Effect of dissolved organic matter on the transformation of contaminants induced by excited triplet states and the hydroxyl radical.
Dissolved organic matter (DOM) has recently been shown to reduce the transformation rate of various aqueous organic contaminants submitted to oxidation by excited triplet states, apparently by inhibiting the transformation of oxidation intermediates. The main goals of the present study were to evaluate in more detail the effect of concentration and type of DOM on the triplet-induced transformation rate of four selected organic compounds and to check for an analogous inhibition effect in the case of oxidation induced by hydroxyl radical. A marked inhibition by DOM of triplet-induced oxidation was observed for N,N-dimethylaniline (DMA) and the two antibiotics sulfamethoxazole (SMX) and trimethoprim (TRI), with DOM of terrestrial origin being a more effective inhibitor than DOM of aquatic origin. The results are important to understand the role of DOM both as a photosensitizer and as an inhibitor for the triplet-induced transformation of aquatic contaminants. In contrast, no DOM-induced reduction in second-order rate constant could be observed in competition kinetics experiments for the reaction of hydroxyl radical with a series of 15 organic compounds, covering several classes of aromatic contaminants, indicating that Suwannee River fulvic acid (SRFA) used as reference DOM does not affect this reaction mechanism.


Barcoded pyrosequencing reveals that consumption of galactooligosaccharides results in a highly specific bifidogenic response in humans.
Prebiotics are selectively fermented ingredients that allow specific changes in the gastrointestinal microbiota that confer health benefits to the host. However, the effects of prebiotics on the human gut microbiota are incomplete as most studies have relied on methods that fail to cover the breadth of the bacterial community. The goal of this research was to use high throughput multiplex community sequencing of 16S rDNA tags to gain a community wide perspective of the impact of prebiotic galactooligosaccharide (GOS) on the fecal microbiota of healthy human subjects. Fecal samples from eighteen healthy adults were previously obtained during a feeding trial in which each subject consumed a GOS-containing product for twelve weeks, with four increasing dosages (0, 2.5, 5, and 10 gram) of GOS. Multiplex sequencing of the 16S rDNA tags revealed that GOS induced significant compositional alterations in the fecal microbiota, principally by increasing the abundance of organisms within the Actinobacteria. Specifically, several distinct lineages of Bifidobacterium were enriched. Consumption of GOS led to five- to ten-fold increases in bifidobacteria in half of the subjects. Increases in Firmicutes were also observed, however, these changes were detectable in only a few individuals. The enrichment of bifidobacteria was generally at the expense of one group of bacteria, the Bacteroides. The responses to GOS and the magnitude of the response varied between individuals, were reversible, and were in accordance with dosage. The bifidobacteria were the only bacteria that were consistently and significantly enriched by GOS, although this substrate supported the growth of diverse colonic bacteria in mono-culture experiments. These results suggest that GOS can be used to enrich bifidobacteria in the human gastrointestinal tract with remarkable specificity, and that the bifidogenic properties of GOS that occur in vivo are caused by selective fermentation as well as by competitive interactions within the intestinal environment.


The health of the james bay cree.
The health of the James Bay Cree of Quebec reflects their history and environment. Their ancestors were living in Northern Quebec for centuries before the Europeans arrived bringing new infectious diseases and developing a health-care structure that has relegated traditional Cree medicine to the background. The James Bay and Northern Quebec Agreement of 1975 led to the creation of the Cree Board of Health and Social Services under the Quebec Ministry of Health. Various changes have resulted in the eight Cree villages over the past 15 years, both in the socio-economic situation and in the health status of the Cree. Improvements in health will come about through increased participation of Native people in the delivery and control of health services, more accessible health services, and the creation of healthy and health-promoting environments.


Effects of high gravity on amphibian development.
In order to clarify the possible effects of high gravity environments on eggs and developing embryos, Rana rugosa and Xenopus laevis fertilized eggs and early embryos were raised in 2 G, 5 G, 7 G and 10 G up to the hatched tadpole stage. The results showed that: (1) High gravity significantly retarded the development of eggs and embryos beginning treatment before the blastula stage and induced various abnormalities, including two heads and microcephally suggesting that high gravity is apt to disrupt the animal-vegital axis. On the other hand, embryos beginning treatment after the gastrula stage showed a striking increase in the number of normal-appearing feeding tadpoles. (2) Autopsy revealed that brains, notochords and muscles were reduced in development and differentiation for embryos and tadpoles developed in high gravity. (3) It seems likely that the system for hydrogen peroxide detoxification develops abnormally in high gravity-treated embryos and tadpoles, which probably results in oxidative stress, leading to considerable cell damage.


Absence of an association between mannose-binding lectin polymorphism and rheumatoid arthritis.
It has been proposed that mannose-binding lectin (MBL) interactions with agalactosyl forms of IgG immunoglobulins found in rheumatoid synovial fluid might lead to enhanced complement activation, an important mediator of the joint damage in rheumatoid arthritis (RA). In order to investigate this possible link between increased MBL-mediated activation of complement and perpetuation of rheumatoid synovitis, we have compared the frequency of an allelic form of MBL, known to be incapable of activating complement, in a group of hospital patients with severe RA and control subjects. No evidence was found to support an association between the presence of this MBL allele and protection from rheumatoid disease; genotype frequencies were similar in both groups. This suggests that complement activation via MBL-agalactosyl IgG complexes is unlikely to play a major role in the pathophysiology of RA.


Mapping nonlinear gravity into General Relativity with nonlinear electrodynamics.
We show that families of nonlinear gravity theories formulated in a metric-affine approach and coupled to a nonlinear theory of electrodynamics can be mapped into general relativity (GR) coupled to another nonlinear theory of electrodynamics. This allows to generate solutions of the former from those of the latter using purely algebraic transformations. This correspondence is explicitly illustrated with the Eddington-inspired Born-Infeld theory of gravity, for which we consider a family of nonlinear electrodynamics and show that, under the map, preserve their algebraic structure. For the particular case of Maxwell electrodynamics coupled to Born-Infeld gravity we find, via this correspondence, a Born-Infeld-type nonlinear electrodynamics on the GR side. Solving the spherically symmetric electrovacuum case for the latter, we show how the map provides directly the right solutions for the former. This procedure opens a new door to explore astrophysical and cosmological scenarios in nonlinear gravity theories by exploiting the full power of the analytical and numerical methods developed within the framework of GR.


CdSe QD Biosynthesis in Yeast Using Tryptone-Enriched Media and Their Conjugation with a Peptide Hecate for Bacterial Detection and Killing.
The physical and chemical synthesis methods of quantum dots (QDs) are generally unfavorable for biological applications. To overcome this limitation, the development of a novel "green" route to produce highly-fluorescent CdSe QDs constitutes a promising substitute approach. In the present work, CdSe QDs were biosynthesized in yeast Saccharomyces cerevisiae using a novel method, where we showed for the first time that the concentration of tryptone highly affects the synthesis process. The optimum concentration of tryptone was found to be 25 g/L for the highest yield. Different methods were used to optimize the QD extraction from yeast, and the best method was found to be by denaturation at 80 °C along with an ultrasound needle. Multiple physical characterizations including transmission electron microscopy (TEM), dynamic light scattering (DLS), energy-dispersive X-ray spectroscopy (EDX), and spectrophotometry confirmed the optical features size and shape distribution of the QDs. We showed that the novel conjugate of the CdSe QDs and a cell-penetrating peptide (hecate) can detect bacterial cells very efficiently under a fluorescent microscope. The conjugate also showed strong antibacterial activity against vancomycin-resistant Staphylococcus aureus (VRSA), methicillin-resistant Staphylococcus aureus (MRSA), and Escherichia coli, which may help us to cope with the problem of rising antibiotic resistance.


A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6.
Cell cycle deregulation is central to the initiation and fatality of multiple myeloma, the second most common hematopoietic cancer, although impaired apoptosis plays a critical role in the accumulation of myeloma cells in the bone marrow. The mechanism for intermittent, unrestrained proliferation of myeloma cells is unknown, but mutually exclusive activation of cyclin-dependent kinase 4 (Cdk4)-cyclin D1 or Cdk6-cyclin D2 precedes proliferation of bone marrow myeloma cells in vivo. Here, we show that by specific inhibition of Cdk4/6, the orally active small-molecule PD 0332991 potently induces G(1) arrest in primary bone marrow myeloma cells ex vivo and prevents tumor growth in disseminated human myeloma xenografts. PD 0332991 inhibits Cdk4/6 proportional to the cycling status of the cells independent of cellular transformation and acts in concert with the physiologic Cdk4/6 inhibitor p18(INK4c). Inhibition of Cdk4/6 by PD 0332991 is not accompanied by induction of apoptosis. However, when used in combination with a second agent, such as dexamethasone, PD 0332991 markedly enhances the killing of myeloma cells by dexamethasone. PD 0332991, therefore, represents the first promising and specific inhibitor for therapeutic targeting of Cdk4/6 in multiple myeloma and possibly other B-cell cancers.


Pregnancy and stroke risk in women.
Stroke, the sudden onset of brain dysfunction from a vascular cause, is one of the most common causes of long-term disability. Although rare during childbearing years, stroke is even more devastating when it occurs in a young woman trying to start a family. Pregnancy and the postpartum period are associated with an increased risk of ischemic stroke and intracerebral hemorrhage, although the incidence estimates have varied. There are several causes of stroke that are in fact unique to pregnancy and the postpartum period, such as preeclampsia and eclampsia, amniotic fluid embolus, postpartum angiopathy and postpartum cardiomyopathy. Data regarding these individual entities are scant. Most concerning is the lack of data regarding both prevention and acute management of pregnancy-related stroke. The purpose of this article is to summarize existing data regarding incidence, risk factors and potential etiologies, as well as treatment strategies for stroke in pregnancy.


Complete avulsion of the extensor mechanism of a finger with simultaneous dislocation of the proximal interphalangeal joint.
We report a rare case of open dislocation of the proximal interphalangeal (PIP) joint, associated with simultaneous avulsion of the central band and distal insertion of the extensor mechanism, rapture of the proximal volar plate, and rapture of the ulnar collateral ligament of the PIP joint.Although isolated IP joint injuries are common, they rarely occur simultaneously in a single finger. Even more rarely are they accompanied by a complete avulsion of the extensor mechanism. Operative restoration of the injured structures is a necessity in order to achieve a good functional outcome.An initial forceful flexion of the finger resulting to rapture of the extensor apparatus and then followed by finger hyperextension and PIP joint dislocation is our perception of the possible mechanism of this extremely rare injury.


