Using entropy maximization to understand the determinants of structural dynamics beyond native contact topology.
Comparison of elastic network model predictions with experimental data has provided important insights on the dominant role of the network of inter-residue contacts in defining the global dynamics of proteins. Most of these studies have focused on interpreting the mean-square fluctuations of residues, or deriving the most collective, or softest, modes of motions that are known to be insensitive to structural and energetic details. However, with increasing structural data, we are in a position to perform a more critical assessment of the structure-dynamics relations in proteins, and gain a deeper understanding of the major determinants of not only the mean-square fluctuations and lowest frequency modes, but the covariance or the cross-correlations between residue fluctuations and the shapes of higher modes. A systematic study of a large set of NMR-determined proteins is analyzed using a novel method based on entropy maximization to demonstrate that the next level of refinement in the elastic network model description of proteins ought to take into consideration properties such as contact order (or sequential separation between contacting residues) and the secondary structure types of the interacting residues, whereas the types of amino acids do not play a critical role. Most importantly, an optimal description of observed cross-correlations requires the inclusion of destabilizing, as opposed to exclusively stabilizing, interactions, stipulating the functional significance of local frustration in imparting native-like dynamics. This study provides us with a deeper understanding of the structural basis of experimentally observed behavior, and opens the way to the development of more accurate models for exploring protein dynamics.


Clinical validation of dialysable calcium in relation to other methods of serum calcium measurement.
Dialysable calcium (CaD) values were measured by a simple technique not interfered with by protein bound calcium and validation attempted by comparison with concentrations of ionised calcium (CaI) and clinical categorisation. CaD values were also compared with total calcium (CaT) and albumin adjusted calcium (CaA) concentrations. The normal ranges for CaD, CaT, CaA, and CaI were calculated from the results in healthy blood donors. In 50 normal subjects CaD was more highly correlated with CaI than CaT or CaA. The effects of lying down and of venous stasis in 10 normal subjects showed that CaD was slightly influenced by posture only, whereas CaT was noticeably affected by posture and venous stasis; CaA reduced but did not abolish these effects on CaT. The correlation coefficient of CaD and CaI in patients with chronic renal failure was 0.81. CaD was compared with CaT and CaA values in 293 consecutive hospital patients; discrepant results were obtained in 14.3% and 13.0% of cases respectively and there were some clinical grounds for accepting CaD as correct in 86% and 74% of these cases. Measurement of CaD is a simple, reliable method for estimating accurately the calcium concentration free from biologically inactive protein bound calcium.


cDNA cloning and nuclear localization of the circadian neuropeptide designated as pigment-dispersing factor PDF in the cricket Gryllus bimaculatus.
Pigment-dispersing factor (PDF) was recently reported to be a principal circadian neuromodulator involved in transmitting circadian rhythms of daily locomotion in insects. In Drosophila, PDF functions in some of the neurons expressing the clock genes period, timeless, Clock, and cycle, and those clock genes in turn regulate pdf gene expression. In the present study, we cloned a cDNA encoding PDF in the brain of a nocturnal insect, the cricket Gryllus bimaculatus, and found that an isolated clone (310 bp) codes for an extraordinarily short precursor protein with no definite signal sequence, but a nuclear localization signal (NLS)-like sequence instead. The cricket PDF exhibits high sequence identity (78-94%) and similarity (89-100%) to insect PDFs and also to crustacean beta-PDH peptides. In the optic lobes of G. bimaculatus there are PDF-immunoreactive neurons in both the medulla and lamina neuropiles. Among the strongly immunoreactive lamina PDF neurons, on electron microscopy we identified cells exhibiting distinct staining that is not only cytoplasmic but also nuclear. When GFP-fused PDF precursor proteins were expressed in COS-7 cells, distinct translocation of the fusion protein into the nucleus was observed. This is the first finding of PDF peptide in the nucleus, which suggests a fundamental role of PDF peptide per se in the circadian clock system.


Consensus conference on heart-kidney transplantation.
Simultaneous heart-kidney transplant (sHK) has enabled the successful transplantation of patients with end-stage heart disease and concomitant kidney disease, with non-inferior outcomes to heart transplant (HT) alone. The decision for sHK is challenged by difficulties in differentiating those patients with a significant component of reversible kidney injury due to cardiorenal syndrome who may recover kidney function after HT, from those with intrinsic advanced kidney disease who would benefit most from sHK. A consensus conference on sHK took place on June 1, 2019 in Boston, Massachusetts. The conference represented a collaborative effort by experts in cardiothoracic and kidney transplantation from centers across the United States to explore the development of guidelines for the interdisciplinary criteria for kidney transplantation in the sHK candidate, to evaluate the current allocation of kidneys to follow the heart for sHK, and to recommend standardized care for the management of sHK recipients. The conference served as a forum to unify criteria between the different specialties and to forge a pathway for patients who may need dual organ transplantation. Due to the continuing shortage of available donor organs, ethical problems related to multi-organ transplantation were also debated. The findings and consensus statements are presented.


Does magnetoreception mediate biological effects of power-frequency magnetic fields?
The question of possible biological effects of power-frequency magnetic fields (PF-MF) remains controversial, notably because no valid mechanism of interaction could be proposed so far for intensities relevant to human and animal exposure (e.g. such as near high-tension power lines). In rodents, however, a few consistent effects of weak PF-MF have been reported. These are, notably, influence on spatial memory and partial inhibition of melatonin secretion under long-lasting exposure. Recent developments in study of magnetoreception in mammals justify reviving the hypothesis previously proposed of the intervention of the magnetic sense in melatonin disruption by PF-MF. We revisit this hypothesis and revise and extend it with respect to current knowledge and, particularly, with respect to reported effects on spatial memory. Proposals are made for experimental testing of the hypothesis. We argue that these tests may provide further insight into mechanisms of biological interactions of PF-MF and also, into mechanisms of magnetoreception per se.


Relapsing peritonitis in children who undergo chronic peritoneal dialysis: a prospective study of the international pediatric peritonitis registry.
The International Pediatric Peritonitis Registry (IPPR) was established to collect prospective data regarding peritoneal dialysis (PD)-associated peritonitis in children. In this report, we present the IPPR results that pertain to relapsing peritonitis (RP). This was an online, prospective entry into the IPPR of data that pertain to peritonitis cases by participating centers. Of 490 episodes of nonfungal peritonitis, 52 (11%) were followed by a relapse. There was no significant difference between RP and non-RP in distribution of causative organisms and antibiotic sensitivities. Initial empiric therapy-ceftazidime with either first-generation cephalosporin or glycopeptide (vancomycin or teicoplanin)-was not associated with relapse. Switching to monotherapy with a first-generation cephalosporin on the basis of culture results was associated with higher relapse rate (23%) than other final antibiotic therapies (0 to 9%). Culture-negative RP was less likely to have a satisfactory early treatment response than non-RP (82 versus 98%). Young age, single-cuff catheter, downward-pointing exit site, and chronic systemic antibiotic prophylaxis were additional independent risk factors for RP in the multivariate analysis. Compared with non-RP, RP was associated with a lower rate of full functional recovery (73 versus 91%), higher ultrafiltration problems (14 versus 2%), and higher rate of permanent PD discontinuation (17 versus 7%). This is the largest multicenter, prospective study to date to examine RP in children. In addition, this is the first report in the literature to examine specifically the relationship of postempiric antibiotic treatment regimens to the subsequent risk for relapse.


Interrogating the Relationship Between Schizotypy, the Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism, and Neuronal Oscillatory Activity.
The COMT Val158Met polymorphism affects the availability of synaptic dopamine in the prefrontal cortex and has been widely studied as a genetic risk factor for psychosis. Schizotypy is associated with an increased risk of psychosis, with some studies implicating similar neurobiological mechanisms to schizophrenia. The present study sought to interrogate the link between the COMT Val158Met polymorphism and schizotypy using electroencephalogram (EEG) to identify neurophysiological mechanisms underpinning psychosis risk. Neurotypical (N = 91) adults were genotyped for the COMT Val158Met polymorphism, completed the Schizotypal Personality Questionnaire (SPQ), and had eyes open resting-state EEG recorded for 4 min. SPQ suspiciousness subscale scores were higher for individuals homozygous for Val/Val and Met/Met versus Val/Met genotypes. Delta, theta, alpha-2, beta-1, and beta-2 amplitudes were lower for Val/Val than Met/Met individuals. Lower theta amplitudes were correlated with higher total SPQ scores (P = 0.050), and multiple regression revealed that higher delta, and lower theta and beta-2 amplitudes (but not COMT genotype) best predicted total SPQ scores (P = 0.014). This study demonstrates the importance of COMT genotype in determining trait suspiciousness and EEG oscillatory activity. It also highlights relationships between dopaminergic alterations, EEG and schizotypy that are dissimilar to those observed in schizophrenia.


Use of computed tomography and positron emission tomography/computed tomography for staging of local extent in patients with malignant pleural mesothelioma.
The objective of this study was to determine the diagnostic value of computed tomography (CT) and positron emission tomography (PET)/CT for staging of malignant pleural mesothelioma (MPM) in patients undergoing induction chemotherapy. Sixty-two patients (median age, 61 years; female: n = 9) with proven MPM underwent CT after induction chemotherapy. Of these, 28 underwent additional PET/CT. Extrapleural pneumonectomy was performed for pathological TNM staging. Clinical TNM stage was assessed by 3 independent readers. Relative and absolute underestimation and overestimation were compared with pathological tumor stage. Sensitivity, specificity, and accuracy for differentiation between stages T2 and T3 were assessed. Interobserver agreement between the readers was analyzed (κ). Positron emission tomography/CT and CT underestimated T stage in up to 30% of the cases. Positron emission tomography/CT had a higher accuracy for tumor extent compared with CT (PET/CT: 0.92; CT: 0.84). The accuracy for nodal staging was higher for CT than for PET/CT (PET/CT: 0.78; CT: 0.87). Concerning International Mesothelioma Interest Group classification, PET/CT improved the accuracy of preoperative staging compared with CT (PET/CT: 0.91; CT: 0.82). Interobserver agreement was moderate for CT (0.48-0.62) and good for PET/CT (0.64-0.83) for T staging. For nodal staging, interobserver agreement was fair to moderate for CT and good for PET/CT (CT: 0.37-0.51; PET/CT: 0.73-0.76). Positron emission tomography/CT is more accurate and has a lower interobserver variability for clinical intrathoracic staging of MPM compared with CT. Nevertheless PET/CT underestimated tumor stage in a substantial number of cases, showing the need for a more accurate imaging technology or approach.


