Clinical pharmacokinetics in patients with liver disease.
From considerations of hepatic physiology and pathology coupled with pharmacokinetic principles, it appears that altered drug elimination in liver disease may result from the following mechanisms: reduction in absolute cell mass, in cellular enzyme content and/or activity, in portal vein perfusion due to extrahepatic/intrahepatic shunting, or of portal perfusion of hepatocyte mass due to decreased portal flow or sinusoidal perfusion; increase in arterial perfusion relative to portal perfusion; preferential perfusion of the sinusoidal midzone and terminal zones by arterioles; potential for direct mixing of arterial blood within the space of Disse; reduced exchange across the endothelial lining; and impaired diffusion within the space of Disse. In general, oxidative drug metabolism is impaired in liver disease and the degree of impairment of oxidisation differs between drugs but correlates best with the degree of sinusoidal capillarisation, i.e. the degree of access of the drug from the sinusoid to the hepatocyte. Drug conjugation appears to be relatively unaffected by liver disease, whereas elimination by biliary excretion correlates best with the degree of intrahepatic shunting and not with sinusoidal capillarisation. As the latter should impair hepatocyte access of all compounds similarly, a potentially important mechanism could be impaired access of oxygen to hepatocytes as oxidative metabolism is much more sensitive to oxygen supply than are conjugation or biliary excretion. This suggests a potentially important therapeutic role for agents which increase the hepatic oxygen supply. Useful adjunctive strategies may also derive from the oxygen limitation hypothesis. Anaemia should be targeted as a critically important variable, as should oxygen-carrying capacity, i.e. modification of the smoking habit. Additionally, enzyme inducers such as barbiturates may be used if overriding hypoxic constraints are removed by oxygen supplementation. Agents likely to seriously compromise arterial perfusion of the hepatic vascular bed should be avoided, e.g. those causing postural hypotension or vasospasm. Vasodilators can be used to actively promote arterial perfusion. While the effect of liver disease on drug handling is highly variable and difficult to predict, there are well recognised principles for modifying dosage. These include halving the dose of drugs given systemically (or of low clearance drugs given orally) and a 50 to 90% reduction in the dose of drugs with a high hepatic clearance given orally. Changes in the pharmacodynamic effects of drugs (either alone or in addition to pharmacokinetic changes) can also be profound, and awareness of this possibility should be increased.


The Differences in Preference for Truth-telling of Patients With Cancer of Different Genders.
Patients' personality traits, especially age, gender, and cancer stage, tend to affect doctors' truth-telling methods. However, there is a lack of studies investigating the influence of patients' gender on truth-telling, especially for Asian cultures. The aims of this study were to qualitatively investigate the differences in preferences for truth-telling for patients with cancer of different genders and explore patients' preferences for decision making. For this descriptive qualitative study, in-depth interviews were conducted with 20 patients with cancer (10 men and 10 women) using a semistructured interview guide. All interviews were audiotaped and transcribed verbatim. Data collection and analysis occurred concurrently; content analysis developed categories and themes. Data analysis revealed 2 themes: (1) similar gender preferences for truth-telling and decision making: knowledge of their medical condition, direct and frank truthfulness, and assistance in decision making for subsequent treatment programs, and (2) preferences in truth-telling that differed by gender: women wanted family members present for confirmation of diagnosis, whereas men did not; men preferred truth-telling for only key points of their cancer, whereas women wanted detailed information; and men did not want to know their survival period, whereas women wanted this information. Our study revealed similar gender preferences for truth-telling regarding knowledge and decision making; however, preferences differed for family support, scope of information, and survival time. These findings can serve as a reference for nurses and other healthcare personnel when implementing truth-telling for patients given a diagnosis of cancer. Strategies can be targeted for specific preferences of men and women.


Normal dendrite growth in Drosophila motor neurons requires the AP-1 transcription factor.
During learning and memory formation, information flow through networks is regulated significantly through structural alterations in neurons. Dendrites, sites of signal integration, are key targets of activity-mediated modifications. Although local mechanisms of dendritic growth ensure synapse-specific changes, global mechanisms linking neural activity to nuclear gene expression may have profound influences on neural function. Fos, being an immediate-early gene, is ideally suited to be an initial transducer of neural activity, but a precise role for the AP-1 transcription factor in dendrite growth remains to be elucidated. Here we measure changes in the dendritic fields of identified Drosophila motor neurons in vivo and in primary culture to investigate the role of the immediate-early transcription factor AP-1 in regulating endogenous and activity-induced dendrite growth. Our data indicate that (a) increased neural excitability or depolarization stimulates dendrite growth, (b) AP-1 (a Fos, Jun hetero-dimer) is required for normal motor neuron dendritic growth during development and in response to activity induction, and (c) neuronal Fos protein levels are rapidly but transiently induced in motor neurons following neural activity. Taken together, these results show that AP-1 mediated transcription is important for dendrite growth, and that neural activity influences global dendritic growth through a gene-expression dependent mechanism gated by AP-1.


A cross sectional survey to estimate prevalence and associated factors of asthma on Reunion Island, Indian Ocean.
Previous studies on asthma mortality and hospitalizations in Reunion Island indicate that this French territory is particularly affected by this pathology. Epidemiological studies conducted in schools also show higher prevalence rates in Reunion than in Mainland France. However, no estimates are provided on the prevalence of asthma among adults. In 2016, a cross-sectional survey was conducted to estimate the prevalence of asthma and to identify its associated factors in the adult population of Reunion Island. A random sample of 2419 individuals, aged 18-44 years, was interviewed by telephone using a standardized, nationally validated questionnaire. Information was collected on the respiratory symptoms, description of asthma attacks and triggering factors for declared asthmatics, as well as data on the indoor and outdoor home environment. "Current asthma" was defined as an individual declaring, at the time of the survey, having already suffered from asthma at some point during his/her life, whose asthma was confirmed by a doctor, and who had experienced an asthma attack in the last 12 months or had been treated for asthma in the last 12 months. "Current suspected asthma" was defined as an individual presenting, in the 12 months preceding the study, groups of symptoms suggestive of asthma consistent with the literature. The estimated prevalence of asthma was 5.4% [4.3-6.5]. After adjustment, women, obesity, a family member with asthma, tenure in current residence and presence of indoor home heating were associated with asthma. The prevalence of symptoms suggestive of asthma was 12.0% [10.2-13.8]. After adjustment, marital status, passive smoking, use of insecticide sprays, presence of mold in the home and external sources of atmospheric nuisance were associated with the prevalence of suspected asthma. Preventive actions including asthma diagnosis, promotion of individual measures to reduce risk exposure as well as the development of study to improve knowledge on indoor air allergens are recommended.


Encapsidation of the flavivirus kunjin replicon RNA by using a complementation system providing Kunjin virus structural proteins in trans.
Kunjin virus (KUN) replicon RNA was encapsidated by a procedure involving two consecutive electroporations of BHK-21 cells, first with KUN replicon RNA C20DXrep (with prME and most of C deleted) and about 24 h later with a recombinant Semliki Forest virus (SFV) replicon RNA(s) expressing KUN structural proteins. The presence of KUN replicon RNA in encapsidated particles was demonstrated by its amplification and expression in newly infected BHK-21 cells, detected by Northern blotting with a KUN-specific probe and by immunofluorescence analysis with anti-NS3 antibodies. No infectious particles were produced when C20DXrep RNA and recombinant SFV RNAs were electroporated simultaneously. When the second electroporation was performed with a single SFV replicon RNA expressing the KUN contiguous prME genes and the KUN C gene together but under control of two separate 26S subgenomic promoters (SFV-prME-C107), a 10-fold-higher titer of infectious particles was achieved than when two different SFV replicon RNAs expressing the KUN C gene (SFV-C107) and prME genes (SFV-prME) separately were used. No SFV replicon RNAs expressing KUN structural proteins were encapsidated in secreted particles. Infectious particles pelleted by ultracentrifugation of the culture fluid from cells sequentially transfected with C20DXrep and SFV-prME-C107 RNAs were neutralized by preincubation with monoclonal antibodies to KUN E protein. Radioimmunoprecipitation analysis with anti-E antibodies of the culture fluid of the doubly transfected cells showed the presence of C, prM/M, and E proteins in the immunoprecipitated particles. Reverse transcription-PCR analysis showed that the immunoprecipitated particles also contained KUN-specific RNA. The encapsidated replicon particles sedimented more slowly than KUN virions in a 5 to 25% sucrose density gradient and were uniformly spherical, with an approximately 35-nm diameter, compared with approximately 50 nm for KUN virions. The results of this study demonstrate for the first time packaging of flavivirus RNA in trans, and they exclude a role in packaging for virtually all of the structural region. Possible applications of the developed packaging system include the definition of the packaging signal(s) in flavivirus RNA as well as the amino acid motif(s) in the structural proteins involved in RNA encapsidation, virion assembly, and secretion. Furthermore, it could facilitate the development of a noninfectious vaccine delivery system based on encapsidation of a noncytopathic flavivirus replicon expressing heterologous genes.


Tuberculosis in lung transplant recipients.
Post-lung transplant infection is one of the leading causes of morbidity and mortality. The cause and incidence are similar in many series; however, infections such as Mycobacterium tuberculosis are influenced by the epidemiologic situation. The authors present a prospective and observational study to define the incidence, clinical presentation, and course of tuberculosis in a cohort of lung transplant patients at a single center in Spain. Between 1990 and 2002, cutaneous delayed-type hypersensitivity testing and pathologic and microbiologic study of explanted lungs were conducted in 187 lung transplant patients. Serial bronchoscopies with transbronchial biopsy and bronchioalveolar lavage were performed during follow-up. The diagnosis of tuberculosis was established only when M. tuberculosis was identified in any sample or when histopathologic study was conclusive. Forty-eight patients were classified as anergic (25.6%) and 61 (32.6%) were classified as having a positive tuberculin skin test. Of the 109 patients, 95 received latent tuberculosis infection prophylaxis. Tuberculosis was diagnosed in 12 patients (6.41%); in six of them, diagnosis was determined from the explanted lungs. The remainder were diagnosed during follow-up. Fever and dyspnea were the most common symptoms. Chest radiographic findings presented an alveolar pattern. All patients responded well to antituberculous therapy; no deaths were attributable to tuberculosis. In the authors' experience, tuberculosis is not rare in lung transplant patients and can be managed successfully with antituberculous therapy without rifampin. A systematic protocol for diagnosing tuberculosis of the explanted lung is useful for reducing tuberculous complications of the implanted lung.


