Ophthalmoplegic migraine with isolated third cranial nerve palsy in a known case of juvenile myoclonic epilepsy.
Among the various forms of migraine headaches, ophthalmoplegic migraine is an uncommon and rare form, the incidence of which is approximately 0.7 per million. It presents predominantly with headache and ophthalmoplegia. One of more cranial nerves can be affected, however the third cranial nerve is most often affected. As a result, symptoms wise, mydriasis and ptosis are commonly seen. Patients generally recover completely within a few days or weeks, however residual deficits are known to occur in a minority of patients. One of the common generalised epilepsy syndromes is the juvenile myoclonic epilepsy (JME), its prevalence being roughly up to 10% of all patients with epilepsy. It usually begins in the second decade of life. Generalised tonic-clonic seizures myoclonic jerks absences constitute the main seizure types in JME. Studies indicate a definite association of epilepsy with migraine headaches and a significant number of migraneurs are found to be epileptic. Conversely, patients with epilepsy are two times more likely to have migraine, as compared to their first degree relatives without migraine. We report a known case of a female patient of JME having a history of classical migraine with aura presenting to us with headache and ophthalmoplegia. She was extensively evaluated to rule out other causes of isolated third cranial nerve palsy, with all the investigations being negative for any obvious cause. She was treated with non-steroidal anti-inflammatory drugs for the acute attack and was subsequently put on antimigraine medication, propranolol during her hospital stay, with which her ptosis recovered completely after 2 weeks. The patient was later started on tablet divalproex sodium, which the patient continues to take on a long-term basis, especially because of its efficacy as an antimigraine prophylaxis agent and a potent drug against JME.


Role of the hydrogen bond lifetimes and rotations at the water/amorphous silica interface on proton transport.
Using a highly robust and reactive all-atom potential, molecular dynamics computer simulations have been used to provide detailed analysis of the behavior of water and protons at a large-scale amorphous silica surface that offers the heterogeneity of surface sites and water/silica interactions. Structural data of the H-O distances as a function of distance from the glass surface showed variation in hydrogen bond (H-bond) lengths to second and third nearest oxygen neighbors that play an important role in H-bond lifetimes, rotations, and proton transfer, especially at the glass surface. The higher density and inherently closer average spacing between oxygens in the glass surface (2.6 Å) in comparison to that in water (2.8 Å) create a significantly different environment for H-bond lifetimes and proton transfers. Continuous H-bond lifetime autocorrelation functions for water H-bonded to the surface are considerably shorter than those of bulk water, whereas the intermittent lifetime autocorrelation functions are longer. Such results affect proton transfers that are over an order of magnitude higher at the surface than farther from the surface or in bulk water. However, most of these transfers are rattling events between the participating oxygens, one of which is the newly formed H3O+ ion adjacent to the interface. Such a H3O+ ion has an extremely low barrier to proton transfer back to the surface site in comparison to a H3O+ ion in bulk water. Nonetheless, the simulations showed that rotation of the H3O+ ion away from the initial transfer site allowed for structural diffusion of an excess proton away from the surface. Proton conduction from such rotations could be enhanced by external forces.


Targeted temperature management at 33°C versus 36°C after cardiac arrest.
Unconscious survivors of out-of-hospital cardiac arrest have a high risk of death or poor neurologic function. Therapeutic hypothermia is recommended by international guidelines, but the supporting evidence is limited, and the target temperature associated with the best outcome is unknown. Our objective was to compare two target temperatures, both intended to prevent fever. In an international trial, we randomly assigned 950 unconscious adults after out-of-hospital cardiac arrest of presumed cardiac cause to targeted temperature management at either 33°C or 36°C. The primary outcome was all-cause mortality through the end of the trial. Secondary outcomes included a composite of poor neurologic function or death at 180 days, as evaluated with the Cerebral Performance Category (CPC) scale and the modified Rankin scale. In total, 939 patients were included in the primary analysis. At the end of the trial, 50% of the patients in the 33°C group (235 of 473 patients) had died, as compared with 48% of the patients in the 36°C group (225 of 466 patients) (hazard ratio with a temperature of 33°C, 1.06; 95% confidence interval [CI], 0.89 to 1.28; P=0.51). At the 180-day follow-up, 54% of the patients in the 33°C group had died or had poor neurologic function according to the CPC, as compared with 52% of patients in the 36°C group (risk ratio, 1.02; 95% CI, 0.88 to 1.16; P=0.78). In the analysis using the modified Rankin scale, the comparable rate was 52% in both groups (risk ratio, 1.01; 95% CI, 0.89 to 1.14; P=0.87). The results of analyses adjusted for known prognostic factors were similar. In unconscious survivors of out-of-hospital cardiac arrest of presumed cardiac cause, hypothermia at a targeted temperature of 33°C did not confer a benefit as compared with a targeted temperature of 36°C. (Funded by the Swedish Heart-Lung Foundation and others; TTM ClinicalTrials.gov number, NCT01020916.).


Desmosines in human urine. Amounts in early development and in Marfan's syndrome.
Desmosines from 24 h human urine samples were isolated, characterized and quantified. The desmosines are in peptidyl form (1000--1500 molecular weight), and their amount is decreased by two-thirds between 7 and 25 years of age. Patients with Marfan's syndrome have significantly lower urinary amounts of desmosines than do comparable controls during the early development period.


The role of social context in shaping student-athlete opinions.
How do student-athletes form opinions? This is a particularly important question given ongoing debates about whether student-athletes should be paid and/or allowed to unionize. These debates concern the rights and benefits accrued directly to student-athletes, and thus, understanding their attitudes is of obvious import. Yet, virtually no recent work has delved into how student-athletes form opinions on these issues. We fill this gap with a theoretical framework that predicts changes in social context alter opinions. This leads to the hypothesis that opinions will change once a student-athlete completes his/her career and finds him/herself in a distinct social network. We test the prediction with a survey, implemented in 2012, of one of the most notable athletic conferences in the National Collegiate Athletic Association (NCAA): the Big Ten. We find that post-career student-athletes demonstrate higher levels of support for pay for play and unionization. Our results suggest that student-athletes' opinions seem to depend on their extant social contexts. While our data, from 2012, neither speak to current opinions - given the quickly evolving landscape of college athletics - nor demonstrate what reforms may be "best," they do accentuate the power of social context in shaping student-athletes' attitudes.


An image based vibration sensor for soft tissue modal analysis in a Digital Image Elasto Tomography (DIET) system.
Digital Image Elasto Tomography (DIET) is a non-invasive elastographic breast cancer screening technology, based on image-based measurement of surface vibrations induced on a breast by mechanical actuation. Knowledge of frequency response characteristics of a breast prior to imaging is critical to maximize the imaging signal and diagnostic capability of the system. A feasibility analysis for a non-invasive image based modal analysis system is presented that is able to robustly and rapidly identify resonant frequencies in soft tissue. Three images per oscillation cycle are enough to capture the behavior at a given frequency. Thus, a sweep over critical frequency ranges can be performed prior to imaging to determine critical imaging settings of the DIET system to optimize its tumor detection performance.


An anthropomorphic soft skeleton hand exploiting conditional models for piano playing.
The development of robotic manipulators and hands that show dexterity, adaptability, and subtle behavior comparable to human hands is an unsolved research challenge. In this article, we considered the passive dynamics of mechanically complex systems, such as a skeleton hand, as an approach to improving adaptability, dexterity, and richness of behavioral diversity of such robotic manipulators. With the use of state-of-the-art multimaterial three-dimensional printing technologies, it is possible to design and construct complex passive structures, namely, a complex anthropomorphic skeleton hand that shows anisotropic mechanical stiffness. We introduce a concept, termed the "conditional model," that exploits the anisotropic stiffness of complex soft-rigid hybrid systems. In this approach, the physical configuration, environment conditions, and conditional actuation (applied actuation) resulted in an observable conditional model, allowing joint actuation through passivity-based dynamic interactions. The conditional model approach allowed the physical configuration and actuation to be altered, enabling a single skeleton hand to perform three different phrases of piano music with varying styles and forms and facilitating improved dynamic behaviors and interactions with the piano over those achievable with a rigid end effector.


PLA2G1B is involved in CD4 anergy and CD4 lymphopenia in HIV-infected patients.
The precise mechanism leading to profound immunodeficiency of HIV-infected patients is still only partially understood. Here, we show that more than 80% of CD4+ T cells from HIV-infected patients have morphological abnormalities. Their membranes exhibited numerous large abnormal membrane microdomains (aMMDs), which trap and inactivate physiological receptors, such as that for IL-7. In patient plasma, we identified phospholipase A2 group IB (PLA2G1B) as the key molecule responsible for the formation of aMMDs. At physiological concentrations, PLA2G1B synergized with the HIV gp41 envelope protein, which appears to be a driver that targets PLA2G1B to the CD4+ T cell surface. The PLA2G1B/gp41 pair induced CD4+ T cell unresponsiveness (anergy). At high concentrations in vitro, PLA2G1B acted alone, independently of gp41, and inhibited the IL-2, IL-4, and IL-7 responses, as well as TCR-mediated activation and proliferation, of CD4+ T cells. PLA2G1B also decreased CD4+ T cell survival in vitro, likely playing a role in CD4 lymphopenia in conjunction with its induced IL-7 receptor defects. The effects on CD4+ T cell anergy could be blocked by a PLA2G1B-specific neutralizing mAb in vitro and in vivo. The PLA2G1B/gp41 pair constitutes what we believe is a new mechanism of immune dysfunction and a compelling target for boosting immune responses in HIV-infected patients.


Interpreting patient-reported outcome results: US FDA guidance and emerging methods.
In recent years, the US FDA has become more critical of instruments used to measure patient-reported outcomes (PROs) in clinical trials. To facilitate decisions related to the approval of drugs, labels and promotional claims based on PROs, the FDA created the Study Endpoints and Label Development (SEALD) group. SEALD has developed a PRO guidance related to the use of PRO measures used to support drug approvals and label claims, including recommendations for establishing thresholds for meaningful change at the individual level (i.e., defining a responder). This article examines in detail the FDA-recommended methodology for defining a responder and analyzing responder-based PRO measure results. We also present other responder analysis approaches for consideration in furthering the precision and interpretation of this methodology.