Regulation of nuclear factor of activated T cells (NFAT) and downstream myogenic proteins during dehydration in the African clawed frog.
Xenopus laevis, otherwise known as the African clawed frog, undergoes natural dehydration of up to 30% of its total body water during the dry season in sub-Saharan Africa. To survive under these conditions, a variety of physiological and biochemical changes take place in X. laevis. We were interested in understanding the role that the calcineurin-NFAT pathway plays during dehydration stress response in the skeletal muscles of X. laevis. Immunoblotting was performed to characterize the protein levels of NFATc1-4, calcium signalling proteins, in addition to myogenic proteins (MyoD, MyoG, myomaker). In addition, DNA-protein interaction ELISAs were used to assess the binding of NFATs to their consensus binding sequence, and to identify the effect of urea on NFAT-binding. Our results showed that NFATc1 and c4 protein levels decreased during dehydration, and there were no changes in NFATc2, c3, and calcium signalling proteins. However, MyoG and myomaker both showed increases in protein levels during dehydration, thus indicating that the late myogenic program involving myoblast differentiation, but not satellite cell activation and myoblast proliferation, could be involved in preserving the skeletal muscle of X. laevis during dehydration. In addition, we observed that urea seems to reduce NFATc3-binding to DNA during control, but not during dehydration, possibly indicating that NFATc3 is protected from the denaturing effects of urea as it accumulates during dehydration. These findings expand upon our knowledge of adaptive responses to dehydration, and they identify specific protein targets that could be used to protect the skeletal muscle from damage during stress.


Optical control of sphingosine-1-phosphate formation and function.
Sphingosine-1-phosphate (S1P) plays important roles as a signaling lipid in a variety of physiological and pathophysiological processes. S1P signals via a family of G-protein-coupled receptors (GPCRs) (S1P1-5) and intracellular targets. Here, we report on photoswitchable analogs of S1P and its precursor sphingosine, respectively termed PhotoS1P and PhotoSph. PhotoS1P enables optical control of S1P1-3, shown through electrophysiology and Ca2+ mobilization assays. We evaluated PhotoS1P in vivo, where it reversibly controlled S1P3-dependent pain hypersensitivity in mice. The hypersensitivity induced by PhotoS1P is comparable to that induced by S1P. PhotoS1P is uniquely suited for the study of S1P biology in cultured cells and in vivo because it exhibits prolonged metabolic stability compared to the rapidly metabolized S1P. Using lipid mass spectrometry analysis, we constructed a metabolic map of PhotoS1P and PhotoSph. The formation of these photoswitchable lipids was found to be light dependent, providing a novel approach to optically probe sphingolipid biology.


Mortality, risk indicators for death, and mode of death in younger and elderly patients during five years after coronary artery bypass graft.
The number of elderly patients who may be candidates for coronary artery bypass graft (CABG) for severe coronary artery disease has increased. Cardiac surgery in the elderly is a high-risk procedure because many of these patients have concomitant systemic disease and other disabilities. The study was undertaken to evaluate mortality, risk indicators for death, and mode of death in younger and elderly patients during 5 years after CABG. The study included all patients in western Sweden who underwent CABG without concomitant valve surgery and without previously performed CABG between June 1988 and June 1991. In all, 2,000 patients, of whom 953 (48%) were > or = 65 years, were divided into two age groups (< 65 years and > or = 65 years). Compared with the younger patients, the elderly had a relative risk of death of 2.3 (95% confidence interval 1.8-3.0). The increased risk of death in the elderly was significantly more marked in men, in patients with more severe angina pectoris, and in patients without a history of cerebrovascular diseases. The mode and place of death appeared similar regardless of age; neither was there marked difference in symptoms of angina pectoris among survivors 5 years after CABG. Compared with patients < 65 years, the elderly have more than twice as high a risk of death during the subsequent 5 years, and this risk is higher in men, in patients with severe symptoms of angina pectoris, and in those with no history of cerebrovascular disease.


Endothelial YAP Mediates Hyperglycemia-Induced Platelet Hyperactivity and Arterial Thrombosis.
Hyperglycemia-a symptom that characterizes diabetes-is highly associated with atherothrombotic complications. However, the underlying mechanism by which hyperglycemia fuels platelet activation and arterial thrombus formation is still not fully understood. The profiles of polyunsaturated fatty acid metabolites in the plasma of patients with diabetes and healthy controls were determined with targeted metabolomics. FeCl3-induced carotid injury model was used to assess arterial thrombus formation in mice with endothelial cell (EC)-specific YAP (yes-associated protein) deletion or overexpression. Flow cytometry and clot retraction assay were used to evaluate platelet activation. RNA sequencing and multiple biochemical analyses were conducted to unravel the underlying mechanism. The plasma PGE2 concentration was elevated in patients with diabetes with thrombotic complications and positively correlated with platelet activation. The PGE2 synthetases COX-2 and mPGES-1 were found to be highly expressed in ECs but not in other type of vessel cells in arteries from both patients with diabetes and hyperglycemic mice, compared with nondiabetic individuals and control mice, respectively. A combination of RNA sequencing and ingenuity pathway analyses indicated the involvement of YAP signaling in ECs. EC-specific deletion of YAP limited platelet activation and arterial thrombosis in hyperglycemic mice, whereas endothelial-specific overexpression of YAP in mice mimicked the prothrombotic state of diabetes, without affecting hemostasis. Mechanistically, we found that hyperglycemia/high glucose-induced endothelial YAP nuclear translocation and subsequently transcriptional expression of COX-2 and mPGES-1 contributed to the elevation of PGE2 and platelet activation. Blockade of EP3 activation by oral administration of DG-041 reversed the hyperactivity of platelets and delayed thrombus formation in both EC-specific YAP-overexpressing and hyperglycemic mice. Collectively, our data suggest that hyperglycemia-induced endothelial YAP activation aggravates platelet activation and arterial thrombus formation via PGE2/EP3 signaling. Targeting EP3 with DG-041 might be therapeutic for diabetes-related thrombosis.


Future perspectives in melanoma research: meeting report from the "Melanoma Bridge": Napoli, December 3rd-6th 2014.
The fourth "Melanoma Bridge Meeting" took place in Naples, December 3-6th, 2014. The four topics discussed at this meeting were: Molecular and Immunological Advances, Combination Therapies, News in Immunotherapy, and Tumor Microenvironment and Biomarkers. Until recently systemic therapy for metastatic melanoma patients was ineffective, but recent advances in tumor biology and immunology have led to the development of new targeted and immunotherapeutic agents that prolong progression-free survival (PFS) and overall survival (OS). New therapies, such as mitogen-activated protein kinase (MAPK) pathway inhibitors as well as other signaling pathway inhibitors, are being tested in patients with metastatic melanoma either as monotherapy or in combination, and all have yielded promising results. These include inhibitors of receptor tyrosine kinases (BRAF, MEK, and VEGFR), the phosphatidylinositol 3 kinase (PI3K) pathway [PI3K, AKT, mammalian target of rapamycin (mTOR)], activators of apoptotic pathway, and the cell cycle inhibitors (CDK4/6). Various locoregional interventions including radiotherapy and surgery are still valid approaches in treatment of advanced melanoma that can be integrated with novel therapies. Intrinsic, adaptive and acquired resistance occur with targeted therapy such as BRAF inhibitors, where most responses are short-lived. Given that the reactivation of the MAPK pathway through several distinct mechanisms is responsible for the majority of acquired resistance, it is logical to combine BRAF inhibitors with inhibitors of targets downstream in the MAPK pathway. For example, combination of BRAF/MEK inhibitors (e.g., dabrafenib/trametinib) have been demonstrated to improve survival compared to monotherapy. Application of novel technologies such sequencing have proven useful as a tool for identification of MAPK pathway-alternative resistance mechanism and designing other combinatorial therapies such as those between BRAF and AKT inhibitors. Improved survival rates have also been observed with immune-targeted therapy for patients with metastatic melanoma. Immune-modulating antibodies came to the forefront with anti-CTLA-4, programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) pathway blocking antibodies that result in durable responses in a subset of melanoma patients. Agents targeting other immune inhibitory (e.g., Tim-3) or immune stimulating (e.g., CD137) receptors and other approaches such as adoptive cell transfer demonstrate clinical benefit in patients with melanoma as well. These agents are being studied in combination with targeted therapies in attempt to produce longer-term responses than those more typically seen with targeted therapy. Other combinations with cytotoxic chemotherapy and inhibitors of angiogenesis are changing the evolving landscape of therapeutic options and are being evaluated to prevent or delay resistance and to further improve survival rates for this patient population. This meeting's specific focus was on advances in combination of targeted therapy and immunotherapy. Both combination targeted therapy approaches and different immunotherapies were discussed. Similarly to the previous meetings, the importance of biomarkers for clinical application as markers for diagnosis, prognosis and prediction of treatment response was an integral part of the meeting. The overall emphasis on biomarkers supports novel concepts toward integrating biomarkers into contemporary clinical management of patients with melanoma across the entire spectrum of disease stage. Translation of the knowledge gained from the biology of tumor microenvironment across different tumors represents a bridge to impact on prognosis and response to therapy in melanoma.


Brain networks associated with cognitive and hedonic responses to a meal.
We recently reported interrelated digestive, cognitive, and hedonic responses to a meal. The aim of this study was to identify brain networks related to the hedonic response to eating. Thirty-eight healthy subjects (20-38 age range) were evaluated after a 5-hour fast and after ingestion of a test meal (juice and warm ham and cheese sandwich, 300 mL, 425 kcal). Perceptual and affective responses (satiety, abdominal fullness, digestive well-being, and positive mood), and resting scans of the brain using functional MRI (3T Trio, Siemens, Germany) were evaluated immediately before and after the test meal. A high-order group independent component analysis was performed to investigate ingestion-related changes in the intrinsic connectivity of brain networks, with a focus on thalamic and insular networks. Ingestion induced satiation (3.3±0.4 score increase; P<.001) and abdominal fullness (2.4±0.3 score increase; P<.001). These sensations included an affective dimension involving digestive well-being (2.8±0.3 score increase; P<.001) and positive mood (1.8±0.2 score increase; P<.001). In general, thalamo-cortical connectivity increased with meal ingestion while insular-cortical connectivity mainly decreased. Furthermore, larger meal-induced changes (increase/decrease) in specific thalamic connections were associated with smaller changes in satiety/fullness. In contrast, a larger meal-induced decrease in insular-anterior cingulate cortex connectivity was associated with increased satiety, fullness, and digestive well-being. Perceptual and emotional responses to food intake are related to brain connectivity in defined functional networks. Brain imaging may provide objective biomarkers of subjective effects of meal ingestion.


