Marginally low copper causes lesions of the midbrain in animal models: the implications for man.
Serum copper levels must be maintained between very strict limits for the maintenance of good health. High levels have recently been linked to Alzheimer's disease while low levels during pregnancy cause enzootic ataxia (swayback disease) in offspring. In this study, we investigated the prolonged effect of serum copper that was maintained at and around 0.5 ppm, the level presently regarded as safe. Pregnant sheep and rabbits in the last trimester (1-4 weeks) of pregnancy were treated with the copper chelator ammonium tetrathiomolybdate (ATM). Treatment was continued until the young were one month old at which time the animals were sacrificed Serum copper levels of the parents and offspring were monitored by atomic absorption. The difference spectra (400-630 nm) was examined and SDS PAGE was used to evaluate the protein composition of the brain mitochondria. The anatomy of the midbrain was also studied. Although the young sheep and rabbits from the ATM-treated mothers showed no visible signs of disability or swayback disease, the midbrain of those young animals with serum copper between 0.3-0.9 ppm showed evidence of vacuolation, cavitation and chromatolysis. In contrast, the difference spectra and the protein composition of the brain mitochondria from these animals were all normal. These results suggest that although animals may appear normal and exhibit some normal biochemical markers, serum copper in the region of 0.5 ppm may not be safe for some breeds of sheep or rabbits. It is possible that a similar situation applies to man.


Pterygium and genetic polymorphisms of the DNA repair enzymes XRCC1, XPA, and XPD.
Pterygium is an ultraviolet (UV) related disease. UV radiation can produce DNA damage, which is repaired by the DNA repair systems. Among the DNA repair systems, the base excision repair (BER) and nucleotide excision repair (NER) systems are the major ones involved in repairing UV-induced DNA damage; X-ray repair cross complementary 1 (XRCC1) and human 8-oxoguanine DNA glycosylase 1 (hOGG1) are two BER genes, and xeroderma pigmentosum group A (XPA) and xeroderma pigmentosum group D (XPD) are two NER genes. Polymorphisms of these genes are associated with the differences in their repair DNA damage capacity, and they modulate the susceptibility to cancer. Because the polymorphism of hOGG1 was reported to be associated with pterygium, it is logical to assume the correlation between XRCC1, XPA, and XPD polymorphisms and pterygium formation. One hundred and twenty-seven pterygium patients and 103 volunteers without pterygium were enrolled in this study. Polymerase chain reaction based analysis was used to resolve the XRCC1 codon 107, 194, 280, and 399; XPA A23G; XPA codon 228; and XPD codon 751 polymorphisms. There were significant differences in the frequency of genotypes and alleles of XRCC1 codon 194 and 399 polymorphisms between the groups. In codon 194, individuals who carried at least 1 Trp allele had a decreased risk of developing pterygium compared to those who carried the Arg/Arg wild-type genotype (odds ratio [OR]=0.58; 95% CI: 0.34-0.98). In codon 399, individuals who carried at least 1 Gln allele had a threefold increased risk of developing pterygium compared to those who carried the Arg/Arg wild-type genotype (OR=3.06; 95% CI: 1.78-5.26). There were no significant differences in the frequency of the genotypes and alleles of XRCC1 codon 107 and 280, XPA A23G, and XPD codon 751 polymorphisms between the groups. The XPA codon 228 polymorphism was not detected in any of the cases or controls. The XRCC1 codon 194 polymorphism causes a decreased risk of developing pterygium, but the codon 399 polymorphism increases the risk. There is no correlation between pterygium and XRCC1 codon 107 and 280, XPA A23G, and XPD codon 751 polymorphisms.


Mitochondrial signaling contributes to disuse muscle atrophy.
It is well established that long durations of bed rest, limb immobilization, or reduced activity in respiratory muscles during mechanical ventilation results in skeletal muscle atrophy in humans and other animals. The idea that mitochondrial damage/dysfunction contributes to disuse muscle atrophy originated over 40 years ago. These early studies were largely descriptive and did not provide unequivocal evidence that mitochondria play a primary role in disuse muscle atrophy. However, recent experiments have provided direct evidence connecting mitochondrial dysfunction to muscle atrophy. Numerous studies have described changes in mitochondria shape, number, and function in skeletal muscles exposed to prolonged periods of inactivity. Furthermore, recent evidence indicates that increased mitochondrial ROS production plays a key signaling role in both immobilization-induced limb muscle atrophy and diaphragmatic atrophy occurring during prolonged mechanical ventilation. Moreover, new evidence reveals that, during denervation-induced muscle atrophy, increased mitochondrial fragmentation due to fission is a required signaling event that activates the AMPK-FoxO3 signaling axis, which induces the expression of atrophy genes, protein breakdown, and ultimately muscle atrophy. Collectively, these findings highlight the importance of future research to better understand the mitochondrial signaling mechanisms that contribute to disuse muscle atrophy and to develop novel therapeutic interventions for prevention of inactivity-induced skeletal muscle atrophy.


Massive transfusion in trauma patients: tissue hemoglobin oxygen saturation predicts poor outcome.
Severely bleeding trauma patients requiring massive transfusion (MT) often experience poor outcomes. Our purpose was to determine the potential role of near infrared spectrometry derived tissue hemoglobin oxygen saturation (StO2) monitoring in early prediction of MT, and in the identification of those MT patients who will have poor outcomes. Data from a prospective multi-institution StO2 monitoring study were analyzed to determine the current epidemiology of MT (defined as transfusion volume >/=10 units packed red blood cells in 24 hours of hospitalization). Multivariate logistic regression was used to develop prediction models. Seven US level I trauma centers (TC) enrolled 383 patients. 114 (30%) required MT. MT progressed rapidly (40% exceeded MT threshold 2 hours after TC arrival, 80% after 6 hours). One third of MT patients died. Two thirds of deaths were due to early exsanguination and two thirds of early exsanguination patients died within 6 hours. One third of the early MT survivors developed multiple organ dysfunction syndrome. MT could be predicted with standard, readily available clinical data within 30 minutes and 60 minutes of TC arrival (area under the receiver operating characteristic curve = 0.78 and 0.80). In patients who required MT, StO2 was the only consistent predictor of poor outcome (multiple organ dysfunction syndrome or death). MT progresses rapidly to significant morbidity and mortality despite level I TC care. Patients who require MT can be predicted early, and persistent low StO2 identifies those MT patients destined to have poor outcome. The ultimate goal is to identify these high risk patients as early as possible to test new strategies to improve outcome. Further validation studies are needed to analyze appropriate allocation and study appropriate use of damage control interventions.


Frontal white matter hyperintensities, clasmatodendrosis and gliovascular abnormalities in ageing and post-stroke dementia.
White matter hyperintensities as seen on brain T2-weighted magnetic resonance imaging are associated with varying degrees of cognitive dysfunction in stroke, cerebral small vessel disease and dementia. The pathophysiological mechanisms within the white matter accounting for cognitive dysfunction remain unclear. With the hypothesis that gliovascular interactions are impaired in subjects with high burdens of white matter hyperintensities, we performed clinicopathological studies in post-stroke survivors, who had exhibited greater frontal white matter hyperintensities volumes that predicted shorter time to dementia onset. Histopathological methods were used to identify substrates in the white matter that would distinguish post-stroke demented from post-stroke non-demented subjects. We focused on the reactive cell marker glial fibrillary acidic protein (GFAP) to study the incidence and location of clasmatodendrosis, a morphological attribute of irreversibly injured astrocytes. In contrast to normal appearing GFAP+ astrocytes, clasmatodendrocytes were swollen and had vacuolated cell bodies. Other markers such as aldehyde dehydrogenase 1 family, member L1 (ALDH1L1) showed cytoplasmic disintegration of the astrocytes. Total GFAP+ cells in both the frontal and temporal white matter were not greater in post-stroke demented versus post-stroke non-demented subjects. However, the percentage of clasmatodendrocytes was increased by >2-fold in subjects with post-stroke demented compared to post-stroke non-demented subjects (P = 0.026) and by 11-fold in older controls versus young controls (P < 0.023) in the frontal white matter. High ratios of clasmotodendrocytes to total astrocytes in the frontal white matter were consistent with lower Mini-Mental State Examination and the revised Cambridge Cognition Examination scores in post-stroke demented subjects. Double immunofluorescent staining showed aberrant co-localization of aquaporin 4 (AQP4) in retracted GFAP+ astrocytes with disrupted end-feet juxtaposed to microvessels. To explore whether this was associated with the disrupted gliovascular interactions or blood-brain barrier damage, we assessed the co-localization of GFAP and AQP4 immunoreactivities in post-mortem brains from adult baboons with cerebral hypoperfusive injury, induced by occlusion of three major vessels supplying blood to the brain. Analysis of the frontal white matter in perfused brains from the animals surviving 1-28 days after occlusion revealed that the highest intensity of fibrinogen immunoreactivity was at 14 days. At this survival time point, we also noted strikingly similar redistribution of AQP4 and GFAP+ astrocytes transformed into clasmatodendrocytes. Our findings suggest novel associations between irreversible astrocyte injury and disruption of gliovascular interactions at the blood-brain barrier in the frontal white matter and cognitive impairment in elderly post-stroke survivors. We propose that clasmatodendrosis is another pathological substrate, linked to white matter hyperintensities and frontal white matter changes, which may contribute to post-stroke or small vessel disease dementia.


Targeted detection of in vivo endogenous DNA base damage reveals preferential base excision repair in the transcribed strand.
Endogenous DNA damage is removed mainly via base excision repair (BER), however, whether there is preferential strand repair of endogenous DNA damage is still under intense debate. We developed a highly sensitive primer-anchored DNA damage detection assay (PADDA) to map and quantify in vivo endogenous DNA damage. Using PADDA, we documented significantly higher levels of endogenous damage in Saccharomyces cerevisiae cells in stationary phase than in exponential phase. We also documented that yeast BER-defective cells have significantly higher levels of endogenous DNA damage than isogenic wild-type cells at any phase of growth. PADDA provided detailed fingerprint analysis at the single-nucleotide level, documenting for the first time that persistent endogenous nucleotide damage in CAN1 co-localizes with previously reported spontaneous CAN1 mutations. To quickly and reliably quantify endogenous strand-specific DNA damage in the constitutively expressed CAN1 gene, we used PADDA on a real-time PCR setting. We demonstrate that wild-type cells repair endogenous damage preferentially on the CAN1 transcribed strand. In contrast, yeast BER-defective cells accumulate endogenous damage preferentially on the CAN1 transcribed strand. These data provide the first direct evidence for preferential strand repair of endogenous DNA damage and documents the major role of BER in this process.