SECRET domain of variola virus CrmB protein can be a member of poxviral type II chemokine-binding proteins family.
Variola virus (VARV) the causative agent of smallpox, eradicated in 1980, have wide spectrum of immunomodulatory proteins to evade host immunity. Recently additional biological activity was discovered for VARV CrmB protein, known to bind and inhibit tumour necrosis factor (TNF) through its N-terminal domain homologous to cellular TNF receptors. Besides binding TNF, this protein was also shown to bind with high affinity several chemokines which recruit B- and T-lymphocytes and dendritic cells to sites of viral entry and replication. Ability to bind chemokines was shown to be associated with unique C-terminal domain of CrmB protein. This domain named SECRET (Smallpox virus-Encoded Chemokine Receptor) is unrelated to the host proteins and lacks significant homology with other known viral chemokine-binding proteins or any other known protein. De novo modelling of VARV-CrmB SECRET domain spatial structure revealed its apparent structural homology with cowpox virus CC-chemokine binding protein (vCCI) and vaccinia virus A41 protein, despite low sequence identity between these three proteins. Potential ligand-binding surface of modelled VARV-CrmB SECRET domain was also predicted to bear prominent electronegative charge which is characteristic to known orthopoxviral chemokine-binding proteins. Our results suggest that SECRET should be included into the family of poxviral type II chemokine-binding proteins and that it might have been evolved from the vCCI-like predecessor protein.


Non-uniform dwell times in line source high dose rate brachytherapy: physical and radiobiological considerations.
The ability to vary source dwell times in high dose rate (HDR) brachytherapy allows for the use of non-uniform dwell times along a line source. This may have advantages in the radical treatment of tumours depending on individual tumour geometry. This study investigates the potential improvements in local tumour control relative to adjacent normal tissue isoeffects when intratumour source dwell times are increased along the central portion of a line source (technique A) in radiotherapy schedules which include a relatively small component of HDR brachytherapy. Such a technique is predicted to increase the local control for tumours of diameters ranging between 2 cm and 4 cm by up to 11% compared with a technique in which there are uniform dwell times along the line source (technique B). There is no difference in the local control rates for the two techniques when used to treat smaller tumours. Normal tissue doses are also modified by the technique used. Technique A produces higher normal tissue doses at points perpendicular to the centre of the line source and lower doses at points nearer the ends of the line source if the prescription point is not in the central plane of the line source. Alternatively, if the dose is prescribed at a point in the central plane of the line source, the dose at all the normal tissue points are lower when technique A is used.


Identification of a functionally critical GXXG motif and its relationship to the folate binding site of the proton-coupled folate transporter (PCFT-SLC46A1).
The proton-coupled folate transporter (PCFT) mediates intestinal folate absorption, and loss-of-function mutations in this gene result in the autosomal recessive disorder hereditary folate malabsorption. The current study, focused on a structure-functional analysis of this transporter, identified Gly-189 and Gly-192 (a GxxG motif) located in the fifth transmembrane domain as residues that could not be replaced with alanine without a loss of function. In contrast, function was preserved when Gly-56 and Gly-59 (the other conservative GXXG motif in human PCFT) were replaced with alanine. Similarly, Gly-93 and Gly-97, which constitute the only conserved GXXXG dimerization motif in human PCFT, tolerated alanine substitution. To explore the role of this region in folate binding, the residues around Gly-189 and Gly-192 were analyzed by the substituted cysteine accessibility method. Both I188C and M193C mutants were functional and were inhibited by membrane-impermeable sulfhydryl-reactive reagents; this could be prevented with PCFT substrate, but the protection was sustained at 0°C only for the I188C mutant, consistent with localization of Ile-188 in the PCFT folate binding pocket. The functional role of residues around Gly-189 and Gly-192 is consistent with a molecular structural model in which these two residues along with Ieu-188 are accessible to the PCFT aqueous translocation pathway.


Effects of imatinib mesylate on renin-angiotensin system (RAS) activity during the clinical course of chronic myeloid leukaemia.
The renin-angiotensin system (RAS) is involved in cell growth, proliferation and differentiation in bone marrow in an autocrine-paracrine manner, and it modulates normal and neoplastic haematopoietic cell proliferation. This study aimed to assess expressions of the RAS components, renin, angiotensinogen and angiotensin-converting enzyme (ACE), during imatinib mesylate treatment of patients with chronic myeloid leukaemia (CML). Expressions of RAS components were studied in patients with CML at the time of diagnosis (n = 83) and at 3, 6 and 12 months after diagnosis (n = 35) by quantitative real-time polymerase chain reaction. De novo CML patients had increased ACE, angiotensinogen and renin mRNA levels and these expression levels decreased following administration of imatinib. The RAS activities were significantly different among Sokal risk groups of CML, highlighting the altered biological activity of RAS in neoplastic disorders. The results of this study confirm that haematopoietic RAS affects neoplastic cell production, which may be altered via administration of tyrosine kinase inhibitors such as imatinib mesylate.


Whole genome scanning identifies genotypes associated with recurrence and metastasis in prostate tumors.
Prostate cancer is the most commonly diagnosed non-cutaneous neoplasm among American males and is the second leading cause of cancer-related death. Prostate specific antigen screening has resulted in earlier disease detection, yet approximately 30% of men will die of metastatic disease. Slow disease progression, an aging population and associated morbidity and mortality underscore the need for improved disease classification and therapies. To address these issues, we analyzed a cohort of patients using array comparative genomic hybridization (aCGH). The cohort comprises 64 patients, half of whom recurred postoperatively. Analysis of the aCGH profiles revealed numerous recurrent genomic copy number aberrations. Specific loss at 8p23.2 was associated with advanced stage disease, and gain at 11q13.1 was found to be predictive of postoperative recurrence independent of stage and grade. Moreover, comparison with an independent set of metastases revealed approximately 40 candidate markers associated with metastatic potential. Copy number aberrations at these loci may define metastatic genotypes.


Stereodivergent hydrodefluorination of gem-difluoroalkenes: selective synthesis of (Z)- and (E)-monofluoroalkenes.
We have developed a novel approach for the stereodivergent hydrodefluorination of gem-difluoroalkenes using copper(i) catalysts to obtain stereodefined monofluoroalkenes. Both (Z)- and (E)-terminal monofluoroalkenes were obtained by the hydrodefluorination of gem-difluoroalkenes in the presence of copper(i) catalysts and diboron or hydrosilane, respectively, with high stereoselectivity. DFT calculations were conducted to elucidate the stereoselectivity.


Electrophysiological Correlates of Racial In-group Bias in Observing Nonverbal Social Encounters.
Despite evidence identifying the role of group membership in social cognition, the neural mechanisms associated with the perception and evaluation of nonverbal behaviors displayed by in-group versus out-group members remain unclear. Here, 42 white participants underwent electroencephalographic recording while observing social encounters involving dynamic displays of nonverbal behaviors by racial in-group and out-group avatar characters. Dynamic behaviors included approach and avoidance poses and expressions, followed by the participants' ratings of the avatars displaying them. Behaviorally, participants showed longer RTs when evaluating in-group approach behavior compared with other behaviors, possibly suggesting increased interest and attention devoted to processing positive social encounters with their in-group members. Analyses of ERPs revealed differential sensitivity of the N450 and late positivity components to social cues, with the former showing initial sensitivity to the presence of a humanoid avatar character at the beginning of social encounters and the latter showing sensitivity to dynamic nonverbal behaviors displayed by the avatars. Moreover, time-frequency analysis of electroencephalography data also identified suppression of beta-range power linked to the observation of dynamic nonverbal behaviors. Notably, the magnitude of these responses was modulated by the degree of behavioral racial in-group bias. This suggests that differential neural sensitivity to nonverbal cues while observing social encounters is associated with subsequent in-group bias manifested in the evaluation of such encounters. Collectively, these findings shed light on the mechanisms of racial in-group bias in social cognition and have implications for understanding factors related to successful interactions with individuals from diverse racial backgrounds.


Turning body and self inside out: visualized heartbeats alter bodily self-consciousness and tactile perception.
Prominent theories highlight the importance of bodily perception for self-consciousness, but it is currently not known whether bodily perception is based on interoceptive or exteroceptive signals or on integrated signals from these anatomically distinct systems. In the research reported here, we combined both types of signals by surreptitiously providing participants with visual exteroceptive information about their heartbeat: A real-time video image of a periodically illuminated silhouette outlined participants' (projected, "virtual") bodies and flashed in synchrony with their heartbeats. We investigated whether these "cardio-visual" signals could modulate bodily self-consciousness and tactile perception. We report two main findings. First, synchronous cardio-visual signals increased self-identification with and self-location toward the virtual body, and second, they altered the perception of tactile stimuli applied to participants' backs so that touch was mislocalized toward the virtual body. We argue that the integration of signals from the inside and the outside of the human body is a fundamental neurobiological process underlying self-consciousness.


Safety of vaccines used for routine immunization of U.S. children: a systematic review.
Concerns about vaccine safety have led some parents to decline recommended vaccination of their children, leading to the resurgence of diseases. Reassurance of vaccine safety remains critical for population health. This study systematically reviewed the literature on the safety of routine vaccines recommended for children in the United States. Data sources included PubMed, Advisory Committee on Immunization Practices statements, package inserts, existing reviews, manufacturer information packets, and the 2011 Institute of Medicine consensus report on vaccine safety. We augmented the Institute of Medicine report with more recent studies and increased the scope to include more vaccines. Only studies that used active surveillance and had a control mechanism were included. Formulations not used in the United States were excluded. Adverse events and patient and vaccine characteristics were abstracted. Adverse event collection and reporting was evaluated by using the McHarm scale. We were unable to pool results. Strength of evidence was rated as high, moderate, low, or insufficient. Of 20 478 titles identified, 67 were included. Strength of evidence was high for measles/mumps/rubella (MMR) vaccine and febrile seizures; the varicella vaccine was associated with complications in immunodeficient individuals. There is strong evidence that MMR vaccine is not associated with autism. There is moderate evidence that rotavirus vaccines are associated with intussusception. Limitations of the study include that the majority of studies did not investigate or identify risk factors for AEs; and the severity of AEs was inconsistently reported. We found evidence that some vaccines are associated with serious AEs; however, these events are extremely rare and must be weighed against the protective benefits that vaccines provide.