Presymptomatic genetic testing in minors at risk of paraganglioma and pheochromocytoma: our experience of oncogenetic multidisciplinary consultation.
The aim of the work was to define quality criteria for presymptomatic genetic testing in minors at risk of paraganglioma/pheochromocytoma. A 3-step multidisciplinary procedure was developed: 1) preparatory consultations for parents, providing decision support and advice concerning the way of informing the children; 2) consultation with the minor and blood sampling; and 3) announcement of the result of the genetic test to the minor and his/her parents. Twenty-three minors (mean age=9.22) were tested. The result was positive in 16 cases (presence of the familial mutation) and negative in 7. The 23 procedures were classified according to emotional reactions at the announcement of the result: calm (18/23) or tense (5/23). In parallel, 4 criteria for a good testing procedure was defined: 1) both parents agreeing to have their child tested when they felt ready; 2) parents being given advice concerning the way to inform their child; 3) the most appropriate time for testing being discussed for each child; and 4) avoidance of testing during medical examination periods for the carrier parent. The frequencies of the above criteria were as follows: 1 (17/23); 2 (19/23); 3 (17/23); and 4 (17/23). The overall quality of the testing procedure, calculated as the sum of the four criteria, differed significantly between calm and tense announcements (p<0.01). This study highlights the important role of careful preparation with the parents in emotional acceptance of the result of testing. The 4 criteria identified should be evaluated in further prospective studies.


Comparison of mortality and rates of cerebral palsy in two populations of very low birthweight infants.
Comparisons of mortality and rates of cerebral palsy in different populations can be confusing. This is illustrated by comparing two populations of very low birthweight infants born in the 1980s, one from the Netherlands, the other from the UK (Oxford region). Although a number of biases were controlled for while comparing two large geographically defined populations, by assessing the survivors at similar ages and describing their health status in a standard way, some problems in interpretation of outcome remained. Differences in registration practice of live births at early gestational ages, as well as differences in withholding or withdrawing treatment, which occurred in about half of the cases of neonatal death in the Netherlands and in about one third of those in the Oxford region, may have influenced the incidence of registered live births, neonatal mortality, and the rate of cerebral palsy.


NAMI-A inhibits the PMA-induced ODC gene expression in ECV304 cells: involvement of PKC/Raf/Mek/ERK signalling pathway.
Imidazolium trans-imidazole dimethyl sulfoxide tetrachlororuthenate (NAMI-A) is a new compound active against lung metastasis of solid metastasizing tumours. While its in vivo effect has been studied, the molecular insights that underlie its action are largely unknown. Among the possible pathways responsible for malignant transformation, PKC arose as one of the most promising targets for new antineoplastic drugs. We demonstrated the capability of NAMI-A of inhibiting PMA induced-PKC activity in ECV304 in a dose-dependent fashion. Furthermore, NAMI-A through modulation of PKC activity has been proved capable of reducing the phorbol ester induced expression of ornithine decarboxilase (ODC) gene and to abrogate the activation of the Raf/MEK/ERK pathway. Taken together these results suggest that many of the in vivo outcomes of NAMI-A treatment may be the result of a direct action on PKC.


Caesarean Birth is Associated with Both Maternal and Paternal Origin in Immigrants in Sweden: a Population-Based Study.
To investigate the association between maternal country of birth and father's origin and unplanned and planned caesarean birth in Sweden. Population-based register study including all singleton births in Sweden between 1999 and 2012 (n = 1 311 885). Multinomial regression was conducted to estimate odds ratios (OR) for unplanned and planned caesarean with 95% confidence intervals for migrant compared with Swedish-born women. Analyses were stratified by parity. Women from Ethiopia, India, South Korea, Chile, Thailand, Iran, and Finland had statistically significantly higher odds of experiencing unplanned (primiparous OR 1.10-2.19; multiparous OR 1.13-2.02) and planned caesarean (primiparous OR 1.18-2.25; multiparous OR 1.13-2.46). Only women from Syria, the former Yugoslavia and Germany had consistently lower risk than Swedish-born mothers (unplanned: primiparous OR 0.76-0.86; multiparous OR 0.74-0.86. Planned; primiparous OR 0.75-0.82; multiparous OR 0.60-0.94). Women from Iraq and Turkey had higher odds of an unplanned caesarean but lower odds of a planned one (among multiparous). In most cases, these results remained after adjustment for available social characteristics, maternal health factors, and pregnancy complications. Both parents being foreign-born increased the odds of unplanned and planned caesarean in primiparous and multiparous women. Unplanned and planned caesarean birth varied by women's country of birth, with both higher and lower rates compared with Swedish-born women, and the father's origin was also of importance. These variations were not explained by a wide range of social, health, or pregnancy factors.


No impact of passive smoke on the somatic profile of lung cancers in never-smokers.
EGFR and HER2 mutations and ALK rearrangement are known to be related to lung cancer in never-smokers, while KRAS, BRAF and PIK3CA mutations are typically observed among smokers. There is still debate surrounding whether never-smokers exposed to passive smoke exhibit a "smoker-like" somatic profile compared with unexposed never-smokers. Passive smoke exposure was assessed in the French BioCAST/IFCT-1002 never-smoker lung cancer cohort and routine molecular profiles analyses were compiled. Of the 384 patients recruited into BioCAST, 319 were tested for at least one biomarker and provided data relating to passive smoking. Overall, 219 (66%) reported having been exposed to passive smoking. No significant difference was observed between mutation frequency and passive smoke exposure (EGFR mutation: 46% in never exposed versus 41% in ever exposed; KRAS: 7% versus 7%; ALK: 13% versus 11%; HER2: 4% versus 5%; BRAF: 6% versus 5%; PIK3CA: 4% versus 2%). We observed a nonsignificant trend for a negative association between EGFR mutation and cumulative duration of passive smoke exposure. No association was found for other biomarkers. There is no clear association between passive smoke exposure and somatic profile in lifelong, never-smoker lung cancer.


The effect of total hysterectomy on sexual function and depression.
To investigate whether the operations of Type 1 hysterectomy and bilateral salpingo-oophorectomy performed for benign reasons have any effect on sexual life and levels of depression. This is a multi-center, comparative, prospective study. Healthy, sexual active patients aged between 40 and 60 were included into the study. Data was collected with the technique of face-to-face meeting held three months before and after the operation by using the demographic data form developed by the researchers i.e. the Female Sexual Function Index (FSFI) and the Beck Depression Scale (BDS). In the post-operative third month, there was an improvement in dysuria in terms of symptomatology (34% and 17%, P<0.001), while in FSFI (41.47±25.46 to 34.20±26.67, P<0.001) and BDS (12.87±11.19 to 14.27±10.95, P=0.015) there was a deterioration. For FSFI, 50-60 age range, extended family structure; and for BDS, educational status, not working and extended family structure were statistically important confounding factors for increased risk in the post-operative period. While hysterectomy and bilateral salpingo-oophorectomy performed for benign reasons brought about short-term improvement in urinary problems after the operation for sexually active and healthy women, they resulted in sexual dysfunction and increase in depression. The age, educational status, working condition and family structure is also important.


Epidermal growth factor stimulates phospholipase A2 in vasopressin-treated rat glomerular mesangial cells.
Epidermal growth factor (EGF) enhances vasopressin- and ionophore-A23187-induced prostaglandin production and arachidonate release by rat glomerular mesangial cells in culture. The purpose of the present study was to delineate the phospholipid pathways involved in this effect. In cells labelled with [14C]arachidonate, EGF significantly enhanced the free arachidonate released in response to A23187 or vasopressin without enhancing the production of [14C]arachidonate-labelled diacylglycerol. EGF increased the [14C]arachidonate-labelled phosphatidic acid formed in response to vasopressin, but to a much smaller extent than it increased free arachidonate release. These results indicate that activation of phospholipase C is not sufficient to explain the increase in free arachidonate release observed on addition of EGF. To examine if EGF enhanced phospholipase A2 activity, mesangial cells were labelled with [2-2H]glycerol and [14C]-arachidonate, and the formation of arachidonate-poor lysophospholipids was studied. When combined with vasopressin, EGF significantly enhanced the formation of arachidonate-poor lysophospholipids as compared with vasopressin alone. The fate of exogenously added lysophosphatidylcholine was not altered after stimulation with vasopressin plus EGF, indicating that decreased deacylation or reacylation of the lysophospholipids was not responsible for their accumulation. Taken together, these results indicate that EGF enhances free arachidonate release by activation of phospholipase A2. The signalling mechanism responsible for the change in phospholipase A2 activity is not known, but could conceivably involve phosphorylation of modulating proteins such as lipocortin or G-proteins.


The meniscal tear outcome (METRO) review: A systematic review summarising the clinical course and outcomes of patients with a meniscal tear.
Meniscal tears affect 222 per 100,000 of the population and can be managed non-operatively or operatively with an arthroscopic partial meniscectomy (APM), meniscal repair or meniscal transplantation. The purpose of this review is to summarise the outcomes following treatment with a meniscal tear and explore correlations between outcomes. A systematic review was performed of MEDLINE, EMBASE, AMED and the Cochrane Central Register of Controlled Trials to identify prospective studies describing the outcomes of patients with a meniscal tear. Comparisons were made of outcomes between APM and non-operative groups. Outcomes were graphically presented over time for all treatment interventions. Pearson's correlations were calculated between outcome timepoints. 35 studies were included, 28 reported outcomes following APM; four following meniscal repair and three following meniscal transplant. Graphical plots demonstrated a sustained improvement for all treatment interventions. A moderate to very strong correlation was reported between baseline and three-month outcomes. In the medium term, there was small significant difference in outcome between APM and non-operative measures (SMD 0.17; 95 % CI 0.04, 0.29), however, this was not clinically significant. Patients with a meniscal tear demonstrated a sustained initial improvement in function scores, which was true of all treatments examined. APM may have little benefit in older people, however, previous trials did not include patients who meet the current indications for surgery as a result the findings should not be generalised to all patients with a meniscal tear. Further trials are required in patients who meet current operative indications.