Shifts of spatial attention underlie numerical comparison and mental arithmetic: Evidence from a patient with right unilateral neglect.
Recent findings suggest that mental arithmetic involves shifting attention on a mental continuum in which numbers would be ordered from left to right, from small to large numbers, with addition and subtraction causing rightward or leftward shifts, respectively. Neuropsychological data showing that brain-damaged patients with left neglect experience difficulties in solving subtraction but not addition problems support this hypothesis. However, the reverse dissociation is needed to establish the causal role of spatial attention in mental arithmetic. R.H., a 65-year-old left-brain-damaged patient exhibiting right unilateral visuospatial and representational neglect, was tested with various numerical tasks including numerical comparison, arithmetic problem-solving, and numerical interval bisection. In numerical comparison, R.H. showed a selective response latency increase when judging numbers larger than the references whereas his performance was normal for numbers smaller than the references. In the arithmetic task, R.H. was impaired in solving addition but not subtraction problems. In contrast, performance in number bisection shows a deviation toward larger numbers. These results establish a double dissociation between subtraction and addition solving in patients with left versus right neglect and demonstrate clear evidence that attentional mechanisms are crucial for mental arithmetic. We suggest that attention shifts are involved whenever a number is represented relative to another on a mental continuum, be it during numerical comparison or arithmetic problem-solving. R.H.'s performance in numerical interval bisection indicates that this task involves processes that are distinct from those involved in number comparison and mental arithmetic. (PsycINFO Database Record


Decreased noradrenergic and serotonergic reactivity of vas deferens of newborn rats from mothers treated with the serotonin reuptake inhibitor fluoxetine during pregnancy and breast-feeding.
Female Wistar rats were treated with the serotonin reuptake inhibitor fluoxetine (10 mg/kg/i.p/day), during pregnancy and breast-feeding, for the study of the corresponding newborn rats. At the end of the preweaning period, the 30-day old litters had their vas deferens removed for testing peripheral sympathetic reactivity, through the following experiments in vitro: (a) concentration-contraction curves for serotonin and for the adrenergic agonists noradrenaline, phenylephrine, clonidine and dopamine or for the indirect agonist tyramine (b) contractions induced by electric field stimulation, as an indicator of sympathetic neurotransmission (c) release of endogenous noradrenaline, measured by real-time determinations on HPLC (d) Ca(+2) time-contraction curves, to check for changes on Ca(+2) translocation. Our results showed that the affinity (pD(2)) for serotonin was strikingly decreased by about 1.5 log units. The pD(2) for adrenergic agonists was decreased by about 0.5 log units, except for dopamine and clonidine. The maximum effects and intrinsic activity were decreased only for dopamine. On the other hand, the response to Ca(+2) and the release of noradrenaline from nerve terminals were not modified. In additional experiments, the mother's body weights were measured, showing a decrease during gestation and a recovery during lactation while the offspring's weights were lower than controls. It is concluded that, besides the alterations on body weights, changes on noradrenergic and serotonergic mechanisms were observed and persisted in the newborn, at least one month after parturition.


Effective expression of human proteins on bacterial magnetic particles in an anchor gene deletion mutant of Magnetospirillum magneticum AMB-1.
Biologically synthesized magnetic particles by magnetotactic bacteria (BacMPs) have promising potential in the area of functional protein display technology for various biotechnological and biomedical applications. Functional proteins fused with an anchor protein, Mms13, have been demonstrated to be an effective and stable method for the display of functional proteins on BacMPs. However, the expression of some human proteins is relatively low. Useful host strains of Escherichia coli have been developed for the enhanced expression of recombinant proteins using a genetic engineering approach. To improve human protein expression level on BacMPs in Magnetospirillummagneticum AMB-1, a mutant strain with a deleted native mms13 gene (Δmms13 strain) was established and evaluated for effective functional protein display technology. As a result, the Δmms13 strain synthesized BacMPs with significantly improved expression of two human proteins, thyroid-stimulating hormone receptor (TSHR) and the class II major histocompatibility complex (MHC II) molecules. The Δmms13 strain could therefore be an effective strain for the display of other important human proteins on BacMPs and may be useful for further applications.


Use of methylphenidate for attention-deficit hyperactivity disorder in patients with epilepsy or electroencephalographic abnormalities.
Methylphenidate is commonly believed to lower seizure threshold. The safe use of methylphenidate has not been clarified in patients with attention-deficit hyperactivity disorder (ADHD) and concomitant active seizure or electroencephalographic (EEG) abnormalities. Patients with ADHD and active seizures (n = 57) and patients with ADHD and EEG abnormalities (n = 62), 6 to 16 years of age, were included in the study. The safety and efficacy of treatment with antiepilepsy drugs combined with methylphenidate were determined by assessing seizure frequency, changes in ADHD symptoms, the Conners' Rating Scales, EEG differences, and side effects. The Conners' Rating Scales, performed by parents and teachers, and mean total ADHD symptom scores at the beginning of the study and at the end were significantly different (P = .05 for the Conners' Rating Scales and P = .001 for ADHD symptom scores). Methylphenidate had a beneficial effect on EEG. Seizure frequency did not change from baseline. The side effects of methylphenidate were mild and transient Methylphenidate is safe and effective in children with ADHD and concomitant active seizures or EEG abnormalities.


Comparison of melatonin and curcumin effect at the light and dark periods on regeneration of sciatic nerve crush injury in rats.
Being one of the acute clinical problems, peripheral nerve injury can bring about a number of consequences including severe disability, reduced Quality of life (QOL) and immense costs. Currently, melatonin and curcumin are widely applied because of their immunomodulatory, anti-inflammatory, neuro-protective and antioxidant properties. The present study aims to compare the effects of melatonin and curcumin during light and dark periods on sciatic nerve crush injury repair. Accordingly, rats received IP injections of curcumin (100 mg/kg) and melatonin (10 mg/kg) over two periods of light (9:00 a.m.) and dark (9:00 p.m.) for 4 weeks. In order to evaluate rats, functional (walking track analysis and electrophysiological measurements), histomorphometric and gastrocnemius muscle mass investigations were administered. No statistically significant difference was identified between dark and light curcumin groups while curcumin groups displayed better results than did melatonin groups. In addition, dark melatonin group displayed better results than the light melatonin. On the whole, this study found that melatonin and curcumin can be used to quicken neural recovery and help treat nerve injury. It was also found that better neuroregeneration or nerve regeneration was induced when rats were treated by melatonin during the dark period while effects and injection time did not correlate in curcumin application.


Synectin promotes fibrogenesis by regulating PDGFR isoforms through distinct mechanisms.
The scaffold protein synectin plays a critical role in the trafficking and regulation of membrane receptor pathways. As platelet-derived growth factor receptor (PDGFR) is essential for hepatic stellate cell (HSC) activation and liver fibrosis, we sought to determine the role of synectin on the PDGFR pathway and development of liver fibrosis. Mice with deletion of synectin from HSC were found to be protected from liver fibrosis. mRNA sequencing revealed that knockdown of synectin in HSC demonstrated reductions in the fibrosis pathway of genes, including PDGFR-β. Chromatin IP assay of the PDGFR-β promoter upon synectin knockdown revealed a pattern of histone marks associated with decreased transcription, dependent on p300 histone acetyltransferase. Synectin knockdown was found to downregulate PDGFR-α protein levels, as well, but through an alternative mechanism: protection from autophagic degradation. Site-directed mutagenesis revealed that ubiquitination of specific PDGFR-α lysine residues was responsible for its autophagic degradation. Furthermore, functional studies showed decreased PDGF-dependent migration and proliferation of HSC after synectin knockdown. Finally, human cirrhotic livers demonstrated increased synectin protein levels. This work provides insight into differential transcriptional and posttranslational mechanisms of synectin regulation of PDGFRs, which are critical to fibrogenesis.


A Critical Review and Meta-Analysis of Impacts of Per- and Polyfluorinated Substances on the Brain and Behavior.
Per- and polyfluoroalkyl substances (PFAS) are a class of structurally diverse synthetic organic chemicals that are chemically stable, resistant to degradation, and persistent in terrestrial and aquatic environments. Widespread use of PFAS in industrial processing and manufacturing over the last 70 years has led to global contamination of built and natural environments. The brain is a lipid rich and highly vascularized organ composed of long-lived neurons and glial cells that are especially vulnerable to the impacts of persistent and lipophilic toxicants. Generally, PFAS partition to protein-rich tissues of the body, primarily the liver and blood, but are also detected in the brains of humans, wildlife, and laboratory animals. Here we review factors impacting the absorption, distribution, and accumulation of PFAS in the brain, and currently available evidence for neurotoxic impacts defined by disruption of neurochemical, neurophysiological, and behavioral endpoints. Emphasis is placed on the neurotoxic potential of exposures during critical periods of development and in sensitive populations, and factors that may exacerbate neurotoxicity of PFAS. While limitations and inconsistencies across studies exist, the available body of evidence suggests that the neurobehavioral impacts of long-chain PFAS exposures during development are more pronounced than impacts resulting from exposure during adulthood. There is a paucity of experimental studies evaluating neurobehavioral and molecular mechanisms of short-chain PFAS, and even greater data gaps in the analysis of neurotoxicity for PFAS outside of the perfluoroalkyl acids. Whereas most experimental studies were focused on acute and subchronic impacts resulting from high dose exposures to a single PFAS congener, more realistic exposures for humans and wildlife are mixtures exposures that are relatively chronic and low dose in nature. Our evaluation of the available human epidemiological, experimental, and wildlife data also indicates heightened accumulation of perfluoroalkyl acids in the brain after environmental exposure, in comparison to the experimental studies. These findings highlight the need for additional experimental analysis of neurodevelopmental impacts of environmentally relevant concentrations and complex mixtures of PFAS.


Electronic Properties of Si-Hx Vibrational Modes at Si Waveguide Interface.
Attenuated total reflectance (ATR) and X-ray photoelectron spectroscopy in suite with Kelvin probe were conjugated to explore the electronic properties of Si-Hx vibrational modes by developing Si waveguide with large dynamic detection range compared with conventional IR. The Si 2p emission and work-function related to the formation and elimination of Si-Hx bonds at Si surfaces are monitored based on the detection of vibrational mode frequencies. A transition between various Si-Hx bonds and thus related vibrational modes is monitored for which effective momentum transfer could be demonstrated. The combination of the aforementioned methods provides for results that permit a model for the kinetics of hydrogen termination of Si surfaces with time and advanced surface characterizing of hybrid-terminated semiconducting solids.