Cation-Directed Selective Polysulfide Stabilization in Alkali Metal-Sulfur Batteries.
Alkali metal sulfur redox chemistry offers promising potential for high-energy-density energy storage. Fundamental understanding of alkali metal sulfur redox reactions is the prerequisite for rational designs of electrode and electrolyte. Here, we revealed a strong impact of alkali metal cation (Li+, Na+, K+, and Rb+) on polysulfide (PS) stability, redox reversibility, and solid product passivation. We employed operando UV-vis spectroscopy to show that strongly negatively charged short-chain PS (e.g., S42-/S32-) is more stabilized in the electrolyte with larger cation (e.g., Rb+) than that with the smaller cation (e.g., Li+), which is attributed to a stronger cation-anion electrostatic interaction between Rb+ and S42-/S32- owing to its weaker solvation energy. In contrast, Li+ is much more strongly solvated by solvent and thus exhibits a weaker electrostatic interaction with S42-/S32-. The stabilization of short-chain PS in K+-, Rb+-sulfur cells promotes the reduction of long-chain PS to short-chain PS, leading to high discharge potential. However, it discourages the oxidation of short-chain PS to long-chain PS, leading to poor charge reversibility. Our work directly probes alkali metal-sulfur redox chemistry in operando and provides critical insights into alkali metal sulfur reaction mechanism.


Cytometry and DNA ploidy: clinical uses and molecular perspective in gastric and lung cancer.
Flow cytometry is one of the most powerful and specific methods used for the integrated study of the molecular and morphological events occurring during cell proliferation. Many methods have been described for investigating this process. Several cell cycle regulators controlling the correct entry and progression through the cell cycle are altered in tumors. In fact, in most, if not all, human cancers there is a deregulated control of G1 phase progression, the period when cells decide if they will start proliferation or stay quiescent. Cytometry (flow and image) is able to analyze DNA content thanks to the use of the same "molecule" conjugates with a fluorochrome that permits to identify DNA content of single cell in a sample. Most important results of studies on DNA ploidy have been reviewed during the last years and as a result the analyses of DNA ploidy in cancer may provide clinically useful information on diagnostic, therapeutic and prognostic aspects. In fact, aneuploid cancer has a high proliferative activity and a metastatic or invasive potential, markers of a poor prognosis. Multiparametric flow cytometry should allow the simultaneous determination of morphology, phenotype, intracellular protein expression, and status of chromatin and DNA. Evaluating if a particular protein is responsible for the aggressiveness of cancer, or the alteration of DNA content, or if the activation of its state is the cause of rapid growth of cancer cells, is very important and it can facilitate the clinical treatment of patients.


The Biodemography of Fertility: A Review and Future Research Frontiers.
The social sciences have been reticent to integrate a biodemographic approach to the study of fertility choice and behaviour, resulting in theories and findings that are largely socially-deterministic. The aim of this paper is to first reflect on reasons for this lack of integration, provide a review of previous examinations, take stock of what we have learned until now and propose future research frontiers. We review the early foundations of proximate determinants followed by behavioural genetic (family and twin) studies that isolated the extent of genetic influence on fertility traits. We then discuss research that considers gene and environment interaction and the importance of cohort and country-specific estimates, followed by multivariate models that explore motivational precursors to fertility and education. The next section on molecular genetics reviews fertility-related candidate gene studies and their shortcomings and on-going work on genome wide association studies. Work in evolutionary anthropology and biology is then briefly examined, focusing on evidence for natural selection. Biological and genetic factors are relevant in explaining and predicting fertility traits, with socio-environmental factors and their interaction still key in understanding outcomes. Studying the interplay between genes and the environment, new data sources and integration of new methods will be central to understanding and predicting future fertility trends.


TSE eradication in small ruminants--quo vadis?
The term of 'TSE infections in small ruminants' summarises BSE as well as classical and the recently discovered atypical scrapie infections in sheep and goats. There are fundamental differences between the TSE infections in small and large ruminants. Other than in bovines the TSE pathogenesis in small ruminants implies that various peripheral tissues become infectious long before the onset of clinical symptoms. At least in sheep, classical scrapie is efficiently transmitted horizontally within affected flocks. On the other hand, BSE poses a distinctly higher zoonotic risk than scrapie. Therefore, regulatory measures for the protection of animals and humans from a BSE infection must be substantially different for large and small ruminants. While culling of the birth and feeding cohort of a BSE affected cattle is considered to be effective to prevent any further BSE cases in the affected herd, an effective BSE and classical scrapie eradication programme in small ruminants requires a much more stringent eradication strategy and the rendering of all susceptible animals. The situation became even more complicated when atypical scrapie cases with divergent transmission and pathogenesis characteristics and with a novel biochemical phenotype of the infectious agent came into play. The discovery of these atypical scrapie cases has initiated a discussion about the suitability of the current TSE eradication measures in sheep (which are selective breeding and genotype based culling), in particular when such cases were also found in sheep carrying the believed scrapie resistant genotypes.


First-Principles Monte Carlo Simulations of Reaction Equilibria in Compressed Vapors.
Predictive modeling of reaction equilibria presents one of the grand challenges in the field of molecular simulation. Difficulties in the study of such systems arise from the need (i) to accurately model both strong, short-ranged interactions leading to the formation of chemical bonds and weak interactions arising from the environment, and (ii) to sample the range of time scales involving frequent molecular collisions, slow diffusion, and infrequent reactive events. Here we present a novel reactive first-principles Monte Carlo (RxFPMC) approach that allows for investigation of reaction equilibria without the need to prespecify a set of chemical reactions and their ideal-gas equilibrium constants. We apply RxFPMC to investigate a nitrogen/oxygen mixture at T = 3000 K and p = 30 GPa, i.e., conditions that are present in atmospheric lightning strikes and explosions. The RxFPMC simulations show that the solvation environment leads to a significantly enhanced NO concentration that reaches a maximum when oxygen is present in slight excess. In addition, the RxFPMC simulations indicate the formation of NO2 and N2O in mole fractions approaching 1%, whereas N3 and O3 are not observed. The equilibrium distributions obtained from the RxFPMC simulations agree well with those from a thermochemical computer code parametrized to experimental data.


Ten repeat collections for urinary iodine from spot samples or 24-hour samples are needed to reliably estimate individual iodine status in women.
Although the median urinary iodine concentration (UIC) is a good indicator of iodine status in populations, there is no established biomarker for individual iodine status. If the UIC were to be used to assess individuals, it is unclear how many repeat urine collections would be needed and if the collections should be spot samples or 24-h samples. In a prospective, longitudinal, 15-mo study, healthy Swiss women (n = 22) aged 52-77 y collected repeated 24-h urine samples (total n = 341) and corresponding fasting, second-void, morning spot urine samples (n = 177). From the UIC in spot samples, 24-h urinary iodine excretion (UIE) was extrapolated based on the age- and sex-adjusted iodine:creatinine ratio. Measured UIE in 24-h samples, estimated 24-h UIE, and UIC in spot samples were (geometric mean ± SD) 103 ± 28 μg/24 h, 86 ± 33 μg/24 h, and 68 ± 28 μg/L, respectively, with no seasonal differences. Intra-individual variation (mean CV) was comparable for measured UIE (32%) and estimated UIE (33%). The CV tended to be higher for the spot UIC (38%) than for the estimated 24-h UIE (33%) (P = 0.12). In this population, 10 spot urine samples or 24-h urine samples were needed to assess individual iodine status with 20% precision. Spot samples would likely be preferable because of their ease of collection. However, the large number of repeated urine samples needed to estimate individual iodine status is a major limitation and emphasizes the need for further investigation of more practical biomarkers of individual iodine status.


Operative release of complete ankylosis of the elbow due to heterotopic bone in patients without severe injury of the central nervous system.
Although uncommon, complete ankylosis of the elbow secondary to heterotopic ossification results in severe disability. The results of surgical management remain unclear. A single surgeon used a consistent operative technique to treat complete osseous ankylosis of the elbow in eleven limbs in seven patients after severe burns and in nine elbows in eight patients after trauma. The elbows in the burn cohort were more often ankylosed in extension (average, 47 degrees of flexion) compared with those in the trauma cohort (66 degrees of flexion), and they had more skin problems (three elbows required a free microvascular muscle transfer for coverage) and associated problems of the shoulder, wrist, and hand. Four patients in the burn cohort and three patients in the trauma cohort failed to regain at least 80 degrees of ulnohumeral motion. After a repeat release in three burn patients and three trauma patients, and at an average follow-up of forty months, the average arc of ulnohumeral motion was 81 degrees in the burn cohort and 94 degrees in the trauma cohort. Six of the eleven limbs in the burn cohort and five of the nine in the trauma cohort had a good result. The average score according to the American Shoulder and Elbow Surgeons elbow assessment form was 72 points for the burn cohort and 76 points for the trauma cohort. Osseous ankylosis of the elbow is a severely disabling problem, and attempts to regain mobility are both worthwhile and safe. The results are comparable when the ankylosis is caused by burns or trauma despite the greater complexity of osseous ankylosis in the burned arm. Patients and surgeons should be aware of the small risk of recurrent heterotopic ossification and the moderate risk of pain or recurrent contracture after operative release.


