PDAC via a dual mechanism: inhibiting cancer cell cycle progression and activating anti-tumour immunity by inducing interferon signalling.


Cytokine pattern during rejection and infection after liver transplantation--improvements in postoperative monitoring?
Despite improvements in immunosuppression, rejection occurs in 50% of liver transplant patients and may cause significant morbidity. The most frequent cause of death after liver transplantation is severe infection. Determination of the cytokine network may lead to earlier detection of patients at risk for severe rejection and infection. For this purpose, 81 patients with 85 liver transplants were monitored for cytokines and neopterin on a daily basis. During the first postoperative month, 28 patients (34.6%) developed acute rejection; 14 patients were successfully treated with methylprednisolone (steroid-sensitive rejection), while 14 patients required additional treatment with FK506 and OKT3 (steroid-resistant rejection). Ten patients developed severe infections, and 11 patients experienced asymptomatic cholangitis. Patients with an uneventful postoperative course (n=37) were the control group. One-year patient survival was 88.9%: 1 patient died because of chronic rejection and Pseudomonas urosepsis; a further 4 patients died of aspergillus pneumonia and bacterial sepsis. Soluble TNF-RII, sIL-2R-, and IL-10 levels were significantly elevated 3 days prior to or at the onset of acute steroid-resistant rejection (P < or = 0.01 versus steroid-sensitive rejection and on uneventful postoperative course). An increase in IL-8, neopterin, and sTNF-RII was indicative of severe infection 3 days prior to onset of infection. In this group of patients, a simultaneous increase in IL-10 indicated a lethal outcome of severe infection. During the second week of acute steroid-resistant rejection and lethal infection, a significant rise in IL-1beta, IFN-gamma, and IL-6 was observed (P < or = 0.01 versus control groups). The different patterns in neopterin- and cytokine-increase could differentiate between severe rejection and severe infection. Furthermore, the increase in these parameters indicated severe rejection--i.e., steroid resistance at the onset of acute rejection--which could prompt us to initiate rescue therapy immediately. The ability to detect patients at risk for severe or lethal infection may result in intensified infectious screening and more aggressive antiinfectious treatment. Therefore, routine monitoring of these parameters may lead to changes in therapeutic management of severe acute rejection and infection after liver transplantation.


Isolation, characterization and community diversity of indigenous putative toluene-degrading bacterial populations with catechol-2,3-dioxygenase genes in contaminated soils.
Indigenous bacterial assemblages with putative hydrocarbon-degrading capabilities were isolated, characterized and screened for the presence of the catechol-2,3-dioxygenase (C23O) gene after exposure to toluene in two different (i.e., pristine and conditioned) soil communities. The indigenous bacterial populations were exposed to the hydrocarbon substrate by the addition of toluene concentrations, ranging from 0.5 % to 10 % V/W in 10 g of each soil and incubated at 30 °C for upwards of 12 days. In total, 25 isolates (11 in pristine soil and 14 in conditioned soil) were phenotypically characterized according to standard microbiological methods and also screened for the 238-bp C23O gene fragment. Additionally, 16S rRNA analysis of the isolates identified some of them as belonging to the genera Bacillus, Exiguobacterium, Enterobacter, Pseudomonas and Stenotrophomonas. Furthermore, the two clone libraries that were constructed from these toluene-contaminated soils also revealed somewhat disparate phylotypes (i.e., 70 % Actinobacteria and Firmicutes to 30 % Proteobacteria in conditioned soil, whereas in pristine soil: 66 % Actinobacteria and Firmicutes; 21 % Proteobacteria and 13 % Bacteroidetes). The differences observed in bacterial phylotypes between these two soil communities may probably be associated with previous exposure to hydrocarbon sources by indigenous populations in the conditioned soil as compared to the pristine soil.


Changes in the Anterior Lamina Cribrosa Morphology with Glaucoma Severity.
This study was designed to evaluate if primary open angle glaucoma (POAG) and its severity are associated with the shape of the lamina cribrosa (LC) as measured by a global shape index (LC-GSI), or other indices of LC curvature or depth. Optical coherence tomography (OCT) scans of the optic nerve head (OHN) were obtained from subjects with POAG (n = 99) and non-glaucomatous controls (n = 76). ONH structures were delineated, the anterior LC morphology reconstructed in 3D, and the LC-GSI calculated (more negative values denote greater posterior concavity). Anterior LC depth and 2D-curvature were also measured. Severity of glaucoma was defined by the extent of visual field loss, based on the Hodapp-Parrish-Anderson grading. Linear regression analyses compared LC characteristics between controls, mild-moderate, and advanced POAG groups. After adjusting for age, gender, ethnicity, intraocular pressure, axial length and corneal curvature, the LC-GSI was most negative in the advanced POAG group (mean [standard error] = -0.34 [0.05]), followed by the mild-moderate POAG group (-0.31 [0.02]) and then controls (-0.23 [0.02], PTrend = 0.01). There was also a significant trend of increasing LC depth and greater LC horizontal curvature with increasing severity of glaucoma (PTrend = 0.04 and 0.02, respectively). Therefore, with more severe glaucoma, the LC-GSI was increasingly more negative, and the anterior LC depth and curvature greater. These observations collectively correspond to greater cupping of the ONH at the level of the LC. As the LC-GSI describes the 3D anterior LC morphology, its potential usage may be complementary to existing ONH parameters measured on OCT.