Secretion from permeabilised mast cells is enhanced by addition of gelsolin: contrasting effects of endogenous gelsolin.
Permeabilised rat mast cells were exposed to gelsolin and its N-terminal half (S1-3), proteins that sever actin filaments in a calcium-dependent and independent manner, respectively. Gelsolin and S1-3 induced a decrease in cellular F-actin content and an increase in the extent of the secretory response. The calcium sensitivities of both these effects were consistent with the differential calcium requirements of the two proteins. Segment 1 (S1), which binds G-actin and caps filaments but does not sever them, did not show these effects. Thus, secretion of mast cells is promoted as a consequence of the severing activity of exogenous gelsolin or S1-3. Most of the endogenous gelsolin remained within permeabilised, washed mast cells and its distribution in resting state was predominantly cortical. Addition of calcium in the absence of MgATP did not reduce the F-actin content; by contrast, calcium with MgATP induced F-actin loss that was unaffected by the presence of anti-gelsolin. Because this antibody inhibits the severing activity of gelsolin, these results indicate that in permeabilised mast cells the severing activity of the remaining endogenous gelsolin is not involved in cortical actin filaments disassembly. Upon exposure to GTP-gamma-S in the absence of calcium, the content of cortical gelsolin was reduced. This parallels our previous observation of a GTP-gamma-S induced reduction of cortical actin filaments followed by their relocation to the cell's interior (Norman et al. (1994) J. Cell Biol. 126, 1005-1015) and suggests that actin redistribution may be a consequence of dissociation of gelsolin caps brought about by activation of a GTP-binding protein.


Hemodialysis for end-stage renal disease: a cost-effectiveness analysis of treatment-options.
During 2001, over 32,000 patients in the United Kingdom received renal replacement therapy (RRT). Approximately half had a functioning transplant, with the remainder receiving dialysis therapy. The main form of dialysis is hemodialysis (HD), which is provided to 37.1 percent of the RRT population. HD is provided in three main settings: hospital (24.5 percent), satellite (10.9 percent), or home (1.7 percent). The objective of this study is to explore the cost-effectiveness of these different modalities. By using clinical and cost data from a systematic review, a Markov model was developed to assess the costs and benefits of the three different modalities. The model included direct health service costs and quality-adjusted life years (QALYs). Sensitivity analyses were performed to assess the robustness of the results. Satellite HD has lower costs 46,000 pounds sterling and 62,050 pounds sterling at 5 and 10 years than home HD 47,660 pounds sterling and 63,540 pounds sterling. The total effectiveness of home HD was slightly greater than for satellite HD, so the incremental cost per QALY of home versus satellite HD was modest at 6,665 pounds sterling at 5 years and 3,943 pounds sterling at 10 years. Both modalities dominated hospital HD. Results from the study reveal that satellite HD was less costly than home HD, and home HD was less costly than hospital HD. The lack of robust data on the effectiveness and new dialysis equipment, which were not included in this review, throws some caution on these results. Nonetheless, the results are supportive of a shift from hospital HD to satellite and home HD.


Deep Neural Networks as Scientific Models.
Artificial deep neural networks (DNNs) initially inspired by the brain enable computers to solve cognitive tasks at which humans excel. In the absence of explanations for such cognitive phenomena, in turn cognitive scientists have started using DNNs as models to investigate biological cognition and its neural basis, creating heated debate. Here, we reflect on the case from the perspective of philosophy of science. After putting DNNs as scientific models into context, we discuss how DNNs can fruitfully contribute to cognitive science. We claim that beyond their power to provide predictions and explanations of cognitive phenomena, DNNs have the potential to contribute to an often overlooked but ubiquitous and fundamental use of scientific models: exploration.


Expert opinion: use of valproate in girls and women of childbearing potential with epilepsy: recommendations and alternatives based on a review of the literature and clinical experience-a European perspective.
Valproate is a broad-spectrum antiepileptic drug (AED) of particular interest in pediatric epilepsy syndromes and idiopathic generalized epilepsy, as it is relatively more effective in these syndromes than other AEDs. In 2018, the European Medicines Agency introduced new restrictions on the use of valproate in girls and women of childbearing potential to avoid exposure during pregnancy. The strengthening of existing restrictions sparked controversy and debate among patients and the medical community. The high prevalence of epilepsy syndromes amenable to valproate treatment in women of childbearing age and the little information available on the teratogenic potential of alternative treatments have created uncertainty on how to manage these patients. In this consensus statement, based on a review of the literature and the clinical experience of a panel of European epilepsy experts, we present general recommendations for the optimal clinical management of AED treatment in girls, women of childbearing potential, and pregnant women across the different epilepsy syndromes.


Solar simulator for a 3-m space environment chamber.
The geometric-optical principles of a solar simulator for 1.5-m diam test objects are described and discussed. The characteristic features of the optical arrangement are a special configuration of nine individual radiation sources, and a mosaic mirror, consisting of more than 1000 single mirrors. The mosaic mirror permits the reference plane (rated diameter 1.5 m) to be evenly illuminated by well collimated light. For lesser demands with regard to uniformity and collimation the mosaic mirror can be readjusted so as to serve larger or smaller test objects (the latter refers, for instance, to solar research satellites exposed to intense irradiation). The method of adjusting the mosaic mirror is described. A possible modification of the system for larger solar simulators is also discussed.


How Did Multiple FDA Actions Affect the Utilization and Reimbursed Costs of Thiazolidinediones in US Medicaid?
The US Food and Drug Administration (FDA) communicated the potential cardiovascular risk of thiazolidinediones (rosiglitazone and pioglitazone) in 2007 and required a Risk Evaluation and Mitigation Strategy (REMS) for rosiglitazone in 2010. It also communicated in 2010 the potential risk of bladder cancer with pioglitazone use. This study examined the effects of these multiple FDA actions on utilization and reimbursed costs of thiazolidinediones in state Medicaid programs. State Drug Utilization Data from the Centers for Medicare & Medicaid Services were assessed. An interrupted time series design and segmented linear regression models were used to examine changes in market shares according to both prescription volume and reimbursed costs for rosiglitazone and pioglitazone in the Northeast and Midwest regions of the United States after multiple FDA actions. Compared with expected rates, there were relative reductions of 65.84% (Northeast region) and 55.09% (Midwest region) in the use of rosiglitazone at 1 year after the 2007 FDA actions for thiazolidinediones and cardiac risk. At the same time, relative increases of 7.30% and 9.28% in the use of pioglitazone were observed in the Northeast and Midwest regions, respectively. Changes in both use and costs of rosiglitazone after the 2010 REMS program could not be estimated because of the already low rates (~1%) before REMS was implemented. One year after the 2010 FDA actions for pioglitazone and its possible association with bladder cancer, relative reductions in pioglitazone use of 21.41% (Northeast region) and 18.12% (Midwest region) were detected. The Northeast and Midwest regions reported similar patterns of changes after the FDA actions. Use and costs of rosiglitazone were substantially reduced after the 2007 FDA actions for cardiovascular risk, and this drug was rarely used after the 2010 REMS program. Conversely, use and costs of pioglitazone were substantially reduced after the 2010 FDA actions regarding the drug's possible risk of bladder cancer.


Antisense oligonucleotide-mediated correction of CFTR splicing improves chloride secretion in cystic fibrosis patient-derived bronchial epithelial cells.
Cystic fibrosis (CF) is an autosomal recessive disorder caused by mutations in the CF transmembrane conductance regulator (CFTR) gene, encoding an anion channel that conducts chloride and bicarbonate across epithelial membranes. Mutations that disrupt pre-mRNA splicing occur in >15% of CF cases. One common CFTR splicing mutation is CFTR c.3718-2477C>T (3849+10 kb C>T), which creates a new 5' splice site, resulting in splicing to a cryptic exon with a premature termination codon. Splice-switching antisense oligonucleotides (ASOs) have emerged as an effective therapeutic strategy to block aberrant splicing. We test an ASO targeting the CFTR c.3718-2477C>T mutation and show that it effectively blocks aberrant splicing in primary bronchial epithelial (hBE) cells from CF patients with the mutation. ASO treatment results in long-term improvement in CFTR activity in hBE cells, as demonstrated by a recovery of chloride secretion and apical membrane conductance. We also show that the ASO is more effective at recovering chloride secretion in our assay than ivacaftor, the potentiator treatment currently available to these patients. Our findings demonstrate the utility of ASOs in correcting CFTR expression and channel activity in a manner expected to be therapeutic in patients.


Are anti-LGBT homicides in the United States unique?
An integral issue to the study of bias crimes is how violence targeting lesbian, gay, bisexual, and transgender (LGBT) victims is different from other more common forms of violent crimes. Limitations in official bias crimes data have inhibited our understanding of the relative nature of anti-LGBT crimes. The purpose of this study is to examine the similarities and differences in anti-LGBT homicides and average homicides in the United States between 1990 and 2008. The current study addresses methodological issues by relying on an open-source database of anti-LGBT homicides. This study found that the nature of these homicides is both similar and significantly different from the average homicide. Implications for the ongoing bias crimes discourse are discussed.


Financial Conflicts of Interest Among Authors of Clinical Practice Guidelines for Routine Screening Mammography.
Financial conflicts of interest (FCOIs) may influence or undermine the credibility of clinical practice guidelines or society recommendations. Given the wide regard of such publications, understanding the prevalence and extent of FCOIs among their authors is essential. The most current guidelines containing recommendations for breast cancer screening from the US Preventive Services Task Force, American Cancer Society, American College of Obstetricians and Gynecologists, International Agency for Research on Cancer, ACR, and American College of Physicians were retrieved from their respective organizational websites. Industry payments received by authors were then extracted using CMS Open Payments database (OPD), and the values and types of these payments were evaluated. Finally, financial disclosures were compared with open payments. Among a total of 43 authors and 7 guideline documents, 14 authors (33%) received at least one industry payment according to OPD payment records, whereas a majority of 29 authors (67%) had none. The median total payment from all sources across all breast imaging guidelines was $0 (interquartile range, $0-$84). Four authors (9%) declared at least one significant FCOI, five (12%) received more than $5,000 from a single company in a single year, and one author had a significant FCOI (2%) identified from OPD records but not disclosed within the guideline document. These findings suggest that FCOIs likely have little to no influence on the adoption of consensus recommendations regarding routine screening mammography for all cohorts of women.