The commercialisation of GP services: a survey of APMS contracts and new GP ownership.
Alternative provider of medical services (APMS) legislation enables private commercial firms to provide NHS primary care. There is no central monitoring of APMS adoption by primary care trusts (PCTs), the new providers, or market competition. The aims were to: examine APMS contract data on bidders and providers, patient numbers, contract value, duration, and services; present a typology of primary care providers; establish the extent of competition; and identify which commercial providers have entered the English primary care market. Cross-sectional study. All PCTs in England. A survey was carried out in March 2008 gathering information on the number of APMS contracts, their value and duration, patient numbers, the successful tender, and other bidders. A total of 141 out of 152 PCTs provided information on 71 APMS contracts that had been awarded and 66 contracts that were out to tender. Of those contracts awarded, 36 went to 14 different commercial companies, 28 to independent GP contractors, seven to social enterprises, and two to a PCT-managed service; one contract is shared by three different provider types. In more than half of the responses information on competition was not disclosed. In a fifth of those contracts awarded to the commercial sector, for which there is information on other bidders, there was no competition. Contracts varied widely, covering from one to several hundred thousand patients, with a value of pound6000-12 million, and lasting from 1 year to being open-ended. Most contracts offered standard, essential, additional, and enhanced services; only a few were for specialist services. The lack of data on cost, patient services, and staff makes it impossible to evaluate value for money or quality, and the absence of competition is a further concern. There needs to be a proper evaluation of the APMS policy from the perspective of value for money and quality of care, as well as patient access and coverage.


Transitions into and out of intercollegiate athletic involvement and risky drinking.
Cross-sectional data show that college athletes consume more alcohol and experience more general alcohol-related problems than those not participating in athletics. To our knowledge, the current study is the first to use a longitudinal design to examine the extent to which the course of drinking and alcohol-related problems relates to involvement in intercollegiate athletics, including transitioning into and out of athletic involvement. Participants were drawn from a sample of 3,720 college students from the Intensive Multivariate Prospective Alcohol College-Transitions Study who completed a survey every semester through their fourth year. Four groups were created based on athletic involvement status at baseline (freshman year) and follow-up (senior year): nonathlete, nonathlete (no reported athletic involvement at either time point), nonathlete, athlete (nonathlete at freshman year, athlete at senior year), athlete, nonathlete (athlete at freshman year, nonathlete at senior year), and athlete, athlete (athlete at freshman year, athlete at senior year). A series of repeated measures analyses were then conducted to test for developmental differences among the athlete groups involving alcohol consumption and alcohol-related problems. Although findings differed as a function of alcohol outcome and comparison among various groups with differing athletic involvement, the general pattern of results showed that individuals who were more athletically involved demonstrated sharper increases in problem drinking (i.e., heavy drinking, frequency of intoxication, alcohol-related problems) during the college years. These findings highlight the apparent risk associated with participation in intercollegiate athletics on college drinking.


Evolutionary Medicine: The Ongoing Evolution of Human Physiology and Metabolism.
The field of evolutionary medicine uses evolutionary principles to understand changes in human anatomy and physiology that have occurred over time in response to environmental changes. Through this evolutionary-based approach, we can understand disease as a consequence of anatomical and physiological "trade-offs" that develop to facilitate survival and reproduction. We demonstrate how diachronic study of human anatomy and physiology is fundamental for an increased understanding of human health and disease.


The effect of transcranial direct current stimulation on contrast sensitivity and visual evoked potential amplitude in adults with amblyopia.
Amblyopia is a neurodevelopmental disorder of vision that occurs when the visual cortex receives decorrelated inputs from the two eyes during an early critical period of development. Amblyopic eyes are subject to suppression from the fellow eye, generate weaker visual evoked potentials (VEPs) than fellow eyes and have multiple visual deficits including impairments in visual acuity and contrast sensitivity. Primate models and human psychophysics indicate that stronger suppression is associated with greater deficits in amblyopic eye contrast sensitivity and visual acuity. We tested whether transcranial direct current stimulation (tDCS) of the visual cortex would modulate VEP amplitude and contrast sensitivity in adults with amblyopia. tDCS can transiently alter cortical excitability and may influence suppressive neural interactions. Twenty-one patients with amblyopia and twenty-seven controls completed separate sessions of anodal (a-), cathodal (c-) and sham (s-) visual cortex tDCS. A-tDCS transiently and significantly increased VEP amplitudes for amblyopic, fellow and control eyes and contrast sensitivity for amblyopic and control eyes. C-tDCS decreased VEP amplitude and contrast sensitivity and s-tDCS had no effect. These results suggest that tDCS can modulate visual cortex responses to information from adult amblyopic eyes and provide a foundation for future clinical studies of tDCS in adults with amblyopia.


A radio-high-performance liquid chromatography dual-flow cell gamma-detection system for on-line radiochemical purity and labeling efficiency determination.
In this study, a method of determining radiochemical yield and radiochemical purity using radio-HPLC detection employing a dual-flow-cell system is evaluated. The dual-flow cell, consisting of a reference cell and an analytical cell, was constructed from two PEEK capillary coils to fit into the well of a NaI(Tl) detector. The radio-HPLC flow was directed from the injector to the reference cell allowing on-line detection of the total injected sample activity prior to entering the HPLC column. The radioactivity eluted from the column was then detected in the analytical cell. In this way, the sample will act as its own standard, a feature enabling on-line quantification of the processed radioactivity passing through the system. All data were acquired on-line via an analog signal from a rate meter using chromatographic software. The radiochemical yield and recovery could be simply and accurately determined by integration of the peak areas in the chromatogram obtained from the reference and analytical cells using an experimentally determined volume factor to correct for the effect of different cell volumes.


Arterial structural changes in hypertension: a consideration of methodology, terminology and functional consequence.
Alteration of resistance artery geometric design is a hallmark of established hypertension. In particular, there is an increased media thickness: lumen diameter ratio. In this review, consideration is given to the methods available for assessment of vascular structure, the terminology used to describe vascular structural changes in hypertension and the possible functional consequences of altered arterial design in the maintenance of the hypertensive state. In light of these considerations, a number of proposals are made concerning quantification strategies and descriptor terminologies. In particular, a simple descriptor terminology is proposed that describes such structural differences but makes no assumptions concerning the underlying processes that account for altered arterial structure in hypertension.


Colonic capacitance and transit in man: modulation by luminal contents and drugs.
We have examined whether the human colon is able to adapt its capacity to receive fluid, specifically, whether the caecum and ascending colon ('right colon') exhibited any reservoir function. Healthy volunteers had the caecum intubated from above with a device that permitted intraluminal pressures to be recorded while fluids were instilled into the caecum. Perfusates contained 99mTc-DTPA (diethylenetriamine pentaacetic acid) and volumes of the right colon were determined by two plane scintigraphy using gamma cameras. Different individuals received caecal infusions of 154 mM NaC1 (saline), an emulsion of oleic acid (with bile acids and lecithin) or a 100 mM solution of mixed short chain fatty acids. Each person was pretreated by intravenous saline (placebo), morphine sulphate (100 micrograms/kg) or naloxone (5.5 mg as a bolus, followed by 10 micrograms/kg/min). Volumes of the right colon were smallest during oleic acid infusion; morphine reversed the effect of luminal fat and allowed the colon to accommodate larger volumes. Transit from the right colon was more rapid for the emulsion of oleic acid than it was for saline or solutions of mixed short chain fatty acids. We conclude that the right colon may act as a reservoir and that this function can be modified by the nature of the contents and by pharmacological agents.


Mixed hypomania in 908 patients with bipolar disorder evaluated prospectively in the Stanley Foundation Bipolar Treatment Network: a sex-specific phenomenon.
The prevalence of depressive symptoms co-occurring with hypomanic symptoms has not been quantified. Whether there is a greater likelihood for women to experience mixed symptoms has not been resolved. To determine whether mixed hypomania is observed more frequently than euphoric hypomania and whether a sex effect exists in patients with bipolar disorder. Academic research settings in the United States (4 sites) and Europe (3 sites). Subjects were enrolled in a naturalistic prospective study after providing written informed consent. Mixed hypomania was defined at a given visit as a Young Mania Rating Scale score of 12 or higher and an Inventory of Depressive Symptomatology-Clinician-Rated Version score of 15 or higher. Given partial overlap of items from these scales, exploratory analyses were completed assessing instrument overlap affecting the findings. In 908 patients, 14 328 visits over 7 years were evaluated. Patients with bipolar I disorder were significantly more likely to experience hypomania than those with bipolar II disorder. Of all 1044 visits by patients with hypomanic symptoms, 57% met criteria for mixed hypomania. The likelihood of depression was significantly greater for women during hypomania (P<.001). For women, the probability of mixed symptoms increased with the severity of hypomania and then decreased at the most severe levels of hypomania or mania. When a modified Inventory of Depressive Symptomatology-Clinician-Rated Version was evaluated by removing the 5 overlapping Young Mania Rating Scale items, a significant sex effect persisted for women (P<.001) but not for men (P = .95), owing to the elimination of the items "irritability" and "agitation." Mixed hypomania is common in patients with symptoms of hypomania and particularly common in women. Potential overlap of clinical symptom scales should be assessed before study of patients with bipolar disorder symptoms is undertaken.


Discovery of novel representatives of bilaterian neuropeptide families and reconstruction of neuropeptide precursor evolution in ophiuroid echinoderms.
Neuropeptides are a diverse class of intercellular signalling molecules that mediate neuronal regulation of many physiological and behavioural processes. Recent advances in genome/transcriptome sequencing are enabling identification of neuropeptide precursor proteins in species from a growing variety of animal taxa, providing new insights into the evolution of neuropeptide signalling. Here, detailed analysis of transcriptome sequence data from three brittle star species, Ophionotus victoriae, Amphiura filiformis and Ophiopsila aranea, has enabled the first comprehensive identification of neuropeptide precursors in the class Ophiuroidea of the phylum Echinodermata. Representatives of over 30 bilaterian neuropeptide precursor families were identified, some of which occur as paralogues. Furthermore, homologues of endothelin/CCHamide, eclosion hormone, neuropeptide-F/Y and nucleobinin/nesfatin were discovered here in a deuterostome/echinoderm for the first time. The majority of ophiuroid neuropeptide precursors contain a single copy of a neuropeptide, but several precursors comprise multiple copies of identical or non-identical, but structurally related, neuropeptides. Here, we performed an unprecedented investigation of the evolution of neuropeptide copy number over a period of approximately 270 Myr by analysing sequence data from over 50 ophiuroid species, with reference to a robust phylogeny. Our analysis indicates that the composition of neuropeptide 'cocktails' is functionally important, but with plasticity over long evolutionary time scales.