Effect of non-ionic surfactants on the formation of DNA/emulsion complexes and emulsion-mediated gene transfer.
To study the structure-function relationship of non-ionic surfactants in emulsion-mediated gene delivery. Four different types of non-ionic surfactants including Tween, Span, Brij and pluronic copolymers were used as co-emulsifiers for preparation of emulsions composed of Castor oil, dioleoylphosphatidylethanolamine (DOPE) and 3 beta [N-(N', N'-dimethylaminoethane) carbamoyl] cholesterol (DC-Chol). The effect of different surfactants on the formation of DNA/emulsion complexes and transfection activity were analyzed using plasmid DNA containing luciferase cDNA as a reporter gene. Non-ionic surfactants containing branched polyoxyethylene chains as the hydrophilic head group were more effective in preventing the formation of large DNA/emulsion complexes than those containing one or no polyoxyethylene chain. All emulsion formulations except those containing Brij 700 exhibited high activity in transfecting mouse BL-6 cells in the absence of serum. In the presence of serum, however, transfection activity of each formulation varied significantly. Emulsions containing Tween, Brij 72, pluronic F68 and F127 demonstrated increased activity in transfecting cells in the presence of 20% serum. In contrast to emulsions containing Span, long chain polyoxyethylene of Brij showed decreased transfection activity. The particle size of the DNA/emulsion complexes and their ability to transfect cells are dependent on the concentration of non-ionic surfactant in the formulation. The structure of the hydrophilic head group of the non-ionic surfactants in the emulsion is important in determining how DNA molecules interact with emulsions and the extent to which DNA is transferred inside the cell.


Antiphospholipid antibodies and the antiphospholipid syndrome: an update on treatment and pathogenic mechanisms.
The antiphospholipid syndrome is a disorder of recurrent thrombosis, pregnancy loss and thrombocytopenia associated with the presence of antiphospholipid antibodies and persistently positive anticardiolipin or lupus anticoagulant positive tests. Since its recognition in the 1980s, growing interest in the field, not only with respect to diagnosis and treatment, but also regarding the pathogenesis of antiphospholipid antibodies, has emerged. First, this review addresses the recently updated classification criteria for diagnosis and treatment of the antiphospholipid syndrome. A discussion on the newly described potential beneficial roles of hydroxychloroquine and the statins for the treatment of antiphospholipid syndrome-associated clinical manifestations is included. Importantly, this article analyzes recent data that examine the molecular and intracellular events that antiphospholipid antibodies trigger in target cells, as well as new findings in the identification of the receptors for these antibodies on the membrane of those cells. A separate section discusses novel pathogenic mechanisms of antiphospholipid antibodies, including the activation of complement and their interaction with homologous catalytic domains of several serine proteases of the coagulation system. Understanding the molecular interactions and the intracellular signaling that antiphospholipid antibodies trigger, new therapeutic and targeted strategies to ameliorate clinical manifestations in patients with antiphospholipid syndrome may be established.


Raised corticomotor excitability of M1 forearm area following anodal tDCS is sustained during robotic wrist therapy in chronic stroke.
Anodal transcranial direct current stimulation (tDCS) can transiently increase corticomotor excitability of intrinsic hand muscles and improve upper limb function in patients with chronic stroke. As a preliminary study, we tested whether increased corticomotor excitability would be similarly observed in muscles acting about the wrist, and remain present during robotic training involving active wrist movements, in six chronic stroke patients with residual motor deficit. Transcranial magnetic stimulation (TMS) generated motor evoked potentials (MEP) in the flexor carpi radialis (FCR) and provided a measure of corticomotor excitability and short-interval cortical inhibition (SICI) before and immediately after a period of tDCS (1 mA, 20 min, anode and TMS applied to the lesioned hemisphere), and robotic wrist training (1hr). Following tDCS, the same TMS current strength evoked an increased MEP amplitude (mean 168 +/- 22%SEM; p < 0.05), that remained increased after robot training (166 +/- 23%; p < 0.05). Conditioned MEPs were of significantly lower amplitude relative to unconditioned MEPs prior to tDCS (62 +/- 6%, p < 0.05), but not after tDCS (89 +/- 14%, p = 0.40), or robot training (91 +/- 8%, p = 0.28), suggesting that the increased corticomotor excitability is associated with reduced intracortical inhibition. The persistence of these effects after robotic motor training, indicates that a motor learning and retraining program can co-exist with tDCS-induced changes in cortical motor excitability, and supports the concept of combining brain stimulation with physical therapy to promote recovery after brain injury.