Meta-analysis of prediction model performance across multiple studies: Which scale helps ensure between-study normality for the C-statistic and calibration measures?
If individual participant data are available from multiple studies or clusters, then a prediction model can be externally validated multiple times. This allows the model's discrimination and calibration performance to be examined across different settings. Random-effects meta-analysis can then be used to quantify overall (average) performance and heterogeneity in performance. This typically assumes a normal distribution of 'true' performance across studies. We conducted a simulation study to examine this normality assumption for various performance measures relating to a logistic regression prediction model. We simulated data across multiple studies with varying degrees of variability in baseline risk or predictor effects and then evaluated the shape of the between-study distribution in the C-statistic, calibration slope, calibration-in-the-large, and E/O statistic, and possible transformations thereof. We found that a normal between-study distribution was usually reasonable for the calibration slope and calibration-in-the-large; however, the distributions of the C-statistic and E/O were often skewed across studies, particularly in settings with large variability in the predictor effects. Normality was vastly improved when using the logit transformation for the C-statistic and the log transformation for E/O, and therefore we recommend these scales to be used for meta-analysis. An illustrated example is given using a random-effects meta-analysis of the performance of QRISK2 across 25 general practices.


Modeling disease severity in multiple sclerosis using electronic health records.
To optimally leverage the scalability and unique features of the electronic health records (EHR) for research that would ultimately improve patient care, we need to accurately identify patients and extract clinically meaningful measures. Using multiple sclerosis (MS) as a proof of principle, we showcased how to leverage routinely collected EHR data to identify patients with a complex neurological disorder and derive an important surrogate measure of disease severity heretofore only available in research settings. In a cross-sectional observational study, 5,495 MS patients were identified from the EHR systems of two major referral hospitals using an algorithm that includes codified and narrative information extracted using natural language processing. In the subset of patients who receive neurological care at a MS Center where disease measures have been collected, we used routinely collected EHR data to extract two aggregate indicators of MS severity of clinical relevance multiple sclerosis severity score (MSSS) and brain parenchymal fraction (BPF, a measure of whole brain volume). The EHR algorithm that identifies MS patients has an area under the curve of 0.958, 83% sensitivity, 92% positive predictive value, and 89% negative predictive value when a 95% specificity threshold is used. The correlation between EHR-derived and true MSSS has a mean R(2) = 0.38±0.05, and that between EHR-derived and true BPF has a mean R(2) = 0.22±0.08. To illustrate its clinical relevance, derived MSSS captures the expected difference in disease severity between relapsing-remitting and progressive MS patients after adjusting for sex, age of symptom onset and disease duration (p = 1.56×10(-12)). Incorporation of sophisticated codified and narrative EHR data accurately identifies MS patients and provides estimation of a well-accepted indicator of MS severity that is widely used in research settings but not part of the routine medical records. Similar approaches could be applied to other complex neurological disorders.


Bayesian inference of protein conformational ensembles from limited structural data.
Many proteins consist of folded domains connected by regions with higher flexibility. The details of the resulting conformational ensemble play a central role in controlling interactions between domains and with binding partners. Small-Angle Scattering (SAS) is well-suited to study the conformational states adopted by proteins in solution. However, analysis is complicated by the limited information content in SAS data and care must be taken to avoid constructing overly complex ensemble models and fitting to noise in the experimental data. To address these challenges, we developed a method based on Bayesian statistics that infers conformational ensembles from a structural library generated by all-atom Monte Carlo simulations. The first stage of the method involves a fast model selection based on variational Bayesian inference that maximizes the model evidence of the selected ensemble. This is followed by a complete Bayesian inference of population weights in the selected ensemble. Experiments with simulated ensembles demonstrate that model evidence is capable of identifying the correct ensemble and that correct number of ensemble members can be recovered up to high level of noise. Using experimental data, we demonstrate how the method can be extended to include data from Nuclear Magnetic Resonance (NMR) and structural energies of conformers extracted from the all-atom energy functions. We show that the data from SAXS, NMR chemical shifts and energies calculated from conformers can work synergistically to improve the definition of the conformational ensemble.


Optochiasmatic tuberculomas: a vision-threatening paradoxical response in tuberculous meningitis.
The single main cause of death from infectious diseases worldwide is tuberculosis, which is more prevalent in developing countries. Tuberculous meningitis (TBM) is a severe form of TB in which morbidity and mortality depend upon the stage of presentation. Intracranial brain parenchymal tuberculomas may form paradoxically, days to months after starting antituberculous drug therapy. Tuberculomas may develop in and around he optic chiasm and optic nerves after institution of antituberculous treatment as a quite rare occurrence in TBM; this may lead to severe visual loss if not treated properly. We describe a 56-year-old man with documented TBM being treated with first line antituberculous drugs who developed visual impairment 2 months after starting the treatment. MRI after gadolinium administration revealed multiple perichiasmatic and a few parenchymal ring enhancing lesions due to tuberculomas. The patient was treated with corticosteroids and antituberculous therapy was continued after which he recovered his vision gradually. Visual impairment developing in a patient on treatment with antituberculous drugs should give rise to a suspicion of rare optochiasmatic tuberculomas; this necessitates urgent contrast-enhanced MRI of the brain and prompt treatment with steroids.


Optimal Placement of Needle Electromyography in Extensor Indicis: A Cadaveric Study.
To identify the center of extensor indicis (EI) muscle through cadaver dissection and compare the accuracy of different techniques for needle electromyography (EMG) electrode insertion. Eighteen upper limbs of 10 adult cadavers were dissected. The center of trigonal EI muscle was defined as the point where the three medians of the triangle intersect. Three different needle electrode insertion techniques were introduced: M1, 2.5 cm above the lower border of ulnar styloid process (USP), lateral aspect of the ulna; M2, 2 finger breadths (FB) proximal to USP, lateral aspect of the ulna; and M3, distal fourth of the forearm, lateral aspect of the ulna. The distance from USP to the center (X) parallel to the line between radial head to USP, and from medial border of ulna to the center (Y) were measured. The distances between 3 different points (M1- M3) and the center were measured (marked as D1, D2, and D3, respectively). The median value of X was 48.3 mm and that of Y was 7.2 mm. The median values of D1, D2 and D3 were 23.3 mm, 13.3 mm and 9.0 mm, respectively. The center of EI muscle is located approximately 4.8 cm proximal to USP level and 7.2 mm lateral to the medial border of the ulna. Among the three methods, the technique placing the needle electrode at distal fourth of the forearm and lateral to the radial side of the ulna bone (M3) is the most accurate and closest to the center of the EI muscle.


Flavonol-containing phosphorylated pullulan may attenuate pulp inflammation.
To find possible reagents to minimize inflammatory responses by using an established pulpitis models for the purpose of developing new pulp-capping materials, and to test the possible use of phosphorylated pullulan as a carrier for such an anti-inflammatory reagent. Co-culturing was performed using transwell systems. Inflammatory responses were evaluated by measuring cytokines produced by the cells. The effects of two flavonoids, luteolin and quercetin, as anti-inflammatory reagents, and phosphorylated pullulan, which potentially achieves a sufficient marginal sealing to hydroxyapatite and slowly releases luteolin, as a carrier for flavonoids, were tested. Flavonols, particularly luteolin, dramatically attenuated inflammatory cytokine production, which was augmented by co-cultures. Luteolin was successfully enclosed by phosphorylated pullulan. Finally, it was confirmed that luteolin released from phosphorylated pullulan was effective in reducing cytokine production by co-cultures. Combination of phosphorylated pullulan and luteolin could be potentially used in the treatment of dental pulp inflammation.


Risk factors for biliary tract cancers.
Little is known regarding risk factors for biliary tract cancer, i.e., gallbladder carcinoma and extrahepatic bile duct carcinoma. This is the first case-control study conducted in the U.S. regarding risk factors for these cancers. In this hospital-based case-control study, we reviewed the medical records of 69 patients with primary biliary tract cancer who were admitted to Columbia-Presbyterian Medical Center for surgery between January 1, 1980, and April 4, 1994, and of 138 controls, consisting of patients admitted for surgery for benign conditions. We found a significant association between cholelithiasis and biliary tract cancers (odds ratio, 19.5; 95% confidence interval, 6.4-59.4). Risk factors associated with gallbladder cancer included female gender, age, cigarette smoking, and postmenopausal status in women. Risk factors associated with extrahepatic bile duct cancer included history of cholecystectomy and hysterectomy in women. The risk factors for biliary tract cancers that have been identified in our study delineate a high-risk population, which in the future may be targeted for preventive measures.