Auditory short-term memory behaves like visual short-term memory.
Are the information processing steps that support short-term sensory memory common to all the senses? Systematic, psychophysical comparison requires identical experimental paradigms and comparable stimuli, which can be challenging to obtain across modalities. Participants performed a recognition memory task with auditory and visual stimuli that were comparable in complexity and in their neural representations at early stages of cortical processing. The visual stimuli were static and moving Gaussian-windowed, oriented, sinusoidal gratings (Gabor patches); the auditory stimuli were broadband sounds whose frequency content varied sinusoidally over time (moving ripples). Parallel effects on recognition memory were seen for number of items to be remembered, retention interval, and serial position. Further, regardless of modality, predicting an item's recognizability requires taking account of (1) the probe's similarity to the remembered list items (summed similarity), and (2) the similarity between the items in memory (inter-item homogeneity). A model incorporating both these factors gives a good fit to recognition memory data for auditory as well as visual stimuli. In addition, we present the first demonstration of the orthogonality of summed similarity and inter-item homogeneity effects. These data imply that auditory and visual representations undergo very similar transformations while they are encoded and retrieved from memory.


[Age-dependent peculiarities of functional state of the cardiovascular system in children with cerebral palsy].
The age-dependent peculiarities of the functional state of the cardiovascular system (CVS) in children of 7-9 years old with cerebral palsy (CP) with moderately marked functional disorders have been studied. Statistically significant age difference in multiple indicators of central circulation has been detected. Age-dependent peculiarities of hemodynamic response in children with CP in response to dosed physical load have been revealed. The adaptive capacity of the CVS was calculated by the method of comparative analysis of the amplitude and the variation heart rate monitoring. We found that 38% of the studied children had a high level of adaptive capacity of the CVS, while 50% of the children had a low level of adaptive capacity of the CVS.


User fees in private non-for-profit hospitals in Uganda: a survey and intervention for equity.
BACKGROUND: In developing countries, user fees may represent an important source of revenues for private-non-for-profit hospitals, but they may also affect access, use and equity. METHODS: This survey was conducted in ten hospitals of the Uganda Catholic Medical Bureau to assess differences in user fees policies and to propose changes that would better fit with the social concern explicitly pursued by the Bureau. Through a review of relevant hospital documents and reports, and through interviews with key informants, health workers and users, hospital and non-hospital cost was calculated, as well as overall expenditure and revenues. Lower fees were applied in some pilot hospitals after the survey. RESULTS: The percentage of revenues from user fees varied between 6% and 89% (average 40%). Some hospitals were more successful than others in getting external aid and government subsidies. These hospitals were applying lower fees and flat rates, and were offering free essential services to encourage access, as opposed to the fee-for-service policies implemented in less successful hospitals. The wide variation in user fees among hospitals was not justified by differences in case mix. None of the hospitals had a policy for exemption of the poor; the few users that actually got exempted were not really poor. To pay hospital and non-hospital expenses, about one third of users had to borrow money or sell goods and property. The fee system applied after the survey, based on flat and lower rates, brought about an increase in access and use of hospital services. CONCLUSION: Our results confirm that user fees represent an unfair mechanism of financing for health services because they exclude the poor and the sick. To mitigate this effect, flat rates and lower fees for the most vulnerable users were introduced to replace the fee-for-service system in some hospitals after the survey. The results are encouraging: hospital use, especially for pregnancy, childbirth and childhood illness, increased immediately, with no detrimental effect on overall revenues. A more equitable user fees system is possible.


Csf1r or Mer inhibition delays liver regeneration via suppression of Kupffer cells.
Murine Kupffer cells (KCs) comprise CD11bhi and F4/80hi subsets. Tissue-resident macrophages are known to express the tyrosine kinase receptors colony-stimulating factor 1 receptor (Csf1r) and Mer. However, the expression of Csf1r and Mer on KC subsets and the importance of these tyrosine kinases during liver regeneration (LR) are unknown. KCs from wild-type and Csf1r-GFP mice were characterized by flow cytometry. Partial hepatectomy (PH) was performed in mice treated with clodronate liposomes, a Csf1r small molecule inhibitor or depleting antibody, or a small molecule Mer inhibitor. Sera and livers were analyzed. The function of sorted KC subsets was tested in vitro. Mer was specifically expressed on tissue-resident F4/80hi KCs, 55% of which also expressed Csf1r. Mer+Csf1r+ and Mer+Csf1r- KCs had distinct expression of macrophage markers. Csf1r inhibition in mice reduced F4/80hi KCs by approximately 50%, but did not affect CD11bhi KCs. Clodronate liposomes depleted F4/80hi KCs, but also altered levels of other intrahepatic leukocytes. Csf1r inhibition delayed LR, as demonstrated by a 20% reduction in liver-to-body weight ratios 7 days after PH. At 36h after PH, Csf1r inhibition increased serum ALT and histological liver injury, and decreased liver cell proliferation. A small molecule inhibitor of Mer did not alter the percentage of KCs or their proliferation and just modestly delayed LR. In vitro, Csf1r or Mer inhibition did not decrease KC viability, but did attenuate their cytokine response to stimulation. F4/80hi KCs are Mer+ and can be subdivided based on Csf1r expression. Csf1r or Mer inhibition each reduces KC cytokine production and delays LR.


Carriage rate of Haemophilus influenzae among preschool children in Turkey.
This study was designed to determine the prevalence of healthy Haemophilus influenzae carriers in a random sample of the preschool population in Kayseri, Turkey. The lack of H. influenzae type b (Hib) disease surveillance and epidemiological data on the throat carriage of Turkish children has caused a delay in the introduction of conjugated Hib vaccination into proposed national vaccination programs. Oropharyngeal cultures were collected and cultured on chocolate agar supplemented with 260 microg/ml bacitracin from 683 children between May and June, 2006. One hundred seven (15,6%) of the 683 children studied were found to be as H. influenzae carriers, and 29 (4,2%) isolates were serotype b. Beta-lactamase production was detected in four isolates (3.7%). According to multivariate analysis, the sex of the child and the number of people sharing the same room with the child significantly influenced the odds of carrying H. influenzae. Age, having older siblings, passive smoking, respiratory infection during the last 30 days, number of people in the household, attending kindergarten or a day-care center, and household income were not significant variables. Our results suggest that there is a strong relationship between exposure to large numbers of children and H. influenzae carriage.


Age at menarche and body mass index: a population study.
To test the hypothesis that age at menarche is inversely related to body mass index (BMI). A questionnaire was filled in by 11,293 young women at the time of discharge from compulsory military service, in order to determine the self-reported age at onset of menarche. The participants were weighed and measured and BMI was calculated. Obesity was defined as BMI >30 and leanness as BMI <20. The age at menarche was significantly and inversely correlated with BMI (R = -0.11, p <0.001). The age at menarche of obese women (12.9+/-1.3 years) was significantly lower than that of non-obese, non-lean women (13.3+/-1.4 years), who themselves had a lower age at menarche than lean women (13.5+/-1.4 years) (p <0.001). We conclude from our data that the relationship between BMI and pubertal development in girls appears to be a continuum.


Using partition designs to enhance purification process understanding.
Characterization of purification processes by identifying significant input parameters and establishing predictive models is vital to developing robust processes. Current experimental design approaches restrict analysis to one process step at a time, which can severely limit the ability to identify interactions between process steps. This can be overcome by the use of partition designs which can model multiple, sequential process steps simultaneously. This paper presents the application of partition designs to a monoclonal antibody purification process. Three sequential purification steps were modeled using both traditional experimental designs and partition designs and the results compared as a proof of concept study. The partition and traditional design approaches identified the same input parameters within each process step that significantly affected the product quality output examined. The partition design also identified significant interactions between input parameters across process steps that could not be uncovered by the traditional approach.


Identifying materials with charge-spin physics using charge-spin susceptibility computed from first principles.
The authors present a quantity termed charge-spin susceptibility, which measures the charge response to spin degrees of freedom in strongly correlated materials. This quantity is simple to evaluate using both standard density functional theory and many-body electronic structure techniques, enabling comparison between different levels of theory. A benchmark on 28 layered magnetic materials shows that large values of charge-spin susceptibility correlate with unconventional ground states such as disordered magnets and unconventional superconductivity.


Association and interplay of surgeon and hospital volume with mortality after open abdominal aortic aneurysm repair in the modern era.
Operative volume has been used as a marker of quality. Research from previous decades has suggested minimum open abdominal aortic aneurysm (AAA) repair volume requirements for surgeons of 9 to 13 open AAA repairs annually and for hospitals of 18 open AAA repairs annually to purportedly achieve acceptable results. Given concerns regarding the decreased frequency of open repairs in the endovascular era, we examined the association of surgeon and hospital volume with the 30- and 90-day mortality in the Vascular Quality Initiative (VQI) registry. Patients who had undergone elective open AAA repair from 2013 to 2018 were identified in the VQI registry. We performed a cross-sectional evaluation of the association between the average hospital and surgeon volume and 30-day postoperative mortality using a hierarchical Bayesian model. Cross-level interactions were permitted, and random surgeon- and hospital-level intercepts were used to account for clustering. The mortality results were adjusted by standardizing to the observed distribution of relevant covariates in the overall cohort. The outcomes were compared to the Society for Vascular Surgery guidelines recommended criteria of <5% perioperative mortality. A total of 3078 patients had undergone elective open AAA repair by 520 surgeons at 128 hospitals. The 30- and 90-day risks of postoperative mortality were 4.1% (n = 126) and 5.4% (n = 166), respectively. The mean surgeon volume and hospital volume both correlated inversely with the 30-day mortality. Averaged across all patients and hospitals, we found a 96% probability that surgeons who performed an average of four or more repairs per year achieved <5% 30-day mortality. Substantial interplay was present between surgeon volume and hospital volume. For example, at lower volume hospitals performing an average of five repairs annually, <5% 30-day mortality would be expected 69% of the time for surgeons performing an average of three operations annually. In contrast, at higher volume hospitals performing an average of 40 repairs annually, a <5% 30-day mortality would be expected 96% of the time for surgeons performing an average of three operations annually. As hospital volume increased, a diminishing difference occurred in 30-day mortality between lower and higher volume surgeons. Likewise, as surgeon volume increased, a diminishing difference was found in 30-day mortality between the lower and higher volume hospitals. Surgeons and hospitals in the VQI registry achieved mortality outcomes of <5% (Society for Vascular Surgery guidelines), with an average surgeon volume that was substantially lower compared with previous reports. Furthermore, when considering the development of minimal surgeon volume guidelines, it is important to contextualize the outcomes within the hospital volumes.