The form of a trade-off determines the response to competition.
Understanding how populations and communities respond to competition is a central concern of ecology. A seminal theoretical solution first formalised by Levins (and re-derived in multiple fields) showed that, in theory, the form of a trade-off should determine the outcome of competition. While this has become a central postulate in ecology it has evaded experimental verification, not least because of substantial technical obstacles. We here solve the experimental problems by employing synthetic ecology. We engineer strains of Escherichia coli with fixed resource allocations enabling accurate measurement of trade-off shapes between bacterial survival and multiplication in multiple environments. A mathematical chemostat model predicts different, and experimentally verified, trajectories of gene frequency changes as a function of condition-specific trade-offs. The results support Levins' postulate and demonstrates that otherwise paradoxical alternative outcomes witnessed in subtly different conditions are predictable.


Economic evaluation of the effects of planting date and application rate of imidacloprid for management of cereal aphids and barley yellow dwarf in winter wheat.
The effects of planting date and application rate of imidacloprid for control of Schizaphis graminum Rondani, Rhopalosiphum padi L. (Homoptera: Aphididae), and barley yellow dwarf virus (BYDV) in hard red winter wheat were studied. The first experiment was conducted from 1997 to 1999 at two locations and consisted of three planting dates and four rates of imidacloprid-treated seed. The second experiment was conducted from 2001 to 2002 in Stillwater, OK, and consisted of two varieties of hard red winter wheat seed and four rates of imidacloprid. Aphid densities, occurrence of BYDV, yield components, and final grain yield were measured, and yield differences were used to estimate the economic return obtained from using imidacloprid. In the first study, aphid populations responded to insecticide rate in the early and middle plantings, but the response was reduced in the late planting. Yields increased as insecticide rate increased but did not always result in a positive economic return. In the second study, imidacloprid seed treatments reduced aphid numbers and BYD occurrence, protected yield, and resulted in a positive economic return. The presence of aphids and BYDV lowered yield by reducing fertile head density, total kernel weight, and test weight. Whereas the application of imidacloprid seed treatments often provided positive yield protection, it did not did not consistently provide a positive economic return. A positive economic return was consistently obtained if the cereal aphid was carrying and transmitting BYDV and was more likely to occur if wheat was treated with a low rate if imidacloprid and planted in a "dual purpose" planting date window.


Random sets of stadiums in square and collective behavior of bacteria.
Collective motion of swimmers can be detected by hydrodynamic interactions through the eective (macroscopic) viscosity. It follows form the general hydrodynamics that the eective viscosity of non-dilute random suspensions depends on the shape of particles and of their spacial probabilistic distribution. Therefore, a comparative analysis of disordered and collectively interacting particles of the bacteria shape can be done in terms of the probabilistic geometric parameters which determine the eective viscosity. In this paper, we develop a quantitative criterion to detect the collective behavior of bacteria. This criterion is based on the basic statistic moments (e-sums or generalized Eisenstein-Rayleigh sums) which characterize the high-order correlation functions. The locations and the shape of bacteria are modeled by stadiums randomly embedded in medium without overlapping. This shape models can be considered as improvement of the previous segment model.We calculate the e-sums of the simulated disordered sets and of the observed experimental locations of bacteria subtilis. The obtained results show a dierence between these two sets that demonstrates the collective motion of bacteria.


Quantification of Maternal Microchimeric Cells in the Liver of Children With Biliary Atresia.
Biliary atresia (BA) is a rare disorder of unknown etiology. There is a debate as to whether maternal microchimerism plays a significant role in the development of BA or in graft tolerance after liver transplantation. Here, we performed quantitative-PCR-based assays for liver tissues of children with BA and other diseases. Maternal cells were detected in 4/13 and 1/3 of the BA and control groups, respectively. The estimated number of maternal cells ranged between 0 and 34.7 per 106 total cells. The frequency and severity of maternal microchimerism were similar between the BA and control groups, and between patients with and without acute rejection of maternal grafts. These results highlight the high frequency of maternal microchimerism in the liver. This study provides no evidence for roles of microchimerism in the etiology of BA or in graft tolerance. Thus, the biological consequences of maternal microchimerism need to be clarified in future studies.