First Report of Leaf Blight Caused by Phomopsis ipomoeae-batatas on Sweet Potato in Korea.
Ipomoea batatas (L.) Lam., belonging to the Convolvulaceae, is widely cultivated and used as an industrial resource as well as for food and feed worldwide (2). In September 2010, an unknown leaf blight was observed on leaves in Hoengseong County and Jecheon City in Korea. Symptoms were mostly observed in older leaves as cream to tan-brown lesions surrounded by purplish brown-to-dark brown margin. Each lesion was circular to irregular, not exceeding 10 mm, but coalesced to form larger lesions. Necrotic tissue fell out giving rise to shot-holes. A number of black pycnidia were present in the lesions of diseased leaves. The same symptoms were observed at several localities in Korea during 2010 and 2011 seasons. The voucher specimens (n = 5) were preserved in the Korea University Herbarium (KUS). Two isolates were obtained from the two samples (KUS-F25274 and KUS-F25361) and deposited in the Korean Agricultural Culture Collection (Accession Nos. KACC45680 and KACC45702). Pycnidia were amphigenous, but mostly epigenous, scattered, dark brown-to-rusty brown, globose, embedded in host tissue or partly erumpent, 110 to 170 μm in diameter, and with an ostiole of 25 to 40 μm in diameter. Alpha conidia were aseptate, lageniform, biguttulate, hyaline, and 5.5 to 8.0 × 3.5 to 4.5 μm. Beta conidia were absent. Based on the morphological characteristics, the fungus was consistent with Phomopsis ipomoeae-batatas Punith. (1,3). Preliminary identification of the fungal isolate was confirmed by molecular data. Genomic DNA was extracted from the two isolates. The D1/D2 region of 28S rDNA was amplified using the primers LROR and LR7, and sequenced. The resulting sequences of the two isolates were identical to each other, and were deposited in GenBank (Accession Nos. JX157848 and JX157849). A BLAST search showed that there was no matching sequence of P. ipomoeae-batatas. Therefore, these were the first 28S sequences for the species submitted to GenBank. The present sequences showed >98% similarity with 24 entries of Phomopsis spp. and Diaporthe spp. (teleomorph of Phomopsis spp.), indicating their close phylogenetic relationship. Pathogenicity was tested by spraying leaves of three potted plants with a conidial suspension (2 × 106 conidia/ml), which was harvested from a 3-week-old culture on potato dextrose agar. Control leaves were sprayed with sterile water. The plants were placed in a dew chamber at 24°C in darkness and continuous dew for the first 24 h and then moved to a greenhouse bench. After 10 days, leaf blight symptoms that were identical to those observed in the field started to develop on the leaves inoculated with the fungus. No symptoms were observed on control plants. P. ipomoeae-batatas was reisolated from the lesions of inoculated plants, confirming Koch's postulates. Occurrence of leaf blight caused by P. ipomoeae-batatas on sweet potato has been reported in many countries (1,3). To our knowledge, this is the first report of the disease in Korea. The economic losses are of minor importance, because the disease is mostly present toward the end of growing season; however, attention must be paid considering that the pathogen may reduce the quality of vines used as fodder. References: (1) C. A. Clark and J. W. Moyer. Compendium of Sweet Potato Diseases. The American Phytopathological Society. St. Paul, MN, 1988. (2) I. G. Mok et al. J. Plant Biotechnol. 36:202, 2009. (3) E. Punithalingam. Phomopsis ipomoeae-batatas. IMI Descriptions of Fungi and Bacteria. Sheet 739, 1982.


Combined study with FDG PET and Tl SPECT in patients with idiopathic dilated cardiomyopathy.
This study aimed to determine whether combined examinations of myocardial 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) and stress-redistribution 201Tl single-photon emission computed tomography (Tl SPECT) were useful in clarifying myocardial ischaemia and evaluating the prognosis in patients with idiopathic dilated cardiomyopathy (IDCM). Twenty-two patients with IDCM underwent echocardiography, cardiac catheterization, FDG PET, and Tl SPECT. In scintigraphic analysis, the total defect score (TDS) was semiquantitatively determined as the sum of scores of the 17 left ventricular (LV) segments with a 5-point scale (0 as normal to 4 as absent). Patients were classified according to the scintigraphic findings as follows: eight patients with small defects on Tl and FDG (TDS < or = 20) (group I), eight patients with small defects on FDG (TDS < or = 20) with FDG uptake increased relative to Tl or 'mismatch' (group II), and six patients with large defects on FDG and Tl (TDS >20) (group III). Eleven patients (50%) showed reversible defects on Tl and all showed preserved FDG uptake. The patients in group III had significantly lower LV ejection fraction (LVEF) (P<0.05, respectively) and a poorer prognosis as shown by the Kaplan-Meier event-free curve compared with those in groups I and II (P<0.01, respectively). Although patients in group II had significantly greater TDS on Tl compared with those in group I (P<0.01), no significant differences in LVEF and prognosis were found between patients in groups I and II. In multivariate analysis, a TDS on FDG revealed an independent predictor of subsequent cardiac events. In conclusion, such mismatched areas can be assumed to consist of impaired but viable myocardium, and may be associated with ischaemia of the microvasculature. Impaired myocardial glucose metabolism is a more powerful predictor of future cardiac events than perfusion abnormality in patients with IDCM.


A double mutant LDL receptor allele in a cypriot family with heterozygous familial hypercholesterolemia.
Two novel mutations Q363X and D365E were identified in the low-density lipoprotein receptor gene in a Cypriot patient with heterozygous familial hypercholesterolemia. Restriction enzyme analysis of the index case and seven of her family members, by using AvaII and PvuII respectively, demonstrated that the two exon 8 mutations are transmitted in cis within the family. The disease phenotype is probably caused by the stop-363 mutation; this would result in a truncated protein that would probably be rapidly degraded in the extracellular space.


Msx genes define a population of mural cell precursors required for head blood vessel maturation.
Vessels are primarily formed from an inner endothelial layer that is secondarily covered by mural cells, namely vascular smooth muscle cells (VSMCs) in arteries and veins and pericytes in capillaries and veinules. We previously showed that, in the mouse embryo, Msx1(lacZ) and Msx2(lacZ) are expressed in mural cells and in a few endothelial cells. To unravel the role of Msx genes in vascular development, we have inactivated the two Msx genes specifically in mural cells by combining the Msx1(lacZ), Msx2(lox) and Sm22α-Cre alleles. Optical projection tomography demonstrated abnormal branching of the cephalic vessels in E11.5 mutant embryos. The carotid and vertebral arteries showed an increase in caliber that was related to reduced vascular smooth muscle coverage. Taking advantage of a newly constructed Msx1(CreERT2) allele, we demonstrated by lineage tracing that the primary defect lies in a population of VSMC precursors. The abnormal phenotype that ensues is a consequence of impaired BMP signaling in the VSMC precursors that leads to downregulation of the metalloprotease 2 (Mmp2) and Mmp9 genes, which are essential for cell migration and integration into the mural layer. Improper coverage by VSMCs secondarily leads to incomplete maturation of the endothelial layer. Our results demonstrate that both Msx1 and Msx2 are required for the recruitment of a population of neural crest-derived VSMCs.


Acute kidney injury and kidney replacement therapy in COVID-19: a systematic review and meta-analysis.
Acute kidney injury (AKI) can affect hospitalized patients with coronavirus disease 2019 (COVID-19), with estimates ranging between 0.5% and 40%. We performed a systematic review and meta-analysis of studies reporting incidence, mortality and risk factors for AKI in hospitalized COVID-19 patients. We systematically searched 11 electronic databases until 29 May 2020 for studies in English reporting original data on AKI and kidney replacement therapy (KRT) in hospitalized COVID-19 patients. Incidences of AKI and KRT and risk ratios for mortality associated with AKI were pooled using generalized linear mixed and random-effects models. Potential risk factors for AKI were assessed using meta-regression. Incidences were stratified by geographic location and disease severity. A total of 3042 articles were identified, of which 142 studies were included, with 49 048 hospitalized COVID-19 patients including 5152 AKI events. The risk of bias of included studies was generally low. The pooled incidence of AKI was 28.6% [95% confidence interval (CI) 19.8-39.5] among hospitalized COVID-19 patients from the USA and Europe (20 studies) and 5.5% (95% CI 4.1-7.4) among patients from China (62 studies), whereas the pooled incidence of KRT was 7.7% (95% CI 5.1-11.4; 18 studies) and 2.2% (95% CI 1.5-3.3; 52 studies), respectively. Among patients admitted to the intensive care unit, the incidence of KRT was 20.6% (95% CI 15.7-26.7; 38 studies). Meta-regression analyses showed that age, male sex, cardiovascular disease, diabetes mellitus, hypertension and chronic kidney disease were associated with the occurrence of AKI; in itself, AKI was associated with an increased risk of mortality, with a pooled risk ratio of 4.6 (95% CI 3.3-6.5). AKI and KRT are common events in hospitalized COVID-19 patients, with estimates varying across geographic locations. Additional studies are needed to better understand the underlying mechanisms and optimal treatment of AKI in these patients.


The impact of sex and gender on adaptation to space: executive summary.
This review article is a compendium of six individual manuscripts, a Commentary, and an Executive Summary. This body of work is entitled "The Impact of Sex and Gender on Adaptation to Space" and was developed in response to a recommendation from the 2011 National Academy of Sciences Decadal Survey, "Recapturing a Future for Space Exploration: Life and Physical Sciences for a New Era," which emphasized the need to fully understand sex and gender differences in space. To ensure the health and safety of male and female astronauts during long-duration space missions, it is imperative to examine and understand the influences that sex and gender have on physiological and psychological changes that occur during spaceflight. In this collection of manuscripts, six workgroups investigated and summarized the current body of published and unpublished human and animal research performed to date related to sex- and gender-based differences in the areas of cardiovascular, immunological, sensorimotor, musculoskeletal, reproductive, and behavioral adaptations to human spaceflight. Each workgroup consisted of scientists and clinicians from academia, the National Aeronautics and Space Administration (NASA), and other federal agencies and was co-chaired by one representative from NASA and one from the external scientific community. The workgroups met via telephone and e-mail over 6 months to review literature and data from space- and ground-based studies to identify sex and gender factors affecting crew health. In particular, the Life Sciences Data Archive and the Lifetime Surveillance of Astronaut Health were extensively mined. The groups identified certain sex-related differences that impact the risks and the optimal medical care required by space-faring women and men. It represents innovative research in sex and gender-based biology that impacts those individuals that are at the forefront of space exploration.


Mucosal tube technique for creation of esophageal anastomosis after esophagectomy.
The definitive treatment of esophageal cancer remains surgical resection. Morbidity and mortality are highly influenced by the success of the anastomosis created in the reconstruction of the resected esophagus. The results of an anastomotic technique that creates an esophageal mucosal tube are analyzed. The medical records of all patients undergoing esophagectomy at a single institution by 3 surgeons between January 2002 and July 2008 were reviewed. Patients who underwent a 2-layer, hand-sewn, esophageal anastomosis using a mucosal tube were included. The unique aspect of the anastomosis was the creation of an esophageal mucosal tube that facilitates a tension-free, precise mucosal approximation. Of the 61 patients who underwent esophageal reconstructions (60 gastric, 1 colonic), 49 (80%) had a diagnosis of esophageal neoplasm. Of those with cancer, 20 (41%) had neoadjuvant therapy before the resection. Two patients presented with perforation. The anastomoses were intrathoracic in 57 of 61 (93%) and cervical in 4 cervical. There were no operative deaths. All patients underwent contrast study at an average of 5 days postoperatively. The anastomotic leak rate was 2% (1 of 61). Postoperative dilations (mean, 1.3 dilations) were done in 12 of 61 patients (20%), using a low symptom threshold for endoscopy and dilation. The use of the esophageal mucosal tube and 2-layer anastomosis is a robust technique that results in a low leak rate. Strictures are minimal and easily dilated if they occur. Use of a gastrotomy larger than 2.5 cm may decrease stricture rates.