Heparan 2-O-sulfotransferase, hst-2, is essential for normal cell migration in Caenorhabditis elegans.
The importance of heparan sulfate proteoglycans has been highlighted by a number of human genetic disorders associated with mutations in genes encoding for heparan sulfate proteoglycan protein cores or biosynthetic enzymes required for heparan sulfate (HS) assembly. To study the functional role of HS in Caenorhabditis elegans development cosmid sequence C34F6.4 was identified as the C. elegans ortholog of vertebrate heparan 2-O-sulfotransferase (HS2ST) and the gene named hst-2. HS2ST activity is present in C. elegans and is completely absent in a deletion mutant of hst-2, ok595, and specifically reduced by hst-2 RNA interference. Expression of hst-2 in CHO cells deficient in HS2ST rescues enzyme activity and binding of FGF2 to cell surface HS. hst-2 expression is found in the hypodermis, muscle, distal tip cells (DTCs), and in neurons. A null mutation in hst-2 causes cell migration defects. This work demonstrates sulfotransferase activity in C. elegans and indicates that specific 2-O-sulfate modifications are critical for normal HS functions in controlling cell migration.


Import Security: Assessing the Risks of Imported Food.
We use data on food import violations from the FDA Operational and Administrative System for Import Support (OASIS) to address rising concerns associated with imported food, quantify import risks by product and by country of origin, and explore the usefulness of OASIS data for risk assessment. In particular, we assess whether there are significant trends in violations, whether import violations can be used to quantify risks by country and by product, and how import risks depend on economic factors of the country of origin. The results show that normalizing import violations by volume of imports provides a meaningful indicator of risk. We then use regression analysis to characterize import risks. Using this model, we analyze import risks by product type, violation type, and economic factors of the country of origin. We find that OASIS data are useful in quantifying food import risks, and that the rate of refusals provides a useful decision tool for risk management. Furthermore, we find that some economic factors are significant indicators of food import risk by country.


Efficacy and feasibility of home-based training for individuals with homonymous visual field defects.
Homonymous visual field defects (HVFDs) are one of the most common consequences of stroke. Compensatory training encourages affected individuals to develop more efficient eye movements to improve function. However, training is typically supervised, which can be time consuming and costly. To develop and evaluate the efficacy and feasibility of an unsupervised reading and exploration computer training for individuals with HVFDs. Seventy individuals with chronic HVFDs were randomly assigned to 1 of 2 groups: intervention or control. The former received 35 hours of reading and exploration training, and the latter received 35 hours of control training. Visual and attentional abilities were assessed before and after training using perimetry, visual search, reading, activities of daily living, the Test of Everyday Attention, and a Sustained Attention to Response task. Eighteen individuals failed to complete the training; analyses were conducted on the remaining 28 intervention and 24 control group participants. Individuals in the intervention group demonstrated significant improvements in the primary outcomes of exploration (12.87%, 95% confidence interval [CI] = 8.44% to 17.30%) and reading (18.45%, 95% CI = 9.93% to 26.97%), which were significantly greater than those observed following the control intervention (exploration = 4.80%, 95% CI = 0.09% to 9.51%; reading = 1.95%, 95% CI = -4.78% to 8.68%). Participants in the intervention group also reported secondary subjective improvements, although these were not matched by objective gains in tasks simulating activities of daily living. Home-based compensatory training is an inexpensive accessible rehabilitation option for individuals with HVFDs, which can result in objective benefits in searching and reading, as well as improving quality of life.


Spatial mapping of functional pelvic bone marrow using FLT PET.
The purpose of this study was to determine the ability of regions identified with bony landmarks on CT imaging to accurately represent active bone marrow when compared to FLT PET imaging. These surrogate regions could then be used to create a bone marrow sparing radiation therapy plan when FLT PET imaging is not available. Whole body (WB) FLT PET images were obtained of 18 subjects prior to chemoradiation therapy. The FLT image of each subject was registered to a CT image acquired for that subject to obtain anatomic information of the pelvis. Seventeen regions were identified based on features of the pelvic bones, sacrum, and femoral heads. The probability of FLT uptake being located in each of 17 different CT-based regions of the bony pelvis was calculated using Tukey's multiple comparison test. Statistical analysis of FLT uptake in the pelvis indicated four distinct groups within the 17 regions that had similar levels of activity. Regions located in the central part of the pelvis, including the superior part of the sacrum, the inner halves of the iliac crests, and the L5 vertebral body, had greater FLT uptake than those in the peripheral regions (p-value < 0.05). We have developed a method to use CT-defined pelvic bone regions to represent FLT PET-identified functional bone marrow. Individual regions that have a statistically significant probability of containing functional bone marrow can be used as avoidance regions to reduce radiation dose to functional bone marrow in radiation therapy planning. However, because likely active bone marrow regions and pelvic targets typically overlap, patient-specific spatial detail may be advantageous in IMRT planning scenarios and may best be provided using FLT PET imaging.


Differential performance of a specialist and two generalist herbivores and their parasitoids on Plantago lanceolata.
The ability to cope with plant defense chemicals differs between specialist and generalist species. In this study, we examined the effects of the concentration of the two main iridoid glycosides (IGs) in Plantago lanceolata, aucubin and catalpol, on the performance of a specialist and two generalist herbivores and their respective endoparasitoids. Development of the specialist herbivore Melitaea cinxia was unaffected by the total leaf IG concentration in its host plant. By contrast, the generalist herbivores Spodoptera exigua and Chrysodeixis chalcites showed delayed larval and pupal development on plant genotypes with high leaf IG concentrations, respectively. This result is in line with the idea that specialist herbivores are better adapted to allelochemicals in host plants on which they are specialized. Melitaea cinxia experienced less post-diapause larval and pupal mortality on its local Finnish P. lanceolata than on Dutch genotypes. This could not be explained by differences in IG profiles, suggesting that M. cinxia has adapted in response to attributes of its local host plants other than to IG chemistry. Development of the specialist parasitoid Cotesia melitaearum was unaffected by IG variation in the diet of its host M. cinxia, a response that was concordant with that of its host. By contrast, the development time responses of the generalist parasitoids Hyposoter didymator and Cotesia marginiventris differed from those of their generalist hosts, S. exigua and C. chalcites. While their hosts developed slowly on high-IG genotypes, development time of H. didymator was unaffected. Cotesia marginiventris actually developed faster on hosts fed high-IG genotypes, although they then had short adult longevity. The faster development of C. marginiventris on hosts that ate high-IG genotypes is in line with the "immunocompromized host" hypothesis, emphasizing the potential negative effects of toxic allelochemicals on the host's immune response.


Expansion of Adult Human Pancreatic Tissue Yields Organoids Harboring Progenitor Cells with Endocrine Differentiation Potential.
Generating an unlimited source of human insulin-producing cells is a prerequisite to advance β cell replacement therapy for diabetes. Here, we describe a 3D culture system that supports the expansion of adult human pancreatic tissue and the generation of a cell subpopulation with progenitor characteristics. These cells display high aldehyde dehydrogenase activity (ALDHhi), express pancreatic progenitors markers (PDX1, PTF1A, CPA1, and MYC), and can form new organoids in contrast to ALDHlo cells. Interestingly, gene expression profiling revealed that ALDHhi cells are closer to human fetal pancreatic tissue compared with adult pancreatic tissue. Endocrine lineage markers were detected upon in vitro differentiation. Engrafted organoids differentiated toward insulin-positive (INS+) cells, and circulating human C-peptide was detected upon glucose challenge 1 month after transplantation. Engrafted ALDHhi cells formed INS+ cells. We conclude that adult human pancreatic tissue has potential for expansion into 3D structures harboring progenitor cells with endocrine differentiation potential.


State policy influence on the early diffusion of buprenorphine in community treatment programs.
Buprenorphine was approved for use in the treatment of opioid dependence in 2002, but its diffusion into everyday clinical practice in community-based treatment programs has been slow. This study examines the net impact of efforts by state agencies, including provision of Medicaid coverage, on program-level adoption of buprenorphine as of 2006. Interviews were conducted with key informants in 49 of the 50 state agencies with oversight responsibility for addiction treatment services. Information from these interviews was integrated with organizational data from the 2006 National Survey of Substance Abuse Treatment Services. A multivariate logistic regression model was estimated to identify the effects of state efforts to promote the use of this medication, net of a host of organizational characteristics. The availability of Medicaid coverage for buprenorphine was a significant predictor of its adoption by treatment organizations. Inclusion of buprenorphine on state Medicaid formularies appears to be a key element in ensuring that patients have access to this state-of-the-art treatment option. Other potential barriers to the diffusion of buprenorphine require identification, and the value of additional state-level policies to promote its use should be evaluated.


Central thalamic contributions to arousal regulation and neurological disorders of consciousness.
This review focuses on the contributions of the central thalamus to normal mechanisms of arousal regulation and to neurological disorders of consciousness. Forebrain arousal is regulated by ascending influences from brainstem/basal forebrain neuronal populations ("arousal systems") and control signals descending from frontal cortical systems. These subcortical and cortical systems have converging projections to the central thalamus that emphasize their role in maintaining organized behavior during wakefulness. Central thalamic neurons appear to be specialized both anatomically and physiologically to support distributed network activity that maintains neuronal firing patterns across long-range cortico-cortical pathways and within cortico-striatopallidal-thalamocortical loop connections. Recruitment of central thalamic neurons occurs in response to increasing cognitive demand, stress, fatigue, and other perturbations that reduce behavioral performance. In addition, the central thalamus receives projections from brainstem pathways evolved to rapidly generate brief shifts of arousal associated with the appearance of salient stimuli across different sensory modalities. Through activation of the central thalamus, neurons across the cerebral cortex and striatum can be depolarized and their activity patterns selectively gated by descending or ascending signals related to premotor attention and alerting stimuli. Direct injury to the central thalamus or prominent deafferentation of these neurons as a result of complex, multifocal, brain insults are both associated with severe impairment of forebrain functional integration and arousal regulation. Interventions targeting neurons within the central thalamus may lead to rational therapeutic approaches to the treatment of impaired arousal regulation following nonprogressive brain injuries. A model accounting for present therapeutic strategies is proposed.