Injection-seeded pulsed alexandrite laser for differential absorption lidar application.
We describe a Q-switched alexandrite laser injection seeded with a cw single-mode titanium-sapphire laser. The reported experimental results show that this system meets the frequency stabilization required for differential absorption lidar measurement of humidity, pressure, and temperature. The emission of the cw titanium-sapphire master oscillator is locked to an atmospheric absorption line by means of a servoloop with derivative spectroscopy. The spectral position is stabilized within ±3.5 × 10(-4) cm(-1) (10 MHz) of the peak of the line over 1 hr. The alexandrite laser emits pulses of 30 mJ in 500 ns, with a spectral linewidth of ≈ 3.3 × 10(-3) cm(-1) (100 MHz). The position of the centroid of the emitted spectrum has a standard deviation of 6 × 10(-4) cm(-1) (18 MHz) and is held within ±1.3 × 10(-3) cm(-1) (40 MHz) of the peak of the absorption line over 1 h.


Seasonal variations in out of hospital cardiopulmonary arrest.
To determine whether there are seasonal variations in survival following out of hospital cardiopulmonary arrest. Prospective cohort study using the Heartstart (Scotland) database. All of Scotland. 10 890 people who suffered out of hospital cardiopulmonary arrest in the summer or winter between December 1988 and August 1997 inclusive. Univariate comparisons of 5406 arrests occurring in summer with 5484 in winter, in terms of patient characteristics, management, and survival using chi(2) and Mann-Whitney U tests. Multivariate analysis of the association between season and survival following adjustment for case mix. Survival to discharge from hospital, survival pre-admission, in-hospital survival. Only 6% of people who arrested in winter survived to discharge, compared to 8% of those who arrested in summer (odds ratio 0.77, p < 0.001). People who arrested in winter had a poorer risk profile in that they were older, more likely to arrest at home, less likely to have a witness, and less likely to receive defibrillation. However, after adjustment for case mix, people who arrested in winter were still 19% less likely to survive compared to those who arrested in summer. Deaths pre-admission were significantly higher in winter (odds ratio 1.18, p < 0.05) but in-hospital deaths were not. People who suffer cardiopulmonary arrest in winter have a significantly lower likelihood of surviving. This is, in part, caused by the higher frequency of a number of recognised risk factors. However, their prognosis remains poorer even after adjustment for these factors.


Fluid processes in subduction zones.
Fluids play a critical role in subduction zones and arc magmatism. At shallow levels in subduction zones (<40 kilometers depth), expulsion of large volumes of pore waters and CH(4)-H(2)O fluids produced by diagenetic and low-grade metamorphic reactions affect the thermal and rheological evolution of the accretionary prism and provide nutrients for deep-sea biological communities. At greater depths, H(2)O and CO(2) released by metamorphic reactions in the subducting oceanic crust may alter the bulk composition in the overlying mantle wedge and trigger partial melting reactions. The location and conse-quences of fluid production in subduction zones can be constrained by consideration of phase diagrams for relevant bulk compositions in conjunction with fluid and rock pressure-temperature-time paths predicted by numerical heat-transfer models. Partial melting of subducting, amphibole-bearing oceanic crust is predicted only within several tens of million years of the initiation of subduction in young oceanic lithosphere. In cooler subduction zones, partial melting appears to occur primarily in the overlying mantle wedge as a result of fluid infiltration.


Evaluation of the assumptions of an ontogeny model of rat hepatic cytochrome P450 activity.
We previously reported an ontogeny model of hepatic cytochrome P450 (P450) activity that predicts in vivo P450 elimination from in vitro intrinsic clearance. The purpose of this study was to conduct investigations into key assumptions of the P450 ontogeny model using the developing rat model system. We used two developmentally dissimilar enzymes, CYP2E1 and CYP1A2, and male rats (n = 4) at age groups representing critical developmental stages. Total body and liver weights and hepatic microsomal protein contents were measured. Following high-performance liquid chromatography analysis, apparent K(M) and V(max) estimates were calculated using nonlinear regression analysis for CYP2E1- and CYP1A2-mediated chlorzoxazone 6-hydroxylation and methoxyresorufin O-dealkylation, and V(max) estimates for p-nitrophenol and phenacetin hydroxylations, respectively. Hepatic scaling factors and V(max) values provided estimates for infant scaling factors (ISF). The data show microsomal protein contents increased with postnatal age and reached adult values after postnatal day (PD) 7. Apparent K(M) values were similar at all developmental stages except at < or =PD7. Developmental increases in probe substrate V(max) values did not correlate with the biphasic increase in immunoquantifiable P450. The activity of two different probe substrates for each P450 covaried as a function of age. A plot of observed ISF values as a function of age reflected the developmental pattern of rat hepatic P450. In summation, these observations diverge from several of the model's assumptions. Further investigations are required to explain these inconsistencies and to investigate whether the developing rat may provide a predictive paradigm for pediatric risk assessment for P450-mediated elimination processes.


PPOs: the employer perspective.
This paper reports the results of a national survey on employer experiences with preferred provider organizations (PPOs). The survey, conducted in 1987, included information from almost 700 telephone interviews with employee benefit managers. We found that 11 percent of employees are in PPOs. PPOs now have a strong presence among employers of all sizes. However, whereas they are a major force in the West, where almost one-third of employees are members, they have garnered only a 1 percent market share in the East. We examine the impact of PPOs on health insurance premiums and on employer satisfaction. The results show that in 1987, the year of the survey, PPOs appeared to provide mild cost savings compared to conventional insurance, and that employers were very satisfied with almost all aspects of PPOs, whereas they were surprisingly critical of their HMOs.


Alopecia areata: light and electron microscopic pathology of the regrowing white hair.
Light and electron microscopic studies have been carried out on fifteen regrowing white anagen hair follicles from seven patients with alopecia areata. Seven bulbs showed evidence of cell injury that was concentrated in cortical keratocytes. Lower bulb matrix cells appeared undamaged though in six bulbs apoptotic degeneration was seen in the lower bulb keratocytes, perhaps indicating early catagen transformation. Melanocytes were identified in all the bulbs except those from one patient. The number of melanocytes and their melanization were much less than in the normal pigmented follicle, and pigment transfer was rarely seen. It is proposed that alopecia areata is a disease of differentiating cortical keratocytes. The failure of pigmentation in the regrowing white hair may be post-inflammatory, but the various other pigmentary features of alopecia areata, especially the sparing of senile white hairs, suggest that pigmentary mechanisms in the hair bulb are of primary importance in the pathogenesis of this disorder.


Increasing levels of the endocannabinoid 2-AG is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.
Parkinson's disease (PD) is a common chronic neurodegenerative disorder, usually of idiopathic origin. Symptoms including tremor, bradykinesia, rigidity and postural instability are caused by the progressive loss of dopaminergic neurons in the nigrostriatal region of the brain. Symptomatic therapies are available but no treatment slows or prevents the loss of neurons. Neuroinflammation has been implicated in its pathogenesis. To this end, the present study utilises the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxin to reproduce the pattern of cell death evident in PD patients. Herein, the role of a potential regulator of an immune response, the endocannabinoid system (ECS), is investigated. The most prevalent endocannabinoid, 2-arachidonoylglycerol (2-AG) (3 and 5mg/kg), was added exogenously and its enzymatic degradation inhibited to provide protection against MPTP-induced cell death. Furthermore, the addition of DFU (25mg/kg), a selective inhibitor of inflammatory mediator cyclooxygenase-2 (COX-2), potentiated these effects. Levels of 2-AG were shown to be upregulated in a time- and region-specific manner following MPTP administration, indicating that the ECS represents a natural defence mechanism against inflammation, potentiation of which could provide therapeutic benefits. The results expand the current understanding of the role that this signalling system has and its potential influence in PD.


Effect of transcranial magnetic stimulation (TMS) on parietal and premotor cortex during planning of reaching movements.
Cerebral activation during planning of reaching movements occurs both in the superior parietal lobule (SPL) and premotor cortex (PM), and their activation seems to take place in parallel. The activation of the SPL and PM has been investigated using transcranial magnetic stimulation (TMS) during planning of reaching movements under visual guidance. A facilitory effect was found when TMS was delivered on the parietal cortex at about half of the time from sight of the target to hand movement, independently of target location in space. Furthermore, at the same stimulation time, a similar facilitory effect was found in PM, which is probably related to movement preparation. This data contributes to the understanding of cortical dynamics in the parieto-frontal network, and suggests that it is possible to interfere with the planning of reaching movements at different cortical points within a particular time window. Since similar effects may be produced at similar times on both the SPL and PM, parallel processing of visuomotor information is likely to take place in these regions.


Availability of Ferritin-Bound Iron to Enterobacteriaceae.
The sequestration of iron in case of infection, termed nutritional immunity, is an established strategy of host defense. However, the interaction between pathogens and the mammalian iron storage protein ferritin is hitherto not completely understood. To better characterize the function of ferritin in Gram-negative infections, we incubated iron-starved cultures of Salmonella Typhimurium and knockout mutant strains defective for major iron uptake pathways or Escherichia coli with horse spleen ferritin or ionic iron as the sole iron source. Additionally, we added bovine superoxide dismutase and protease inhibitors to the growth medium to assess the effect of superoxide and bacterial proteases, respectively, on Salmonella proliferation and reductive iron release. Compared to free ionic iron, ferritin-bound iron was less available to Salmonella, but was still sufficient to significantly enhance the growth of the bacteria. In the absence of various iron acquisition genes, the availability of ferritin iron further decreased. Supplementation with superoxide dismutase significantly reduced the growth of the ΔentC knockout strain with holoferritin as the sole iron source in comparison with ionic ferrous iron. In contrast, this difference was not observed in the wildtype strain, suggesting that superoxide dismutase undermines bacterial iron uptake from ferritin by siderophore-independent mechanisms. Ferritin seems to diminish iron availability for bacteria in comparison to ionic iron, and its iron sequestering effect could possibly be enhanced by host superoxide dismutase activity.