Holoprosencephaly and agnathia spectrum: Presentation of two new patients and review of the literature.
Holoprosencephaly (HPE), the most common developmental disorder of the human forebrain, is occasionally associated with the spectrum of agnathia, or virtual absence of the mandible. This condition results in a constellation of structural cerebral and craniofacial abnormalities. Here we present two new patients and review 30 patients from the literature with HPE and variants of agnathia. The majority of these patients are female and have the most severe forms of HPE, with cyclopia present more frequently than is usually observed in cohorts of patients with HPE. Also, many patients have additional clinical findings not typical in patients with classic HPE, particularly situs abnormalities. Recent animal studies suggest that the association of HPE and agnathia may relate to alterations in signaling from forebrain and foregut endoderm organizing centers and subsequent first pharyngeal arch development, although present models are inadequate to explain all of the clinical findings of this enigmatic human syndrome. Further research is required to better elucidate the causal and pathogenic basis of this association.


Inhibitor antibody development and T cell response to human factor VIII in murine hemophilia A.
In order to understand better the mechanism of inhibitor formation in hemophilia A patients, we have characterized the immune response to human factor VIII in a murine model of hemophilia A. Mice with severe factor VIII deficiency caused by targeted gene disruptions in exons 16 and 17 were injected intravenously with human factor VIII. Anti-factor VIII was absent or was detected at only very low levels in hemophilic mice of both strains after a single injection of 0.2 microg factor VIII, but it was present in most mice after a second exposure. Subsequent exposures led to high titer anti-factor VIII antibodies in both ELISA and inhibitor assays. A human factor VIII-specific T cell proliferative response was detected with spleen cells obtained three days after a single injection with human factor VIII, before mice had detectable anti-factor VIII antibodies. Subsequent exposures to factor VIII were followed by an increased T cell proliferative response. These studies indicate that murine hemophilia A is a good model for the study of the immune response to human factor VIII, especially the role of the T cell in the early steps in inhibitor antibody formation.


[Metastatic disease of the penis. Report of 3 cases].
Metastatic lesions of the penis are uncommon, only some 200 cases having been reported in the literature. Priapism is the most frequent symptom, although increased penis size, ulceration and nodes formation have also been described; metastasis happens simultaneously in 20% cases while in 50% of cases they appear 2 years after initial diagnosis. Survival of untreated patients has not exceed 24 weeks, whereas treated patients have survived 47 weeks.


Validating two systems for estimating force and power.
This study examined the validity of 2 kinematic systems for estimating force and power during squat jumps. 12 weight-trained males each performed single repetition squat jumps with a 20-kg, 40-kg, 60-kg and 80-kg load on a Kistler portable force plate. A commercial linear position transducer (Gymaware [GYM]) and accelerometer (Myotest® [MYO]) were attached to the bar to assess concentric peak force (PF) and peak power (PP). Across all loads tested, the GYM and MYO estimates of PF and PP were moderately to strongly correlated ( P≤0.05-0.001) with the force plate measurements ( R=0.59-0.87 and R=0.66-0.97), respectively. The mean PF and PP values were not significantly different between the 2 kinematic systems and the force plate, but the estimates did produce some systematic bias and relatively large random errors, especially with the 20-kg load (PF bias >170 N, PF error >335 N, PP bias >400 W, PP error >878 W). Some proportional bias was also identified. In summary, the estimation of PF and PP by a linear position transducer and accelerometer showed moderate to strong relative validity and equivalent absolute validity, but these estimates are limited by the presence of bias and large random errors.


Frailty and maximal exercise capacity in adult lung transplant candidates.
Frail lung transplant candidates are more likely to be delisted or die without receiving a transplant. Further knowledge of what frailty represents in this population will assist in developing interventions to prevent frailty from developing. We set out to determine whether frail lung transplant candidates have reduced exercise capacity independent of disease severity and diagnosis. Sixty-eight adult lung transplant candidates underwent cardiopulmonary exercise testing (CPET) and a frailty assessment (Fried's Frailty Phenotype (FFP)). Primary outcomes were peak workload and peak aerobic capacity (V˙O2). We used linear regression to adjust for age, gender, diagnosis, and lung allocation score (LAS). The mean ± SD age was 57 ± 11 years, 51% were women, 57% had interstitial lung disease, 32% had chronic obstructive pulmonary disease, 11% had cystic fibrosis, and the mean LAS was 40.2 (range 19.2-94.5). In adjusted models, peak workload decreased by 10 W (95% CI 4.7 to 14.6) and peak V˙O2 decreased by 1.8 mL/kg/min (95% CI 0.6 to 2.9) per 1 unit increment in FFP score. After adjustment, exercise tolerance was 38 W lower (95% CI 18.4 to 58.1) and peak V˙O2 was 8.5 mL/kg/min lower (95% CI 3.3 to 13.7) among frail participants compared to non-frail participants. Frailty accounted for 16% of the variance (R2) of watts and 19% of the variance of V˙O2 in adjusted models. Frailty contributes to reduced exercise capacity among lung transplant candidates independent of disease severity.