Modulation of Litter Decomposition by the Soil Microbial Food Web Under Influence of Land Use Change.
Soil microbial communities modulate soil organic matter (SOM) dynamics by catalyzing litter decomposition. However, our understanding of how litter-derived carbon (C) flows through the microbial portion of the soil food web is far from comprehensive. This information is necessary to facilitate reliable predictions of soil C cycling and sequestration in response to a changing environment such as land use change in the form of agricultural abandonment. To examine the flow of litter-derived C through the soil microbial food web and it's response to land use change, we carried out an incubation experiment with soils from six fields; three recently abandoned and three long term abandoned fields. In these soils, the fate of 13C-labeled plant litter was followed by analyzing phospholipid fatty acids (PLFA) over a period of 56 days. The litter-amended soils were sampled over time to measure 13CO2 and mineral N dynamics. Microbial 13C-incorporation patterns revealed a clear succession of microbial groups during litter decomposition. Fungi were first to incorporate 13C-label, followed by G- bacteria, G+ bacteria, actinomycetes and micro-fauna. The order in which various microbial groups responded to litter decomposition was similar across all the fields examined, with no clear distinction between recent and long-term abandoned soils. Although the microbial biomass was initially higher in long-term abandoned soils, the net amount of 13C-labeled litter that was incorporated by the soil microbial community was ultimately comparable between recent and long-term abandoned fields. In relative terms, this means there was a higher efficiency of litter-derived 13C-incorporation in recent abandoned soil microbial communities compared to long-term abandoned soils, most likely due to a net shift from SOM-derived C toward root-derived C input in the soil microbial food web following land-abandonment.


Improved vaccine protection against retrovirus infection after co-administration of adenoviral vectors encoding viral antigens and type I interferon subtypes.
Type I interferons (IFNs) exhibit direct antiviral effects, but also distinct immunomodulatory properties. In this study, we analyzed type I IFN subtypes for their effect on prophylactic adenovirus-based anti-retroviral vaccination of mice against Friend retrovirus (FV) or HIV. Mice were vaccinated with adenoviral vectors encoding FV Env and Gag proteins alone or in combination with vectors encoding IFNα1, IFNα2, IFNα4, IFNα5, IFNα6, IFNα9 or IFNβ. Only the co-administration of adenoviral vectors encoding IFNα2, IFNα4, IFNα6 and IFNα9 resulted in strongly improved immune protection of vaccinated mice from subsequent FV challenge infection with high control over FV-induced splenomegaly and reduced viral loads. The level of protection correlated with augmented virus-specific CD4(+) T cell responses and enhanced antibody titers. Similar results were obtained when mice were vaccinated against HIV with adenoviral vectors encoding HIV Env and Gag-Pol in combination with various type I IFN encoding vectors. Here mainly CD4(+) T cell responses were enhanced by IFNα subtypes. Our results indicate that certain IFNα subtypes have the potential to improve the protective effect of adenovirus-based vaccines against retroviruses. This correlated with augmented virus-specific CD4(+) T cell and antibody responses. Thus, co-expression of select type I IFNs may be a valuable tool for the development of anti-retroviral vaccines.


Auditory time thresholds in the range of milliseconds but not seconds are impaired in ADHD.
The literature on time perception in individuals with ADHD is extensive but inconsistent, probably reflecting the use of different tasks and performances indexes. A sample of 40 children/adolescents (20 with ADHD, 20 neurotypical) was engaged in two identical psychophysical tasks measuring auditory time thresholds in the milliseconds (0.25-1 s) and seconds (0.75-3 s) ranges. Results showed a severe impairment in ADHD for milliseconds thresholds (Log10BF = 1.9). The deficit remained strong even when non-verbal IQ was regressed out and correlation with age suggests a developmental delay. In the seconds range, thresholds were indistinguishable between the two groups (Log10BF = - 0.5) and not correlated with milliseconds thresholds. Our results largely confirm previous evidence suggesting partially separate mechanisms for time perception in the ranges of milliseconds and seconds. Moreover, since the evidence suggests that time perception of milliseconds stimuli might load relatively less on cognitive control and working memory, compared to longer durations, the current results are consistent with a pure timing deficit in individuals with ADHD.


Nutritional state reveals complex consequences of risk in a wild predator-prey community.
Animal populations are regulated by the combined effects of top-down, bottom-up and abiotic processes. Ecologists have struggled to isolate these mechanisms because their effects on prey behaviour, nutrition, security and fitness are often interrelated. We monitored how forage, non-consumptive effects (NCEs), consumptive predation and climatic conditions influenced the demography and nutritional state of a wild prey population during predator recolonization. Combined measures of nutrition, survival and population growth reveal that predators imposed strong effects on the prey population through interacting non-consumptive and consumptive effects, and forage mechanisms. Predation was directly responsible for adult survival, while declining recruitment was attributed to predation risk-sensitive foraging, manifested in poor female nutrition and juvenile recruitment. Substituting nutritional state into the recruitment model through a shared term reveals that predation risk-sensitive foraging was nearly twice as influential as summer forage conditions. Our findings provide a novel, mechanistic insight into the complex means by which predators and forage conditions affect prey populations, and point to a need for more ecological studies that integrate behaviour, nutrition and demography. This line of inquiry can provide further insight into how NCEs interactively contribute to the dynamics of terrestrial prey populations; particularly, how predation risk-sensitive foraging has the potential to stabilize predator-prey coexistence.


Genome-wide pathway analysis for diabetic nephropathy in type 1 diabetes.
The aim of this study was to identify candidate single-nucleotide polymorphisms (SNPs) that might play a role in susceptibility to diabetic nephropathy (DN) in type 1 diabetes, elucidate their potential mechanisms, and generate SNP-to-gene-to-pathway hypotheses. A genome-wide association study (GWAS) dataset of DN in type 1 diabetes, which included 345,363 SNPs from a total of 1,705 samples (820 DN cases and 885 normoalbuminuric controls) of European ancestry, was used in this study. The Identify Candidate Causal SNPs and Pathways (ICSNPathway) analysis was applied to the GWAS dataset. ICSNPathway analysis identified 14 candidate SNPs, 10 genes, and 19 pathways, which in turn revealed 10 hypothetical biological mechanisms. The strongest hypothetical biological mechanism was one in which rs4740 altered the role of EBI3 in various pathways and processes, including regulation of the cytokine biosynthetic process, cytokine metabolic process, positive regulation of the cytokine biosynthetic process, regulation of the interferon gamma biosynthetic process, and interferon gamma production (0.008 ≤ p < 0.001; 0.047 ≤ false discovery rate [FDR] ≤ 0.002). This next most strongly supported hypothesis was the modulation of NMUR2 by rs982715, rs4958531, 4958532, rs1895245, and rs4958535 to affect its role in various pathways and processes, including calcium-mediated signaling and peptide receptor activity, and G-protein activity (p < 0.001, 0.002; FDR = 0.005, 0.049, respectively). By using the ICSNPathway to analyze the DN GWAS data, we identified 14 candidate SNPs, 10 genes (including EBI3, NMUR2, and EFNA1), and 19 pathways that likely contribute to the susceptibility to DN in type 1 diabetes.


Professional Ethical Competence in nursing: the role of nursing instructors.
Teaching ethics to nurses leads to their involvement in providing high quality care, enable them to duly encounter ethical issues. One of the key elements of educational systems is nursing instructors. Even though lots of studies show the role of instructors in students' learning, their role in promotion of professional ethics has been attended to less. The objective of this study is surveying the experience of nursing students with respect to the role of instructors in promotion of professional ethics. This qualitative study enrolled 15 undergraduate nursing students from three nursing schools in Teheran whom depth interview was performed. The interview was semi-structured with open ended questions. The analysis was accomplished by use of qualitative content-analysis method. Data analysis demonstrated 2 main themes and 7 subcategories in regard to the role of instructors in promotion of professional ethics in nursing students including: 1) the effective professional role model 2) facilitating creative learning. The effective professional role model encompasses individual characteristics and beliefs, clinical skills and professional commitment of role model. Creative learning facilitates by encouraging critical thinking and decision-making, Providing supportive learning conditions, providing proper space for sharing knowledge followed by evaluation and creative feedback. The findings of this study provides a background for strengthening the role of instructors in promotion of professional ethics with more emphasis on research which increase capability of instructors at nursing education centers.


Trends in Taxonomic and Functional Composition of Soil Microbiome Along a Precipitation Gradient in Israel.
The soil microbiome is important for the functioning of terrestrial ecosystems. However, the impacts of climate on taxonomic and functional diversity of soil microbiome are not well understood. A precipitation gradient along regional scale transects may offer a model setting for understanding the effect of climate on the composition and function of the soil microbiome. Here, we compared taxonomic and functional attributes of soil microorganisms in arid, semiarid, Mediterranean, and humid Mediterranean climatic conditions of Israel using shotgun metagenomic sequencing. We hypothesized that there would be a distinct taxonomic and functional soil community for each precipitation zone, with arid environments having lower taxonomic and functional diversity, greater relative abundance of stress response and sporulation-related genes, and lower relative abundance of genes related to nutrient cycling and degradation of complex organic compounds. As hypothesized, our results showed a distinct taxonomic and functional community in each precipitation zone, revealing differences in soil taxonomic and functional selection in the different climates. Although the taxonomic diversity remained similar across all sites, the functional diversity was-as hypothesized-lower in the arid environments, suggesting that functionality is more constrained in "extreme" environments. Also, with increasing aridity, we found a significant increase in genes related to dormancy/sporulation and a decrease in those related to nutrient cycling (genes related to nitrogen, potassium, and sulfur metabolism), respectively. However, relative abundance of genes related to stress response were lower in arid soils. Overall, these results indicate that climatic conditions play an important role in shaping taxonomic and functional attributes of soil microbiome. These findings have important implications for understanding the impacts of climate change (e.g., precipitation change) on structure and function of the soil microbiome.


Importance of sequence specific hydrophobicity in synthetic protein transduction domain mimics.
A new series of synthetic protein transduction domain mimics (PTDMs) was designed to analyze the importance of guanidine and phenyl group segregation along the backbone on their membrane interaction and cellular internalization abilities. ROMP was utilized to synthesize three polymers: nonsegregated homopolymers, intermediately segregated gradient copolymers, and strongly segregated block copolymers. In order to understand the role of functional group segregation on activity, it was important to design monomers that enabled these three different polymer topologies, or constitutional macromolecular isomers, to be prepared with identical chemical compositions. The structure-activity relationships were evaluated by both a biophysical assay, using dye-loaded vesicles, and by in vitro cellular uptake studies of fluorescently labeled chains. The results showed that functional group segregation impacts activity. In general, the nonsegregated homopolymer was the most active in both assays but also showed larger, ill-defined aggregates compared to either the gradient or block copolymers. It was also the most cytotoxic of the three isomers. As a result, the gradient copolymer with intermediate segregation optimizes activity and solubility with low cytotoxicity. This study gives new design guidelines for the development of PTDMs.