Cloning of human androgen receptor complementary DNA and localization to the X chromosome.
The androgen receptor (AR) mediates the actions of male sex steroids. Human AR genomic DNA was cloned from a flow-sorted human X chromosome library by using a consensus nucleotide sequence from the DNA-binding domain of the family of nuclear receptors. The AR gene was localized on the human X chromosome between the centromere and q13. Cloned complementary DNA, selected with an AR-specific oligonucleotide probe, was expressed in monkey kidney (COS) cells and yielded a high-affinity androgen-binding protein with steroid-binding specificity corresponding to that of native AR. A predominant messenger RNA species of 9.6 kilobases was identified in human, rat, and mouse tissues known to contain AR and was undetectable in tissues lacking AR androgen-binding activity, including kidney and liver from androgen-insensitive mice. The deduced amino acid sequence of AR within the DNA-binding domain has highest sequence identity with the progesterone receptor.


When Is "Gay Panic" Accepted? Exploring Juror Characteristics and Case Type as Predictors of a Successful Gay Panic Defense.
"Gay panic" refers to a situation in which a heterosexual individual charged with a violent crime against a homosexual individual claims they lost control and reacted violently because of an unwanted sexual advance that was made upon them. This justification for a violent crime presented by the defendant in the form of a provocation defense is used as an effort to mitigate the charges brought against him. There has been relatively little research conducted concerning this defense strategy and the variables that might predict when the defense is likely to be successful in achieving a lesser sentence for the defendant. This study utilized 249 mock jurors to assess the effects of case type (assault or homicide) and juror characteristics (homophobia, religious fundamentalism, and political orientation) on the success of the gay panic defense compared with a neutral provocation defense. Participant homophobia was found to be the driving force behind their willingness to accept the gay panic defense as legitimate. Higher levels of homophobia and religious fundamentalism were found to predict more leniency in verdict decisions when the gay panic defense was presented. This study furthers the understanding of decision making in cases involving the gay panic defense and highlights the need for more research to be conducted to help understand and combat LGBT (lesbian, gay, bisexual, and transgender) prejudice in the courtroom.


Putting recommendations into practice: Australian rheumatologists' opinions on leflunomide use in rheumatoid arthritis.
Leflunomide is the most recently introduced conventional disease-modifying anti-rheumatic drugs in Australia. It has several unique methods for initiation, unique monitoring recommendations and a distinctive cessation protocol in the event of serious toxicity. The aim of this study was to evaluate initiation and monitoring practices of Australian rheumatologists using leflunomide. A survey was emailed twice, approximately 3 months apart to 332 rheumatologist members of the Australian Rheumatology Association. Wave analysis was used to assess evidence of non-response bias. The response rate to the survey was 20% and there was no difference between the responses of waves 1 and 2. Fifty percent of the respondents indicated that 20 mg once daily was the initial dose of leflunomide that they most commonly prescribed, 45% indicated 10 mg once daily, whilst only 3% preferred to initiate leflunomide at 100 mg daily for 2-3 days followed by 10 mg once a day as recommended when first marketed. Of the responders, 12% had used doses above 20 mg daily and 70% had used alternate daily dosing with leflunomide. In a patient taking leflunomide with an ALT or AST >3 times the ULN on two or more blood tests, 75% of responders indicated they would stop leflunomide immediately and 20% would follow cessation by administering a cholestyramine washout. The choice of initial leflunomide dose among responding Australian rheumatologists varied considerably, although most preferred not to use the loading dose. Despite the recommendation of clinical guidelines, the use of a cholestyramine washout procedure for hepatic toxicity is not universal.


Myeloid IKKβ promotes antitumor immunity by modulating CCL11 and the innate immune response.
Myeloid cells are capable of promoting or eradicating tumor cells and the nodal functions that contribute to their different roles are still obscure. Here, we show that mice with myeloid-specific genetic loss of the NF-κB pathway regulatory kinase IKKβ exhibit more rapid growth of cutaneous and lung melanoma tumors. In a BRAF(V600E/PTEN(-/-)) allograft model, IKKβ loss in macrophages reduced recruitment of myeloid cells into the tumor, lowered expression of MHC class II molecules, and enhanced production of the chemokine CCL11, thereby negatively regulating dendritic-cell maturation. Elevated serum and tissue levels of CCL11 mediated suppression of dendritic-cell differentiation/maturation within the tumor microenvironment, skewing it toward a Th2 immune response and impairing CD8(+) T cell-mediated tumor cell lysis. Depleting macrophages or CD8(+) T cells in mice with wild-type IKKβ myeloid cells enhanced tumor growth, where the myeloid cell response was used to mediate antitumor immunity against melanoma tumors (with less dependency on a CD8(+) T-cell response). In contrast, myeloid cells deficient in IKKβ were compromised in tumor cell lysis, based on their reduced ability to phagocytize and digest tumor cells. Thus, mice with continuous IKKβ signaling in myeloid-lineage cells (IKKβ(CA)) exhibited enhanced antitumor immunity and reduced melanoma outgrowth. Collectively, our results illuminate new mechanisms through which NF-κB signaling in myeloid cells promotes innate tumor surveillance.


Psychiatric context of acute/early HIV infection. The NIMH Multisite Acute HIV Infection Study: IV.
Acute/early HIV infection is a period of high risk for HIV transmission. Better understanding of behavioral aspects during this period could improve interventions to limit further transmission. Thirty-four participants with acute/early HIV infection from six US cities were assessed with the Mini International Diagnostic Interview, Beck Depression Inventory II, State-Trait Anxiety Inventory, Brief COPE, and an in-depth interview. Most had a pre-HIV history of alcohol or substance use disorder (85%); a majority (53%) had a history of major depressive or bipolar disorder. However, post-diagnosis coping was predominantly adaptive, with only mild to moderate elevations of anxious or depressive mood. Respondents described challenges managing HIV in tandem with pre-existing substance abuse problems, depression, and anxiety. Integration into medical and community services was associated with adaptive coping. The psychiatric context of acute/early HIV infection may be a precursor to infection, but not necessarily a barrier to intervention to reduce forward transmission of HIV among persons newly infected.


Aesthetic breast shape preferences among plastic surgeons.
There has been little discussion in the plastic surgery literature regarding breast shape preferences among plastic surgeons, despite strong evidence that such aesthetic preferences are influenced by multiple factors. Much effort has been focused on delineating the objective criteria by which an "attractive" breast might be defined. This study aimed at providing a better understanding of the presence and significance of differences in personal aesthetic perception, and how these relate to a plastic surgeon's demographic, ethnic, and cultural background, as well as practice type (academic vs private). An interactive online survey was designed. Modifiable ranges of upper pole fullness and areola size were achieved via digital alteration, enabling participants to interactively change the shape of a model's breasts. The questionnaire was translated into multiple languages and sent to plastic surgeons worldwide. Demographic data were also collected. Analysis of variance was used to elucidate plastic surgeon's breast shape preferences in respect to sex and age, geographic and ethnic background, as well as practice type. The authors gathered 614 responses from 29 different countries. Significant differences regarding preferences for upper pole fullness, areola size in the natural breast, and areola size in the augmented breast were identified across surgeons from the different countries. Further, significant relationships regarding breast shape preferences were distilled between the age and sex of the surgeon, as well as the practice type. No differences were found in respect to the surgeons' self-reported ethnic background. Country of residence, age, and practice type significantly impact breast shape preferences of plastic surgeons. These findings have implications for both patients seeking and surgeons performing cosmetic and reconstructive breast surgery. In an increasingly global environment, cultural differences and international variability must be considered when defining and publishing new techniques and aesthetic outcomes. When both the plastic surgeon and the patient are able to adequately and effectively communicate their preferences regarding the shape and relations of the breast, they will be more successful at achieving satisfying results.


Interfacial engineering of renewable metal organic framework derived honeycomb-like nanoporous aluminum hydroxide with tunable porosity.
Novel honeycomb-like mesoporous aluminum hydroxide (pATH) was synthesized via a facile one-step reaction by employing ZIF-8 as a template. This self-decomposing template was removed automatically under acidic conditions without the need for any tedious or hazardous procedures. Meanwhile, the pore size of pATH was easily modulated by tuning the dimensions of the ZIF-8 polyhedrons. Of paramount importance was the fact that the dissolved ZIF-8 in solution was regenerated upon deprotonation of the ligand under mild alkali conditions, and was reused in the preparation of pATH, thus forming a delicate synthesis cycle. The renewable template conferred cost-effective and sustainable features to the as-synthesized product. As a proof-of-concept application, the fascinating nanoporous structure enabled pATH to load more phosphorous-containing flame retardant and endowed better interaction with epoxy resin over that of commercial aluminum hydroxide. The limiting oxygen index, UL-94 vertical burning test and cone calorimeter test showed that the results of epoxy with the modified pATH rivalled those of epoxy with two times the loading amount of the commercial counterpart, while the former presented better mechanical properties. The proposed "amorphous replica method" used in this work will advance the potential for launching a vast area of research and technology development for the preparation of porous metal hydroxides for use in practical applications.


Pathogenesis of prion diseases: current status and future outlook.
The prion, a conformational variant of a host protein, is the infectious particle responsible for transmissible spongiform encephalopathy (TSE), a fatal neurodegenerative disease of humans and animals. The principal target of prion pathology is the brain, yet most TSEs also display prion replication at extra-cerebral locations, including secondary lymphoid organs and sites of chronic inflammation. Despite significant progress in our understanding of this infectious agent, many fundamental questions relating to the nature of the prion, including the mechanism of replication and the molecular events underlying brain damage, remain unanswered. Here we focus on the unresolved issues pertaining to prion pathogenesis, particularly on the role played by the immune system.


Laparoscopic surgery for distal tubal occlusions: lessons learned from a historical series of 434 cases.
To evaluate the success rate of laparoscopic neosalpingostomy and the factors affecting the results in terms of intrauterine pregnancy (IUP), delivery (DEL), and ectopic pregnancy (EP). Retrospective analysis of prospectively recorded data. Private practice. A total of 434 consecutive infertile patients from 21 to 42 years old with a follow-up of more than 10 years. Laparoscopic neosalpingostomy. Intrauterine pregnancy, delivery, and EP rates obtained without requiring IVF. Statistical analysis includes univariate and multivariate analysis and crude and actuarial success rates. Just over one-quarter (28.8%) of the patients presented an IUP, 24.4% delivered, and 9% presented with an EP. The 5-year actuarial rate of delivery was 37%. This rate was largely dependent on the tubal stage (stage 1: 53.1%; stage 2: 43.1%; stage 3: 24.0%; stage 4: 23.1%). Forty-three percent of the expected IUPs started in the first year, and 75% started in the first two years. Multivariate analysis found some poor-prognosis patterns for tubal stage 3 (odds ratio [OR] 0.24), tubal stage 4 (OR 0.28), repeated neosalpingostomy (OR 0.168), previous EP (OR 0.202), severe adhesion stage (OR 0.211), and positive chlamydial serology (OR 0.515). Eversion with sutures provides nonsignificantly better results (OR 1.63) compared with eversion with coagulation. Neosalpingostomy must not be proposed in selected cases according to the tubal stage, adhesion stage, and chlamydial serology. When neosalpingostomy is performed, fimbrial eversion with sutures provides slightly better results.