Deep epistasis in human metabolism.
We extend and apply a method that we have developed for deriving high-order epistatic relationships in large biochemical networks to a published genome-scale model of human metabolism. In our analysis we compute 33,328 reaction sets whose knockout synergistically disables one or more of 43 important metabolic functions. We also design minimal knockouts that remove flux through fumarase, an enzyme that has previously been shown to play an important role in human cancer. Most of these knockout sets employ more than eight mutually buffering reactions, spanning multiple cellular compartments and metabolic subsystems. These reaction sets suggest that human metabolic pathways possess a striking degree of parallelism, inducing "deep" epistasis between diversely annotated genes. Our results prompt specific chemical and genetic perturbation follow-up experiments that could be used to query in vivo pathway redundancy. They also suggest directions for future statistical studies of epistasis in genetic variation data sets.


Metabolism of rabbit skin collagen. Differences in the apparent turnover rates of type-I- and type-III-collagen precursors determined by constant intravenous infusion of labelled amino acids.
Growing rabbits were infused for up to 10 h with labelled proline, tyrosine and leucine to achieve plateau conditions within body free pools, for [3H]proline infusion, blood free-proline specific radioactivity remained constant after about 1 h. For individual animals, type-I- and type-III-collagen precursors were isolated by precipitation with (NH4)2SO4 and DEAE-cellulose chromatography. Experiments where 3H- and 14C-labelled proline and tyrosine were infused concurrently for different periods of time showed that type I procollagen reached plateau specific radioactivity within 3 h and 90% of the plateau value after 2 h infusion, corresponding to a calculated apparent t 1/2 of less than 26 min. Plateau values for type I procollagen were taken as precursor amino acid pool specific radioactivities. The type-III-collagen-precursor fractions consistently showed lower rates of label incorporation and, by assuming that both type I and type III collagens are synthesized from the same amino acid pools, kinetic analysis revealed an apparent t 1/2 for the isolated type-III-collagen precursors of 3.9 h. For proline, there were large variations between animals in the ratio between the precursor pool for collagen synthesis and the skin homogenate free pool (0.31 +/- 0.13, mean +/- S.D.), so that collagen-synthesis rates based solely on total tissue free-pool values for proline are subject to large and inconsistent errors.


Fluoride concentrations in urine of delivery ward personnel following exposure to low concentrations of methoxyflurane.
Midwives and other delivery ward personnel exposed to methoxyflurane do not have measurable traces of the agent in expired air when examined soon after exposure. This may imply a rapid uptake of the anesthetic. If this is the case, then the products of the metabolism of methoxyflurane, such as fluoride, may appear in the urine of such personnel. The present study investigated urinary fluoride levels in 24 delivery ward personnel and compared the values found after methoxyflurane/nitrous oxide analgesia with those measured in the same individuals after exposure to nitrous oxide alone. A highly significant difference was observed. Thus it would appear that, in spite of an apparently adequate system of environmental ventilation, there is a significant uptake of methoxyflurane by delivery ward personnel when this agent is employed for obstetrical analgesia.


[Customization of hemodialysis therapy: dialysis is not a washing machine].
In recent years, the population of chronic dialysis has grown in number but also in age and frequency of co-morbidies such as cardiac diseases, vascular pathologies, diabetes, etc. The majority of patients on chronic hemodialysis are over 70 years and, given the high number of comorbidities, they often exhibit poor tolerance to dialysis treatments. A non-tolerated dialytic treatment can have side-effects that would require an intensification of the dialysis sessions and many hospitalizations. Consequently, the problematic dialysis treatments, as well as harmful for the patient, become economically more detrimental than other treatments apparently more expensive but more tolerated ones In the current days we have, thanks to the huge developments in dialysis technology, powerful weapons to ensure effective and scarcely symptomatic dialysis treatments to the majority of the HD patients. New, highly biocompatible membranes with defined and modular cut-off and / or absorption capacity may allow us to provide adequate purification. Moreover the monitoring and biofeedback systems such as blood volume tracking, body temperature monitoring (BTM) and blood pressure (BPM) can be very useful in reducing the risk of intra-dialytic hypotension and symptoms. Therefore, the dialytic therapy, as well as all the pharmacological therapies for the chronic patient, must consider the specificity of the patient, basing on his metabolic problems, cardiovascular tolerance, residual renal function and on his dietary and general compliance. The central aim of the nephrologist is to formulate the better prescription for the individual patient, considering the dialysis modalities, the membrane type, the dry weight (ideal post-dialysis body weight), the frequency and the duration of the weekly sessions and the technological tools that can optimize the treatment.


Zone-plate diffraction patterns in gradient-index media.
Diffraction patterns inside gradient-index media in which a complex zone plate is placed at a Fourier transform plane are studied by making use of the optical propagator. The results are illustrated with an example corresponding to a selfoc medium and a Fresnel zone plate of the amplitude and of the phase.


Exacerbated innate host response to SARS-CoV in aged non-human primates.
The emergence of viral respiratory pathogens with pandemic potential, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza A H5N1, urges the need for deciphering their pathogenesis to develop new intervention strategies. SARS-CoV infection causes acute lung injury (ALI) that may develop into life-threatening acute respiratory distress syndrome (ARDS) with advanced age correlating positively with adverse disease outcome. The molecular pathways, however, that cause virus-induced ALI/ARDS in aged individuals are ill-defined. Here, we show that SARS-CoV-infected aged macaques develop more severe pathology than young adult animals, even though viral replication levels are similar. Comprehensive genomic analyses indicate that aged macaques have a stronger host response to virus infection than young adult macaques, with an increase in differential expression of genes associated with inflammation, with NF-kappaB as central player, whereas expression of type I interferon (IFN)-beta is reduced. Therapeutic treatment of SARS-CoV-infected aged macaques with type I IFN reduces pathology and diminishes pro-inflammatory gene expression, including interleukin-8 (IL-8) levels, without affecting virus replication in the lungs. Thus, ALI in SARS-CoV-infected aged macaques developed as a result of an exacerbated innate host response. The anti-inflammatory action of type I IFN reveals a potential intervention strategy for virus-induced ALI.


Genetically engineered mouse models for studying radiation biology.
Genetically engineered mouse models (GEMMs) are valuable research tools that have transformed our understanding of cancer. The first GEMMs generated in the 1980s and 1990s were knock-in and knock-out models of single oncogenes or tumor suppressors. The advances that made these models possible catalyzed both technological and conceptual shifts in the way cancer research was conducted. As a result, dozens of mouse models of cancer exist today, covering nearly every tissue type. The advantages inherent to GEMMs compared to in vitro and in vivo transplant models are compounded in preclinical radiobiology research for several reasons. First, they accurately and robustly recapitulate primary cancers anatomically, histopathologically, and genetically. Reliable models are a prerequisite for predictive preclinical studies. Second, they preserve the tumor microenvironment, including the immune, vascular, and stromal compartments, which enables the study of radiobiology at a systems biology level. Third, they provide exquisite control over the genetics and kinetics of tumor initiation, which enables the study of specific gene mutations on radiation response and functional genomics in vivo. Taken together, these facets allow researchers to utilize GEMMs for rigorous and reproducible preclinical research. In the three decades since the generation of the first GEMMs of cancer, advancements in modeling approaches have rapidly progressed and expanded the mouse modeling toolbox with techniques such as in vivo short hairpin RNA (shRNA) knockdown, inducible gene expression, site-specific recombinases, and dual recombinase systems. Our lab and many others have utilized these tools to study cancer and radiobiology. Recent advances in genome engineering with CRISPR/Cas9 technology have made GEMMs even more accessible to researchers. Here, we review current and future approaches to mouse modeling with a focus on applications in preclinical radiobiology research.


Electrophysiological study of dystrophia myotonica.
A comprehensive electrophysiological study has been made of the extensor digitorum brevis muscle and its motor innervation in 17 patients with dystrophia myotonica. The mean contraction and half-relaxation times were prolonged in the isometric twitches of dystrophic muscles. Decremental responses to repetitive motor nerve stimulation were found in two patients. All the terminal latency measurements were normal and only one patient had a reduced nerve conduction velocity. As the patients aged their muscles became weaker, due to a progressive loss of motor units. This finding, and the normal sizes of many surviving motor units, suggested that the muscle changes resulted from a primary defect of motor innervation.


Increased blood-brain barrier permeability and altered tight junctions in experimental diabetes in the rat: contribution of hyperglycaemia and matrix metalloproteinases.
Although diabetes mellitus is associated with peripheral microvascular complications and increased risk of neurological events, the mechanisms by which diabetes disrupts the blood-brain barrier (BBB) are not known. Matrix metalloproteinase (MMP) activity is increased in diabetic patients, is associated with degradation of tight junction proteins, and is a known mediator of BBB compromise. We hypothesise that diabetes leads to compromise of BBB tight junctions via stimulation of MMP activity. Diabetes was induced in the rat with streptozotocin. At 14 days after injection, BBB function was assessed by in situ brain perfusion. Tight junction proteins were assessed by immunoblot and immunofluorescence. Plasma MMP activity was quantified by fluorometric gelatinase assay and gel zymography. In streptozotocin-treated animals, permeability to [(14)C]sucrose increased concurrently with decreased production of BBB tight junction proteins occludin (also known as OCLN) and zona occludens 1 (ZO-1, also known as tight junction protein 1 or TJP1). Insulin treatment, begun on day 7, normalised blood glucose levels and attenuated BBB hyperpermeability to [(14)C]sucrose. Neither acute hyperglycaemia in naive animals nor acute normalisation of blood glucose in streptozotocin-treated animals altered BBB permeability to [(14)C]sucrose. Plasma MMP activity was increased in streptozotocin-treated animals. These data indicate that diabetes increases BBB permeability via a loss of tight junction proteins, and that increased BBB permeability in diabetes does not result from hyperglycaemia alone. Increased plasma MMP activity is implicated in degradation of BBB tight junction proteins and increased BBB permeability in diabetes. Peripheral MMP activity may present a novel target for protection of the BBB and prevention of neurological complications in diabetes.


Importance of compartment formation for a self-encoding system.
A self-encoding system designed to have strict "compartition" of the molecules, i.e., to contain only a single molecule of DNA in each compartment, was established, and its evolutionary fate was analyzed. The system comprised the Thermus thermophilus DNA polymerase gene as the informational molecule and its protein product replicating the gene as the functional molecule. Imposing strict compartition allows the self-encoding system to last up to at least the tenth generation, whereas the system ceased to work after the third generation when loose compartition initiated with 100 molecules was imposed. These results provide experimental evidence on the importance of compartition for the maintenance of a self-encoding system. In addition, the extent of diversity in self-replication activity of the compartments was found to be another vital difference in the evolutionary dynamics between the strict and loose compartitions. Although the system with strict compartition provides widely diversified activity of the compartments at each generation, the values of the activity diverge only within a small range in the system with loose compartition. When the variety in the activity of a compartment is small, functional selection becomes weak, and to conform Darwinian evolution may become unfeasible. Therefore, strict compartition is essential for the evolvability of a self-encoding system.