The advantages of linear information processing for cerebellar computation.
Purkinje cells can encode the strength of parallel fiber inputs in their firing by using 2 fundamentally different mechanisms, either as pauses or as linear increases in firing rate. It is not clear which of these 2 encoding mechanisms is used by the cerebellum. We used the pattern-recognition capacity of Purkinje cells based on the Marr-Albus-Ito theory of cerebellar learning to evaluate the suitability of the linear algorithm for cerebellar information processing. Here, we demonstrate the simplicity and versatility of pattern recognition in Purkinje cells linearly encoding the strength of parallel fiber inputs in their firing rate. In contrast to encoding patterns with pauses, Purkinje cells using the linear algorithm could recognize a large number of both synchronous and asynchronous input patterns in the presence or absence of inhibitory synaptic transmission. Under all conditions, the number of patterns recognized by Purkinje cells using the linear algorithm was greater than that achieved by encoding information in pauses. Linear encoding of information also allows neurons of deep cerebellar nuclei to use a simple averaging mechanism to significantly increase the computational capacity of the cerebellum. We propose that the virtues of the linear encoding mechanism make it well suited for cerebellar computation.


[Concentrations of interleukin-2 in the nasopharyngeal secretion of children with acute respiratory syncytial virus bronchiolitis].
To assess interleukin-2 concentrations in nasopharyngeal secretion of children (0-24 months) with acute respiratory syncytial virus bronchiolitis, within the first 12 hours of hospital admission, and compare the levels of IL-2 with the severity of the illness. Prospective study performed between June and August 1999. The study included 62 patients, previously healthy, hospitalized with acute viral bronchiolitis characterized by recent prodromes of coryza and/or nasal obstruction, which evolved to at least two of the following signs: respiratory dysfunction, tachypnea, wheezing or rales, and detection of respiratory syncytial virus in nasopharyngeal aspirate. The nasopharyngeal specimens were collected within 12 hours of hospital admission. The interleukin-2 levels were obtained by enzyme immunoassay. Severity of illness was assessed through oxygen saturation by pulse oximetry, Modified Clinical Score System, time of supplemental oxygen required, length of hospital stay, and mechanical ventilation. Spearman's correlation and Kruskal-Wallis test were used to compared these variables in relation to the median of interleukin-2. The chi-square test was used for categorical analysis of interleukin-2. The mean age of patients was 2.2 (1.3-4) months. Males comprised 54% of cases. Hemoglobin oxygen saturation by pulse oximetry at hospital admission was below 95% in 66.1% of patients. The mean time of supplemental oxygen use was 4.7 days (+/-3.54). The mean length of hospital stay was 4.25 days (+/-1.76). Mechanical ventilation was used in 4.8% of patients. The values of interleukin-2 in nasopharyngeal aspirates varied from 0 to 40,256 ng/ml with median of 86 ng/ml (4.4 - 457.3). The study showed no statistical difference between levels of IL-2 and severity of illness. The interleukin-2 levels showed a heterogeneous behavior. We found no association between interleukin-2 levels in nasopharyngeal secretion and respiratory syncytial virus bronchiolitis.


Anesthetic considerations in organ procurement surgery: a narrative review.
While a few publications specify the anesthetic implications of either brain or cardiac death, they lack detail on how to provide anesthesia during organ donation surgery. We provide a thorough description of important anesthetic considerations during organ donation surgery in patients with either brain or cardiac death. A thorough literature review was undertaken to locate all relevant articles that describe systemic effects of brain and cardiac death and their anesthetic implications. We searched PubMed, Pubget, and EMBASE™ for relevant articles using the following search terms: anesthesia, management, donation cardiac death, donation brain death. In addition, we reviewed the relevant protocols at our own institution. Highly specific intraoperative management by an anesthesiologist is required during organ procurement after brain death. To manage the heart-beating brain-dead donor, the anesthesiologist must incorporate knowledge of the effects of brain death on each organ system as well as the effects of the preoperative measures that the donor required in the intensive care unit. It is also important to know which organs are going to be procured in order to establish specific goals and implement strategies (e.g., lung-protective ventilation or intraoperative glycemic control) to optimize donor outcome. During organ procurement after cardiac death, an anesthesiologist's direct involvement is particularly important for lung donors. Anesthesiologist-guided physiological optimization of the brain-dead donor may be a factor in determining the outcome of the organ recipient. Additionally, anesthesiologists have an important role in helping to ensure that the highest quality and most appropriate care are rendered to non-heart-beating donors. This is achieved through establishing protocols in their hospitals for donation after cardiac death that maximize the number of available organs with the best chance for long-term graft viability.


Traditional/restrictive vs patient-centered intensive care unit visitation: perceptions of patients' family members, physicians, and nurses.
Patient-centered intensive care units (ICUs) are advocated by professional organizations for critical care nursing and medicine. The patient-centered ICU paradigm recognizes the patient-family unit as inseparable and supports visitation designed to meet the needs of patients and patients' families. To understand perceptions about patient-centered ICUs among patients' family members, physicians, and nurses from 5 ICUs that had restrictive visitation and to guide development of a patient-centered, open visitation paradigm. Patients' family members, nurses, and physicians from 5 ICUs with a traditional/restrictive visitation policy at a southeastern academic, tertiary care hospital were invited to participate in focus group meetings to understand perceptions about patient-centered care. All qualitative work was taped, transcribed, reviewed, and corrected after each session. Corrected transcripts and observer notes were integrated and coded. Patients' families identified facilitators of patient-centeredness as nurses' and physicians' communication, concern, compassion, closeness, and flexibility. However, competing roles of control over the patient's health care served as barriers to a patient-centered paradigm. Patient-centered care is an expectation among patients, patients' families, and health quality advocates. These exploratory methods increased understanding of the powerful perceptions of family members, physicians, and nurses involved with patient care and provided direction to plan interventions to implement patient-centered, family-supportive ICU services.


A Hierarchical Distance Sampling Approach to Estimating Mortality Rates from Opportunistic Carcass Surveillance Data.
Distance sampling is widely used to estimate the abundance or density of wildlife populations. Methods to estimate wildlife mortality rates have developed largely independently from distance sampling, despite the conceptual similarities between estimation of cumulative mortality and the population density of living animals. Conventional distance sampling analyses rely on the assumption that animals are distributed uniformly with respect to transects and thus require randomized placement of transects during survey design. Because mortality events are rare, however, it is often not possible to obtain precise estimates in this way without infeasible levels of effort. A great deal of wildlife data, including mortality data, is available via road-based surveys. Interpreting these data in a distance sampling framework requires accounting for the non-uniformity sampling. Additionally, analyses of opportunistic mortality data must account for the decline in carcass detectability through time. We develop several extensions to distance sampling theory to address these problems.We build mortality estimators in a hierarchical framework that integrates animal movement data, surveillance effort data, and motion-sensor camera trap data, respectively, to relax the uniformity assumption, account for spatiotemporal variation in surveillance effort, and explicitly model carcass detection and disappearance as competing ongoing processes.Analysis of simulated data showed that our estimators were unbiased and that their confidence intervals had good coverage.We also illustrate our approach on opportunistic carcass surveillance data acquired in 2010 during an anthrax outbreak in the plains zebra of Etosha National Park, Namibia.The methods developed here will allow researchers and managers to infer mortality rates from opportunistic surveillance data.


Characterization of horizontal lipid bilayers as a model system to study lipid phase separation.
Artificial lipid membranes are widely used as a model system to study single ion channel activity using electrophysiological techniques. In this study, we characterize the properties of the artificial bilayer system with respect to its dynamics of lipid phase separation using single-molecule fluorescence fluctuation and electrophysiological techniques. We determined the rotational motions of fluorescently labeled lipids on the nanosecond timescale using confocal time-resolved anisotropy to probe the microscopic viscosity of the membrane. Simultaneously, long-range mobility was investigated by the lateral diffusion of the lipids using fluorescence correlation spectroscopy. Depending on the solvent used for membrane preparation, lateral diffusion coefficients in the range D(lat) = 10-25 mum(2)/s and rotational diffusion coefficients ranging from D(rot) = 2.8 - 1.4 x 10(7) s(-1) were measured in pure liquid-disordered (L(d)) membranes. In ternary mixtures containing saturated and unsaturated phospholipids and cholesterol, liquid-ordered (L(o)) domains segregated from the L(d) phase at 23 degrees C. The lateral mobility of lipids in L(o) domains was around eightfold lower compared to those in the L(d) phase, whereas the rotational mobility decreased by a factor of 1.5. Burst-integrated steady-state anisotropy histograms, as well as anisotropy imaging, were used to visualize the rotational mobility of lipid probes in phase-separated bilayers. These experiments and fluorescence correlation spectroscopy measurements at different focal diameters indicated a heterogeneous microenvironment in the L(o) phase. Finally, we demonstrate the potential of the optoelectro setup to study the influence of lipid domains on the electrophysiological properties of ion channels. We found that the electrophysiological activity of gramicidin A (gA), a well-characterized ion-channel-forming peptide, was related to lipid-domain partitioning. During liquid-liquid phase separation, gA was largely excluded from L(o) domains. Simultaneously, the number of electrically active gA dimers increased due to the increased surface density of gA in the L(d) phase.