Associations of muscle force, power, cross-sectional muscle area and bone geometry in older UK men.
Ageing is associated with sarcopenia, osteoporosis, and increased fall risk, all of which contribute to increased fracture risk. Mechanically, bone strength adapts in response to forces created by muscle contractions. Adaptations can be through changes in bone size, geometry, and bending strength. Muscle mass is often used as a surrogate for muscle force; however, force can be increased without changes in muscle mass. Increased fall risk with ageing has been associated with a decline in muscle power-which is a measure of mobility. The aims of this study were as follows: (i) to investigate the relationship between muscle parameters in the upper and lower limbs with age in UK men and the influence of ethnicity on these relationships; (ii) to examine the relationships between jump force/grip strength/cross-sectional muscle area (CSMA) with bone outcomes at the radius and tibia. White European, Black Afro-Caribbean, and South Asian men aged 40-79 years were recruited from Manchester, UK. Cortical bone mineral content, cross-sectional area, cortical area, cross-sectional moment of inertia, and CSMA were measured at the diaphysis of the radius and tibia using peripheral quantitative computed tomography. Lower limb jump force and power were measured from a single two-legged jump performed on a ground-reaction force platform. Grip strength was measured using a dynamometer. Associations between muscle and bone outcomes was determined using linear regression with adjustments for age, height, weight, and ethnicity. Three hundred and one men were recruited. Jump force was negatively associated with age; for every 10 year increase in age, there was a 4% reduction in jump force (P < 0.0001). There was a significant age-ethnicity interaction for jump power (P = 0.039); after adjustments, this was attenuated (P = 0.088). For every 10 year increase in age, grip strength decreased by 11%. Jump force was positively associated with tibial bone outcomes: a 1 standard deviation greater jump force was associated with significantly higher cortical bone mineral content 3.1%, cross-sectional area 4.2%, cortical area 3.4%, and cross-sectional moment of inertia 6.8% (all P < 0.001). Cross-sectional muscle area of the lower leg was not associated with tibial bone outcomes. Both grip strength and CSMA of the arm were positively associated, to a similar extent, with radius diaphyseal bone outcomes. Jump force and power are negatively associated with age in UK men. In the lower limb, the measurement of jump force is more strongly related to bone outcomes than CSMA. It is important to consider jump force and power when understanding the aetiology of bone loss and mobility in ageing men.


Diet induced maternal obesity affects offspring gut microbiota and persists into young adulthood.
Accumulating evidence suggests that diet could shape the host gut microbiome composition. Herein, we investigated the effects of maternal high fat diet (HFD) consumption on the gut microbiota and serum profile of mice offspring, and attempted to explore the beneficial roles of maternal probiotics intervention. Female C57BL/6J mice were fed with normal diet, HFD or HFD with daily probiotics (B. breve DM8310, L. acidophilus DM8302, L. casei DM8121 and S. thermophilus DM8309) by gavage starting 6 weeks prior to breeding and continued throughout gestation and lactation. Pups of HFD dams had higher levels of total cholesterol (TC), low-density lipoprotein (LDL), glucose, insulin and leptin compared to those of chow-fed dams. Maternal probiotics intervention resulted in a decrease in the lipid levels in all the pups, while the glucose, insulin and leptin levels were decreased only in adult female pups compared to those from HFD-fed dams; the decreased levels were similar to those in the pups of chow-fed dams. In line with these plasma changes, maternal HFD persistently altered the composition of the offspring gut microbiota in a sex specific way. Maternal probiotics intervention could ameliorate gut microbiota dysbiosis in the offspring. Such intervention showed better effects particularly for the female pups at adulthood. In conclusion, maternal HFD-induced gut microbiota dysbiosis and metabolic disorder could persist through the adulthood of the offspring. Maternal probiotics intervention can negate the detrimental effects of maternal HFD on the gut microbiota and metabolism in the offspring in a sex specific way.


Early puberty, negative peer influence, and problem behaviors in adolescent girls.
To determine how early puberty and peer deviance relate to trajectories of aggressive and delinquent behavior in early adolescence and whether these relationships differ by race/ethnicity. In this longitudinal study, 2607 girls from 3 metropolitan areas and their parents were interviewed at ages 11, 13, and 16 years. Girls reported on their age of onset of menarche, best friend's deviant behavior, delinquency, and physical, relational, and nonphysical aggression. Parents provided information on family sociodemographic characteristics and girls' race/ethnicity. Sixteen percent of girls were classified as early maturers (defined by onset of menarche before age 11 years). Overall, relational and nonphysical aggression increased from age 11 to age 16, whereas delinquency and physical aggression remained stable. Early puberty was associated with elevated delinquency and physical aggression at age 11. The relationship with early puberty diminished over time for physical aggression but not for delinquency. Best friend's deviant behavior was linked with higher levels of all problem behaviors, but the effect lessened over time for most outcomes. Early puberty was associated with a stronger link between best friend's deviance and delinquency, suggesting increased vulnerability to negative peer influences among early-maturing girls. A similar vulnerability was observed for relational and nonphysical aggression among girls in the "other" racial/ethnic minority group only. Early puberty and friends' deviance may increase the risk of problem behavior in young adolescent girls. Although many of these associations dissipate over time, early-maturing girls are at risk of persistently higher delinquency and stronger negative peer influences.


Relationship between Semmes-Weinstein Monofilaments perception Test and sensory nerve conduction studies in Carpal Tunnel Syndrome.
The Semmes-Weinstein Monofilament Test (SWMT) is a clinical widely used test to quantify the sensibility in patients with Carpal Tunnel Syndrome (CTS). No study has investigated the relationship between the SWMT and sensory nerve conduction studies (SNCS) in patients with CTS. To assess the relationship between the SWMT and SNCS findings in patients with CTS. This cross-sectional clinical measurement study included 35 patients with CTS (55 hands) with a mean age of 45 ± 12 years. The outcome measures were the SWMT and SNCS measures of distal latency (DLs), amplitude (AMPs), and nerve conduction velocity (NCV). The median innervated fingers were tested using SWMT and electrodiagnostic tests. The primary outcome was the correlations between the SWMTs and NCS measures. All of the patients/hands had abnormal NCS findings. When looking at the three digits of interest (thumb, index and middle), the thumb SWMTs had the highest number of abnormal findings (58.2%), with the middle digit having the lowest (45.5%). All NCS findings were statistically different between abnormal and normal thumb SWMTs and abnormal and normal total summed SWMTs. There were significant moderate correlations between thumb SWMT scores and all NCS outcomes. Although only approximately 50% of the CTS diagnosed through NCS are corroborated through SWMT; the significant associations between SWMT and NCS measures suggest that SWMT is a valid test for assessing sensations in patients with CTS.


Citrobacter freundii empyema in a patient with occult pulmonary histoplasmosis.
The genus Citrobacter includes three species of organisms that are uncommonly associated with human infection. When they are pathogenic, there are usually one or more associated respiratory, urinary, skin-soft tissue, and central nervous system infections and neonatal sepsis. These infections occur in the wake of significant systemic illness or complicate antibiotic usage. Rarely, infection has been associated with active tuberculosis. The authors report a case of Citrobacter freundii empyema in a patient with occult pulmonary histoplasmosis.


Connections of the IMHV in the domestic chick Gallus domesticus.
The responses to single electrical stimuli have been recorded from neurons in the brains of domestic chicks, by using an in vitro preparation consisting of a coronal slice taken from the forebrain. All slices were cut so that they contained the intermediate part of the medial hyperstriatum ventrale (IMHV). When such a slice is bathed in standard Krebs' solution there is no evidence that the excitation produced by a single stimulus can be transmitted more than 1 mm either towards or away from the IMHV. The addition of bicuculline methiodide (more than 3 x 10(-6) M) to Krebs' solution allows the excitation produced by a single stimulus to spread in all directions throughout the dorsal half of a coronal slice. At points remote (more than 1.5 mm) from the stimulated point, the magnitude of the spreading wave of excitation bears an all-or-nothing relation to the strength of stimulus used to excite it. This wave of excitation spreads from the excited point in all directions without attenuation at 0.9 +/- 0.017 (s.d.) m s-1 and consists of a prolonged burst of activity of the invaded neurons. The properties of coronal slices described above are also true of brain slices cut in a parasagittal plane. The spreading response to a single stimulus given in the presence of bicuculline, can be reduced in magnitude by the addition of AP-5 but it still spreads throughout the dorsal part of the slice at the same velocity. The response can be eliminated by the addition of kynurenic acid. The addition of curare to the bathing medium produces similar responses that spread in a similar fashion to those seen under bicuculline. These results suggest that the dorsal part of the forebrain of the domestic chick (in fact, the part derived from the embryological alar plate) contains a network of reciprocally connected local circuits. Transmission throughout the network is normally prevented by active inhibition.