The in vivo invasion assay: preparation and handling of collection needles.
Analysis of the individual steps in metastasis is crucial if insights at the molecular level are to be linked to the cell biology of cancer. A technical hurdle to achieving the analysis of the individual steps of metastasis is the fact that, at the gross level, tumors are heterogeneous in both animal models and patients. Human primary tumors show extensive variation in all properties ranging from growth and morphology of the tumor through tumor-cell density in the blood and formation and growth of metastases. Methods capable of the direct visualization and analysis of tumor-cell behavior at single-cell resolution in vivo have become crucial in advancing the understanding of mechanisms of metastasis, the definition of microenvironment, and the markers related to both. High-resolution multiphoton imaging of tumors in vivo is a valuable tool in this regard. Because tumor cells have been found to be attracted to blood vessels, the in vivo invasion assay was developed to analyze which factors may stimulate invasion of these cells into the vessels. This protocol describes the preparation and handling of collection needles for the assay. A set of 33-gauge needles is used to create artificial or surrogate blood vessels that are injected into tumors, using a special holding device attached to a micromanipulator to stabilize the needle positions during and after insertion into the anesthetized animal. The needles are filled with Matrigel and various growth factors to determine which of these factors may influence the invading tumor cells.


Effect of magnesium complexation by fluoroquinolones on their antibacterial properties.
By using infrared and 19F nuclear magnetic resonance spectroscopies, we localized the binding site and measured the affinity of magnesium for six fluoroquinolones. It was proven that magnesium is situated between the ketone and the carboxylate groups. We determined the binding constants for the 1:1 Mg(2+)-drug complex in solution. Sparfloxacin and pefloxacin, with affinity constants (Ka) of (10.1 +/- 0.6) x 10(2) M-1 and (21 +/- 1) x 10(2) M-1, respectively, were the least and the most bound, respectively. The trend of the affinities of the assayed fluoroquinolones for magnesium was correlated with their antimicrobial activities against four bacteria and with their accumulation by these bacteria. The reference strain, Escherichia coli KL16, and two resistant mutants, NalA (gyrase mutation) and NalB (uptake defect), plus Staphylococcus aureus 209P were used. It appeared that, in every case, an impairment of accumulation is responsible for the increase in the MICs observed upon the addition of magnesium.


Alternatives for energy production in aerobic wastewater treatment facilities.
Using technologies such as anaerobic digestion for energy generation from wastewater demands a change in infrastructure that several treatment works are not prepared to immediately implement. This works explores the use of energy production technologies to increase the sustainability of conventional aerobic wastewater treatment plants. The first option considered sludge (a by-product from wastewater treatment) as raw material for biodiesel production as Fatty Acid Methyl Esters (FAME). The second option consisted of the addition of microalgae during aerobic wastewater treatment and subsequent harvesting of combined microalgae-sludge to produce biodiesel. Results showed that microalgae were able to grow in aerobic wastewater treatment reactors, reaching maximum growth after 6 days. The use of microalgae did not statistically affect chemical oxygen demand removal but provided benefits on ammonia removal (100% removal vs 68 ± 9% when microalgae were not added). Activated sludge contained fewer lipids (13 ± 3%, by dry weight) than the microalgae-sludge mixture (20.8 ± 4.5%). Hence, FAME production when using microalgae-sludge was higher (51.12 ± 12 mg of FAME/g of dry microalgae-sludge) than when using activated sludge (25.6 ± 7 mg of FAME/g of dry activated sludge). This work showed that producing biodiesel from microalgae grown in conjunction with bacteria during aerobic wastewater treatment can reduce energy use and carbon emissions produced by 18.6 and 26.5%, respectively.


Optical two-beam coupling for a surface-induced photorefractive effect in undoped liquid crystals.
We report beam-coupling measurements of undoped nematic planar cells, for which the surface-induced photorefractive effect (SIPRE) has been confirmed to be due to photoelectric interface activation. We show that the energy transfer strongly depends on experimental geometry. Diffraction efficiency and beam-coupling analyses suggest that the unusual local and (or) nonlocal behavior can be ascribed to an additional in-phase-modulated longitudinal electric field component, unaccountable by standard photorefractivity. We consider a simple charge distribution model of the SIPRE, which produces a space-charge field having two orthogonal modulated components, in phase and pi/2 out of phase. Through the liquid crystal's electric response, the exploited geometries verify the presence of the two components.


A water sustainability index for West Java. Part 1: developing the conceptual framework.
Sustainable water resources management is essential since it ensures the integration of social, economical and environmental issues into all stages of water resources management. The development and application of water sustainability indices to achieve sustainable water management has been successfully done in the last few years. Although existing water sustainability indices have successfully provided information on current conditions of water resources and prioritised water related issues, they have been developed for specific case study areas. This study therefore aims at developing a water sustainability index for West Java, Indonesia. The overall steps for developing the index include developing a conceptual framework, application of Delphi technique to finalise the components/indicators of the index, applying the index to case studies and robustness analysis of the index. This paper, which is the first in a two-part series, discusses the first step, namely developing the conceptual framework of the West Java Water Sustainability Index (WJWSI). It outlines the criteria for identifying the initial set of components/indicators and based on those criteria, a detailed justification for selecting each component and indicator is also presented. The second paper of the series presents the application of Delphi technique to finalise the framework of WJWSI based on feedback from selected stakeholders. The remaining steps of developing WJWSI will be undertaken in the future.


Effects of various diets on the calcium and phosphorus composition of mealworms (Tenebrio molitor larvae) and superworms (Zophobas morio larvae).
OBJECTIVE To evaluate whether the nutritive quality of Tenebrio molitor larvae and Zophobas morio larvae, which are commonly cultured as live food sources, is influenced by 4 commercially available diets used as nutritional substrates; identify which diet best improved calcium content of larvae; and identify the feeding time interval that assured the highest calcium intake by larvae. ANIMALS 2,000 Zophobas morio larvae (ie, superworms) and 7,500 Tenebrio molitor larvae (ie, mealworms). PROCEDURES Larvae were placed in control and diet treatment groups for 2-, 7-, and 10-day intervals. Treatment diets were as follows: wheat millings, avian hand feeding formula, organic avian mash diet, and a high-calcium cricket feed. Control groups received water only. After treatment, larvae were flash-frozen live with liquid nitrogen in preparation for complete proximate and mineral analyses. Analyses for the 2-day treatment group were performed in triplicate. RESULTS The nutrient composition of the high-calcium cricket feed groups had significant changes in calcium content, phosphorus content, and metabolizable energy at the 2-day interval, compared with other treatment groups, for both mealworms and superworms. Calcium content and calcium-to-phosphorus ratios for larvae in the high-calcium cricket feed group were the highest among the diet treatments for all treatment intervals and for both larval species. CONCLUSIONS AND CLINICAL RELEVANCE A 2-day interval with the high-calcium cricket feed achieved a larval nutrient composition sufficient to meet National Research Council dietary calcium recommendations for nonlactating rats. Mealworm calcium composition reached 2,420 g/1,000 kcal at 48 hours, and superworm calcium composition reached 2,070g/1,000 kcal at 48 hours. These findings may enable pet owners, veterinarians, insect breeders, and zoo curators to optimize nutritive content of larvae fed to insectivorous animals.


Honeybee flight: a novel 'streamlining' response.
Animals that move rapidly through the air can save considerable energy by reducing the drag that they need to overcome during flight. We describe a novel 'streamlining' response in tethered, flying honeybees in which the abdomen is held in a raised position when the visual system is exposed to a pattern of image motion that is characteristic of forward flight. This visually evoked response, which can be elicited without exposing the insect to any airflow, presumably serves to reduce the aerodynamic drag that would otherwise be produced by the abdomen during real flight. The response is critically dependent on the presence of appropriate image motion everywhere within the large field of view of the insect. Thus, our results also underscore the importance of using panoramic stimulation for the study of visually guided flight in insects, and reveal the relative importance of various regions of the visual field in assessing the speed of flight through the environment.


Evidence-Based Efficacy of Autologous Grated Cartilage in Primary and Secondary Rhinoplasty.
There are numerous methods to mold and shape cartilage grafts for use in rhinoplasty. Each technique has advantages and disadvantages. We are going to introduce a new method for cartilage shaping with long lasting effects confirmed by follow up examination and pathologic evaluation. Grated cartilage was used in 483 patients. For 89 cases, it was wrapped in fascia and in 394 patients, used as a filler per se or in contiguity with solid structural grafts. In 51 patients, the operation was primary rhinoplasty and 432 cases, underwent secondary rhinoplasty. Postoperatively, there was a mean follow up of 2.8 years. Graft viability, and capability to maintain almost original volume, and general durability were assessed. Out of 483 patients, only 23 cases (4.7%) needed later correction. In 11 cases (2%), it was due to overcorrection and some minor imperfections. In the rest 12 cases (2%), there was a need for more augmentation probably due to some degree of graft resorption. Three cases of these 12 patients, were corrected by outpatient shaved cartilage injection. According to the very low revision rate (less than 5%), we strongly recommend our grated cartilage graft for use in primary and secondary rhinoplasty. Our study showed that patient and surgeon`s satisfaction can be achieved with a high degree of confidence.