Real-time mandibular angle reduction surgical simulation with haptic rendering.
Mandibular angle reduction is a popular and efficient procedure widely used to alter the facial contour. The primary surgical instruments, the reciprocating saw and the round burr, employed in the surgery have a common feature: operating at a high-speed. Generally, inexperienced surgeons need a long-time practice to learn how to minimize the risks caused by the uncontrolled contacts and cutting motions in manipulation of instruments with high-speed reciprocation or rotation. A virtual reality-based surgical simulator for the mandibular angle reduction was designed and implemented on a CUDA-based platform in this paper. High-fidelity visual and haptic feedbacks are provided to enhance the perception in a realistic virtual surgical environment. The impulse-based haptic models were employed to simulate the contact forces and torques on the instruments. It provides convincing haptic sensation for surgeons to control the instruments under different reciprocation or rotation velocities. The real-time methods for bone removal and reconstruction during surgical procedures have been proposed to support realistic visual feedbacks. The simulated contact forces were verified by comparing against the actual force data measured through the constructed mechanical platform. An empirical study based on the patient-specific data was conducted to evaluate the ability of the proposed system in training surgeons with various experiences. The results confirm the validity of our simulator.


Three-dimensional finite element computation of laser cavity eigenmodes [corrected].
A new method for computing eigenmodes of a laser resonator by the use of finite element analysis is presented. For this purpose, the scalar wave equation (delta + k2)E(x, y, z) = 0 is transformed into a solvable three-dimensional eigenvalue problem by the separation of the propagation factor exp(-ikz) from the phasor amplitude E(x, y, z) of the time-harmonic electrical field. For standing wave resonators, the beam inside the cavity is represented by a two-wave ansatz. For cavities with parabolic optical elements, the new approach has successfully been verified by the use of the Gaussian mode algorithm. For a diode-pumped solid-state laser with a thermally lensing crystal inside the cavity, the expected deviation between Gaussian approximation and numerical solution could be demonstrated clearly.


Metabolic syndrome, sarcopenia and role of sex and age: cross-sectional analysis of Kashiwa cohort study.
Recent epidemiological evidence suggests that effects of cardiovascular risk factors may vary depending on sex and age. In this study, we assessed the associations of metabolic syndrome (MetS) with sarcopenia and its components in older adults, and examined whether the associations vary by sex and age. We also tested if any one of the MetS components could explain the associations. We conducted a cross-sectional analysis of the baseline data from the cohort study conducted in Kashiwa city, Chiba, Japan in 2012 which included 1971 functionally-independent, community-dwelling Japanese adults aged 65 years or older (977 men, 994 women). Sarcopenia was defined based on appendicular skeletal muscle mass, grip strength and usual gait speed. MetS was defined based on the National Cholesterol Education Program's Adult Treatment Panel-III criteria. The prevalence of sarcopenia was 14.2% in men and 22.1% in women, while the prevalence of MetS was 43.6% in men and 28.9% in women. After adjustment for potential confounders, MetS was positively associated with sarcopenia in men aged 65 to 74 years (odds ratio 5.5; 95% confidence interval 1.9-15.9) but not in older men or women. Among the sarcopenia components, MetS was associated with lower muscle mass and grip strength, particularly in men aged 65 to 74 years. The associations of MetS with sarcopenia and its components were mainly driven by abdominal obesity regardless of sex or age. In conclusion, MetS is positively associated with sarcopenia in older men. The association is modified by sex and age, but abdominal obesity is the main contributor to the association across sex and age.


Pearls and Pitfalls in Imaging of Abusive Head Trauma.
Abusive head trauma (AHT) is the leading cause of fatal head injuries in infants. The mechanism of injury usually involves vigorous shaking of the infant, impact, or a combination of the 2. There are characteristic imaging findings of which the most common are subdural hemorrhages. Parenchymal injuries to the brain are common as well, including hypoxic ischemic injury, diffuse axonal injury, and cerebral contusions. Retinal hemorrhages are common with AHT and are best evaluated by fundoscopy, however, high grade retinal hemorrhages may be detected on cross-sectional imaging. Skull fractures are not specific to AHT but are present in third of the cases and tend to be complex in association with AHT. Injuries to the spine are more common than previously thought and typically involve soft tissues rather than bones, with the most common being ligamentous injuries in the craniocervical junction. In the setting of AHT, an affected infant would typically exhibit multiple findings. While CT of the head is the first modality of choice for assessment of an infant with AHT, magnetic resonance imaging examination of the brain and spine should follow due to its higher sensitivity for detection of these findings.


Treatment of the clinically negative neck in floor of the mouth carcinoma.
A retrospective study of 61 consecutive patients with floor of mouth carcinoma and a clinically negative neck was done to determine the value of elective treatment to the neck. Subsequent histologically proven nodal disease was analyzed according to initial treatment modality (23 surgical, 38 irradiation), stage (29--T1,27--T2,5--T3), hemi-neck at risk (midline lesions placed both hemi-necks at risk), and primary control for a minimum of 2 years (50 patients, 78 hemi-necks at risk). Neck failures were classified by T stage, extent of neck treatment (upper neck or complete) and by primary control at the time of manifest neck metastasis. Of the hemi-necks at risk with the primary controlled, 10% (17% of patients) developed nodal disease without complete neck treatment; 86% (6/7) of these patients were salvaged. The occult positive node incidence, conservatively calculated by elimination of all patients treated with elective partial or total neck irradiation, was 10% for patients with T1 and T2 lesions (7% for hemi-necks at risk). Based on the clinical course of patients with primary control, only 1 patient (2%) might have benefited from initial complete elective neck treatment. These results suggest that elective neck treatment in early (T1 and T2, N0) floor of mouth carcinoma is of doubtful value. Supraomohyoid , rather than suprahyoid dissection, is recommended if surgical treatment of the neck is undertaken.


Genome-wide association study identifies loci associated with liability to alcohol and drug dependence that is associated with variability in reward-related ventral striatum activity in African- and European-Americans.
Genetic influences on alcohol and drug dependence partially overlap, however, specific loci underlying this overlap remain unclear. We conducted a genome-wide association study (GWAS) of a phenotype representing alcohol or illicit drug dependence (ANYDEP) among 7291 European-Americans (EA; 2927 cases) and 3132 African-Americans (AA: 1315 cases) participating in the family-based Collaborative Study on the Genetics of Alcoholism. ANYDEP was heritable (h 2 in EA = 0.60, AA = 0.37). The AA GWAS identified three regions with genome-wide significant (GWS; P < 5E-08) single nucleotide polymorphisms (SNPs) on chromosomes 3 (rs34066662, rs58801820) and 13 (rs75168521, rs78886294), and an insertion-deletion on chromosome 5 (chr5:141988181). No polymorphisms reached GWS in the EA. One GWS region (chromosome 1: rs1890881) emerged from a trans-ancestral meta-analysis (EA + AA) of ANYDEP, and was attributable to alcohol dependence in both samples. Four genes (AA: CRKL, DZIP3, SBK3; EA: P2RX6) and four sets of genes were significantly enriched within biological pathways for hemostasis and signal transduction. GWS signals did not replicate in two independent samples but there was weak evidence for association between rs1890881 and alcohol intake in the UK Biobank. Among 118 AA and 481 EA individuals from the Duke Neurogenetics Study, rs75168521 and rs1890881 genotypes were associated with variability in reward-related ventral striatum activation. This study identified novel loci for substance dependence and provides preliminary evidence that these variants are also associated with individual differences in neural reward reactivity. Gene discovery efforts in non-European samples with distinct patterns of substance use may lead to the identification of novel ancestry-specific genetic markers of risk.


Patterns of Y-STR variation in Italy.
The 17 Y-chromosomal short tandem repeats (STRs) included in the AmpFlSTR Yfiler Amplification Kit (AB Applied Biosystems) (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635 and GATA H4.1) were typed in 292 samples from seven Italian regions. Population comparisons with other European samples were undertaken; for this purpose, two databases were collated from the literature: (a) 19 population samples including >2900 Yfiler profiles, and (b) 67 population samples including >15,000 minimum haplotype profiles. A total of 276 different Yfiler haplotypes were observed in Italy, and only one of them was shared among our seven population samples. The overall haplotype diversity (0.9996) was comparable to other European samples. AMOVA indicates that among population variance depends on the amount of Y-STRs used, being higher when using minimal haplotypes. This is probably due to the fact that Yfiler profiles are represented by singleton haplotypes in all the population samples raising the diversity values to the maximum theoretical value. AMOVA results seems to depend even more strongly on the amount of population samples used, the among population variance in Italy ranging from 2.82% to 11.03% (using 15 and 32 Italian populations samples, respectively). Variance is not as strongly stratified geographically within Italy, although it is notorious that latitude is more important than longitude in the distribution of variance. The results also indicated that Italy is less stratified than other European samples. The present study contributes to enrich the Y-chromosome databases regarding high-resolution Y-chromosome data sets and demonstrates that extended Y-STR profiles substantially increases the discriminatory capacity in individual identification for forensic purposes.


Tibial tuberosity osteotomy for patellofemoral realignment alters tibiofemoral kinematics.
Tibial tuberosity realignment surgery is performed to improve patellofemoral alignment, but it could also alter tibiofemoral kinematics. After tuberosity realignment in the malaligned knee, the reoriented patellar tendon will pull the tuberosity back toward the preoperative position, thereby altering tibiofemoral kinematics. Controlled laboratory study. Ten knees were tested at 40°, 60°, and 80° of flexion in vitro. The knees were loaded with a quadriceps force of 586 N, with 200 N divided between the medial and lateral hamstrings. The position of the tuberosity was varied to represent lateral malalignment, with the tuberosity 5 mm lateral to the normal position; tuberosity medialization, with the tuberosity 5 mm medial to the normal position; and tuberosity anteromedialization, with the tuberosity 10 mm anterior to the medial position. Tibiofemoral kinematics were measured using magnetic sensors secured to the femur and tibia. A repeated measures analysis of variance with a post hoc Student-Newman-Keuls test was used to identify significant (P < .05) differences in the kinematic data between the tuberosity positions at each flexion angle. Medializing the tibial tuberosity primarily rotated the tibia externally compared with the lateral malalignment condition. The largest average increase in external rotation was 13° at 40° of flexion, with the increase significant at each flexion angle. The varus orientation also increased significantly by an average of 1.5° at 40° and 80°. The tibia shifted significantly posteriorly at 40° and 60° by an average of 4 mm and 2 mm, respectively. Shifting the tuberosity from the medial to the anteromedial position translated the tibia significantly posteriorly by an average of 2 mm at 40°. After tibial tuberosity realignment in the malaligned knee, the altered orientation of the patellar tendon alters tibiofemoral kinematics. The kinematic changes reduce the correction applied to the orientation of the patellar tendon and could alter the pressure applied to tibiofemoral cartilage.