Sharpening clinical decision support alert and reminder designs with MINDSPACE: A systematic review.
Clinical decision support (CDS) alerts and reminders aim to influence clinical decisions, yet they are often designed without considering human decision-making behaviour. While this behaviour is comprehensively described by behavioural economics (BE), the sheer volume of BE literature poses a challenge to designers when identifying behavioural effects with utility to alert and reminder designs. This study tackles this challenge by focusing on the MINDSPACE framework for behaviour change, which collates nine behavioural effects that profoundly influence human decision-making behaviour: Messenger, Incentives, Norms, Defaults, Salience, Priming, Affect, Commitment, and Ego. A systematic review searching MEDLINE, Embase, PsycINFO, and CINAHL Plus to explore (i) the usage of MINDSPACE effects in alert and reminder designs and (ii) the efficacy of those alerts and reminders in influencing clinical decisions. The search queries comprised ten Boolean searches, with nine focusing on the MINDSPACE effects and one focusing on the term mindspace. 50 studies were selected from 1791 peer-reviewed journal articles in English from 1970 to 2022. Except for ego, eight of nine MINDSPACE effects were utilised to design alerts and reminders, with defaults and norms utilised the most in alerts and reminders, respectively. Overall, alerts and reminders informed by MINDSPACE effects showed an average 71% success rate in influencing clinical decisions (alerts 73%, reminders 69%). Most studies utilised a single effect in their design, with higher efficacy for alerts (64%) than reminders (41%). Others utilised multiple effects, showing higher efficacy for reminders (28%) than alerts (9%). This review presents sufficient evidence demonstrating the MINDSPACE framework's merits for designing CDS alerts and reminders with human decision-making considerations. The framework can adequately address challenges in identifying behavioural effects pertinent to the effective design of CDS alerts and reminders. The review also identified opportunities for future research into other relevant effects (e.g., framing).


Implementing a nurse-shadowing program for first-year medical students to improve interprofessional collaborations on health care teams.
Although physicians and nurses play critical roles in providing team-based collaborative care, the literature on current relationships between physicians and nurses in typical health care settings reveals troublesome characteristics that affect the quality of the patient care that they provide. Studies report communication failures, poor coordination, and fragmented care within and across organizations, which then have been associated with medication errors, patient safety issues, and patient deaths. Because the physician-nurse relationship is a critical component of a high-functioning patient care team, curricular interventions are needed to improve communication between physicians and nurses and to avoid professional conflict that can potentially compromise the quality of the patient care they offer.Currently, medical schools provide students with limited education and training on the roles of other health care professionals. In 2009, to begin addressing this need in the curriculum, the authors implemented a nurse-shadowing program at the University of Michigan Medical School. They set out to help first-year medical students learn more about the role of nurses in health care to positively influence their attitudes toward nurses and improve their understanding of nurses' roles in health care teams. Pre- and postprogram survey results revealed that medical students' attitudes toward nurses improved and their knowledge of the profession increased as a result of this intervention. In this article, the authors provide a description of the half-day program, evidence of its effectiveness, the implications of those findings, and future directions for teaching medical students about effectively working on interprofessional teams.