Hyperbaric oxygen reduces cerebral blood flow by inactivating nitric oxide.
Based on recent evidence that nitric oxide (NO(.)) is involved in hyperoxic vasoconstriction, we tested the hypothesis that decreases in NO(.) availability in brain tissue during hyperbaric oxygen (HBO(2)) exposure contribute to decreases in regional cerebral blood flow (rCBF). rCBF was measured in rats exposed to HBO(2) at 5 atmospheres (ATA) and correlated with interstitial brain levels of NO(.) metabolites (NO(X)) and production of hydroxyl radical ((.)OH). Changes in rCBF were also correlated with the effects of NO(.) synthase inhibitor (l-NAME), NO(.) donor PAPANONOate, and intravascular superoxide dismutase (MnSOD) during HBO(2). After 30 min of O(2) exposure at 5 ATA, rCBF had decreased in the substantia nigra, caudate putamen, hippocampus, and parietal cortex by 23 to 37%. These reductions in rCBF were not augmented by exposure to HBO(2) in animals pre-treated with l-NAME. After 30 min at 5 ATA, brain NO(X) levels had decreased by 31 +/- 9% and correlated with the decrease in rCBF, while estimated (.)OH production increased by 56 +/- 8%. The decrease in rCBF at 5 ATA was completely abolished by MnSOD administration into the circulation before HBO(2) exposure. Doses of NO(.) donor that significantly increased rCBF in animals breathing air had no effect at 5 ATA of HBO(2). These results indicate that decreases in rCBF with HBO(2) are associated with a decrease in effective NO(.) concentration and an increase in ROS production in the brain. The data support the hypothesis that inactivation of NO(.) antagonizes basal relaxation of cerebral vessels during HBO(2) exposure, although an effect of HBO(2) on NO(.) synthesis has not been excluded.


Epitaxial graphene growth by carbon molecular beam epitaxy (CMBE).
A novel growth method (carbon molecular beam epitaxy (CMBE)) has been developed to produce high-quality and large-area epitaxial graphene. This method demonstrates significantly improved controllability of the graphene growth. CMBE with C(60) produces AB stacked graphene, while growth with the graphite filament results in non-Bernal stacked graphene layers with a Dirac-like electronic structure, which is similar to graphene grown by thermal decomposition on SiC (000-1).


Enhancing the ability of gait analyses to differentiate between groups: scaling gait data to body size.
One goal of gait analysis is to distinguish clearly between a set of abnormal gait values measured from a patient referenced to a comparable population. However, the comparable population is often composed of individuals of various heights and weights, which increases inter-subject gait value variation which reduces the ability of a statistical test to identify a set of gait data outcomes with evaluative properties. Therefore, scaling gait data, based on subject leg length and mass, is commonly used to decrease the inter-subject variation but the efficacy of these methods is unknown. In this paper each of eight scaling strategies (none, ad hoc, dimensionless numbers, and five connected strategies based on similarity, dimensional analysis and muscle properties) were used to modify a set of gait data outcomes acquired from 10 individuals spanning a wide range of height (1.33-1.96 m) and mass (42.3-148.8 kg). These data were then examined to select that strategy and those scaling factors which maximally reduced inter-subject variation. The ad hoc, dimensionless numbers, and dynamic/mechanical/elastic (diameter of a limb (D) proportional to it's length (L) to the 1.5 power; time proportional to L(2) D(-1)) scaling strategies reduced the global inter-subject gait data outcome variation to 44% of its un-scaled value. Considering ten commonly reported gait data outcomes (temporal and spatial (stride time, stride length, progression velocity), kinematic (angles in the sagittal and frontal planes, angles in the transverse plane), external kinetic (ground reaction force and moment), and internal kinetic (joint force, moment, and power)) these three scaling strategies provided the largest number of minimum inter-subject variations (10, 10, and 9, respectively). Reduced inter-subject variation in gait data outcomes increases the ability of a statistical tool to detect a difference between a patient and a comparable group. With a statistically significant difference a clinician can then decide if this patient's gait pattern clinically deviates from that of the comparable group and an appropriate intervention warranted. The ad hoc, dimensionless numbers, and the dynamic/mechanical/elastic scaling strategies all reduce maximally the inter-subject variation in gait data outcomes.


Lowered cAMP and cGMP signalling in the brain during levodopa-induced dyskinesias in hemiparkinsonian rats: new aspects in the pathogenetic mechanisms.
Dysregulation of dopamine receptors is thought to underlie levodopa-induced dyskinesias in experimental models of Parkinson's disease. It is unknown whether an imbalance of the second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), is involved in the alterations of levodopa/dopamine signal transduction. We examined cAMP and cGMP signalling in the interconnected cortico-striatal-pallidal loop at the peak of levodopa-induced dyskinesias in rats with 6-hydroxydopamine lesions in the substantia nigra. In addition, we examined the role of phosphodiesterase (PDE) and the rate of cAMP and cGMP degradation on the severity of levodopa-induced dyskinesias in animals pretreated with PDE inhibitor, zaprinast. Unilateral lesion of substantia nigra led to an increase in cAMP but a decrease in cGMP levels in the ipsilateral basal ganglia. After chronic levodopa treatment, cAMP and cGMP were differentially regulated in eukinetic animals: the cAMP level increased in the cortex and striatum but decreased in the globus pallidus of both hemispheres, whereas the cGMP decreased below baseline levels in the contralateral cortico-striatal-pallidal regions. In dyskinetic animals chronic levodopa treatment led to an absolute decrease in cAMP and cGMP levels in cortico-striatal-pallidal regions of both hemispheres. Pretreatment with zaprinast reduced the severity of levodopa-induced dyskinesias, and partly prevented the decrease in cyclic nucleotides compared with pretreatment with saline-levodopa. In conclusion, using a rat model of hemiparkinsonism, we observed a significant reduction in the levels of cyclic nucleotides in both hemispheres at the peak of levodopa-induced dyskinesias. We propose that such a decrease in cyclic nucleotides may partly result from increased catabolism through PDE overactivity.


A meta-analysis of deep brain structural shape and asymmetry abnormalities in 2,833 individuals with schizophrenia compared with 3,929 healthy volunteers via the ENIGMA Consortium.
Schizophrenia is associated with widespread alterations in subcortical brain structure. While analytic methods have enabled more detailed morphometric characterization, findings are often equivocal. In this meta-analysis, we employed the harmonized ENIGMA shape analysis protocols to collaboratively investigate subcortical brain structure shape differences between individuals with schizophrenia and healthy control participants. The study analyzed data from 2,833 individuals with schizophrenia and 3,929 healthy control participants contributed by 21 worldwide research groups participating in the ENIGMA Schizophrenia Working Group. Harmonized shape analysis protocols were applied to each site's data independently for bilateral hippocampus, amygdala, caudate, accumbens, putamen, pallidum, and thalamus obtained from T1-weighted structural MRI scans. Mass univariate meta-analyses revealed more-concave-than-convex shape differences in the hippocampus, amygdala, accumbens, and thalamus in individuals with schizophrenia compared with control participants, more-convex-than-concave shape differences in the putamen and pallidum, and both concave and convex shape differences in the caudate. Patterns of exaggerated asymmetry were observed across the hippocampus, amygdala, and thalamus in individuals with schizophrenia compared to control participants, while diminished asymmetry encompassed ventral striatum and ventral and dorsal thalamus. Our analyses also revealed that higher chlorpromazine dose equivalents and increased positive symptom levels were associated with patterns of contiguous convex shape differences across multiple subcortical structures. Findings from our shape meta-analysis suggest that common neurobiological mechanisms may contribute to gray matter reduction across multiple subcortical regions, thus enhancing our understanding of the nature of network disorganization in schizophrenia.


Profluorogenic reductase substrate for rapid, selective, and sensitive visualization and detection of human cancer cells that overexpress NQO1.
Achieving the vision of identifying and quantifying cancer-related events and targets for future personalized oncology is predicated on the existence of synthetically accessible and economically viable probe molecules fully able to report the presence of these events and targets in a rapid and highly selective and sensitive fashion. Delineated here are the design and evaluation of a newly synthesized turn-on probe whose intense fluorescent reporter signature is revealed only through probe activation by a specific intracellular enzyme present in tumor cells of multiple origins. Quenching of molecular probe fluorescence is achieved through unique photoinduced electron transfer between the naphthalimide dye reporter and a covalently attached, quinone-based enzyme substrate. Fluorescence of the reporter dye is turned on by rapid removal of the quinone quencher, an event that immediately occurs only after highly selective, two-electron reduction of the sterically and conformationally restricted quinone substrate by the cancer-associated human NAD(P)H:quinone oxidoreductase isozyme 1 (hNQO1). Successes of the approach include rapid differentiation of NQO1-expressing and -nonexpressing cancer cell lines via the unaided eye, flow cytometry, fluorescence imaging, and two-photon microscopy. The potential for use of the turn-on probe in longer-term cellular studies is indicated by its lack of influence on cell viability and its in vitro stability.


An AC electrokinetic technique for collection and concentration of particles and cells on patterned electrodes.
We report an electrohydrodynamic effect arising from the application of alternating electric fields to patterned electrode surfaces. The AC fields were applied to dilute suspensions of latex microspheres enclosed between a patterned silicon wafer and an ITO-coated glass slide in a small chamber. The latex particles became collected in the center of the conductive "corrals" on the silicon wafer acting as bottom electrode. The particle collection efficiency and speed depended only on the frequency and strength of the field and were independent of the material properties of the particles or the electrodes. The leading effect in the particle collection process is AC electrohydrodynamics. We discuss how the electrohydrodynamic flows emerge from the spatially nonuniform field and interpret the experimental results by means of electrostatic and hydrodynamic simulations. The technique allows three-dimensional microfluidic pumping and transport by the use of two-dimensional patterns. We demonstrate on-chip collection of latex particles, yeast cells, and microbes.


The influence of additions of Al and Si on the lattice stability of fcc and hcp Fe-Mn random alloys.
We have studied the influence of additions of Al and Si on the lattice stability of face-centred-cubic (fcc) versus hexagonal-closed-packed (hcp) Fe-Mn random alloys, considering the influence of magnetism below and above the fcc Néel temperature. Employing two different ab initio approaches with respect to basis sets and treatment of magnetic and chemical disorder, we are able to quantify the predictive power of the ab initio methods. We find that the addition of Al strongly stabilizes the fcc lattice independent of the regarded magnetic states. For Si a much stronger dependence on magnetism is observed. Compared to Al, almost no volume change is observed as Si is added to Fe-Mn, indicating that the electronic contributions are responsible for stabilization/destabilization of the fcc phase.


Micro-skills of group formulations in care settings.
This study examines some of the micro-skills associated with the moment-to-moment decisions and actions involved in delivering group formulation sessions in dementia care settings. We discuss the therapeutic framework used by therapists from a number of Challenging Behaviour Services in the UK (Newcastle, Northumberland, South Tyneside, Teesside, Sutton and Merton, Northern Ireland) which is frequently referred to as the Newcastle or Colombo approach. Through a theoretical review and practice illustration, the study pays particular attention to the role of therapists' questions and questioning styles in group formulation sessions, providing a framework which aims to facilitate care staffs' understanding, reflection and empathy regarding their residents who are displaying 'challenging behaviours'. The study also provides a potential guide to the training of therapists working in this area and thereby attempts to benefit clinical practices in an area where pharmacological approaches are usually the treatment of choice.