[Treating cicatricial baldness with scalp expanding and hair autografting].
To investigate the effective method to treat cicatricial baldness. From 1993 to 1998, 21 cases with multi-region or great-dimensional cicatricial baldness were treated with scalp expanding and hair autografting. Among them, there were 17 males and 4 females, aged from 14 to 49 years old. The operation was divided into two stages, stage one meaned to embed the expander under the scalp and stage two meaned to sow the autogenous hair. All cases, no matter what the position and area, were repaired successfully. The biggest dimension of repaired baldness was 340 cm2, one expander exposed and one failed in expanding after operation and be corrected immediately. The normal hair direction changed in two cases. Combined use of scalp expanding and hair autografting is an effective method to treat multi-region or great dimensional cicarticial baldness.


An approach to the design of photovoltaic noise barriers and a case study from Istanbul, Turkey.
Solar energy solutions that do not require additional space are critical. Noise barriers, which are built in low-value lands next to noise sources, provide effective areas for PV modules. There are many studies on using noise barriers as a sub-structure for photovoltaic systems, providing electricity generation besides noise reduction targets. Photovoltaic noise barrier (PVNB) technology combines noise control measures with renewable energy generation. In this study, it is aimed to develop an integrated design method that embeds solar energy technology in noise protection structures. The method is exemplified in an existing settlement located on the side of the road with heavy traffic. According to local climate and solar data, optimum tilt angles have been determined for annual, semi-annual, seasonal, and monthly periods. Noise barrier alternatives are derived with combinations of different diffraction edge sizes of barrier top and determined optimum inclination angles. The performance of the criteria that affect the PVNB effectiveness for alternatives was calculated through software tools. The energy generation potential of PVNB and its shading in adjacent blocks were calculated with PVsyst 6.7.7. The noise control efficiency of the structure was computed via SoundPLAN 7.2. TOPSIS method, one of the most common multi-criteria decision-making (MCDM) techniques, was used in the evaluation. As a result of TOPSIS, the best PVNB solution in the case study is the alternative that has 3-m and 2-m-wide edges and 58° and 31° tilted edges. In comparison with the current situation, the selected alternative will decrease 44% of the number of receiving points affected by noise and provide 524,804 kWh annual electricity generation.


Environmental occurrence and clinical impact of Vibrio vulnificus and Vibrio parahaemolyticus: a European perspective.
Vibrio vulnificus and Vibrio parahaemolyticus are ubiquitous Gram-negative bacterial pathogens found naturally in marine and estuarine waters, and are a leading cause of seafood-associated bacterial illness. These pathogens are commonly reported in the USA and in many Asian countries, including China, Japan and Taiwan; however, there is growing concern that V. vulnificus and V. parahaemolyticus may represent an important and increasing clinical problem in Europe. Several factors underlie the need for a greater understanding of these non-cholera vibrios within a European context. First, there is a growing body of evidence to suggest that V. vulnificus and V. parahaemolyticus infections are increasing, and tend to follow regional climatic trends, with outbreaks typically following episodes of unusually warm weather. Such findings are especially alarming given current predictions regarding warming of marine waters as a result of global climatic change. Second, a myriad of epidemiological factors may greatly increase the incidence as well as clinical burden of these pathogens - including increasing global consumption and trade of seafood produce coupled to an increase in the number of susceptible individuals consuming seafood produce. Finally, there is currently a lack of detailed surveillance information regarding non-cholerae Vibrio infections in Europe, as these pathogens are not notifiable in many countries, which probably masks the true clinical burden of many human infections. This review will present a pertinent overview of both the environmental occurrence and clinical impact of V. vulnificus and V. parahaemolyticus in Europe.


Extracellular Vesicles Derived from Young Neural Cultures Attenuate Astrocytic Reactivity In Vitro.
Extracellular vesicles (EVs) play an important role in intercellular communication and are involved in both physiological and pathological processes. In the central nervous system (CNS), EVs secreted from different brain cell types exert a sundry of functions, from modulation of astrocytic proliferation and microglial activation to neuronal protection and regeneration. However, the effect of aging on the biological functions of neural EVs is poorly understood. In this work, we studied the biological effects of small EVs (sEVs) isolated from neural cells maintained for 14 or 21 days in vitro (DIV). We found that EVs isolated from 14 DIV cultures reduced the extracellular levels of lactate dehydrogenase (LDH), the expression levels of the astrocytic protein GFAP, and the complexity of astrocyte architecture suggesting a role in lowering the reactivity of astrocytes, while EVs produced by 21 DIV cells did not show any of the above effects. These results in an in vitro model pave the way to evaluate whether similar results occur in vivo and through what mechanisms.


Recent trends in asthma hospitalization and mortality in the United States.
To study the recent trends in asthma hospitalization and mortality rates by age, gender, and race categories in the United States. The National Hospital Discharge Survey Database for the years 1995 to 2002 was used to examine trends in asthma hospitalization. An International Classification of Diseases Ninth Revision, Clinical Modification (ICD-9-CM) code of 493.0 was used to identify primary hospitalization for asthma. Hospitalization rates were estimated using U.S. Census Bureau population estimates as denominators. Mortality data was obtained from the Center for Disease Control and Prevention Mortality Database. Death from asthma was identified using ICD-9-CM codes (493.0) for the years between 1995 and 1998 and ICD-10 codes (J45-J45.9) for 1999 and afterwards. Asthma hospitalization and mortality rates were estimated per 10,000 and per 100,000 populations, respectively. Crude relative risks (RR) were estimated to compare risks between various groups. During the study period the age-adjusted asthma hospitalization rate decreased by 16.3% among white females (from 13.4/10,000 in 1995-1996 to 11.2/10,000 in 2001-2002), and by 7% (from 8.14/10,000 in 1995-1996 to 7.56/10,000 in 2001-2002) among white males. Among blacks the decrease in hospitalization rate was by 13.9% (from 38.18/10,000 in 1995-1996 to 32.86/10,000 in 2001-2002) in males and by 14.4% (from 40.21/10,000 in 1995-1996 to 34.42/10,000 in 2001-2002) in females. A narrowing of the black to white disparity in asthma hospitalization rate was noted for children younger than 10 years of age. On the other hand, the racial disparity among subjects 10 years and older narrowed until 2000 but has started to widen since then. The overall decrease in asthma mortality rate was evident for the age group=5, but remained unchanged for the age group less than five. The age adjusted asthma mortality rate has also decreased by 22.2% in blacks (from 3.33/100,000 in 1995 to 2.59/100,000 in 2001) and by 38.4% in whites (from 1.26/100,000 in 1995 to 0.78/100,000 in 2001). This study confirms that both asthma hospitalization and mortality rates decreased during the study period and the black to white racial disparity in asthma hospitalization has narrowed for children younger than 10 years of age. For those subjects 10 years and older the racial disparity in hospitalizations narrowed until 2000 but started to widen since then. The widening racial gap in adults is disconcerting and needs further observation to assess its persistence.


Sentinel lymph node biopsy in breast cancer: Canadian practice patterns.
Recent data suggest sentinel lymph node biopsy (SLNBx) for invasive breast cancer (IBC) is widely performed in the United States, often outside of a clinical trial. We sought to describe SLNBx practice patterns in Canada, as well as criteria for abandonment of concurrent axillary lymph node dissection. All active (n = 1172) general surgeons in Canada were sent a 31-item questionnaire. Of the 519 respondents who treated IBC, 138 (27%) performed SLNBx, whereas 378 (73%) did not. Surgeons who did not perform SLNBx most commonly cited a lack of adequate resources (64%). Of the 138 surgeons who performed SLNBx, 16% participated in one of the ongoing multicenter clinical trials. Of the 39 (28%) surgeons who abandoned routine concurrent axillary lymph node dissection, 20 (51%) performed <30 combined procedures before performing SLNBx alone. On multivariate analysis, surgical oncology training (P =.005), increasing proportion of practice devoted to breast disease (P <.001), and number of days per week in the operating room (P <.001) were associated with the use of SLNBx. In contrast to the United States, SLNBx for IBC in Canada was not as common, and few surgeons participated in clinical trials. Fellowship-trained surgical oncologists and surgeons with a high exposure to breast disease seemed to be most involved in the development of SLNBx for IBC.


Suicidal ideation, risk factors, and communication with parents. An HBSC study on school children in Estonia, Lithuania, and Luxembourg.
Suicide is a leading cause of death among youth. In the year 2002, Lithuania had the 2nd, Luxembourg the 5th, and Estonia the 9th highest suicide rates among 15- to 19-year-olds across 90 countries worldwide. Suicidal ideation is a significant precursor to suicide. To report on the prevalence of and associations between suicidal ideation, smoking, alcohol consumption, physical fighting, bullying, and communication with parents among 15-year-old schoolchildren. The survey analyzes data from the 2005/2006 HBSC study from Estonia, Lithuania, and Luxembourg (N = 4,954). The risk factors were calculated through multinomial logistic regression analyses. The overall prevalence of suicidal ideation in the preceding year was 17%. Suicidal thoughts were associated with communication difficulties with parents (OR from 2.0 to 4.6) and other risk factors, especially multiple risks (OR for 4-5 concurrent risk factors from 4.5 to 13.6). Parent-child communication had a significant mediating effect by decreasing the odds for suicidality and multiple risks. The prevalence estimates were obtained by self-reports. The causal relationships need further investigation. The risk factors studied, particularly multiple risks, were associated with higher odds for suicidal ideation. Good parent-child communication is a significant resource for decreasing suicidal ideation among adolescents.