Specific targeting of tumor angiogenesis by RGD-conjugated ultrasmall superparamagnetic iron oxide particles using a clinical 1.5-T magnetic resonance scanner.
Angiogenesis is essential for the development of malignant tumors and provides important targets for tumor diagnosis and therapy. To noninvasively assess the angiogenic profile of tumors, novel alpha(v)beta(3) integrin-targeted ultrasmall superparamagnetic iron oxide particles (USPIOs) were designed and their specific uptake by endothelial cells was evaluated in vitro and in vivo. USPIOs were coated with 3-aminopropyltrimethoxysilane (APTMS) and conjugated with Arg-Gly-Asp (RGD) peptides. Accumulation in human umbilical vein endothelial cells (HUVECs) was evaluated using Prussian blue staining, transmission electron microscopy, magnetic resonance (MR) imaging, and inductively coupled plasma mass spectrometry. Uptake of RGD-USPIO by HUVECs was significantly increased when compared with unlabeled USPIO and could be competitively inhibited by addition of unbound RGD. The ability of the RGD-USPIO to noninvasively distinguish tumors with high (HaCaT-ras-A-5RT3) and lower (A431) area fractions of alpha(v)beta(3) integrin-positive vessels was evaluated using a 1.5-T MR scanner. Indeed, after RGD-USPIO injection, there was a more pronounced decrease in T(2) relaxation times in HaCaT-ras-A-5RT3 tumors than in A431 tumors. Furthermore, T(2)*-weighted images clearly identified the heterogeneous arrangement of vessels with alpha(v)beta(3) integrins in HaCaT-ras-A-5RT3 tumors by an irregular signal intensity decrease. In contrast, in A431 tumors with predominantly small and uniformly distributed vessels, the signal intensity decreased more homogeneously. In summary, RGD-coupled, APTMS-coated USPIOs efficiently label alpha(v)beta(3) integrins expressed on endothelial cells. Furthermore, these molecular MR imaging probes are capable of distinguishing tumors differing in the degree of alpha(v)beta(3) integrin expression and in their angiogenesis profile even when using a clinical 1.5-T MR scanner.


A comparative study between Chinese propolis and Brazilian green propolis: metabolite profile and bioactivity.
Among different types, Chinese propolis (ChPs) and Brazilian green propolis (BrGPs) have been shown to contain multi-functional properties. Despite extensive research in the field, reports comparing propolis from different geographical areas are still limited, compromising our current understanding of the potential therapeutic effect associated with propolis and its derived compounds. Herein, a comparative study between ChPs and BrGPs including their metabolite profile and bioactivities was performed. Interestingly, even when ChPs and BrGPs showed similar anti-inflammatory potential, our results showed that they contained very different levels of ethanol extract, total flavonoids and total phenolic acids and in fact, LC-MS metabolic profiling and pattern recognition could effectively distinguish ChPs and BrGPs. Moreover, all the propolis samples tested showed good anti-oxidant activity and no significant difference of free radical scavenging capacity existed between ChPs and BrGPs. In conclusion, ChPs and BrGPs have a distinct chemome, but their antioxidant and anti-inflammatory activities are similar.


Further assessment of the complement component 2 and factor B region associated with age-related macular degeneration.
Polymorphic variation in genes involved in regulation of the complement system has been implicated as a major cause of genetic risk, in addition to the LOC387715/HTRA1 locus and other environmental influences. Previous studies have identified polymorphisms in the complement component 2 (CC2) and factor B (CFB) genes, as potential functional variants associated with AMD, in particular CFB R32Q and CC2 rs547154, both of which share strong linkage disequilibrium (LD). Data derived from the HapMap Project were used to select 18 haplotype-tagging SNPs across the extended CC2/CFB region for genotyping, to measure the strength of LD in 318 patients with neovascular AMD and 243 age-matched control subjects to identify additional potential functional variants in addition to those originally reported. Strong LD was measured across this region as far as the superkiller viralicidic activity 2-like gene (SKIV2L). Nine SNPs were identified to be significantly associated with the genetic effect observed at this locus. Of these, a nonsynonymous coding variant SKIV2L R151Q (rs438999; OR, 0.48; 95% confidence interval [CI], 0.31-0.74; P<0.001), was in strong LD with CFB R32Q, rs641153 (r(2)=0.95) and may exert a functional effect. When assessed within a logistic regression model measuring the effects of genetic variation at the CFH and LOC387715/HTRA1 loci and smoking, the effect remained significant (OR, 0.38; 95% CI, 0.22-0.65; P<0.001). Additional variation identified within this region may also confer a weaker but independent effect and implicate additional genes within the pathogenesis of AMD. Because of the high level of LD within the extended CC2/CFB region, variation within SKIV2L may exert a functional effect in AMD.