Intrahepatic Size Regulation in a Surgical Model: Liver Resection-Induced Liver Regeneration Counteracts the Local Atrophy following Simultaneous Portal Vein Ligation.
Liver size regulation is based on the balance between hepatic regeneration and atrophy. To achieve a better understanding of intrahepatic size regulation, we explored the size regulation of a portally deprived liver lobe on a liver subjected to concurrent portal vein ligation (PVL) and partial hepatectomy (PHx). Using a surgical rat model consisting of right PVL (rPVL) plus 70% PHx, we evaluated the size regulation of liver lobes 1, 2, 3, and 7 days after the operation in terms of liver weight and hepatocyte proliferation. Portal hyperperfusion was confirmed by measuring portal flow. The portal vascular tree was visualized by injection of a contrast agent followed by CT imaging of explanted livers. Control groups consisted of 70% PHx, rPVL, and sham operation. The size of the ligated right lobe increased to 1.4-fold on postoperative day 7 when subjected to rPVL + 70% PHx. The right lobe increased to 3-fold when subjected to 70% PHx alone and decreased to 0.3-fold when subjected to rPVL only. The small but significant increase in liver weight after the combined procedure was accompanied by a low proliferative response. In contrast, hepatocyte proliferation was undetectable in the right lobe undergoing atrophy after PVL only. The caudate lobe in the rPVL + 70% PHx group increased to 4.6-fold, which is significantly more than in the other groups. This increase in liver weight was paralleled by persisting portal hyperperfusion and a prolonged proliferative phase of 3 days. A discontinued portal blood supply does not always result in atrophy of the ligated lobe. The concurrent regenerative stimulus induced by 70% PHx seemed to counteract the local atrophy after a simultaneously performed rPVL, leading to a low but prolonged regenerative response of the portally deprived liver lobe. This observation supports the conclusion that portal flow is not necessary for liver regeneration. The persisting portal hyperperfusion may be crucial for the specific kinetics of prolonged liver regeneration after rPVL + 70% PHx in the portally supplied caudate lobe. Both observations deserve more attention regarding the underlying mechanism in further studies.


Imaging powders with the atomic force microscope: from biominerals to commercial materials.
Atomically resolved images of pressed powder samples have been obtained with the atomic force microscope (AFM). The technique was successful in resolving the particle, domain, and atomic structure of pismo clam (Tivela stultorum) and sea urchin (Strongylocentrotus purpuratus) shells and of commercially available calcium carbonate (CaCO(3)) and strontium carbonate (SrCO(3)) powders. Grinding and subsequent pressing of the shells did not destroy the microstructure of these materials. The atomic-resolution imaging capabilities of AFM can be applied to polycrystalline samples by means of pressing powders with a grain size as small as 50 micrometers. These results illustrate that the AFM is a promising tool for material science and the study of biomineralization.


Creating a comprehensive research strategy for cutaneous neurofibromas.
Outside of procedural-based methods, there are currently no established medical treatments for cutaneous neurofibroma (cNF), which afflict up to 99% of patients with NF1. Further, adult patients often report cNF are the greatest burden of living with NF1. The Neurofibromatosis Therapeutic Acceleration Program (NTAP) launched a think tank to address core questions to facilitate development of effective therapeutics for cNF in people with NF1. Experts (with and without explicit experience with NF1 or cNF) from multiple scientific and medical disciplines, representing the ranks of academia, industry, and government agencies, were invited to become a member of a team addressing a specific subset of questions pertinent to cNF. Teams met monthly to review published and unpublished materials, and created summaries about the material known and unknown that may influence therapeutic development for cNF. Teams prioritized questions and organized supporting data, which was presented to the entire body of experts by each team at a research summit. Four themes were identified as being relevant to creating a comprehensive research strategy for cNF: (1) establishing definitions of cNF, (2) determining the biology of cNF with respect to tumor initiation, progression, and maintenance, (3) outlining the factors that guide therapies development, and (4) defining core considerations for clinical trials design and optimization for cNF. Considerations and key questions for each of the thematic areas were identified and provided basis for a request for applications launched by NTAP focused on cNF and are described in the accompanying articles of this supplement.


Mouse glucocorticoid-induced tumor necrosis factor receptor ligand is costimulatory for T cells.
Recently, agonist antibodies to glucocorticoid-induced tumor necrosis factor receptor (GITR) (tumor necrosis factor receptor superfamily 18) have been shown to neutralize the suppressive activity of CD4+CD25+ regulatory T cells. It was anticipated that this would be the role of the physiological ligand. We have identified and expressed the gene for mouse GITR ligand and have confirmed that its interaction with GITR reverses suppression by CD4+CD25+ T cells. It also, however, provides a costimulatory signal for the antigen-driven proliferation of naïve T cells and polarized T helper 1 and T helper 2 clones. RT-PCR and mAb staining revealed mouse GITR ligand expression in dendritic cells, macrophages, and B cells. Expression was controlled by the transcription factor NF-1 and potentially by alternative splicing of mRNA destabilization sequences.


The PP2A-Aβ gene is regulated by multiple transcriptional factors including Ets-1, SP1/SP3, and RXRα/β.
Protein phosphatase-2A (PP-2A) is a major serine/threonine phosphatase abundantly expressed in eukaryotes. PP-2A is a heterotrimer that contains a 65 kD scaffold A subunit, a 36 kD catalytic C subunit, and a regulatory B subunit of variable isoforms ranging from 54-130 kDs. The scaffold subunits, PP2A-Aα/β, act as platforms for both the C and B subunits to bind, and thus are key structural components for PP-2A activity. Mutations in both genes encoding PP2A-Aα and PP2A-Aβ lead to carcinogenesis and likely other human diseases. Our previous work showed that the gene coding for PP2A-Aα is positively regulated by multiple transcription factors including Ets-1, CREB, and AP-2α but negatively regulated by SP-1/SP-3. In the present study, we have functionally dissected the promoter of the mouse PP2A-Aβ gene. Our results demonstrate that three major cis-elements, including the binding sites for Ets-1, SP1/SP3, and RXRα/β, are present in the proximal promoter of the mouse PP2A-Aβ gene. Gel mobility shifting assays reveal that Ets-1, SP1/SP3, and RXRα/β all bind to PP2A-Aβ gene promoter. In vitro mutagenesis and reporter gene activity assays demonstrate that while Ets-1 displays negative regulation, SP1/SP3 and RXRα/β positively regulate the promoter of the PP2A-Aβ gene. Co-expression of the cDNAs encoding Ets-1, SP1/SP3, or RXRα/β and the luciferase reporter gene driven by PP2A-Aβ promoter further confirm their control over the PP2A-Aβ promoter. Finally, ChIP assays demonstrate that Ets-1, SP1/SP3, and RXRα/β can all bind to the PP2A-Aβ gene promoter. Together, our results reveal that multiple transcription factors regulate the PP2A-Aβ gene. Moreover, our results provide important information explaining why PP2A-Aα and PP2A-Aβ display distinct expression levels.


Calcium homeostasis in rabbit ventricular myocytes. Disruption by hypochlorous acid and restoration by dithiothreitol.
Hypochlorous acid (HOCl) is a toxic oxidant produced by neutrophils at sites of cardiac inflammation. To examine the effect of this oxidant on Ca2+ homeostasis in the heart, isolated rabbit ventricular myocytes were iontophoretically loaded with the Ca2+ indicator fura 2 and superfused with 100 microM HOCl under voltage-clamp conditions. Ca2+ transients and the corresponding Ca2+ currents were elicited by 300-msec depolarizing pulses from -40 to 0 mV. Within 200 seconds after HOCl addition, the amplitude of the Ca2+ transients was reduced from 402 +/- 89 to 82 +/- 29 nM (p less than 0.01) while intracellular free ([Ca2+]i increased from 78 +/- 16 to 265 +/- 48 nM (p less than 0.01). During this time, the amplitude of the slow inward currents increased by 10%, while steady-state holding current remained stable. This sustained steady-state rise in [Ca2+]i occurred even in the absence of extracellular Ca2+ but was virtually abolished by a 20-second preexposure to 10 mM caffeine, suggesting that the major source of this Ca2+ was the sarcoplasmic reticulum. Although washout of HOCl failed to induce recovery, subsequent exposure to the dithiol reducing agent dithiothreitol caused a rapid restoration of both the steady-state [Ca2+]i and Ca2+ transient amplitude. We conclude that 1) HOCl caused a rise of [Ca2+]i by inducing the release of Ca2+ from internal stores and impairing cellular extrusion mechanisms and 2) these effects occur through alteration of protein thiol redox status.


Methodological recommendations for a heartbeat detection-based measure of interoceptive sensitivity.
Heartbeat detection tasks are often used to measure cardiac interoceptive sensitivity-the ability to detect sensations from one's heart. However, there is little work to guide decisions on the optimum number of trials to use, which should balance reliability and power against task duration and participant burden. Here, 174 participants completed 100 trials of a widely used heartbeat detection task where participants attempt to detect whether presented tones occurred synchronously or asynchronously with their heartbeats. First, we quantified measurement reliability of the participant's accuracy derived from differing numbers of trials of the task using a correlation metric; we found that at least 40-60 trials were required to yield sufficient reliability. Next, we quantified power by simulating how the number of trials influenced the ability to detect a correlation between cardiac interoceptive sensitivity and other variables that differ across participants, including a variable measured from our sample (body mass index) as well as simulated variables of varying effect sizes. Using these simulations, we quantified the trade-offs between sample size, effect size, and number of trials in the heartbeat detection task such that a researcher can easily determine any one of these variables at given values of the other two variables. We conclude that using fewer than 40 trials is typically insufficient due to poor reliability and low power in estimating an effect size, although the optimal number of trials can differ by study.


Cross-talk between signal transducer and activator of transcription 3 and androgen receptor signaling in prostate carcinoma cells.
Interleukin 6 (IL-6) plays important roles in the immune system, hematopoiesis, as well as the growth of various tumors. Androgens are important in the initiation and progression of prostate cancer and their effects are mediated by androgen receptor (AR). Here we present a molecular mechanism for the effects of IL-6 on prostate cancer cells through a cross-talk between IL-6 and AR signaling pathways. IL-6-induced activation of signal transducer and activator of transcription 3 (STAT3) was augmented by AR in the presence of dihydrotestosterone (DHT). In addition, DHT treatment augmented endogenous STAT3-mediated gene expression by IL-6. Conversely, DHT-induced AR activity was increased by IL-6, and a dominant negative form of STAT3 inhibited AR activation. In contrast, DHT-mediated enhancement of STAT3 activation was inhibited by flutamide, an AR antagonist. We provide evidence that these activities are due to direct physical interactions between STAT3 and AR in prostate cancer cells.