The mGluR theory of fragile X mental retardation.
Many of the diverse functional consequences of activating group 1 metabotropic glutamate receptors require translation of pre-existing mRNA near synapses. One of these consequences is long-term depression (LTD) of transmission at hippocampal synapses. Loss of fragile X mental retardation protein (FMRP), the defect responsible for fragile X syndrome in humans, increases LTD in mouse hippocampus. This finding is consistent with the growing evidence that FMRP normally functions as a repressor of translation of specific mRNAs. Here we present a theory that can account for diverse neurological and psychiatric aspects of fragile X syndrome, based on the assumption that many of the protein-synthesis-dependent functions of metabotropic receptors are exaggerated in fragile X syndrome. The theory suggests new directions for basic research as well as novel therapeutic approaches for the treatment of humans with fragile X, the most frequent inherited cause of mental retardation and an identified cause of autism.


Perceptions and attitudes toward organ procurement and transplantation: a medical community survey analysis.
The practitioner who recognizes and facilitates donor referral plays a pivotal role in the donor process. Mechanisms that help to identify and resolve issues for these practitioners are crucial. To identify barriers and issues that the community perceives as important, a survey to elicit the perceptions, attitudes, and ethical values of its respondents-specifically with regard to the donor process-was commissioned. The main components of the instrument included perceived problems, attitudes and ethical values, knowledge of consent process, medical and legal knowledge of brain death, organ procurement organization problems and suggestions for improvement, future education recommendations, and socio-demographic characteristics of the respondent. The survey confirmed issues of concern and brought to surface issues that have an underlying negative influence on the donor process.


GAGs and GAGs diseases: when pathophysiology supports the clinic.
The urinary epithelium has been the subject of considerable interest and much research in recent years. What has radically changed in the last decade is the concept of what the bladder epithelium really is. It is currently no longer considered just a simple barrier and a non-specific defence against infections, and it has been recognized as a specialized tissue regulating complex bladder functions and playing a fundamental and active role in the pathogenesis of cystitis. Researchers have been focussing on the receptors and mediators that are active in the sub-epithelial layer, with the hope that understanding the role of the urothelium defect will offer the opportunity for new therapeutic strategies. On the surface of the urothelial umbrella-cells there is a thick layer of glycoproteins and proteoglycans, which together are called Glycosaminoglycans (GAGs). They constitute a hydrophilic mucosal coating and act as a barrier against solutes found in urine. In recent years they have received special attention because injury to Gags, due to different noxae, has been identified as the first step in the genesis of chronic inflammatory bladder diseases, such as recurrent urinary tract infections, chemical or radiation cystitis, interstitial cystitis and/or Bladder Pain Syndrome. Aim of this study is to define the importance of the urothelium starting from the anatomy and physiology of the bladder wall. Furthermore, we will underline the role of glycosaminoglycans, focusing both on their pathophysiological role in the principal bladder diseases and on the therapeutic aspects from the clinical point of view.


SIRT1 mediates FOXA2 breakdown by deacetylation in a nutrient-dependent manner.
The Forkhead transcription factor FOXA2 plays a fundamental role in controlling metabolic homeostasis in the liver during fasting. The precise molecular regulation of FOXA2 in response to nutrients is not fully understood. Here, we studied whether FOXA2 could be controlled at a post-translational level by acetylation. By means of LC-MS/MS analyses, we identified five acetylated residues in FOXA2. Sirtuin family member SIRT1 was found to interact with and deacetylate FOXA2, the latter process being dependent on the NAD+-binding catalytic site of SIRT1. Deacetylation by SIRT1 reduced protein stability of FOXA2 by targeting it towards proteasomal degradation, and inhibited transcription from the FOXA2-driven G6pase and CPT1a promoters. While mutation of the five identified acetylated residues weakly affected protein acetylation and stability, mutation of at least seven additional lysine residues was required to abolish acetylation and reduce protein levels of FOXA2. The importance of acetylation of FOXA2 became apparent upon changes in nutrient levels. The interaction of FOXA2 and SIRT1 was strongly reduced upon nutrient withdrawal in cell culture, while enhanced Foxa2 acetylation levels were observed in murine liver in vivo after starvation for 36 hours. Collectively, this study demonstrates that SIRT1 controls the acetylation level of FOXA2 in a nutrient-dependent manner and in times of nutrient shortage the interaction between SIRT1 and FOXA2 is reduced. As a result, FOXA2 is protected from degradation by enhanced acetylation, hence enabling the FOXA2 transcriptional program to be executed to maintain metabolic homeostasis.


Intrahepatic DNA vaccination: unexpected increased resistance against murine cysticercosis induced by non-specific enhanced immunity.
Experimental murine cysticercosis caused by Taenia crassiceps has proved to be a useful model with which to test the efficacy of new vaccine candidates and delivery systems against pig cysticercosis. A high level of protection against murine cysticercosis was previously observed by intramuscular or intradermal DNA immunization with the use of the sequence of the recombinant KETc7 antigen cloned in pcDNA3 (pTc-sp7). To determine the effect of KETc7 differential expression in DNA vaccination, KETc7 was cloned in pGEM 11Zf(+) under the control of the tissue-specific regulatory promoter phosphoenolpyruvate carboxykinase (pPc-sp7). A high level of protection was induced by intrahepatic immunization with pPc-sp7, pTc-sp7 and the empty vector in the absence of any specific immunity. The empty vector pGEM 11Zf(+), the plasmid with the highest content of CpG sequences, provided to the most efficient protection. This protection was related to an increased number of splenocytes, enhanced nonspecific splenocyte proliferation, and intensified intrahepatic INF-gamma production. Overall, intrahepatic plasmid CpG-DNA immunization provokes an exacerbated nonspecific immune response that can effectively control Taenia crassiceps cysticercosis.


Stimulus-specific inhibition of IL-5 by cAMP-elevating agents and IL-10 reveals differential mechanisms of action.
Interleukin-5 (IL-5) is a Th2 cytokine, which is implicated in the pathogenesis of eosinophilic diseases such as asthma. Peripheral blood mononuclear cells (PBMC), costimulated with phorbol 12-myristate 13-acetate (PMA) plus phytohemagglutinin (PHA) or activating antibodies to the CD3 and CD28 T-lymphocyte surface markers, produced similar patterns of IL-5 expression. However, in PMA + PHA-treated cells, 8-bromo-cAMP and PGE(2) did not affect IL-5 expression, whereas in CD3 + CD28-stimulated cells, almost total repression was observed. IL-10 failed to inhibit IL-5 mRNA from PMA + PHA-treated cells, yet reduced release by 40%. By contrast, IL-10 totally inhibited CD3 + CD28-induced IL-5 release and inhibited mRNA by 50-60%. These results highlight important biological differences in the induction of IL-5 by the nonspecific stimulus PMA + PHA and the more physiological CD3 + CD28 costimulation. Finally, the potential for downregulating Th2 responses by cAMP-elevating agents or IL-10 is demonstrated and a significant role for posttranscriptional mechanisms in the inhibition by IL-10 is suggested.


Oxidation of short-chain fatty acids by sulfate-reducing bacteria in freshwater and in marine sediments.
Colony counts of acetate-, propionate- and L-lactate-oxidizing sulfate-reducing bacteria in marine sediments were made. The vertical distribution of these organisms were equal for the three types considered. The highest numbers were found just beneath the border of aerobic and anaerobic layers. Anaerobic mineralization of acetate, propionate and L-lactate was studied in the presence and in the absence of sulfate. In freshwater and in marine sediments, acetate and propionate were oxidized completely with concomitant reduction of sulfate. L-Lactate was always fermented. Lactate-oxidizing, sulfate-reducing bacteria could only be isolated from marine sediments, they belonged to the genus Desulfobacter and oxidized only acetate and ethanol by sulfate reduction. Propionate-oxidizing, sulfate-reducing bacteria belonged to the genus Desulfobulbus. They were isolated from freshwater as well as from marine sediments and showed a relatively large range of usable substrates: hydrogen, formate, propionate, L-lactate and ethanol were oxidized with concomitant sulfate reduction. L-Lactate and pyruvate could be fermented by most of the isolated strains.


A framework for intelligent data acquisition and real-time database searching for shotgun proteomics.
In the analysis of complex peptide mixtures by MS-based proteomics, many more peptides elute at any given time than can be identified and quantified by the mass spectrometer. This makes it desirable to optimally allocate peptide sequencing and narrow mass range quantification events. In computer science, intelligent agents are frequently used to make autonomous decisions in complex environments. Here we develop and describe a framework for intelligent data acquisition and real-time database searching and showcase selected examples. The intelligent agent is implemented in the MaxQuant computational proteomics environment, termed MaxQuant Real-Time. It analyzes data as it is acquired on the mass spectrometer, constructs isotope patterns and SILAC pair information as well as controls MS and tandem MS events based on real-time and prior MS data or external knowledge. Re-implementing a top10 method in the intelligent agent yields similar performance to the data dependent methods running on the mass spectrometer itself. We demonstrate the capabilities of MaxQuant Real-Time by creating a real-time search engine capable of identifying peptides "on-the-fly" within 30 ms, well within the time constraints of a shotgun fragmentation "topN" method. The agent can focus sequencing events onto peptides of specific interest, such as those originating from a specific gene ontology (GO) term, or peptides that are likely modified versions of already identified peptides. Finally, we demonstrate enhanced quantification of SILAC pairs whose ratios were poorly defined in survey spectra. MaxQuant Real-Time is flexible and can be applied to a large number of scenarios that would benefit from intelligent, directed data acquisition. Our framework should be especially useful for new instrument types, such as the quadrupole-Orbitrap, that are currently becoming available.


Ceftaroline activity against bacterial organisms isolated from acute bacterial skin and skin structure infections in United States medical centers (2009-2011).
Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil, is a new cephalosporin with bactericidal activity against resistant Gram-positive organisms including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant strains of Streptococcus pneumoniae, and commonly isolated Gram-negative organisms, including ceftriaxone-susceptible Enterobacteriaceae. We evaluated the in vitro activity of ceftaroline and selected comparator agents against bacterial isolates collected from patients with acute bacterial skin and skin structure infections (ABSSSIs) in the USA. A total of 6222 isolates were collected from 67 medical centers distributed across all nine USA census regions between 2009 and 2011 and tested for susceptibility by reference broth microdilution methods. Ceftaroline was very active against S. aureus (MIC50/90, 0.5/1 μg/mL; 99.6% susceptible), including MRSA (MIC50/90, 0.5/1 μg/mL; 99.1% susceptible). Against β-hemolytic streptococci, the activity of ceftaroline (MIC50/90, ≤0.015/0.03 μg/mL; 100.0% susceptible) was comparable to that of both penicillin (MIC50/90, ≤0.06/≤0.06 μg/mL; 100.0% susceptible) and ceftriaxone (MIC50/90, ≤0.25/≤0.25 μg/mL; 100.0% susceptible). Ceftaroline was also highly active against viridans group streptococci (MIC50/90, 0.03/0.06 μg/mL). Similar to ceftriaxone and ceftazidime, ceftaroline was active against wild-type strains of Escherichia coli (MIC50/90, 0.12/0.25 μg/mL; 94.0% susceptible) and Klebsiella pneumoniae (MIC50/90, 0.12/0.25 μg/mL; 96.8% susceptible); however, the ceftaroline activity was compromised among strains with an extended-spectrum β-lactamase-phenotype (MIC50/90, >32/>32 μg/mL for both E. coli and K. pneumoniae). In summary, ceftaroline showed potent activity against a large contemporary collection (6222) of bacterial isolates associated with ABSSSI in the USA.