Chemotherapeutic agents in noncytotoxic concentrations increase antigen presentation by dendritic cells via an IL-12-dependent mechanism.
Antineoplastic chemotherapeutic agents may indirectly activate dendritic cells (DCs) by inducing the release of "danger" signals from dying tumor cells. Whereas the direct cytotoxic or inhibitory effect of conventional chemotherapy on DCs has been reported, modulation of DC function by chemotherapeutic agents in low noncytotoxic concentrations has not yet been investigated. We have tested the effects of different classes of antineoplastic chemotherapeutic agents used in low noncytotoxic concentrations on the Ag-presenting function of DCs. We revealed that paclitaxel, doxorubicin, mitomycin C, and methotrexate up-regulated the ability of DCs to present Ags to Ag-specific T cells. Stimulation of DC function was associated with the up-regulation of expression of Ag-processing machinery components and costimulatory molecules on DCs, as well as increased IL-12p70 expression. However, the ability of DCs treated with paclitaxel, methotrexate, doxorubicin, and vinblastine to increase Ag presentation to Ag-specific T cells was abolished in DCs generated from IL-12 knockout mice, indicating that up-regulation of Ag presentation by DCs is IL-12-dependent and mediated by the autocrine or paracrine mechanisms. At the same time, IL-12 knockout and wild-type DCs demonstrated similar capacity to up-regulate OVA presentation after their pretreatment with low concentrations of mitomycin C and vincristine, suggesting that these agents do not utilize IL-12-mediated pathways in DCs for stimulating Ag presentation. These findings reveal a new mechanism of immunopotentiating activity of chemotherapeutic agents-a direct immunostimulatory effect on DCs (chemomodulation)-and thus provide a strong rationale for further assessment of low-dose chemotherapy given with DC vaccines for cancer treatment.


Thyrotoxic adenoma followed by atypical hyperthyroidism due to struma ovarii: clinical and genetic studies.
Atypical forms of hyperthyroidism represent a diagnostic challenge for clinicians. Struma ovarii is an ovarian teratoma and constitutes a rare cause of ectopic thyroidal hormonal production. We describe a case of struma ovarii that combined two different sources of hyperthyroidism in the same patient and report genetic studies in order to contribute a better understanding of the autonomy and tumorigenesis of the struma ovarii. A 73-year-old nulliparous woman presented a thyroid toxic adenoma that was successfully treated with 10 mCi radioiodine. Unexpectedly, a new onset of hyperthyroidism prompted us to look for a second etiology. A whole-body scan with (123)I detected a pelvic hyperfixation suggesting struma ovarii, and a thyroid differentiated left ovarian teratoma 3 cm in size was surgically removed. We screened for mutations of thyroid-stimulating hormone receptor and Gs-alpha protein genes, as these mutations are common in thyroid adenomas. We did not identify any mutations. Androgen receptor study demonstrated a monoclonal status. Comparative genomic hybridization did not reveal any chromosomal abnormality. However, loss of heterozygosity analysis showed several structural abnormalities, compared with the majority of benign ovarian teratomas, which show a normal karyotype. This is the first well-documented report of thyrotoxic struma ovarii revealed after treatment of a single thyroid toxic adenoma. We have shown in this case that struma ovarii originates from a single germ cell, and, albeit benign, this tumor presents several chromosomal abnormalities. Struma ovarii-induced hyperthyroidism is likely to be mediated by mechanisms different from those of the classical thyroid toxic adenoma.


Obesity in Saudi Arabia.
Obesity and overweight are well known risk factors for coronary artery disease (CAD), and are expected to be increasing in the Kingdom of Saudi Arabia (KSA) particularly among females. Therefore, we designed this study with the objective to determine the prevalence of obesity and overweight among Saudis of both gender, between the ages of 30-70 years in rural as well as in urban communities. This work is part of a major national project called Coronary Artery Disease in Saudis Study (CADISS) that is designed to look at CAD and its risk factors in Saudi population. This study is a community-based national epidemiological health survey, conducted by examining Saudi subjects in the age group of 30-70 years of selected households over a 5-year period between 1995 and 2000 in KSA. Data were obtained from body mass index (BMI) and were analyzed to classify individuals with overweight (BMI = 25-29.9 kg/m2), obesity (BMI >/=30 kg/m2) and severe (gross) obesity (BMI >/=40 kg/m2) to provide the prevalence of overweight and obesity in KSA. Data were obtained by examining 17,232 Saudi subjects from selected households who participated in the study. The prevalence of overweight was 36.9%. Overweight is significantly more prevalent in males (42.4%) compared to 31.8% of females (p<0.0001). The age-adjusted prevalence of obesity was 35.5% in KSA with an overall prevalence of 35.6% [95% CI: 34.9-36.3], while severe (gross) obesity was 3.2%. Females are significantly more obese with a prevalence of 44% than males 26.4% (p<0.0001). Obesity and overweight are increasing in KSA with an overall obesity prevalence of 35.5%. Reduction in overweight and obesity are of considerable importance to public health. Therefore, we recommend a national obesity prevention program at community level to be implemented sooner to promote leaner and consequently healthier community.