Fetal cranial growth trajectories are associated with growth and neurodevelopment at 2 years of age: INTERBIO-21st Fetal Study.
Many observational studies and some randomized trials demonstrate how fetal growth can be influenced by environmental insults (for example, maternal infections)1 and preventive interventions (for example, multiple-micronutrient supplementation)2 that can have a long-lasting effect on health, growth, neurodevelopment and even educational attainment and income in adulthood3. In a cohort of pregnant women (n = 3,598), followed-up between 2012 and 2019 at six sites worldwide4, we studied the associations between ultrasound-derived fetal cranial growth trajectories, measured longitudinally from <14 weeks' gestation, against international standards5,6, and growth and neurodevelopment up to 2 years of age7,8. We identified five trajectories associated with specific neurodevelopmental, behavioral, visual and growth outcomes, independent of fetal abdominal growth, postnatal morbidity and anthropometric measures at birth and age 2. The trajectories, which changed within a 20-25-week gestational age window, were associated with brain development at 2 years of age according to a mirror (positive/negative) pattern, mostly focused on maturation of cognitive, language and visual skills. Further research should explore the potential for preventive interventions in pregnancy to improve infant neurodevelopmental outcomes before the critical window of opportunity that precedes the divergence of growth at 20-25 weeks' gestation.


The EphB6 receptor cooperates with c-Cbl to regulate the behavior of breast cancer cells.
Cancer invasiveness plays a major role in the mortality of patients with solid tumors, and deregulated cell adhesion and migration are suspected to drive invasive behavior. Since Eph receptor tyrosine kinases control both cell attachment and migration, they may act to define the level of cancer invasiveness. EphB6 is an unusual Eph receptor, lacking catalytic capacity due to alterations in its kinase domain. Interestingly, increased metastatic activity is associated with reduced EphB6 receptor expression in several tumor types, including breast cancer. This emphasizes the potential of EphB6 to act as a suppressor of cancer aggressiveness; however, the mechanism of its action is not well understood. We show that restoration of EphB6 expression in invasive breast cancer cells supports actin-dependent spreading and attachment and blocks invasiveness. EphB6 stimulation induces its tyrosine phosphorylation, which is crucial for its function and is mediated by the EphB4 receptor. This is accompanied by EphB6-c-Cbl interaction and phosphorylation of c-Cbl partner, the Abl kinase. Cbl silencing suppresses Abl phosphorylation, cell adhesion, and morphologic changes and blocks the ability of EphB6 to inhibit invasiveness, confirming its importance for EphB6 activity. Despite its crucial role in EphB6 responses, EphB4 also acts in an EphB6-independent manner to enhance invasive activity, suggesting that cancer invasiveness may be defined by the balance in the EphB6-EphB4 system. Overall, our observations suggest a new role for EphB6 in suppressing cancer invasiveness through c-Cbl-dependent signaling, morphologic changes, and cell attachment and indicate that EphB6 may represent a useful prognostic marker and a promising target for therapeutic approaches.


Effects of intraruminal infusions of sodium salts on selection of hay and concentrate foods by sheep.
Infusion of salts of short-chain fatty acids into the rumen of sheep depresses food intake but the relative importance of the effect of the acids and of osmolality are not fully understood. Three experiments were carried out in which sodium acetate (NaAc) and sodium chloride (NaCl) were infused for 3 h at 4 mM/min and compared with water controls. The effects on the intakes of a concentrate food and hay were examined to study the effect of osmotic and acid manipulation of the rumen on dietary choice. In the first experiment the foods were continuously available while in the second and third the foods were given for 3 min at 1.5-h intervals. Salt infusions depressed concentrate intake without significant effect on the intake of hay. The effect of NaAc tended to be greater than that of NaCl and persisted after the end of infusion. The weight of concentrate eaten during the 3-min tests was significantly and negatively related to both acetate and sodium concentrations in rumen fluid. The weight of hay eaten was negatively related to concentrate intake. The results demonstrate that the treatments imposed had a differential effect on intake, only depressing that of the concentrate food. They also suggest that, as NaAc has a greater effect than NaCl, the influence on feeding is due both to the osmotic load and the acid effect.


Comparison of the Effects of Glucagon-Like Peptide Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors for Prevention of Major Adverse Cardiovascular and Renal Outcomes in Type 2 Diabetes Mellitus.
Glucagon-like peptide 1 receptor agonists (GLP1-RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as 2 new classes of antihyperglycemic agents that also reduce cardiovascular risk. The relative benefits in patients with and without established atherosclerotic cardiovascular disease for different outcomes with these classes of drugs remain undefined. We performed a systematic review and trial-level meta-analysis of GLP1-RA and SGLT2i cardiovascular outcomes trials using the PubMed and EMBASE databases (Excerpta Medica Database). The primary outcomes were the composite of myocardial infarction, stroke, and cardiovascular death (MACE); hospitalization for heart failure; and progression of kidney disease. In total, data from 8 trials and 77 242 patients, 42 920 (55.6%) in GLP1-RA trials, and 34 322 (44.4%) in SGLT2i trials, were included. Both drug classes reduced MACE in a similar magnitude with GLP1-RA reducing the risk by 12% (hazard ratio [HR], 0.88; 95% CI, 0.84-0.94; P<0.001) and SGLT2i by 11% (HR, 0.89; 95% CI, 0.83-0.96; P=0.001). For both drug classes, this treatment effect was restricted to a 14% reduction in those with established atherosclerotic cardiovascular disease (HR, 0.86; 95% CI, 0.80-0.93; P=0.002), whereas no effect was seen in patients without established atherosclerotic cardiovascular disease (HR, 1.01; 95% CI, 0.87-1.19; P=0.81; P interaction, 0.028). SGLT2i reduced hospitalization for heart failure by 31% (HR, 0.69; 95% CI, 0.61-0.79; P<0.001), whereas GLP1-RA did not have a significant effect (HR, 0.93; 95% CI, 0.83-1.04; P=0.20). Both GLP1-RA (HR, 0.82; 95% CI, 0.75-0.89; P<0.001) and SGLT2i (HR, 0.62; 95% CI, 0.58-0.67; P<0.001) reduced the risk of progression of kidney disease including macroalbuminuria, but only SGLT2i reduced the risk of worsening estimated glomerular filtration rate, end-stage kidney disease, or renal death (HR, 0.55; 95% CI, 0.48-0.64; P<0.001). In trials reported to date, GLP1-RA and SGLT2i reduce atherosclerotic MACE to a similar degree in patients with established atherosclerotic cardiovascular disease, whereas SGLT2i have a more marked effect on preventing hospitalization for heart failure and progression of kidney disease. Their distinct clinical benefit profiles should be considered in the decision-making process when treating patients with type 2 diabetes mellitus.


Effect of gender on the acute effects of whey protein ingestion on energy intake, appetite, gastric emptying and gut hormone responses in healthy young adults.
Protein supplements, usually drinks rich in whey protein, are used widely for weight loss purposes in overweight adults. Information comparing the effects of whey protein on appetite and energy intake in men and women is limited. The objective was to compare the acute effects of whey-protein intake on energy intake, appetite, gastric emptying and gut hormones in healthy young men and women. Gastric emptying (3D-ultrasonography), blood glucose and plasma insulin, glucagon, ghrelin, cholecystokinin (CCK), gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) concentrations (0-180 min), appetite (visual analogue scales), and ad libitum energy intake from a buffet meal (180-210 min) were determined after ingestion of 30 g (120 kcal) or 70 g (280 kcal) whey protein, or a flavoured-water control drink (~2 kcal) in 8 healthy young men (25 ± 2 y, 72 ± 3 kg, 23 ± 1 kg/m2) and 8 women (23 ± 1 y, 64 ± 2 kg, 24 ± 0.4 kg/m2). There was a protein-load effect on gastric emptying, blood glucose, plasma insulin, glucagon, ghrelin, CCK, GIP and GLP-1 concentrations, and perceptions of hunger, desire to eat and prospective food consumption (P < 0.05). Ad libitum energy intake (average decrease of 206 ± 39 kcal (15 ± 2%) for men and of 46 ± 54 kcal (0 ± 26%) for women for the mean of the intakes after the 30 and 70 g whey-protein loads) and hunger were suppressed more by whey-protein ingestion in men than women (P = 0.046). There was no difference in suppression of energy intake between the 30 and 70 g protein loads (P = 0.75, interaction effect P = 0.19). Consequently, total energy intake (protein drink plus buffet meal) increased more compared to control in women than men (P = 0.010). The drinks emptied more slowly, and plasma glucagon, CCK and GLP-1 increased less after the protein drinks, in women than men (P < 0.05). The acute effects of whey protein ingestion on appetite, energy intake, gastric emptying and gut hormone responses are influenced by gender in healthy young adults.


[A case of non-tuberculous mycobacteriosis with pleurisy with a past history of dense exposure to environmental asbestos].
We report a case of non-tuberculous mycobacteriosis (NTM) with pleurisy in a 75-year-old man. The patient was admitted with a diagnosis of pneumonia. Chest radiography and CT scans revealed a tumorous shadow that increased rapidly in size despite treatment with antibiotics. Bronchoalveolar lavage fluid (BALF) disclosed numerous asbestos bodies, suggesting dense exposure and pulmonary silicosis. The tumorous chest shadow remained undiagnosed. Repeated microscopic examination of sputum and BALF revealed no acidophilic-bacilli. Diagnostic pneumonectomy was performed to further explore the nature of the tumorous shadow on chest radiography. Ziehl-Neelsen staining of excised lung tissue disclosed no acid-bacilli; however, the washed fluid of the tissue specimen showed acid-fast bacilli that were subsequently verified as M. avium by in vitro culture. The X-ray findings in our case were not consistent with NTM or specific for disease due to asbestos inhalation. A final diagnosis of NTM was confirmed via open biopsy of the lung. Our case suggests that in addition to tuberculosis, NTM should be taken into consideration as a complication of silicosis.