Early malignant transformation of a petroclival meningothelial meningioma.
Although some authors have reported the malignant transformation of meningiomas, there has been no previous report describing that a meningothelial meningioma transformed into an atypical meningioma within 1 year. This report documents a 57-year-old woman who presented with right hearing disturbance. Magnetic resonance imaging revealed a right petroclival meningioma. The tumor was subtotally removed and was diagnosed to be a meningothelial meningioma. Seven months after surgery, a recurrence of the tumor was confirmed. The diagnosis of this recurrent tumor was an atypical meningioma. The MIB-1 index and the percent of p53 protein-positive cells in the primary tumor were 4.6% and 35.4%, respectively, whereas those of the recurrent tumor were 34.7% and 33.1%, respectively. A chromosomal DNA copy number loss was observed on 1p, 6q, 10, 14q, and -22q detected in both the primary and the recurrent tumors. These results suggest that the present case had a potentially malignant tumor in the early stage, although it had the histological features of benign meningiomas. An evaluation of the MIB-1 index, as well as the expression of p53 and chromosomal aberrations, may be useful for predicting the malignant transformation of meningiomas.


[Fibronectin as a diagnostic marker in several determined neurological diseases].
To determinate if fibronectin in CSF can be a useful parameter in the diagnosis of some neurologic illnesses. We have studied 30 patients, subdivided in four groups, depending on the type of neurologic illness. We have chosen as control a 10-patient group, which came to the Emergency Service and were diagnosed as a suspicious of neurologic illness, but after this it was discarded. In the whole group we practiced a lumbar puncture, with cytology, systematic, biochemistry, cultures, immunoglobulins determination and fibronectin quantification by ELISA. We want to emphasize the increase in fibronectin levels in CSF in both the patients with bacterial meningitis and the multiple sclerosis groups, when it's compared with the control group. For this, the determination of fibronectin levels in CSF might be a useful parameter in the diagnosis of some neurologic illnesses.


A high-precision chronological model for the decorated Upper Paleolithic cave of Chauvet-Pont d'Arc, Ardèche, France.
Radiocarbon dates for the ancient drawings in the Chauvet-Pont d'Arc Cave revealed ages much older than expected. These early ages and nature of this Paleolithic art make this United Nations Educational, Scientific and Cultural Organization (UNESCO) site indisputably unique. A large, multidisciplinary dating program has recently mapped the anthropological evolution associated with the cave. More than 350 dates (by (14)C, U-Th, TL and (36)Cl) were obtained over the last 15 y. They include 259 radiocarbon dates, mainly related to the rock art and human activity in the cave. We present here more than 80 previously unpublished dates. All of the dates were integrated into a high-precision Bayesian model based on archaeological evidence to securely reconstruct the complete history of the Chauvet-Pont d'Arc Cave on an absolute timescale. It shows that there were two distinct periods of human activity in the cave, one from 37 to 33,500 y ago, and the other from 31 to 28,000 y ago. Cave bears also took refuge in the cave until 33,000 y ago.


Introducing the SKIN score: a validated scoring system to assess severity of mastectomy skin flap necrosis.
With increasing use of immediate breast reconstruction (IBR), mastectomy skin flap necrosis (MSFN) is a clinical problem that deserves further study. We propose a validated scoring system to discriminate MSFN severity and standardize its assessment. Women who underwent skin-sparing (SSM) or nipple-sparing mastectomy (NSM) and IBR from November 2009 to October 2010 were studied retrospectively. A workgroup of breast and plastic surgeons scored postoperative photographs using the skin ischemia necrosis (SKIN) score to assess depth and surface area of MSFN. We evaluated correlation of the SKIN score with reoperation for MSFN and its reproducibility in an external sample of surgeons. We identified 106 subjects (175 operated breasts: 103 SSM, 72 NSM) who had ≥1 postoperative photograph within 60 days. SKIN scores correlated strongly with need for reoperation for MSFN, with an AUC of 0.96 for SSM and 0.89 for NSM. External scores agreed well with the gold standard scores for the breast mound photographs with weighted kappa values of 0.82 (depth), 0.56 (surface area), and 0.79 (composite score). The agreement was similar for the nipple-areolar complex photographs: 0.75 (depth), 0.63 (surface area), and 0.79 (composite score). A simple scoring system to assess the severity of MSFN is proposed, incorporating both depth and surface area of MSFN. The SKIN score correlates strongly with the need for reoperation to manage MSFN and is reproducible among breast and plastic surgeons.


Arsenic exposure and prevalence of diabetes mellitus in Korean adults.
It has been suggested that there is an association between environmental, low-level arsenic exposure and the risk of diabetes mellitus (DM), but little research has been conducted. Here, the glucose tolerance status and urinary creatinine adjusted total arsenic concentrations were analyzed in 3,602 subjects ≥ 20 yr of age who were registered for the Korea National Health and Nutrition Examination Survey, 2008-2009. Various demographic parameters were associated with urinary arsenic concentrations. After adjusting for these variables, urinary arsenic concentrations in subjects with DM were significantly higher than those in subjects with normal glucose tolerance and those with impaired fasting glucose (P < 0.001). Compared with the lowest quartile ( < 70.7 µg/g creatinine), the odds ratios and 95% confidence intervals for DM were 1.11 (0.73-1.68), 1.42 (0.94-2.13), and 1.56 (1.03-2.36) for urinary arsenic concentrations of 70.7 to < 117.7, 117.7 to < 193.4, and ≥ 193.4 µg/g creatinine, respectively, following multivariate adjustment. Furthermore, the urinary total arsenic concentration was inversely associated with the insulin secretion index, HOMA2 %B (β = -0.033, P = 0.032). These findings suggest that arsenic exposure, possibly involving beta cell dysfunction, is associated with an increased risk of DM in the Korean population.


Human T-cell leukemia virus type 3 (HTLV-3) and HTLV-4 antisense-transcript-encoded proteins interact and transactivate Jun family-dependent transcription via their atypical bZIP motif.
Human T-cell leukemia virus types 3 and 4 (HTLV-3 and HTLV-4) are recently isolated retroviruses. We have previously characterized HTLV-3- and HTLV-4-encoded antisense genes, termed APH-3 and APH-4, respectively, which, in contrast to HBZ, the HTLV-1 homologue, do not contain a typical bZIP domain (M. Larocque É Halin, S. Landry, S. J. Marriott, W. M. Switzer, and B. Barbeau, J. Virol. 85:12673-12685, 2011, doi:10.1128/JVI.05296-11). As HBZ differentially modulates the transactivation potential of various Jun family members, the effect of APH-3 and APH-4 on JunD-, c-Jun-, and JunB-mediated transcriptional activation was investigated. We first showed that APH-3 and APH-4 upregulated the transactivation potential of all tested Jun family members. Using an human telomerase catalytic subunit (hTERT) promoter construct, our results also highlighted that, unlike HBZ, which solely modulates hTERT expression via JunD, both APH-3 and APH-4 acted positively on the transactivation of the hTERT promoter mediated by tested Jun factors. Coimmunoprecipitation experiments demonstrated that these Jun proteins interacted with APH-3 and APH-4. Although no activation domain was identified for APH proteins, the activation domain of c-Jun was very important in the observed upregulation of its activation potential. We further showed that APH-3 and APH-4 required their putative bZIP-like domains and corresponding leucine residues for interaction and modulation of the transactivation potential of Jun factors. Our results demonstrate that HTLV-encoded antisense proteins behave differently, and that the bZIP-like domains of both APH-3 and APH-4 have retained their interaction potential for Jun members. These studies are important in assessing the differences between HBZ and other antisense proteins, which might further contribute to determining the role of HBZ in HTLV-1-associated diseases. IMPORTANCE HBZ, the antisense transcript-encoded protein from HTLV-1, is now well recognized as a potential factor for adult T-cell leukemia/lymphoma development. In order to better appreciate the mechanism of action of HBZ, comparison to antisense proteins from other HTLV viruses is important. Little is known in relation to the seemingly nonpathogenic HTLV-3 and HTLV-4 viruses, and studies of their antisense proteins are limited to our previously reported study (M. Larocque É Halin, S. Landry, S. J. Marriott, W. M. Switzer, and B. Barbeau, J. Virol. 85:12673-12685, 2011, doi:10.1128/JVI.05296-11). Here, we demonstrate that Jun transcription factors are differently affected by APH-3 and APH-4 compared to HBZ. These intriguing findings suggest that these proteins act differently on viral replication but also on cellular gene expression, and that highlighting their differences of action might lead to important information allowing us to understand the link between HTLV-1 HBZ and ATL in infected individuals.


A Rare Case of an Intra-nasal Ectopic Tooth in a Young Woman.
Teeth in non-dentate areas including the intra-sinus and intranasal teeth are rarely encountered in clinical practice. Although the majority of patients remain asymptomatic, the usual presenting complaints are nasal obstruction, epistaxis, hyposmia and headache. In this article, we present a case of an intranasal tooth in a 15-year-old female who presented with complaints of hyposmia and nasal obstruction. Computed tomography (CT) of the paranasal sinuses and nasal cavity showed a tooth-like structure in the left inferior nasal cavity extending from the hard palate. The mainstay of treatment is the surgical removal of the ectopic tooth under anaesthesia. Even in asymptomatic patients, surgical removal of the nasal tooth is advised to prevent complications. Along with a clinician's understanding of the condition, imaging aids in the diagnosis of an ectopic tooth. Imaging, particularly with CT, also helps plan the surgical approach to treatment.