Inhibiting Escherichia coli cytochrome c nitrite reductase: voltammetry reveals an enzyme equipped for action despite the chemical challenges it may face in vivo.
Escherichia coli cytochrome c nitrite reductase is one of a large family of homologous enzymes that are particularly prevalent in pathogenic enterobacteria. The enzymes are periplasmic and in vivo may find themselves challenged by molecules that could enhance or compromise their performance. In the present study, we describe protein film voltammetry in which the activity of E. coli cytochrome c nitrite reductase is challenged by the presence of a number of small molecules. These results are discussed in light of the environment(s) that the enzyme may face before and after colonization of a human host.


Synthesis, spectral characterization, and pharmacological screening of some 4-[{1-(aryl)methylidene}-amino]-3-(4-pyridyl)-5-mercapto-4H-1,2,4-triazole derivatives.
Pain is an unpleasant and subjective sensation that results from a harmful sensorial stimulation, which alerts the body about current or potential damage to its tissues and organs. Fever is a complex physiological response triggered by infections or aseptic stimuli. Elevation in body temperature occurs when the concentration of prostaglandin E(2) (PGE(2)) increases within parts of the brain. Triazole derivatives have been found to possess various pharmacological and biological activities, such as, anti-inflammatory, analgesics, antipyretic, and antifungal. Various 4-[{1-(aryl)methylidene}-amino]-3-(4-pyridyl)-5-mercapto-4H-1,2,4-triazole derivatives were synthesized by a sequence of reactions starting from isonicotinic acid hydrazide. The synthesized compounds were screened for in-vivo analgesic by the tail-flick method and anti-pyretic activities at a dose of 25 and 100 mg/kg body weight respectively. The antipyretic activity was evaluated using Brewer's yeast induced pyrexia in rats. Fever was induced by subcutaneously injecting 20 ml/kg of 20% aqueous suspension of Brewer's yeast in normal saline. The analgesic screening results revealed that the compounds 3b, 3c, and 3d exhibited excellent analgesic activity at 60 and 90 minutes compared to the standard drug (Analgin). Results revealed that the compounds 3a, 3e, and 3f significantly decreased the temperature of pyretic (P<0.001) rats at one, three and six hours after compound administration as compared to Aspirin (standard drug). Compounds 3b, 3c, and 3d exhibited significant analgesic activity comparable with the standard drug analgin, using the tail flick model. Compounds 3a, 3e, and 3f showed significant anti-pyretic activities comparable with the standard drug aspirin using the yeast-induced pyrexia model.


Polymorphisms of the 5-HT2A receptor gene and clinical response to olanzapine in paranoid schizophrenia.
5-HT2A receptor is strongly implicated in the mode of action of atypical antipsychotic drugs. The aim of the study was to investigate whether the 5-HT2A receptor gene's polymorphisms (His452Tyr and T102C) have an influence on the response to olanzapine in patients with schizophrenia. We studied 99 Caucasian schizophrenia patients treated with olanzapine. Psychopathology was measured before and after 6 weeks of treatment. Clinical improvement was quantified as change in Positive and Negative Syndrome Scale (PANSS) total scores and subscores as shown by percentage improvement below the baseline score. The clinical response to antipsychotic treatment was defined as 30% improvement from baseline in PANSS scores. The His/Tyr polymorphism was significantly associated with a percentage improvement in PANSS positive symptom subscore (better response in His/His homozygotes; p<0.05) after treatment with olanzapine. As for the T102C polymorphism, a better response in terms of PANSS positive subscore improvement was observed for C/C homozygotes (p<0.01). A significant association of 5-HT2A genotype distribution of the T102C polymorphism with a categorical measure of response, but only in terms of PANSS positive symptom subscores, was observed (p<0.01). Variations in the 5-HT2A receptor gene may influence individual and particularly positive symptom response to olanzapine.


GPR179 is required for depolarizing bipolar cell function and is mutated in autosomal-recessive complete congenital stationary night blindness.
Complete congenital stationary night blindness (cCSNB) is a clinically and genetically heterogeneous group of retinal disorders characterized by nonprogressive impairment of night vision, absence of the electroretinogram (ERG) b-wave, and variable degrees of involvement of other visual functions. We report here that mutations in GPR179, encoding an orphan G protein receptor, underlie a form of autosomal-recessive cCSNB. The Gpr179(nob5/nob5) mouse model was initially discovered by the absence of the ERG b-wave, a component that reflects depolarizing bipolar cell (DBC) function. We performed genetic mapping, followed by next-generation sequencing of the critical region and detected a large transposon-like DNA insertion in Gpr179. The involvement of GPR179 in DBC function was confirmed in zebrafish and humans. Functional knockdown of gpr179 in zebrafish led to a marked reduction in the amplitude of the ERG b-wave. Candidate gene analysis of GPR179 in DNA extracted from patients with cCSNB identified GPR179-inactivating mutations in two patients. We developed an antibody against mouse GPR179, which robustly labeled DBC dendritic terminals in wild-type mice. This labeling colocalized with the expression of GRM6 and was absent in Gpr179(nob5/nob5) mutant mice. Our results demonstrate that GPR179 plays a critical role in DBC signal transduction and expands our understanding of the mechanisms that mediate normal rod vision.


Performance Analysis in Rugby Union: a Critical Systematic Review.
Performance analysis in rugby union has become an integral part of the coaching process. Although performance analysis research in rugby and data collection has progressed, the utility of the insights is not well understood. The primary objective of this review is to consider the current state of performance analysis research in professional rugby union and consider the utility of common methods of analysing performance and the applicability of these methods within professional coaching practice. SPORTDiscus electronic database was searched for relevant articles published between 1 January 1997 and 7 March 2019. Professional, male 15-a-side rugby union studies that included relevant data on tactical and performance evaluation, and statistical compilation of time-motion analysis were included. Studies were categorised based on the main focus and each study was reviewed by assessing a number of factors such as context, opposition analysis, competition and sample size. Forty-one studies met the inclusion criteria. The majority of these studies measured performance through the collection and analysis of performance indicators. The majority did not provide context relating to multiple confounding factors such as field location, match location and opposition information. Twenty-nine performance indicators differentiated between successful match outcomes; however, only eight were commonly shared across some studies. Five studies considered rugby union as a dynamical system; however, these studies were limited in analysing lower or national-level competitions. The review highlighted the issues associated with assessing isolated measures of performance, lacking contextual information such as the opposition, match location, period within match and field location. A small number of studies have assessed rugby union performance through a dynamical systems lens, identifying successful characteristics in collective behaviour patterns in attacking phases. Performance analysis in international rugby union can be advanced by adopting these approaches in addition to methods currently adopted in other team sports.


Plasma uptake of selected phenolic acids following New Zealand blackcurrant extract supplementation in humans.
New Zealand blackcurrant (NZBC) extract is a rich source of anthocyanins and in order to exert physiological effects, the anthocyanin-derived metabolites need to be bioavailable in vivo. We examined the plasma uptake of selected phenolic acids following NZBC extract supplementation alongside maintaining a habitual diet (i.e. not restricting habitual polyphenol intake). Twenty healthy volunteers (nine females, age: 28 ± 7 years, height 1.73 ± 0.09 m, body mass 73 ± 11 kg) consumed a 300 mg NZBC extract capsule (CurraNZ®; anthocyanin content 105 mg) following an overnight fast. Venous blood samples were taken pre and 1, 1.5, 2, 3, 4, 5, and 6 h post-ingestion of the capsule. Reversed-phase high-performance liquid chromatography (HPLC) was used for analysis of two dihydroxybenzoic acids [i.e. vanillic acid (VA) and protocatechuic acid (PCA)] and one trihydroxybenzoic acid [i.e. gallic acid (GA)] in plasma following NZBC extract supplementation. Habitual anthocyanin intake was 168 (95%CI:68-404) mg⋅day-1 and no associations were observed between this and VA, PCA, and GA plasma uptake by the NZBC extract intake. Plasma time-concentration curves revealed that GA, and PCA were most abundant at 4, and 1.5 h post-ingestion, representing a 261% and 320% increase above baseline, respectively, with VA remaining unchanged. This is the first study to demonstrate that an NZBC extract supplement increases the plasma uptake of phenolic acids GA, and PCA even when a habitual diet is followed in the days preceding the experimental trial, although inter-individual variability is apparent.


Aggresome disruption: a novel strategy to enhance bortezomib-induced apoptosis in pancreatic cancer cells.
The proteasome inhibitor bortezomib (formerly known as PS-341) recently received Food and Drug Administration approval for the treatment of multiple myeloma, and its activity is currently being evaluated in solid tumors. Bortezomib triggers apoptosis in pancreatic cancer cells, but the mechanisms involved have not been fully elucidated. Here, we show that pancreatic cancer cells exposed to bortezomib formed aggregates of ubiquitin-conjugated proteins ("aggresomes") in vitro and in vivo. Bortezomib-induced aggresome formation was determined to be cytoprotective and could be disrupted using histone deacetylase (HDAC) 6 small interfering RNA or chemical HDAC inhibitors, which resulted in endoplasmic reticulum stress and synergistic levels of apoptosis in vitro and in an orthotopic pancreatic cancer xenograft model in vivo. Interestingly, bortezomib did not induce aggresome formation in immortalized normal human pancreatic epithelial cells in vitro or in murine pancreatic epithelial cells in vivo. In addition, these cells did not undergo apoptosis following treatment with bortezomib, suberoylanilide hydroxamic acid, or the combination, showing tumor selectivity. Taken together, our study shows that inhibition of aggresome formation can strongly potentiate the efficacy of bortezomib and provides the foundation for clinical trials of bortezomib in combination with HDAC inhibitors for the treatment of pancreatic cancer.