Pulmonary function following early thoracic fusion in non-neuromuscular scoliosis.
While early spinal fusion may halt progressive deformity in young children with scoliosis, it does not facilitate lung growth and, in certain children, it can result in thoracic insufficiency syndrome. The purpose of this study was to determine pulmonary function at intermediate-term follow-up in patients with scoliosis who underwent thoracic fusion before the age of nine years. Patients who had thoracic spine fusions before the age of nine years with a minimum five-year follow-up underwent pulmonary function testing. Forced vital capacity, forced expiratory volume in one second, and maximum inspiratory pressure were measured and compared with age-matched normal values. Patients with neuromuscular disease, skeletal dysplasias, or preexisting pulmonary disease were excluded, while those with rib malformations were included. The relationships between forced vital capacity and age at the time of surgery, length of follow-up, extent of the fusion, proximal level of the fusion, and revision surgery were studied. Twenty-eight patients underwent evaluation. Twenty patients had congenital scoliosis, three had idiopathic scoliosis, three had scoliosis associated with neurofibromatosis, one had congenital kyphosis, and one had syndromic scoliosis. Seventeen patients had one spinal surgery, while eleven had additional procedures. The average age of the patients was 3.3 years at the time of surgery and 14.6 years at the time of follow-up. The average extent of the thoracic spine fused was 58.7%. The average forced vital capacity was 57.8% of age-matched normal values, and the average forced expiratory volume in one second was 54.7%. The forced vital capacity was <50% of normal in twelve of the twenty-eight patients, and two required respiratory support, implying that substantial restrictive lung disease was present. With the numbers studied, no significant correlation could be detected between the age at the time of fusion or the length of follow-up and pulmonary function. The extent of the spine fused correlated with the forced vital capacity (p = 0.01, r = -0.46). Fusions in the proximal aspect of the spine were found to be associated with diminished pulmonary function as eight of twelve patients with a proximal fusion level of T1 or T2 had a forced vital capacity of <50%, but only four of sixteen patients with a fusion beginning caudad to T2 had a forced vital capacity of <50% (p = 0.0004, r = 0.62). Patients with proximal thoracic deformity who require fusion of more than four segments, especially those with rib anomalies, are at the highest risk for the development of restrictive pulmonary disease. Pulmonary function tests should be performed for all patients who have an early fusion. The pursuit of alternative procedures to treat early spinal deformity is merited.


Hydroquinone 4%, tretinoin 0.05%, fluocinolone acetonide 0.01%: a safe and efficacious 12-month treatment for melasma.
This article describes a long-term, multicenter, open-label, 12-month study of once-daily fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05% (Tri-Luma Cream, hereinafter called TC [triple combination]) application in the treatment of melasma. A total of 228 patients with facial melasma were enrolled and treated; 173 patients (76%) completed the study. Most patients had 1 to 2 courses of treatment lasting approximately 6 months in total. TC cream showed a favorable safety profile. only 3 patients (1%) withdrew from the study due to treatment-related adverse events (AEs). A total of 129 patients (57%) experienced at least one treatment-related AE. Most AEs were expected application-site reactions that were mild and transient in nature and did not require remedial therapy. There were no cases of skin atrophy or skin thinning and only 6 cases of telangiectasia (5 mild and 1 moderate), most of which had improved by the end of the study. Results of the efficacy assessments were positive, with both the patient and the physician assessing melasma to be either completely or nearly cleared by the end of the study in more than 90% of cases. In this study, a once-daily application of TC cream over an extended period of 12 months showed no notable safety concerns and offered an effective treatment for melasma.


Numb activates the E3 ligase Itch to control Gli1 function through a novel degradation signal.
Hedgehog pathway regulates tissue patterning and cell proliferation. Gli1 transcription factor is the major effector of Hedgehog signaling and its deregulation is often associated to medulloblastoma formation. Proteolytic processes represent a critical mechanism by which this pathway is turned off. Here, we characterize the regulation of an ubiquitin-mediated mechanism of Gli1 degradation, promoted by the coordinated action of the E3 ligase Itch and the adaptor protein Numb. We show that Numb activates the catalytic activity of Itch, releasing it from an inhibitory intramolecular interaction between its homologous to E6-AP C-terminus and WW domains. The consequent activation of Itch, together with the recruitment of Gli1 through direct binding with Numb, allows Gli1 to enter into the complex, resulting in Gli1 ubiquitination and degradation. This process is mediated by a novel Itch-dependent degron, composed of a combination of two PPXYs and a phospho-serine/proline motifs, localized in Gli1 C-terminal region, indicating the role of two different WW docking sites in Gli1 ubiquitination. Remarkably, Gli1 protein mutated in these modules is no longer regulated by Itch and Numb, and determines enhanced Gli1-dependent medulloblastoma growth, migration and invasion abilities, as well as in vitro transforming activity. Our data reveal a novel mechanism of regulation of Gli1 stability and function, which influences Hedgehog/Gli1 oncogenic potential.


Three-dimensional micro-diffraction modeling.
Squared elementary cells with correlated radiant point sources are presented as basic structures for characterizing the propagation of the field emitted by two-dimensional planar sources of any shape and in arbitrary state of spatial coherence. The field is transported on a finite expansion of nonparaxial modes, whose propagation in the micro-diffraction domain is discussed under both the diffraction and the interference conditions.


The epidemiological transition: need to incorporate obesity prevention into nutrition programmes.
Trends in the nutritional status for developing countries that are undergoing rapid economic growth indicate a decrease in protein-energy malnutrition (PEM) with an associated rise in obesity prevalence. This paper analyses how supplementary feeding programmes may contribute to rising obesity trends, what factors may explain this phenomenon, and potential strategies to avoid obesity in malnutrition prevention efforts. This is a descriptive study of changes in nutritional status of infants and young children in Chile and the possible impact of supplementary feeding programmes on the rise in prevalence of obesity. We explored the changes in anthropometric indices before and after receiving food programme benefits and the use of targeting strategies as a way to combine the need to promote optimal growth while preventing obesity. Evaluation of the change in nutritional status from participants in Chilean supplementary feeding programmes has shown that targeting strategies have been inadequate as children mainly modify their weight-for-age and weight-for-height, while their length-for-age remains practically unchanged. Monitoring length-for-age as well as weight-for-length is necessary to permit the identification of stunted overweight and obese children, as they should not be given excess energy. Energy supplementation should be adjusted according to activity level, securing adequate micronutrient density. PEM prevention programmes need periodic evaluation, including targeting of beneficiaries, definition of real needs and possible effect on obesity.


Dynamic reconfiguration of long human genes during one transcription cycle.
We analyzed three human genes that were >200 kbp in length as they are switched on rapidly and synchronously by tumor necrosis factor alpha and obtained new insights into the transcription cycle that are difficult to obtain using continuously active, short, genes. First, a preexisting "whole-gene" loop in one gene disappears on stimulation; it is stabilized by CCCTC-binding factor and TFIIB and poises the gene for a prompt response. Second, "subgene" loops (detected using chromosome conformation capture) develop and enlarge, a result that is simply explained if elongating polymerases become immobilized in transcription factories, where they reel in their templates. Third, high-resolution localization confirms that relevant nascent transcripts (detected using RNA fluorescence in situ hybridization) lie close enough to be present on the surface of one factory. These dynamics underscore the complex transitions between the poised, initiating, and elongating transcriptional states.


Towards the implementation of a DNA barcode library for the identification of Peruvian species of Anastrepha (Diptera: Tephritidae).
The genus Anastrepha is a diverse lineage of fruit-damaging tephritid flies widespread across the Neotropical Region. Accurate taxonomic identification of these flies is therefore of paramount importance in agricultural contexts. DNA barcoding libraries are molecular-based tools based on a short sequence of the mitochondrial COI gene enabling rapid taxonomic identification of biological species. In this study, we evaluate the utility of this method for species identification of Peruvian species of Anastrepha and assemble a preliminary barcode profile for the group. We obtained 73 individual sequences representing the 15 most common species, 13 of which were either assigned to previously recognized or newly established BINs. Intraspecific genetic divergence between sampled species averaged 1.01% (range 0-3.3%), whereas maximum interspecific values averaged 8.67 (range 8.26-17.12%). DNA barcoding was found to be an effective method to discriminate between many Peruvian species of Anastrepha that were tested, except for most species of the fraterculus species group, which were all assigned to the same BIN as they shared similar and, in some cases, identical barcodes. We complemented this newly produced dataset with 86 published sequences to build a DNA barcoding library of 159 sequences representing 56 Peruvian species of Anastrepha (approx. 58% of species reported from that country). We conclude that DNA barcoding is an effective method to distinguish among Peruvian species of Anastrepha outside the fraterculus group, and that complementary methods (e.g., morphometrics, additional genetic markers) would be desirable to assist sensu stricto species identification for phytosanitary surveillance and management practices of this important group of pestiferous flies.


Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function.
Mesenchymal stem cells (MSCs) undergo a decline in function following ex vivo expansion and exposure to irradiation. This has been associated with accumulation of DNA damage and has important implications for tissue engineering approaches or in patients receiving radiotherapy. Therefore, interventions, which limit accumulation of DNA damage in MSC, are of clinical significance. We were intrigued by findings showing that zoledronate (ZOL), an anti-resorptive nitrogen containing bisphosphonate, significantly extended survival in patients affected by osteoporosis. The effect was too large to be simply due to the prevention of fractures. Moreover, in combination with statins, it extended the lifespan in a mouse model of Hutchinson Gilford Progeria Syndrome. Therefore, we asked whether ZOL was able to extend the lifespan of human MSC and whether this was due to reduced accumulation of DNA damage, one of the important mechanisms of aging. Here, we show that this was the case both following expansion and irradiation, preserving their ability to proliferate and differentiate in vitro. In addition, administration of ZOL before irradiation protected the survival of mesenchymal progenitors in mice. Through mechanistic studies, we were able to show that inhibition of mTOR signaling, a pathway involved in longevity and cancer, was responsible for these effects. Our data open up new opportunities to protect MSC from the side effects of radiotherapy in cancer patients and during ex vivo expansion for regenerative medicine approaches. Given that ZOL is already in clinical use with a good safety profile, these opportunities can be readily translated for patient benefit.