Renal Medullary and Cortical Correlates in Fibrosis, Epithelial Mass, Microvascularity, and Microanatomy Using Whole Slide Image Analysis Morphometry.
Renal tubulointerstitial injury often leads to interstitial fibrosis and tubular atrophy (IF/TA). IF/TA is typically assessed in the renal cortex and can be objectively quantitated with computerized image analysis (IA). However, the human medulla accounts for a substantial proportion of the nephron; therefore, medullary scarring will have important cortical consequences and may parallel overall chronic renal injury. Trichrome, periodic acid-Schiff (PAS), and collagen III immunohistochemistry (IHC) were visually examined and quantitated on scanned whole slide images (WSIs) (N = 67 cases). When tuned to measure fibrosis, IA of trichrome and Trichrome-PAS (T-P) WSIs correlated for all anatomic compartments (among cortex, medulla, and entire tissue, r = 0.84 to 0.89, P all <0.0001); and collagen III deposition correlated between compartments (r = 0.69 to 0.89, P <0.0001 to 0.0002); however, trichrome and T-P measures did not correlate with collagen deposition, suggesting heterogeneous contributions to extracellular matrix deposition. Epithelial cell mass (EPCM) correlated between cortex and medulla when measured with cytokeratin IHC and with the trichrome red portion (r = 0.85 and 0.66, respectively, all P < 0.0001). Visual assessment also correlated between compartments for fibrosis and EPCM. Correlations were found between increasing medullary inner stripe (IS) width and fibrosis in all of the tissue and the medulla by trichrome morphometry (r = 0.56, P < 0.0001, and r = 0.48, P = 0.00008, respectively). Weak correlations were found between increasing IS width and decreasing visual assessment of all tissue EPCM. Microvessel density (MVD) and microvessel area (MVA) measured using a MVD algorithm applied to CD34 IHC correlated significantly between all compartments (r = 0.76 to 0.87 for MVD and 0.71 to 0.87 for MVA, P all < 0.0001). Overall, these findings demonstrate the interrelatedness of the cortex and medulla and the importance of considering the renal parenchyma as a whole.


Experience and attitudes on vaccinations recommended during pregnancy: survey on an Italian sample of women and consultant gynecologists.
Active immunization in pregnancy is recommended for the influenza and the tetanus, diphtheria, and acellular pertussis (Tdap) vaccines. Evidence indicates vaccine effectiveness in preventing influenza-related hospitalizations and pertussis in early infancy. We investigate vaccine uptake in pregnant and non-pregnant women through a sample of young women and consultant gynecologists, along with the potential predisposing and/or enabling factors affecting attitudes to vaccination (knowledge, beliefs, barriers). A cross-sectional study was conducted between June and September 2019, with a sample of 251 women and 14 consultant gynecologists at the Local Health Authority (ASL01) of the Abruzzo Region (Italy), using an anonymous, self-report questionnaire survey. Among the participants, 5.6% of women had received influenza vaccination, 16.4% had received Tdap during pregnancy and only 1.2% had received both vaccines. The assessment of the psychometric attitudinal variables has suggested a more positive willingness to receive Tdap than influenza vaccine among women, as the former is considered more important for the maternal and neonatal health. Health care workers have reported vaccine safety concerns, lack of information, and misconceptions about the need for vaccination as barriers to immunization in pregnant women. The results of this study will contribute to defining the goals and strategies to increase vaccine uptake under the current recommendations, through promoting effective training programs for all health care workers involved (gynecologists, obstetricians, public health physicians).


A novel RofA-family transcriptional regulator, GadR, controls the development of acid resistance in Listeria monocytogenes.
Stomach acid provides a significant innate barrier to the entry of the food-borne pathogen Listeria monocytogenes into the human gastrointestinal tract. A key determinant of acid resistance in this bacterium is the conserved glutamate decarboxylase system, GadD2 (encoded by the gadT2D2 operon), which helps to maintain the intracellular pH during exposure to gastric acid. In this study, we identified a premature stop codon in a gene located immediately downstream of the gadT2D2 operon that was highly linked to an acid-sensitive phenotype. When this open reading frame was restored through homologous recombination, an acid-resistant phenotype was restored. Through a series of genetic, transcriptomic, and survival experiments, we established that this gene, which we designated gadR, encodes a transcriptional regulator of the gadT2D2 operon. GadR belongs to the RofA family of regulators, primarily found in streptococci, where they are involved in regulating virulence. The data further showed that gadR plays a critical role in the development of acid resistance in response to mild acid exposure, a response that is known as the adaptive acid tolerance response (ATR). A deletion analysis of the gadT2D2 promoter region identified two 18-bp palindromic sequences that are required for the GadR-mediated induction of gadT2D2, suggesting that they act as binding sites for GadR. Overall, this study uncovers a new RofA-like regulator of acid resistance in L. monocytogenes, which plays a significant role in both growth phase-dependent acid resistance and ATR and accounts for previously observed strain-to-strain differences in survival at low pH.IMPORTANCEThe ability to survive the acidic conditions found in the stomach is crucial for the food-borne pathogen Listeria monocytogenes to gain access to the mammalian gastrointestinal tract. Little is currently known about how acid resistance is regulated in this pathogen and why this trait is highly variable between strains. Here, we used comparative genomics to identify a novel RofA-family transcriptional regulator, GadR, that controls the development of acid resistance. The RofA family of regulators was previously found only in a small group of bacterial pathogens, including streptococci, where they regulate virulence properties. We show that gadR encodes the dominant regulator of acid resistance in L. monocytogenes and that its sequence variability accounts for previously observed differences between strains in this trait. Together, these findings significantly advance our understanding of how this important pathogen copes with acid stress and suggest a potential molecular target to aid its control in the food chain.


Examining the interseasonal resurgence of respiratory syncytial virus in Western Australia.
Following a relative absence in winter 2020, a large resurgence of respiratory syncytial virus (RSV) detections occurred during the 2020/2021 summer in Western Australia. This seasonal shift was linked to SARS-CoV-2 public health measures. We examine the epidemiology and RSV testing of respiratory-coded admissions, and compare clinical phenotype of RSV-positive admissions between 2019 and 2020. At a single tertiary paediatric centre, International Classification of Diseases, 10th edition Australian Modification-coded respiratory admissions longer than 12 hours were combined with laboratory data from 1 January 2019 to 31 December 2020. Data were grouped into bronchiolitis, other acute lower respiratory infection (OALRI) and wheeze, to assess RSV testing practices. For RSV-positive admissions, demographics and clinical features were compared between 2019 and 2020. RSV-positive admissions peaked in early summer 2020, following an absent winter season. Testing was higher in 2020: bronchiolitis, 94.8% vs 89.2% (p=0.01); OALRI, 88.6% vs 82.6% (p=0.02); and wheeze, 62.8% vs 25.5% (p<0.001). The 2020 peak month, December, contributed almost 75% of RSV-positive admissions, 2.5 times the 2019 peak. The median age in 2020 was twice that observed in 2019 (16.4 vs 8.1 months, p<0.001). The proportion of RSV-positive OALRI admissions was greater in 2020 (32.6% vs 24.9%, p=0.01). There were no clinically meaningful differences in length of stay or disease severity. The 2020 RSV season was in summer, with a larger than expected peak. There was an increase in RSV-positive non-bronchiolitis admissions, consistent with infection in older RSV-naïve children. This resurgence raises concern for regions experiencing longer and more stringent SARS-CoV-2 public health measures.


HRT III glaucoma probability score and Moorfields regression across the glaucoma spectrum.
To compare the agreement, sensitivity, and specificity of the Heidelberg Retina Tomograph III Glaucoma Probability Score (GPS) and Moorfields Regression Analysis (MRA) across the spectrum of glaucomatous visual field (VF) loss. Retrospective observational study. Data from 247 glaucoma patients and 142 controls who underwent standard achromatic perimetry (SITA-SAP) and Heidelberg Retina Tomograph III imaging within 6 months were analyzed. Sensitivity, specificity, agreement, and discrimination capability of MRA and GPS were assessed. Age-adjusted specificity was 92% and 93% and sensitivity was 76.88 and 80.85 for GPS and MRA, respectively. Sensitivity for early VF loss [mean deviation (MD) < -5 dB] (N=81) was 66.64% and 69.82%, for moderate VF loss (-5 dB <MD < -15 dB) (N=104) was 78.91% and 85.13%, and for advanced VF loss (MD> -15 dB) (N=62) was 87.70% and 86.48% (GPS and MRA, respectively). Age-specific receiver operating characteristics ranged from 0.89 to 0.92 and from 0.87 to 0.90 (GPS and MRA, respectively). Kappa ranged from 0.64 to 0.77. Specificity for MRA and GPS was similar and agreement was good. GPS offered slightly higher age-specific receiver operating characteristic. GPS, which does not require contour line placement, may have a potential role in screening for severe glaucomatous damage.


Chia seed supplementation and disease risk factors in overweight women: a metabolomics investigation.
This study assessed the effectiveness of milled and whole chia seed in altering disease risk factors in overweight, postmenopausal women using a metabolomics approach. Subjects were randomized to chia seed (whole or milled) and placebo (poppy seed) groups, and under double-blinded procedures ingested 25 g chia seed or placebo supplements each day for 10 weeks. Subjects included 62 overweight (body-mass index 25 kg/m(2) and higher), nondiseased, nonsmoking, postmenopausal women, ages 49-75 years, with analysis based on the 56 subjects who completed all phases of the study. Pre- and poststudy measures included body mass and composition, blood pressure and augmentation index, serum lipid profile, inflammation markers from fasting blood samples, plasma fatty acids, and metabolic profiling using gas chromatography-mass spectrometry with multivariate statistical methods including principal component analysis and partial least-square discriminant analysis (PLS-DA). Plasma α-linolenic acid (N=ALA) increased 58% (interaction effect, p=0.002) and eicosapentaenoic acid (EPA) 39% (p=0.016) in the milled chia seed group (N=14) compared to nonsignificant changes in the whole chia seed (N=16) and placebo (N=26) groups. Pre-to-post measures of body composition, inflammation, blood pressure, augmentation index, and lipoproteins did not differ between chia seed (whole or milled) and placebo groups (all interaction effects, p>0.05). Global metabolic difference scores for each group calculated through PLS-DA models were nonsignificant (Q(2)Y<0.40), and fold-changes for 28 targeted metabolites associated with inflammation and disease risk factors did not differ between groups. Ingestion of 25 g/day milled chia seed compared to whole chia seed or placebo for 10 weeks by overweight women increased plasma ALA and EPA, but had no influence on inflammation or disease risk factors using both traditional and metabolomics-based measures.