Activation of the monocytic α7 nicotinic acetylcholine receptor modulates oxidative stress and inflammation-associated development of coronary artery spasm via a p38 MAP-kinase signaling-dependent pathway.
Smoking and high-sensitivity C-reactive protein (hs-CRP) are risk factors for coronary artery spasm (CAS), which is characterized by the increased interleukin-6 (IL-6) level and monocyte counts; however, limited data are available regarding the role of cigarette-embedded nicotine in the modulation of monocytic inflammatory activity in CAS. We investigated and elucidated the putative roles and associations of nicotine, monocytic IL-6, α7 nicotinic acetylcholine receptor (α7-nAChR), and CRP in CAS development. We demonstrated that a significantly increased α7-nAChR (p = 0.001) and IL-6 (p = 0.0036) messenger RNA (mRNA) expression in the serum of patients with CAS. Serum hs-CRP levels exhibited a strong positive correlation with the monocytic mRNA expression of α7-nAChR (r = 0.71, p < 0.001) and IL-6 (r = 0.49, p = 0.006). The α7-nAChR and IL-6 expression levels of the CAS group were also positively correlated (r = 0.63, p < 0.001). Compared with the untreated controls, THP-1 cells and patient-derived monocytes treated with different concentrations of CRP displayed significantly increased expression levels of α7-nAChR mRNA and protein (p = 0.0054), in a dose-dependent manner. We also demonstrated that compared with the IL-6 expression elicited by CRP alone (p = 0.0489), the CRP-induced rise in monocytic IL-6 mRNA and protein expression in the presence of nicotine (p = 0.0002), is mediated by α7-nAChR activation and the deregulation of the human p38 mitogen-activated protein kinases (MAPK) signaling pathway. Our data demonstrate that the elevated monocytic IL-6 and α7-nAChR mRNA and protein expression levels are associated with the interaction between nicotine and CRP positively modulates CAS development. Our study suggests the potential role of α7-nAChR mRNA and/or protein expression as a diagnostic biomarker for CAS.


Influence of Post Length, Post Material, and Substance Loss on the Fracture Resistance of Endodontically Treated Teeth. A Laboratory Study.
To evaluate the effects of post length, post material, and substance loss on the fracture resistance of endodontically treated mandibular premolars. A total of 96 extracted human mandibular first premolars were endodontically treated and divided into 12 test groups (n = 8 each) based on the number of residual walls (one/two), post material (glass-fiber/titanium), and post length (5 mm, 7.5 mm, and 10 mm). After luting the posts, specimens received a composite resin core and a crown preparation with a 1.5-mm ferrule. Cast cobalt-chromium crowns were cemented using glass-ionomer cement. After 1,200,000 chewing cycles with a load of 49 N and simultaneous thermocycling (5°C to 55°C), specimens were quasi-statically loaded at 30 degrees to the longitudinal axis of the tooth until fracture. Fracture loads were analyzed using three-way, two-way, and one-way analysis of variance (α = .05). Fracture modes were examined under a stereomicroscope (×25) and recorded. Fracture loads ranged from 642 ± 190 N (one wall, glass fiber, 5 mm) to 1,170 ± 130 (two walls, titanium, 7.5 mm). The mean fracture load of titanium posts was significantly higher than that of glass-fiber posts (P < .001), and the 7.5-mm post length exhibited significantly higher fracture loads than groups with 5-mm and 10-mm post length (P = .008). Teeth restored with titanium posts revealed considerably higher fracture resistance than teeth restored with glass-fiber posts, especially if 7.5-mm-length posts were used.


Teacher quality moderates the genetic effects on early reading.
Children's reading achievement is influenced by genetics as well as by family and school environments. The importance of teacher quality as a specific school environmental influence on reading achievement is unknown. We studied first- and second-grade students in Florida from schools representing diverse environments. Comparison of monozygotic and dizygotic twins, differentiating genetic similarities of 100% and 50%, provided an estimate of genetic variance in reading achievement. Teacher quality was measured by how much reading gain the non-twin classmates achieved. The magnitude of genetic variance associated with twins' oral reading fluency increased as the quality of their teacher increased. In circumstances where the teachers are all excellent, the variability in student reading achievement may appear to be largely due to genetics. However, poor teaching impedes the ability of children to reach their potential.


Suppressing the surface field during transcranial magnetic stimulation.
Transcranial magnetic stimulation (TMS) is used commonly as both a diagnostic tool and as an alternative to electric shock therapy for the treatment of clinical depression. Among the clinical issues encountered in its use is the mitigation of accompanying pain. The objective becomes one of minimizing the induced surface field while still achieving the target field objective. Three techniques discussed for realizing this end are 1) placing a conducting shield over a portion of the central target region, 2) using supplementary coils of opposite polarity in tandem with the primary field, and 3) opening the core angle to distribute the field. Option (3) shows the greatest promise for reducing the ratio of the maximum surface field to the induced target field.


Folate status in Aboriginal people before and after mandatory fortification of flour for bread-making in Australia.
Mandatory fortification of wheat flour for bread-making was introduced in Australia in September 2009, to assist in the prevention of neural tube defects (NTD). NTD are twice as common in Aboriginal compared with non-Aboriginal infants, and folate levels are lower in the Aboriginal population. This study was undertaken to compare folate status and NTD in the Aboriginal population before and after fortification. Postfortification, 95 Aboriginal men and nonpregnant women aged 16-44 years in metropolitan and regional Western Australia (WA) completed a rapid dietary assessment tool and had blood taken to measure red cell folate. Measures were compared with prefortification values obtained in an earlier study using the same methods. Data on NTD in Aboriginal infants were obtained from the WA Register of Developmental Anomalies. No participant was folate deficient. The mean red cell folate increased after fortification to 443 ng/mL for males and 567 ng/mL for females. The mean difference between red cell folate after fortification compared with before was 129 ng/mL for males (95% CI 81-177); t = 5.4; P < 0.0001) and 186 ng/mL for females (95% CI 139-233); t = 7.9; P < 0.0001). Most participants ate fortified shop-bought bread at least weekly, resulting in an estimated additional folate intake per day of 178 (males) and 145 (females) dietary folate equivalents. NTD prevalence fell by 68% following fortification (prevalence ratio 0.32 (CI 0.15-0.69)). The population health intervention of mandatory fortification of wheat flour for bread-making has had the desired effect of increasing folate status and reducing NTD in the Australian Aboriginal population.


REO-10: a phase I study of intravenous reovirus and docetaxel in patients with advanced cancer.
REOLYSIN (Oncolytics Biotech) consists of a wild-type oncolytic reovirus, which has selective cytotoxicity for tumor cells while sparing normal cells. In a phase I study as a single agent, repeated infusions of reovirus were safe with evidence of antitumor activity. Preclinical studies indicate potential for synergy between reovirus and chemotherapeutic agents. A multicenter, phase I dose escalation study was designed to assess the safety of combining reovirus with docetaxel chemotherapy in patients with advanced cancer. Patients received 75 mg/m(2) docetaxel (day 1) and escalating doses of reovirus up to 3 × 10(10) TCID(50) (days 1-5) every 3 weeks. Twenty-five patients were enrolled, and 24 patients were exposed to treatment, with 23 completing at least one cycle and 16 suitable for response assessment. Dose-limiting toxicity of grade 4 neutropenia was seen in one patient, but the maximum tolerated dose was not reached. Antitumor activity was seen with one complete response and three partial responses. A disease control rate (combined complete response, partial response, and stable disease) of 88% was observed. Immunohistochemical analysis of reovirus protein expression was observed in posttreatment tumor biopsies from three patients. The combination of reovirus and docetaxel is safe, with evidence of objective disease response, and warrants further evaluation in a phase II study at a recommended schedule of docetaxel (75 mg/m(2), three times weekly) and reovirus (3 × 10(10) TCID(50), days 1-5, every 3 weeks).


Insulin pump therapy in children and adolescents with type 1 diabetes: the Italian viewpoint.
A panel of experts of the Italian Society of Paediatric Endocrinology and Diabetology translated into Italian the international insulin pump therapy recommendations in children and adolescents with type 1 diabetes. After an extensive review of the literature using evidence-based recommendations, several issues were taken into account, such as patient selection, advantages and disadvantages, instrument choice, insulin type, therapy planning and follow-up, emergencies, nutrition, particular occasions (like parties, holidays, sick days, travels), exercise, continuous glucose monitoring and integrated system, neonatal diabetes. The panel evaluated the cost-effectiveness of insulin pump therapy compared to multiple daily injection therapy, analysing the cost-benefit ratio. Some tweak was needed due to the Italian dietetic singularity, meal schedule, climate and lifestyle. Insulin pump therapy in neonatal diabetes is a new issue and no guidelines have been published yet for this age-group. Moreover, legal issues according to the Italian law have been added and are peculiarity of our recommendations. An "informed therapeutic agreement" between the patient and his/her family and the diabetic team has to be signed before starting insulin pump therapy. We think that nowadays the need for clinical guidelines is important and worth the effort that all countries develop faithful adaptation into their local languages taking into account specific contexts and local peculiarities, without making substantial modifications to the original text.


Neonatal Acid-Base Status in Term Fetuses: Mathematical Models Investigating Cerebroplacental Ratio and Birth Weight.
Cerebroplacental ratio (CPR) is emerging as a marker of fetal hypoxia at term. The aim of this study was to demonstrate graphically the interrelationships among CPR, birthweight (BW), and neonatal pH, and construct 2D and 3D representations of the areas with potential low pH. This was a retrospective study of 2,927 term fetuses evaluated according to BW and CPR. The outcome was the acid-base status at birth. Multivariate relationships among CPR, BW, and arterial and venous pH were depicted in 3D scattergrams. Subsequently, trend surfaces were calculated and represented in 2D contour graphs. Finally, 3D representations were constructed by smothering pH data using moving average filters. The trend surfaces and the 2D and 3D contour graphs showed the complex association among the three variables. Although pH changed with CPR and BW, the influence of the BW was smaller than the influence of the CPR, with this effect being more evident in the venous than in the arterial pH. Two scenarios threaten fetal well-being at term: a very low birth weight and a very low fetal CPR. Our findings suggest that the importance of fetal hemodynamics in determining the acid-base status at birth surpasses that of fetal weight.