New Paradigms for Patient-Centered Outcomes Research in Electronic Medical Records: An Example of Detecting Urinary Incontinence Following Prostatectomy.
National initiatives to develop quality metrics emphasize the need to include patient-centered outcomes. Patient-centered outcomes are complex, require documentation of patient communications, and have not been routinely collected by healthcare providers. The widespread implementation of electronic medical records (EHR) offers opportunities to assess patient-centered outcomes within the routine healthcare delivery system. The objective of this study was to test the feasibility and accuracy of identifying patient centered outcomes within the EHR. Data from patients with localized prostate cancer undergoing prostatectomy were used to develop and test algorithms to accurately identify patient-centered outcomes in post-operative EHRs - we used urinary incontinence as the use case. Standard data mining techniques were used to extract and annotate free text and structured data to assess urinary incontinence recorded within the EHRs. A total 5,349 prostate cancer patients were identified in our EHR-system between 1998-2013. Among these EHRs, 30.3% had a text mention of urinary incontinence within 90 days post-operative compared to less than 1.0% with a structured data field for urinary incontinence (i.e. ICD-9 code). Our workflow had good precision and recall for urinary incontinence (positive predictive value: 0.73 and sensitivity: 0.84). Our data indicate that important patient-centered outcomes, such as urinary incontinence, are being captured in EHRs as free text and highlight the long-standing importance of accurate clinician documentation. Standard data mining algorithms can accurately and efficiently identify these outcomes in existing EHRs; the complete assessment of these outcomes is essential to move practice into the patient-centered realm of healthcare.


Canalizing Kauffman networks: nonergodicity and its effect on their critical behavior.
Boolean networks have been used to study numerous phenomena, including gene regulation, neural networks, social interactions, and biological evolution. Here, we propose a general method for determining the critical behavior of Boolean systems built from arbitrary ensembles of Boolean functions. In particular, we solve the critical condition for systems of units operating according to canalizing functions and present strong numerical evidence that our approach correctly predicts the phase transition from order to chaos in such systems.


Endocrine pancreas development is altered in foetuses from rats previously showing intra-uterine growth retardation in response to malnutrition.
We have shown that perinatal malnutrition decreases beta-cell mass at birth and impairs the adaptation of the endocrine pancreas to a subsequent pregnancy. The aim of this study is to investigate the impact of this maternal inadaptation on the development of endocrine pancreas in foetuses. Female rats malnourished during their perinatal life and showing intra-uterine growth retardation at birth were mated at 8 months of age. The development of the endocrine pancreas was studied at embryonic days 14, 17 and 20 in their foetuses by immunohistochemistry and morphometrical measurements on pancreatic sections. At embryonic day 20, both alpha and beta-cell fractions were decreased in foetuses from IUGR dams. Beta-cell mass was reduced (197 +/- 27 microg, vs 281 +/- 40 microg in control, p < 0.01) and so were insulin content and islet number per cm(2), as in the first generation foetuses. At embryonic day 14, the number of cells expressing only insulin was decreased by half in foetuses from intra-uterine growth retardation dams. At embryonic day 17, 50 % of the homeodomain protein Pdx-1 cell population expressed insulin but all the insulin cells expressed Pdx-1 in both groups; in foetuses from intra-uterine growth retardation dams the number of epithelial cells expressing Pdx-1 was decreased (415 +/- 40 cells/ mm(2) vs 481 +/- 28 cells/mm(2) in control foetuses, p < 0.05) and the mesenchymal fraction in the pancreas was increased by 36 % ( p < 0.05). Early malnutrition decreases beta-cell mass in the first generation of offspring and impairs the subsequent beta-cell adaptation to pregnancy. The beta-cell alteration is also present in the next generation and involves a decreased expansion of the epithelial population expressing Pdx-1.


Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain.
The human brain is often considered to be the most cognitively capable among mammalian brains and to be much larger than expected for a mammal of our body size. Although the number of neurons is generally assumed to be a determinant of computational power, and despite the widespread quotes that the human brain contains 100 billion neurons and ten times more glial cells, the absolute number of neurons and glial cells in the human brain remains unknown. Here we determine these numbers by using the isotropic fractionator and compare them with the expected values for a human-sized primate. We find that the adult male human brain contains on average 86.1 +/- 8.1 billion NeuN-positive cells ("neurons") and 84.6 +/- 9.8 billion NeuN-negative ("nonneuronal") cells. With only 19% of all neurons located in the cerebral cortex, greater cortical size (representing 82% of total brain mass) in humans compared with other primates does not reflect an increased relative number of cortical neurons. The ratios between glial cells and neurons in the human brain structures are similar to those found in other primates, and their numbers of cells match those expected for a primate of human proportions. These findings challenge the common view that humans stand out from other primates in their brain composition and indicate that, with regard to numbers of neuronal and nonneuronal cells, the human brain is an isometrically scaled-up primate brain.


Back pain--an integrated approach in primary care.
Back pain is common, and although many cases remit quickly, a significant number also continue a relapsing course over many months and years. Psychosocial factors have a significant influence on the condition. The evidence from clinical trials of the effectiveness of various therapies is available in summarised form in several resources, though is often inconclusive. There is good evidence that acute back pain should be managed by staying active and using non-steroidal anti-inflammatory and analgesic drugs, adding cognitive behaviour therapy for subacute pain. For chronic back pain, exercise, pain management programmes, non-steroidal anti-inflammatory and analgesic drugs, and trigger point and ligament injections are also recommended. There appears to be increasing evidence in favour of the use of acupuncture. Acupuncture appears to be useful to treat back pain, but patients should probably be advised to take advantage of any pain relief obtained to maintain or increase their activity. Acupuncturists must be aware of the psychosocial dimensions of back pain, as well as the physical ones, and should be careful to educate their patients about the condition and not make them become dependent on acupuncture to treat every acute episode.


Federated web-accessible clinical data management within an extensible neuroimaging database.
Managing vast datasets collected throughout multiple clinical imaging communities has become critical with the ever increasing and diverse nature of datasets. Development of data management infrastructure is further complicated by technical and experimental advances that drive modifications to existing protocols and acquisition of new types of research data to be incorporated into existing data management systems. In this paper, an extensible data management system for clinical neuroimaging studies is introduced: The Human Clinical Imaging Database (HID) and Toolkit. The database schema is constructed to support the storage of new data types without changes to the underlying schema. The complex infrastructure allows management of experiment data, such as image protocol and behavioral task parameters, as well as subject-specific data, including demographics, clinical assessments, and behavioral task performance metrics. Of significant interest, embedded clinical data entry and management tools enhance both consistency of data reporting and automatic entry of data into the database. The Clinical Assessment Layout Manager (CALM) allows users to create on-line data entry forms for use within and across sites, through which data is pulled into the underlying database via the generic clinical assessment management engine (GAME). Importantly, the system is designed to operate in a distributed environment, serving both human users and client applications in a service-oriented manner. Querying capabilities use a built-in multi-database parallel query builder/result combiner, allowing web-accessible queries within and across multiple federated databases. The system along with its documentation is open-source and available from the Neuroimaging Informatics Tools and Resource Clearinghouse (NITRC) site.


An early loss in membrane protein kinase C activity precedes the excitatory amino acid-induced death of primary cortical neurons.
Several lines of evidence indicate that a rapid loss of protein kinase C (PKC) activity may be important in the delayed death of neurons following cerebral ischemia. However, in primary neuronal cultures, cytotoxic levels of glutamate have been reported not to cause a loss in PKC as measured by immunoblot and conventional activity methods. This apparent contradiction has not been adequately addressed. In this study, the effects of cytotoxic levels of glutamate, NMDA, and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) on membrane PKC activity was determined in cortical neurons using an assay that measures only PKC that is active in isolated membranes, which can be used to differentiate active enzyme from that associated with membranes in an inactive state. A 15-min exposure of day 14-18 cortical neurons to 100 microM glutamate, AMPA, or NMDA caused a rapid and persistent loss in membrane PKC activity, which by 4 h fell to 30-50% of that in control cultures. However, the amount of enzyme present in these membranes remained unchanged during this period despite the loss in enzyme activity. The inactivation of PKC activity was confirmed by the fact that phosphorylation of the MARCKS protein, a PKC-selective substrate, was reduced in intact neurons following transient glutamate treatment. By contrast, activation of metabotropic glutamate receptors by trans-(1S,3R)-1-amino-1,3-cyclopentanedicarboxylic acid was not neurotoxic and induced a robust and prolonged activation of PKC activity in neurons. PKC inactivation by NMDA and AMPA was dependent on extracellular Ca2+, but less so on Na+, although cell death induced by these agents was dependent on both ions. The loss of PKC activity was likely effected by Ca2+ entry through specific routes because the bulk increase in intracellular free [Ca2+] effected by the Ca2+ ionophore ionomycin did not cause the inactivation of PKC. The results indicate that the pattern of PKC activity in neurons killed by glutamate, NMDA, and AMPA in vitro is consistent with that observed in neurons injured by cerebral Ischemia in vivo.


Purification and characterization of a cytochrome P-450 isozyme catalyzing bunitrolol 4-hydroxylation in liver microsomes of male rats.
A cytochrome P-450 isozyme, P-450 bunitrolol (BTL), catalyzing bunitrolol 4-hydroxylation was partially purified from liver microsomes of adult male Sprague-Dawley rats by hydrophobic affinity chromatographic (omega-aminooctyl-Sepharose 4B) and high-performance liquid chromatographic (anion-exchange diethylaminoethyl-5PW) techniques. The specific content of the final preparation was 5.02 nmol/mg protein, which was 7.8-fold that of microsomes. It showed two protein bands of 49 and 32 kDa in sodium dodecylsulfate-polyacrylamide gel electrophoresis. N-Terminal 20 amino acid sequence of the protein of a higher molecular mass (49 kDa) isolated by an electroblotting technique is 94% homologous with that of CYP2D2. In a reconstituted system including NADPH-cytochrome P-450 reductase and an NADPH-generating system, the final preparation had the highest activity toward BTL and debrisoquine 4-hydroxylation among 12 isozymes of cytochrome P-450 examined. Kinetic parameters, KM and Vmax values, of P-450 BTL calculated for BTL 4-hydroxylation were 10.7 microM and 19.68 nmol/min/nmol P-450, respectively, whereas those values (mean +/- SE) of rat liver microsomes were 0.84 +/- 0.05 microM and 2.05 +/- 0.11 nmol/min/nmol P-450. When preincubated with rat liver microsomes, the antibody against the final P-450 BTL preparation suppressed bunitrolol and debrisoquine 4-hydroxylase activities dose-dependently and almost completely. These results suggest that cytochrome P-450 BTL and its immunochemically related P-450 isozyme(s) play a major role in debrisoquine 4-hydroxylation as well as in BTL 4-hydroxylation in rat liver microsomes.