Nonlinear spectroscopy of cold atoms in diffuse laser light.
The nonlinear spectroscopy of cold atoms in the diffuse laser cooling system is studied in this paper. We present the theoretical models of the recoil-induced resonances (RIR) and the electromagnetically-induced absorption (EIA) of cold atoms in diffuse laser light, and show their signals in an experiment of cooling (87)Rb atomic vapor in an integrating sphere. The theoretical results are in good agreement with the experimental ones when the light intensity distribution in the integrating sphere is considered. The differences between nonlinear spectra of cold atoms in the diffuse laser light and in the optical molasses are also discussed.


Perception of Perspective Distortions in Image-Based Rendering.
Image-based rendering (IBR) creates realistic images by enriching simple geometries with photographs, e.g., mapping the photograph of a building façade onto a plane. However, as soon as the viewer moves away from the correct viewpoint, the image in the retina becomes distorted, sometimes leading to gross misperceptions of the original geometry. Two hypotheses from vision science state how viewers perceive such image distortions, one claiming that they can compensate for them (and therefore perceive scene geometry reasonably correctly), and one claiming that they cannot compensate (and therefore can perceive rather significant distortions). We modified the latter hypothesis so that it extends to street-level IBR. We then conducted a rigorous experiment that measured the magnitude of perceptual distortions that occur with IBR for façade viewing. We also conducted a rating experiment that assessed the acceptability of the distortions. The results of the two experiments were consistent with one another. They showed that viewers' percepts are indeed distorted, but not as severely as predicted by the modified vision science hypothesis. From our experimental results, we develop a predictive model of distortion for street-level IBR, which we use to provide guidelines for acceptability of virtual views and for capture camera density. We perform a confirmatory study to validate our predictions, and illustrate their use with an application that guides users in IBR navigation to stay in regions where virtual views yield acceptable perceptual distortions.


Flexible fitting to cryo-EM density map using ensemble molecular dynamics simulations.
Flexible fitting is a computational algorithm to derive a new conformational model that conforms to low-resolution experimental data by transforming a known structure. A common application is against data from cryo-electron microscopy to obtain conformational models in new functional states. The conventional flexible fitting algorithms cannot derive correct structures in some cases due to the complexity of conformational transitions. In this study, we show the importance of conformational ensemble in the refinement process by performing multiple fittings trials using a variety of different force constants. Application to simulated maps of Ca2+ ATPase and diphtheria toxin as well as experimental data of release factor 2 revealed that for these systems, multiple conformations with similar agreement with the density map exist and a large number of fitting trials are necessary to generate good models. Clustering analysis can be an effective approach to avoid over-fitting models. In addition, we show that an automatic adjustment of the biasing force constants during the fitting process, implemented as replica-exchange scheme, can improve the success rate. © 2017 Wiley Periodicals, Inc.


A new perspective on "development" skills and their place within research training programmes in primary care.
The gap between research and policy and practice is well documented. So too is the relative paucity of research undertaken in general practice. Various programmes have been initiated to address these issues in different countries. As an example, the Brisbane International Initiative has been set up to develop a comprehensive curriculum for primary care research training. In order to inform this process, the neglected concept of "development" was explored theoretically and through a small pilot study. A number of issues and concepts are highlighted that may assist in closing the gap between research and practice. These included the consideration of a range of skills not conventionally included in current research training curricula. It is argued that these "development" skills are essential in order to enhance the relevance of researchers' contributions in the highly complex and specialised field of primary care practice. A large international study is proposed to validate this skill set.


Circadian oscillation controlling hatching: its ontogeny during embryogenesis of a moth.
Populations of eggs of the moth Pectinophora gossypiella develop a circadian rhythm of hatching activity under certain circumstances. This rhythm derives from circadian oscillations in each egg, which can be initiated or made synchronous by steps or pulses of either light or temperature, but only if these signals are administered after the midpoint of embryogenesis. Correlations between the development of the oscillation, appearance of a pigment, sensitivity to photoperiodic induction, and a possible effect of light on growth rate are discussed.


Changes in the mouse intestinal microflora during weaning: role of volatile fatty acids.
The influence of volatile fatty acids on the ecology of the bacterial flora of the mouse intestinal tract has been studied in three situations where large fluctuations in the composition of the microflora have been observed. Young mice were shown to ingest solid food particles when 11 days old; this correlated with the appearance of strictly anaerobic fusiform bacilli in the intestinal lumen and a 10,000-fold decrease in numbers of coliform bacilli. Over the same period, volatile fatty acids were shown by gas-liquid chromatography to appear in the intestinal content. It is suggested that the fusiform bacilli are responsible for the presence of the volatile acids (especially butyric acid) which exert an inhibitory effect on the coliform bacteria, resulting in the decline in numbers. When germ-free mice are placed in a specific pathogen-free mouse colony, changes in the intestinal flora occurred which were similar to those observed in the young mice approaching weaning. Once again, the decline in the coliform population correlated with the appearance of significant levels of butyric acid in the large intestine. In a further series of experiments, mice were fed penicillin and levels of the intestinal fatty acids were measured. The antibiotic eliminated the anaerobic fusiforms from the intestine, resulting in the disappearance of significant levels of butyric acid and a million-fold increase in the numbers of coliform bacilli.


Period Poverty from a Public Health and Legislative Perspective.
Period poverty is a global issue that needs to be addressed as a public health crisis. It is directly related to Sustainable Health Goals three, four, five, six, and eight. Period poverty adversely affects the health of anyone capable of menstruating, which is nearly half of the world population, at the physiological, emotional, and psychosocial level. Biases, cultural beliefs, ethical reproductive justice issues, social stigma, and systemic factors contribute to period poverty. Every month, certain menstruators are disproportionately impacted by period poverty and struggle to access basic hygienic necessities. Important stakeholders include not only the individual who experiences menses but also educators and school systems, healthcare professionals, policymakers, public health officials, and researchers. Everyone has a role in addressing period poverty by voting for officials that proactively support legislation, policy, and programs at all levels to effectively advocate for menstrual equity and address barriers contributing to period poverty. This includes policies that increase access to menstrual hygiene products, safe menstrual management methods, and reproductive and women's health education. Programs globally that focus on capacity building and sustainability strategies can be used as models to reduce period poverty, thereby fostering a sense of empowerment and menstruators' sense of autonomy, dignity, and equality.


The Development of Sensor Applications in the Sectors of Energy and Environment in Italy, 1976-2015.
Although sensor technologies have been developing quite similarly all over the world, the investigation of their applications has been more affected by the specific industrial and economic characteristics of each country. This paper aims to investigate the development of applications based on sensor devices in the sectors of energy and the environment, in Italy, throughout the last forty years (1976-2015), examining the most relevant papers published by Italian R & D groups working in this field. Italy depends on foreign imports for more than 80% of its primary energy needs, and this has directed the research effort on the development of sensor applications both to improve load shaping and consumers' awareness and to develop specific equipment to maximize renewable energy production. Similarly, for the environment sector, there are increasing efforts to develop solutions to support a more and more capillary control of the environment itself using a cooperative approach. In both the sectors it seems that the solutions proposed can help to relieve the structural problems that Italy suffers and that the scientific and technical results obtained so far also have significant international relevance.


[The effect of carbon dioxide gas on the growth of Candida utilis yeasts during continuous cultivation in a chemostat].
The cells of Candida utilis were cultivated in the conditions of chemostat, and the growth was limited by a nitrogen source. Accumulation in the medium of carbon dioxide inhibited the growth of the microbial population. The growth was now limited not by a source of nitrogen but by an excess of one of the forms of carbon dioxide--hydrocarbonate. This inhibition was reversible and could be eliminated either by intensifying ventilation of the apparatus or by varying pH of the medium within the range optimal for the growth, which changed the ratio between free and hydrocarbonate forms of carbon dioxide in the growth medium.


Neurological dysfunctioning in offspring of schizophrenics in Israel and Denmark. A replication analysis.
Neurological functioning was compared in children at risk for schizophrenia from samples recruited in Israel and Denmark. In both samples neurological signs were assessed in school-age children with one schizophrenic parent and a matched group of children with no mentally ill parents. Multidimensional Scalogram Analysis of data identified, in both samples, a radex structure of neurological functioning, radiating from motor to sensory-perceptual signs. In both samples, the gradient of neurological functioning differed between the offspring of schizophrenics and controls. For both the offspring of schizophrenics and controls, the largest number of children showed no or few signs of neurological dysfunctioning. A subgroup of the offspring of schizophrenics, but not the controls, showed multiple signs of neurological dysfunctioning that varied in pattern among individuals.


Risk of progression in complex and atypical endometrial hyperplasia: clinicopathologic analysis in cases with and without progestogen treatment.
In most cases, the endometrioid adenocarcinoma of the endometrium is preceded by hyperplasia with different risk of progression into carcinoma. The original histologic slides from 560 consecutive cases with complex and atypical hyperplasia were re-examined to assess the interobserver-correlation. The hyperplasias were analyzed separately for their likelihood of progression to carcinoma in patients with and without progestogen hormonal therapy. In all cases, a fractional re-curreting was performed to establish the state of the disease. The leading symptom was vaginal bleeding in 65.5% of the cases in the postmenopausal period. Eighty-six percent of the patients presented with obesity (BMI > 30 kg/m(2)), 23% had had an exogeneous use of estrogens. Twenty-two cases were reclassified as simple hyperplasia and excluded from further analysis. The interobserver-correlation was 91% for complex, 92% for atypical hyperplasia, and 89% for endometrioid carcinoma, representing an overall correlation of 90%. Two percent of the cases with complex hyperplasia (8/390) progressed into carcinoma and 10.5% into atypical hyperplasia. Fifty-two percent of the atypical hyperplasias (58/112) progressed into carcinomas. In the case of progestogen treatment (n = 208; P < 0.0001) 61.5% showed remission confirmed by re-curetting, compared with 20.3% of the cases without hormonal treatment (n = 182; P < 0.0001). Endometrial hyperplasia without atypia is likely to respond to hormonal treatment. Especially in postmenopausal situation, atypical hyperplasia should be treated with total hysterectomy.