Predictable NHEJ Insertion and Assessment of HDR Editing Strategies in Plants.
Canonical CRISPR-Cas9 genome editing technique has profoundly impacted the fields of plant biology, biotechnology, and crop improvement. Since non-homologous end joining (NHEJ) is usually considered to generate random indels, its high efficiency mutation is generally not pertinent to precise editing. Homology-directed repair (HDR) can mediate precise editing with supplied donor DNA, but it suffers from extreme low efficiency in higher plants. Therefore, precision editing in plants will be facilitated by the ability to predict NHEJ repair outcome and to improve HDR efficiency. Here, we report that NHEJ-mediated single nucleotide insertion at different rice genes is predictable based on DNA sequences at the target loci. Three mutation prediction tools (inDelphi, FORECasT, and SPROUT) have been validated in the rice plant system. We also evaluated the chimeric guide RNA (cgRNA) and Cas9-Retron precISe Parallel Editing via homologY (CRISPEY) strategies to facilitate donor template supply for improving HDR efficiency in Nicotiana benthamiana and rice. However, neither cgRNA nor CRISPEY improved plant HDR editing efficiency in this study. Interestingly, our data indicate that tethering of 200-250 nucleotides long sequence to either 5' or 3' ends of guide RNA did not significantly affect Cas9 cleavage activity.


[Comments on the treatment of rhinocerebral mucormycosis].
Rhinocerebral mucormycosis is a serious infectious disease with a high mortality rate that requires early medical treatment. Liposomal amphotericin B is the medical treatment of choice because of its low renal toxicity and good tissue diffusion. Surgical treatment is necessary, even if all affected areas cannot be reached. The surgical indication should be based on individual characteristics and disease evolution. The case of a 56-year-old man with rhinocerebral mucormycosis caused by Rhizopus and treated with liposomal amphotericin B and extensive rhino-orbital surgical treatment is commented.


Brevican in the developing hippocampal fimbria: differential expression in myelinating oligodendrocytes and adult astrocytes suggests a dual role for brevican in central nervous system fiber tract development.
Brevican is one of the most abundant extracellular matrix proteoglycans in the mammalian brain. We have previously shown that brevican produced by gray matter astrocytes constitutes a major component of perineuronal extracellular matrix in the adult brain. In this paper, we investigate the expression of brevican in the postnatal hippocampal fimbria to explore the role of the proteoglycan in central nervous system fiber tract development. We demonstrate that brevican is expressed by both oligodendrocytes and white matter astrocytes in the fimbria, but the expression of brevican in these two glial cell types is differently regulated during development. At P14, brevican immunoreactivity was observed throughout the fimbria, with particularly strong immunoreactivity in the developing interfascicular glial rows. In situ hybridization showed that oligodendrocytes in the glial rows strongly express brevican during the second and third postnatal weeks. Expression in oligodendrocytes was then down-regulated after P21. In the adult fimbria, no brevican expression was observed in oligodendrocytes. The time window of brevican expression coincides with the phase in which immature oligodendrocytes actively extend membrane processes and enwrap axon fibers. In contrast, the expression in astrocytes started around P21 as oligodendrocytes began to down-regulate the expression. In the adult fimbria, brevican expression was restricted to astrocytes. In situ hybridization with isoform-specific probes and RNase protection assays showed that the authentic, secreted form of brevican, not the glycosylphosphatidylinositol-anchored variant, is the predominant species expressed in the developing fimbria. Our results suggest that brevican plays a dual role in developing and adult fiber tracts.


Liver cancer arterial perfusion modelling and CFD boundary conditions methodology: a case study of the haemodynamics of a patient-specific hepatic artery in literature-based healthy and tumour-bearing liver scenarios.
Some of the latest treatments for unresectable liver malignancies (primary or metastatic tumours), which include bland embolisation, chemoembolisation, and radioembolisation, among others, take advantage of the increased arterial blood supply to the tumours to locally attack them. A better understanding of the factors that influence this transport may help improve the therapeutic procedures by taking advantage of flow patterns or by designing catheters and infusion systems that result in the injected beads having increased access to the tumour vasculature. Computational analyses may help understand the haemodynamic patterns and embolic-microsphere transport through the hepatic arteries. In addition, physiological inflow and outflow boundary conditions are essential in order to reliably represent the blood flow through arteries. This study presents a liver cancer arterial perfusion model based on a literature review and derives boundary conditions for tumour-bearing liver-feeding hepatic arteries based on the arterial perfusion characteristics of normal and tumorous liver segment tissue masses and the hepatic artery branching configuration. Literature-based healthy and tumour-bearing realistic scenarios are created and haemodynamically analysed for the same patient-specific hepatic artery. As a result, this study provides boundary conditions for computational fluid dynamics simulations that will allow researchers to numerically study, for example, various intravascular devices used for liver disease intra-arterial treatments with different cancer scenarios. Copyright © 2016 John Wiley & Sons, Ltd.