Manganese exposure alters extracellular GABA, GABA receptor and transporter protein and mRNA levels in the developing rat brain.
Unlike other essential trace elements (e.g., zinc and iron) it is the toxicity of manganese (Mn) that is more common in human populations than its deficiency. Data suggest alterations in dopamine biology may drive the effects associated with Mn neurotoxicity, though recently gamma-aminobutyric acid (GABA) has been implicated. In addition, iron deficiency (ID), a common nutritional problem, may cause disturbances in neurochemistry by facilitating accumulation of Mn in the brain. Previous data from our lab have shown decreased brain tissue levels of GABA as well as decreased (3)H-GABA uptake in synaptosomes as a result of Mn exposure and ID. These results indicate a possible increase in the concentration of extracellular GABA due to alterations in expression of GABA transport and receptor proteins. In this study weanling-male Sprague-Dawley rats were randomly placed into one of four dietary treatment groups: control (CN; 35mg Fe/kg diet), iron-deficient (ID; 6mg Fe/kg diet), CN with Mn supplementation (via the drinking water; 1g Mn/l) (CNMn), and ID with Mn supplementation (IDMn). Using in vivo microdialysis, an increase in extracellular GABA concentrations in the striatum was observed in response to Mn exposure and ID although correlational analysis reveals that extracellular GABA is related more to extracellular iron levels and not Mn. A diverse effect of Mn exposure and ID was observed in the regions examined via Western blot and RT-PCR analysis, with effects on mRNA and protein expression of GAT-1, GABA(A), and GABA(B) differing between and within the regions examined. For example, Mn exposure reduced GAT-1 protein expression by approximately 50% in the substantia nigra, while increasing mRNA expression approximately four-fold, while in the caudate putamen mRNA expression was decreased with no effect on protein expression. These data suggest that Mn exposure results in an increase in extracellular GABA concentrations via altered expression of transport and receptor proteins, which may be the basis of the neurological characteristics of manganism.


Computational strategies for genome-based natural product discovery and engineering in fungi.
Fungal natural products possess biological activities that are of great value to medicine, agriculture and manufacturing. Recent metagenomic studies accentuate the vastness of fungal taxonomic diversity, and the accompanying specialized metabolic diversity offers a great and still largely untapped resource for natural product discovery. Although fungal natural products show an impressive variation in chemical structures and biological activities, their biosynthetic pathways share a number of key characteristics. First, genes encoding successive steps of a biosynthetic pathway tend to be located adjacently on the chromosome in biosynthetic gene clusters (BGCs). Second, these BGCs are often are located on specific regions of the genome and show a discontinuous distribution among evolutionarily related species and isolates. Third, the same enzyme (super)families are often involved in the production of widely different compounds. Fourth, genes that function in the same pathway are often co-regulated, and therefore co-expressed across various growth conditions. In this mini-review, we describe how these partly interlinked characteristics can be exploited to computationally identify BGCs in fungal genomes and to connect them to their products. Particular attention will be given to novel algorithms to identify unusual classes of BGCs, as well as integrative pan-genomic approaches that use a combination of genomic and metabolomic data for parallelized natural product discovery across multiple strains. Such novel technologies will not only expedite the natural product discovery process, but will also allow the assembly of a high-quality toolbox for the re-design or even de novo design of biosynthetic pathways using synthetic biology approaches.


Effect of simulator training on fitness-to-drive after stroke: a 5-year follow-up of a randomized controlled trial.
No long-term studies have been reported on the effect of training programs on driving after stroke. The authors' primary aim was to determine the effect of simulator versus cognitive rehabilitation therapy on fitness-to-drive at 5 years poststroke. A second aim was to investigate differences in clinical characteristics between stroke survivors who resumed and stopped driving. In a previously reported randomized controlled trial, 83 stroke survivors received 15 hours of simulator training (n = 42) or cognitive therapy (n = 41). In this 5-year follow-up study, 61 participants were reassessed. Fitness-to-drive decisions were obtained from medical, visual, neuropsychological, and on-road tests; 44 participants (simulator group, n = 21; cognitive group, n = 23) completed all assessments. The primary outcome measures were fitness-to-drive decision and current driving status. The authors found that 5 years after stroke, 18 of 30 participants (60%) in the simulator group were considered fit to drive, compared with 15 of 31 (48%) in the cognitive group (P = .36); 34 of 61 (56%) participants were driving. Current drivers were younger (P = .04), had higher Barthel scores (P = .008), had less comorbidity (P = .01), and were less severely depressed (P = .02) than those who gave up driving. The advantage of simulator-based driving training over cognitive rehabilitation therapy, evident at 6 months poststroke, had faded 5 years later. Poststroke drivers were younger and less severely affected and depressed than nondrivers.


Effects of step rate manipulation on joint mechanics during running.
the objective of this study was to characterize the biomechanical effects of step rate modification during running on the hip, knee, and ankle joints so as to evaluate a potential strategy to reduce lower extremity loading and risk for injury. three-dimensional kinematics and kinetics were recorded from 45 healthy recreational runners during treadmill running at constant speed under various step rate conditions (preferred, ± 5%, and ± 10%). We tested our primary hypothesis that a reduction in energy absorption by the lower extremity joints during the loading response would occur, primarily at the knee, when step rate was increased. less mechanical energy was absorbed at the knee (P < 0.01) during the +5% and +10% step rate conditions, whereas the hip (P < 0.01) absorbed less energy during the +10% condition only. All joints displayed substantially (P < 0.01) more energy absorption when preferred step rate was reduced by 10%. Step length (P < 0.01), center of mass vertical excursion (P < 0.01), braking impulse (P < 0.01), and peak knee flexion angle (P < 0.01) were observed to decrease with increasing step rate. When step rate was increased 10% above preferred, peak hip adduction angle (P < 0.01) and peak hip adduction (P < 0.01) and internal rotation (P < 0.01) moments were found to decrease. we conclude that subtle increases in step rate can substantially reduce the loading to the hip and knee joints during running and may prove beneficial in the prevention and treatment of common running-related injuries.


Encephalitis-associated hospitalizations among American Indians and Alaska Natives.
Encephalitis produces considerable morbidity in the United States, but morbidity rates among American Indian/Alaska Native (AI/AN) people have not been described. Hospitalization records listing an encephalitis diagnosis were analyzed by using Indian Health Service direct/contract inpatient data. For 1998-2010, there were 436 encephalitis-associated hospitalizations among AI/AN people, an average annual age-adjusted hospitalization rate of 3.1/100,000 population. The rate for infants (11.9) was more than double that for any other age group. Death occurred for 4.1% of hospitalizations. Consistent with reports for the general U.S. population, the rate was high among infants and most (53.9%) hospitalizations were of unexplained etiology. The average annual rate during the study period appeared lower than for the general U.S. population, due particularly to lower rates in the elderly. Future community-based surveillance and mortality studies are needed to confirm these findings and examine reasons underlying the low rates of encephalitis in AI/AN people.


School-level disadvantage and failed cessation treatment among adolescent smokers.
While understanding factors that lead to successful adolescent smoking cessation outcomes is necessary, it is also prudent to determine factors and conditions that contribute to failure to quit smoking. The present study posits that adolescents' proximal environments, such as schools, may influence cessation treatment outcomes. Using aggregated and geographically-referenced data from multi-year school-based cessation trials with 14-19 year olds seeking cessation in 5 States of the USA, the present study developed and applied a tobacco-specific socio-spatial model inclusive of Hierarchical Linear Modeling. Specifically, this novel approach spatially joined individual data files (n=8855) with measures of school (n=807) and county socio-economic factors. Once linked multi-level analyses explored the extent to which cessation treatment failure was explained by the interplay of individual, school and county-level factors. Treatment was deemed as failing to meet its primary goals if participants continued to smoke cigarettes, measured 3-months post baseline. Ten per cent of the variation in cessation treatment failure was attributable to school-level variables. Adolescent smokers were more likely to experience failure to quit in: a) school districts with large percentages of the population having less than high-school education, and b) schools with a higher ratio of students to teachers. The strength of the relationship between cessation self-efficacy and treatment success was further weakened among adolescents attending schools with higher percentages of students eligible for free or reduced lunch programs. Findings implicate school-level socio-economic disadvantage as a significant factor inhibiting cessation, regardless of adolescent self-efficacy to quit smoking. Understanding the interplay of proximal school environments and individual-level factors may provide insights to educators, policy makers and practitioners into the complexities that inhibit or strengthen an adolescent's smoking cessation treatment experience.


Cellular Membrane Trafficking Machineries Used by the Hepatitis Viruses.
While the life cycles of hepatitis viruses (A, B, C, D, and E) have been modestly characterized, recent intensive studies have provided new insights. Because these viruses "hijack" the membrane trafficking of the host cell machinery during replicative propagation, it is essential to determine and understand these specific cellular pathways. Hepatitis B virus (HBV) and hepatitis C virus are well known as leading causes of liver cirrhosis and hepatocellular carcinoma. While substantial inroads toward treating hepatitis C virus patients have recently been made, patients with HBV continue to require lifelong treatment, which makes a thorough understanding of the HBV life cycle essential. Importantly, these viruses have been observed to "hijack" the secretory and endocytic membrane trafficking machineries of the hepatocyte. These can include the canonical clathrin-mediated endocytic process that internalizes virus through cell surface receptors. While these receptors are encoded by the host genome for normal hepatocellular functions, they also exhibit virus-specific recognition. Further, functions provided by the multivesicular body, which include endosomal sorting complexes required for transport, are now known to envelope a variety of different hepatitis viruses. In this review, we summarize the recent findings regarding the cellular membrane trafficking machineries used by HBV in the context of other hepatitis viruses. (Hepatology 2018; 00:000-000).


Low Expression of Transforming Growth Factor β in the Epithelium of Barrett's Esophagus.
The aim of this study was to investigate the expression of transforming growth factor β (TGF-β) in the different stages of Barrett's esophagus (BE). Paired endoscopic esophageal biopsy samples were obtained from patients with BE prospectively. Subjects were classified into three groups: BE, BE with dysplasia, and adenocarcinoma (AC) arising from BE. Biopsy specimens over normal esophageal epithelium and gastric cardiac epithelium of limited cases were done. Four cell lines, HETA1 (human esophageal epithelium), CA-A and CP-C (non-dysplastic metaplasia), and OE33 (AC) were analyzed for quantitative mRNA and Western blotting of TGF-β. All 30 subjects with BE were enrolled. Expression of TGF-β mRNA in BE were significantly (P < 0.01) lower than that in the normal esophagus and cardiac epithelium. The BE tissue showed a lower positive ratio of TGF-β immunohistochemical (IHC) stain than the cardiac epithelium. The expression of TGF-β mRNA in the cell lines CA-A, CP-3, OE-33, was significantly (P < 0.05) lower than that in the cell line HETA-1. The Western blotting result showed lower TGF-β protein expression of the cell lines CA-A, CP-3, and OE-33. The expression of TGF-β was lower in the tissue of BE.