Maternal cocaine administration in mice alters DNA methylation and gene expression in hippocampal neurons of neonatal and prepubertal offspring.
Previous studies documented significant behavioral changes in the offspring of cocaine-exposed mothers. We now explore the hypothesis that maternal cocaine exposure could alter the fetal epigenetic machinery sufficiently to cause lasting neurochemical and functional changes in the offspring. Pregnant CD1 mice were administered either saline or 20 mg/kg cocaine twice daily on gestational days 8-19. Male pups from each of ten litters of the cocaine and control groups were analyzed at 3 (P3) or 30 (P30) days postnatum. Global DNA methylation, methylated DNA immunoprecipitation followed by CGI(2) microarray profiling and bisulfite sequencing, as well as quantitative real-time RT-PCR gene expression analysis, were evaluated in hippocampal pyramidal neurons excised by laser capture microdissection. Following maternal cocaine exposure, global DNA methylation was significantly decreased at P3 and increased at P30. Among the 492 CGIs whose methylation was significantly altered by cocaine at P3, 34% were hypermethylated while 66% were hypomethylated. Several of these CGIs contained promoter regions for genes implicated in crucial cellular functions. Endogenous expression of selected genes linked to the abnormally methylated CGIs was correspondingly decreased or increased by as much as 4-19-fold. By P30, some of the cocaine-associated effects at P3 endured, reversed to opposite directions, or disappeared. Further, additional sets of abnormally methylated targets emerged at P30 that were not observed at P3. Taken together, these observations indicate that maternal cocaine exposure during the second and third trimesters of gestation could produce potentially profound structural and functional modifications in the epigenomic programs of neonatal and prepubertal mice.


Infertility in South Africa: women's reproductive health knowledge and treatment-seeking behaviour for involuntary childlessness.
Infertility is a major reproductive health problem in Africa. This paper presents the findings of two studies which focus on the knowledge that infertile women have about fertility and the causes of infertility, their treatment-seeking behaviour and their expectations of an infertility clinic. A total of 150 infertile women from a culturally diverse, urban community in South Africa participated in the two studies. Both qualitative and quantitative research methods were applied using in-depth, semi-structured interviews and structured questionnaires. The women who participated had little knowledge about human reproduction and modern treatment options for infertility. They were highly motivated to find treatment and accessed both traditional and modern health care. Treatment barriers within modern health care were identified. The importance of health education and counselling is recognized, and both need to be integrated into infertility management, particularly in the developing world. The introduction of clinical guidelines is recommended in order to overcome treatment barriers and improve the delivery of health services.


[Analysis of fluoride concentration in mineral waters in the Araraquara region in Brazil].
It has been shown that people of all ages can benefit from the topical and systemic effects of water fluoridation. However, the increase in consumption of bottled water, either to substitute for or supplement consumption of water from public sources, has implications for safe fluoride supplementation. Taking that into consideration, in 1995 we analyzed the fluoride content in 31 commercial brands of mineral water in the region of Araraquara, state of São Paulo, Brazil. Fluoride concentration as determined by our analysis was compared to the concentration of fluoride specified on each label. Only 25% of the products studied listed the fluoride concentration on their labels. In addition, among 31 mineral water brands, 26 listed the date when the chemical analysis to determine chemical composition had been performed. Of these, 20 had not been put through the annual chemical analysis determined by Brazilian law. Based on these results, if the mineral waters tested had been the only source of drinking water, fluoride supplementation would have been necessary in 69% of the samples analyzed. In the case of children up to 6 years of age who use products containing fluoride, such as topical gels, mouthwashes or toothpastes, supplementation should be recommended only if commercially bottled water is the only source of water used, not only for drinking but for cooking as well.


Laparoscopic radical versus partial nephrectomy: assessment of complications.
We evaluated the short-term morbidity and complications of laparoscopic radical nephrectomy (LRN) compared with laparoscopic partial nephrectomy (LPN). From May 1998 to May 2002, 114 patients were identified with a single unilateral sporadic renal tumor and a normal contralateral kidney. These individuals had undergone LRN (35) or LPN (79). The LRN and LPN groups were analyzed for age, sex, American Society of Anesthesiologists score and body mass index. Mean tumor size in patients undergoing LRN and LPN was 2.8 +/- 1.2 (range 0.9 to 4.5) and 2.5 +/- 1.0 cm (range 1 to 4.5), respectively (p = 0.17). There were no differences between the 2 groups in terms of mean hospital stay, blood transfusion or surgical complications. There was no difference in mean preoperative and postoperative serum creatinine in patients in the LPN group. Mean postoperative serum creatinine was significantly higher than the mean preoperative level in patients in the LRN group (1.51 +/- 0.22 vs 1.18 +/- 0.37 mg/ml, range 0.6 to 2.4, p = 0.02). In each group 1 case was converted to open surgery due to bleeding. LPN is associated with similar postoperative convalescence and complications compared with LRN. The increase in serum creatinine noted in patients undergoing radical extirpation supports the use of LPN when clinically indicated.


The screening method of a bifidogenic dietary fiber extracted from inedible parts of vegetables.
Total dietary fiber (DF) was extracted from the inedible parts of vegetables such as peel of taro and Chinese yam, pea pod, broad bean pod, and broad bean testa. Effects of these fibers on the growth of bifidobacteria were determined by two kinds of experiments: one was to determine the increase of Bifidobacterium longum JCM1217 (B. longum) in medium containing DF, the other was an in vitro fermentation of the DF by anaerobic slurries of mixed human fecal or rat cecal microbiota. Anaerobic culture was carried out for 48 h in both experiments. In the pure culture of B. longum, the significant increase of bacterial number was observed as compared with 0 h in the medium containing the DF from peel of Chinese yam, pea pod and broad bean pod (p<0.05). On the other hand, bacterial number was decreased in the medium containing the DF from the peel of taro and broad bean testa. We selected the DF from pea pod because of its highest bifidogenic property in human fecal microbiota. In the fermentation of DF from pea pod by rat cecal microbiota, bifidobacteria and lactobacilli were increased. Bacteroidaceae and clostridia were decreased. These results suggested that DF from pea pod had possibility as a prebiotic. The bifidogenic property was affected by the sugar composition of DF.


Atmospheric refraction: a history.
We trace the history of atmospheric refraction from the ancient Greeks up to the time of Kepler. The concept that the atmosphere could refract light entered Western science in the second century B.C. Ptolemy, 300 years later, produced the first clearly defined atmospheric model, containing air of uniform density up to a sharp upper transition to the ether, at which the refraction occurred. Alhazen and Witelo transmitted his knowledge to medieval Europe. The first accurate measurements were made by Tycho Brahe in the 16th century. Finally, Kepler, who was aware of unusually strong refractions, used the Ptolemaic model to explain the first documented and recognized mirage (the Novaya Zemlya effect).


Treating Brain Metastases from Breast Cancer: Outcomes after Stereotactic Radiosurgery.
Stereotactic radiosurgery (SRS) is an alternative to surgery or whole brain radiotherapy for the control of single or multiple brain metastases in patients with breast cancer. To date, there is no clear consensus on factors that might predict overall survival following SRS. The aim of this study was to assess the overall survival of breast cancer patients with brain metastases treated with SRS at a single centre and to examine the factors that might influence survival. A retrospective analysis of consecutive patients with breast cancer and brain metastases, considered suitable for SRS by the regional neuro-oncology multidisciplinary team. All patients were treated at a single National Health Service centre. In total, 91 patients received SRS between 2013 and 2017, of whom 15 (16.5%) were alive at the time of analysis. The median overall survival post-SRS was 15.7 months (interquartile range 7.7-23.8 months) with no significant effect of age on survival (67 patients ≤ 65 years, 16.3 months; 26 patients > 65 years, 11.4 months, P = 0.129). The primary tumour receptor status was an important determinant of outcome: 31 oestrogen receptor positive (ER+)/human epidermal growth factor receptor 2 negative (HER2-) patients had a median overall survival of 13.8 months, 14 ER+/HER2+ patients had a median overall survival of 21.4 months, 30 ER-/HER2+ patients had a median overall survival of 20.4 months and 16 patients with triple negative breast cancer (TNBC) had a median overall survival of 8.5 months. A larger total volume of tumour treated (>10 cm3), but not the number of individual metastases treated, was associated with worse survival (P = 0.0002) in this series. Patients with stable extracranial disease at the time of SRS had improved overall survival compared with those with progressive extracranial disease (30 patients stable extracranial disease overall survival = 20.1 months versus 33 patients progressive extracranial disease overall survival = 11.4 months; P = 0.0011). Seventeen patients had no extracranial disease at the time of SRS, with a median overall survival of 13.1 months. This single-centre series of consecutive patients with brain metastases from breast cancer, treated with SRS, had a similar overall survival compared with previous studies of SRS. TNBC and ER+/HER2- histology, metastatic volumes >10 cm3 and progressive extracranial disease at the time of SRS were associated with worse survival.


Change in centromeric and acentromeric micronucleus frequencies in human populations after chronic radiation exposure.
Acute radiation exposure of humans was observed to induce various forms of cytogenetic damage, including increased frequencies of micronuclei and chromosomal aberrations. However, the cytogenetic effects of chronic low dose radiation exposure in vivo needs further characterization. Sixteen subjects with chronic low dose rates of gamma-radiation exposure from 60Co-contaminated steel in radioactive buildings were compared with seven non-exposed reference subjects for micronucleus frequencies after they relocated. By in situ hybridization using a digoxigenin-labeled anti-alpha all human centromere probe, the exposed subjects were shown to have a significant increase in cytochalasin B-modulated micronucleus (CBMN) frequencies, as well as a significant increase in centromere-positive (C+) CBMN, centromere-negative (C-) CBMN, total C+signals, single C+ MN signals and multiple C+ signals/1000 binucleated cells (BN). However, decreases in the ratios C+MN/C- MN and C+MN/total CBMN (%) were also noted in the exposed subjects. By mixed effects analysis, considering individuals from the same families, the C- MN and single C+ MN/1000 BN were both positively and moderately associated with previous cumulative exposure. When the time period of relocation post-exposure (relocation time or RT) was considered, total C+MN and multiple C+MN/1000 BN were negatively and significantly associated with RT. Moreover, the C+MN, C- MN, C+MN/C- MN ratio and single C+MN/1000 BN were all negatively and moderately associated with RT, but not with exposure dose. This suggested that acentromeric and single or multiple centromeric CBMN cytogenetic damage seems to disappear differentially in human subjects post chronic low dose radiation exposure.