Close topographical relationship between mitochondria and ergastoplasm of liver cells in a definite phase of cellular activity.
1. In most rat liver cells, no special topographical relationship between mitochondria and ergastoplasmic lamellae is to be observed. In some cells, nevertheless, the two organelles are grouped together in dense zones clearly separated from the hyaloplasm. 2. Such an association can be produced at will in the livers of animals refed after prolonged fasting, or in the regenerative phases after partial hepatectomy and intoxication with carbon tetrachloride. In all these cells, the ergastoplasm, after having disappeared, suddenly reappears in the cytoplasm, either along the nucleus or cell membranes, where the mitochondria are grouped. 3. It may be supposed that these topographical relationships between mitochondria and ergastoplasm during a definite period of cellular activity indicate a close functional link between chondrioma and basophilic structures. Mitochondria seem to play an important part in the elaboration of hepatic ergastoplasm.


The next generation of therapies for chronic myeloid leukemia.
Therapy with the tyrosine kinase inhibitor (TKI) represents the current standard first-line therapy for the management of patients with chronic myeloid leukemia (CML). Although most patients respond satisfactorily to imatinib, a subset of patients develops resistance mainly because of the acquisition of mutations within the kinase domain of BCR-ABL1 that impair the ability of TKIs to block the activity of the enzyme. Moreover, BCR-ABL1 transcripts can be detected in most patients by molecular techniques, underscoring the limitations of imatinib to eradicate minimal residual disease. Although the resistance conferred by most BCR-ABL1 mutations can be overcome with the use of second-generation TKIs such as nilotinib, dasastinib, bosutinib, or bafetinib, the T315I mutation, which represents a common resistance pathway in CML, remains unassailable to TKI therapy. We herein discuss current research efforts in 2 areas of vital importance in CML research, the management of patients with imatinib-resistant mutations, with particular emphasis on those carrying T315I, and the eradication of residual disease.


Non-employment and changes in smoking, drinking, and body weight.
To assess the effect of unemployment and early retirement on cigarette smoking, alcohol consumption, and body weight in middle aged British men. Prospective cohort study (British regional heart study). One general practice in 24 towns in Britain. 6057 men aged 40-59 who had been continuously employed for five years before the initial screening. Five years after screening 4412 men had been continuously employed and 1645 had experienced some unemployment or retired. Numbers of cigarettes smoked and units of alcohol consumed per week and body mass index (kg/m2). An initial screening significantly higher percentages of men who subsequently experienced non-employment smoked or had high alcohol consumption than of men who remained continuously employed: 43.0% versus 37.0% continuously employed for cigarette smoking (95% confidence interval for difference 3.2% to 9.0%) and 12.1% versus 9.0% for heavy drinking (1.3% to 5.1%). There was no evidence that men increased their smoking or drinking on becoming non-employed. Men non-employed through illness were significantly more likely to reduce their smoking and drinking than men who remained continuously employed. Men who experienced non-employment were significantly more likely to gain over 10% in weight than men who remained continuously employed: 7.5% versus 5.0% continuously employed (0.9% to 4.0%). Loss of employment was not associated with increased smoking or drinking but was associated with an increased likelihood of gaining weight. The long term effects of the higher levels of smoking and alcohol consumption before nonemployment should be taken into account when comparing mortality and morbidity in groups of unemployed and employed people.


Patterns of Biomarkers in Cord Blood During Pregnancy and Preeclampsia.
Umbilical cord blood (UCB) is in contact with all the fetal tissues and can reflect the state of fetus and UCB can be compared with maternal blood. Inflammatory, metabolic and immunological disorders during pregnancy can affect the environment in which the fetus is developing and may produce various alterations. To analyze different biochemical parameters in maternal venous blood and new born umbilical cord blood from healthy normotensive pregnant and preeclamptic women. Homocysteine, folate, B12, heme oxygenase-1 (HO-1), endoglin, leptin, cholinesterase, IGF-1, Apo A, lipoproteins, TSH, fT3, fT4 were analyzed in maternal sera and venous umbilical cord sera of newborns of twenty five preeclamptics (group II) and twenty five normotensive pregnant women (group I). Homocysteine, folic acid, vitamin B12, Apo A I & II, TSH, fT3, fT4 levels were estimated by competitive immunoassay using direct chemiluminiscence technology. Heme oxygenase-1 (HO-1), endoglin, leptin, cholinesterase, IGF-1 were analyzed by ELISA. Maternal and cord blood levels of homocysteine, folic acid, lipid profile (namely, total cholesterol, triglycerides, LDL-C, VLDL-C and HDL-C), TSH, heme oxygenase 1, were higher in preeclamptic women as compared to normotensive pregnant women. Endoglin levels were significantly lower in cord blood of preeclamptic mother as compared to normotensive mothers. Serum and cord blood vitamin B12, Apo A-I and Apo B l, cholinesterase, leptin levels, IGF-I were lower in preeclamptic women as compared to normotensive pregnant. Findings of the present study suggest that biochemical alterations occur in mothers and fetuses and modifications of uterine environment (in terms of thyroxine and folate and vitamin B12 supplementation) can be of help.


The c-Mpl ligand (thrombopoietin) stimulates tyrosine phosphorylation of Jak2, Shc, and c-Mpl.
c-Mpl is a member of the cytokine receptor superfamily, expressed primarily on hematopoietic cells. Recently, the c-Mpl ligand was cloned and found to have thrombopoietic activity. In this paper we report that ligand binding induced tyrosine phosphorylation in BaF3 cells engineered to express the murine Mpl receptor (BaF3/mMpl). Phosphorylation occurred within 1 min at cytokine concentrations sufficient for proliferation of receptor-bearing cells. Using specific antibodies for immunoprecipitation and Western blotting, several of these phosphorylated proteins were identified. Shc and Jak2, known cytokine signaling molecules, and the c-Mpl receptor were shown to be major substrates for tyrosine phosphorylation. In contrast, phospholipase C-gamma and phosphatidylinositol 3-kinase displayed little and no tyrosine phosphorylation, respectively, after thrombopoietin stimulation. Co-immunoprecipitation studies demonstrated that Jak2 became physically associated with c-Mpl relatively late in the observed time course (20-60 min), significantly later than tyrosine phosphorylation of Jak2 (1-5 min). These results suggest that c-Mpl induces signal transduction pathways similar to those of other known cytokines. Additionally, in light of its late physical association with c-Mpl following ligand binding, Jak2 may not be the initiating tyrosine kinase in the thrombopoietin-induced signaling cascade.


The costs of bipolar disorder in the United Kingdom.
To estimate the individual cost and population-level economic burden of Bipolar Disorder (BD), and explore the impact of clinical and sociodemographic factors on costs in the United Kingdom. Annual UK health care, social care and societal cost data were collected from a prospective cohort of 91 BD patients using digital monitoring of symptoms. Costs (in £) were calculated for the year of resource use collection (2010-2011) and main results inflated to year 2018-2019. A Generalized Estimating Equation framework was used to investigate individual factors influencing costs. An economic burden estimate was derived by multiplying the mean annual cost per patient with literature-based population prevalence. The average annual cost of BD per patient was £12,617 (SE = ±£1085) or £14,938 (SE = ±£1281) at 2018-2019 prices with 68% of the total costs attributed to lost productivity and informal care, 31% to health care costs, 1% to private out-of-pocket expenses, and 0.5% to social care costs. A unit increase in average levels of depressive or manic symptoms were associated with 7% and 11% higher societal costs, respectively. The estimated annual prevalence of BD in the United Kingdom was 0.8% resulting in a population-level economic burden estimate of £5.1 billion for 2010-2011 or £6.43 billion for 2018-2019. BD is a disease of substantial costs in the United Kingdom with the majority of the economic burden falling outside the health care system in the form of productivity losses and informal care. These costs highly correlate with patient outcomes highlighting further needs for improved treatment efforts into functionality.


Pre-stimulus phase and amplitude regulation of phase-locked responses are maximized in the critical state.
Understanding why identical stimuli give differing neuronal responses and percepts is a central challenge in research on attention and consciousness. Ongoing oscillations reflect functional states that bias processing of incoming signals through amplitude and phase. It is not known, however, whether the effect of phase or amplitude on stimulus processing depends on the long-term global dynamics of the networks generating the oscillations. Here, we show, using a computational model, that the ability of networks to regulate stimulus response based on pre-stimulus activity requires near-critical dynamics-a dynamical state that emerges from networks with balanced excitation and inhibition, and that is characterized by scale-free fluctuations. We also find that networks exhibiting critical oscillations produce differing responses to the largest range of stimulus intensities. Thus, the brain may bring its dynamics close to the critical state whenever such network versatility is required.


Biomechanics of bird flight.
Power output is a unifying theme for bird flight and considerable progress has been accomplished recently in measuring muscular, metabolic and aerodynamic power in birds. The primary flight muscles of birds, the pectoralis and supracoracoideus, are designed for work and power output, with large stress (force per unit cross-sectional area) and strain (relative length change) per contraction. U-shaped curves describe how mechanical power output varies with flight speed, but the specific shapes and characteristic speeds of these curves differ according to morphology and flight style. New measures of induced, profile and parasite power should help to update existing mathematical models of flight. In turn, these improved models may serve to test behavioral and ecological processes. Unlike terrestrial locomotion that is generally characterized by discrete gaits, changes in wing kinematics and aerodynamics across flight speeds are gradual. Take-off flight performance scales with body size, but fully revealing the mechanisms responsible for this pattern awaits new study. Intermittent flight appears to reduce the power cost for flight, as some species flap-glide at slow speeds and flap-bound at fast speeds. It is vital to test the metabolic costs of intermittent flight to understand why some birds use intermittent bounds during slow flight. Maneuvering and stability are critical for flying birds, and design for maneuvering may impinge upon other aspects of flight performance. The tail contributes to lift and drag; it is also integral to maneuvering and stability. Recent studies have revealed that maneuvers are typically initiated during downstroke and involve bilateral asymmetry of force production in the pectoralis. Future study of maneuvering and stability should measure inertial and aerodynamic forces. It is critical for continued progress into the biomechanics of bird flight that experimental designs are developed in an ecological and evolutionary context.