Hypertension as a risk factor for spontaneous intracerebral hemorrhage.
To better define the etiologic importance of hypertension for spontaneous intracerebral hemorrhage, hospital records were studied for all patients sustaining intracerebral hemorrhage during 1982 in the Cincinnati metropolitan area. Hypertension pre-dating the hemorrhage was present in 45% (69 of 154), as determined by history. A more inclusive definition of hypertension, combining those with a positive history with those found to have left ventricular hypertrophy by electrocardiogram or cardiomegaly by chest radiography, applied in 56% (87 of 154). The cases were compared to controls with and without hypertension derived from the NHANES II study of blood pressure (n = 16,204) to determine relative risk. For the presence of hypertension by history, the relative risk of intracerebral hemorrhage was 3.9 (95% confidence interval, 2.7 to 5.7). For the inclusive definition of hypertension, the relative risk was 5.4 (3.7 to 7.9). Relative risk was also determined for hypertension in blacks (= 4.4), age greater than 70 (= 7), prior cerebral infarction (= 22), and diabetes (= 3). We conclude that the term "hypertensive hemorrhage" should be used very selectively, particularly in whites, and propose that hypertension be viewed as one of several important risk factors for spontaneous intracerebral hemorrhage.


Contribution of Dry Needling to Individualized Physical Therapy Treatment of Shoulder Pain: A Randomized Clinical Trial.
Study Design Multicenter, parallel randomized clinical trial. Background Myofascial trigger points (MTrPs) are implicated in shoulder pain and functional limitations. An intervention intended to treat MTrPs is dry needling. Objectives To investigate the effectiveness of dry needling in addition to evidence-based personalized physical therapy treatment in the treatment of shoulder pain. Methods One hundred twenty patients with nonspecific shoulder pain were randomly allocated into 2 parallel groups: (1) personalized, evidencebased physical therapy treatment; and (2) trigger point dry needling in addition to personalized, evidence-based physical therapy treatment. Patients were assessed at baseline, posttreatment, and 3-month follow-up. The primary outcome measure was pain assessed by a visual analog scale at 3 months, and secondary variables were joint range-of-motion limitations, Constant-Murley score for pain and function, and number of active MTrPs. Clinical efficacy was assessed using intention-to-treat analysis. Results Of the 120 enrolled patients, 63 were randomly assigned to the control group and 57 to the intervention group. There were no significant differences in outcome between the 2 treatment groups. Both groups showed improvement over time. Conclusion Dry needling did not offer benefits in addition to personalized, evidencebased physical therapy treatment for patients with nonspecific shoulder pain. Level of Evidence Therapy, level 1b. Registered February 11, 2009 at www.isrctn.com (ISRCTN30907460). J Orthop Sports Phys Ther 2017;47(1):11-20. Epub 9 Dec 2016. doi:10.2519/jospt.2017.6698.


A systematic review and critical assessment of health state utilities: weight change and type 2 diabetes mellitus.
The study aimed to conduct a systematic literature search to identify health state utilities for weight change in type 2 diabetes mellitus (T2DM) and to review those values for appropriateness for inclusion in a submission to the National Institute for Health and Clinical Excellence (NICE). The search was conducted using keywords and Medical Subject Heading (MeSH) terms designed to exhaustively capture health state utility values across a variety of known economic, health technology assessment and peer-reviewed publication databases. The values were then critically reviewed from the perspective of the NICE reference case (2008 methods guide). The search resulted in a large number of repeat references across databases suggesting good sensitivity. Thirty-three articles were selected for inclusion and subjected to a critical review including their methodological quality, symmetry with the NICE reference case, sample size and country source. This critical review led to a shortlist of nine utility studies, all of which had potential for inclusion in cost-utility models or a meta-analysis. A relatively large number of utilities have been collected in weight change and T2DM. Many of these utility values are not suitable for inclusion in a NICE submission. A better way of reviewing the methodological quality of utilities is needed.


Thyroid hormone concentrations in captive and free-ranging West Indian manatees (Trichechus manatus).
Because thyroid hormones play a critical role in the regulation of metabolism, the low metabolic rates reported for manatees suggest that thyroid hormone concentrations in these animals may also be reduced. However, thyroid hormone concentrations have yet to be examined in manatees. The effects of captivity, diet and water salinity on plasma total triiodothyronine (tT(3)), total thyroxine (tT(4)) and free thyroxine (fT(4)) concentrations were assessed in adult West Indian manatees (Trichechus manatus). Free-ranging manatees exhibited significantly greater tT(4) and fT(4) concentrations than captive adults, regardless of diet, indicating that some aspect of a captive existence results in reduced T(4) concentrations. To determine whether this reduction might be related to feeding, captive adults fed on a mixed vegetable diet were switched to a strictly sea grass diet, resulting in decreased food consumption and a decrease in body mass. However, tT(4) and fT(4) concentrations were significantly elevated over initial values for 19 days. This may indicate that during periods of reduced food consumption manatees activate thyroid-hormone-promoted lipolysis to meet water and energetic requirements. Alterations in water salinity for captive animals did not induce significant changes in thyroid hormone concentrations. In spite of lower metabolic rates, thyroid hormone concentrations in captive manatees were comparable with those for other terrestrial and marine mammals, suggesting that the low metabolic rate in manatees is not attributable to reduced circulating thyroid hormone concentrations.


Oral L-citrulline supplementation improves erectile function in rats with acute arteriogenic erectile dysfunction.
Oral L-citrulline supplementation increases serum L-arginine levels more efficiently than L-arginine itself and increases nitric oxide (NO) production. To investigate whether oral L-citrulline supplementation improves erectile function in rats with acute arteriogenic erectile dysfunction (ED). We divided 8-week-old male Wistar-ST rats into 3 groups: sham-operated rats (control group), arteriogenic ED rats who underwent ligation of both internal iliac arteries (ligation group), and arteriogenic ED rats receiving oral 2% L-citrulline water supplementation (citrulline group). Citrulline water was given to arteriogenic ED rats for 3 weeks from 1 week after surgery. Erectile function was evaluated by maximum intracavernous pressure/mean arterial pressure (ICP/MAP) ratios via cavernous nerve stimulation at 4 weeks after surgery. Then, the penises were resected, stained with Masson's trichrome, and observed microscopically. Serum nitrogen oxides (NOx) levels were measured by high-performance liquid chromatography. Bonferroni's multiple t-test was used for statistical analysis. The main outcome measures were changes in ICP/MAP, smooth muscle (SM)/collagen ratios, and NOx levels following L-citrulline supplementation. The ICP/MAP ratio in the ligation group was significantly lower than that in the control group (P<0.05), denoting ED. The ICP/MAP ratio of the citrulline group was significantly higher than that of the ligation group (P<0.05), indicating ED amelioration. Levels of NOx in the ligation group were significantly lower than in the control group (P<0.05), while those in the citrulline group were significantly higher than in the ligation group (P<0.05). SM/collagen ratios in the ligation group were significantly lower than in the control group (P<0.05), while ratios in the citrulline group were significantly higher than those in the ligation group (P<0.05). Oral L-citrulline supplementation improved ICP/MAP and SM/collagen ratios and increased NOx. Therefore, oral L-citrulline supplementation might be a useful novel therapy for acute arteriogenic ED.


Characterization of a second human cyclin A that is highly expressed in testis and in several leukemic cell lines.
In this study, we isolated and characterized a human cyclin A-like gene that we named cyclin A1. Cyclin A1 has 48% identity with human cyclin A and is more related to the recently cloned murine cyclin A1 (84% identity). The human cyclin A1 is specifically expressed in testis and brain among all of the normal tissues that we studied by Northern blot analysis; in addition, it is expressed in several myeloid leukemia cell lines, including ML-1, U937, NB4, KG-1, and THP1. A sensitive reverse transcription-PCR-Southern blot method also detected low-level expression of this gene in many other hematopoietic and nonhematopoietic cell lines. The expression of cyclin A1 mRNA is differentiation- and cell cycle-regulated in the ML-1 cells. We raised polyclonal antibodies against a glutathione S-transferase-cyclin A1 fusion protein produced in Escherichia coli. In immunoblot analyses, the antibodies recognized the Mr 65,000 cyclin A1 protein in ML-1 cells. The anti-cyclin A1 also immunoprecipitated the Mr 65,000 cyclin A1, along with the Mr 33,000 cyclin-dependent kinase (CDK) 2 and other proteins at Mr 39,000, 42,000, 45,000, 95,000, and 110,000. In an in vitro kinase assay, the CDK2-cyclin A1 complex precipitated by anti-cyclin A1 showed kinase activities against histone H1. In a yeast two-hybrid assay, cyclin A1 can bind to CDK2 but not to CDC2, CDK4, and CDK5. We mapped the human cyclin A1 gene to chromosome 13q12.3-q13, approximately 1000 kb from the sequence-tagged site marker WI-3374.


Adult hippocampal neurogenesis is abundant in neurologically healthy subjects and drops sharply in patients with Alzheimer's disease.
The hippocampus is one of the most affected areas in Alzheimer's disease (AD)1. Moreover, this structure hosts one of the most unique phenomena of the adult mammalian brain, namely, the addition of new neurons throughout life2. This process, called adult hippocampal neurogenesis (AHN), confers an unparalleled degree of plasticity to the entire hippocampal circuitry3,4. Nonetheless, direct evidence of AHN in humans has remained elusive. Thus, determining whether new neurons are continuously incorporated into the human dentate gyrus (DG) during physiological and pathological aging is a crucial question with outstanding therapeutic potential. By combining human brain samples obtained under tightly controlled conditions and state-of-the-art tissue processing methods, we identified thousands of immature neurons in the DG of neurologically healthy human subjects up to the ninth decade of life. These neurons exhibited variable degrees of maturation along differentiation stages of AHN. In sharp contrast, the number and maturation of these neurons progressively declined as AD advanced. These results demonstrate the persistence of AHN during both physiological and pathological aging in humans and provide evidence for impaired neurogenesis as a potentially relevant mechanism underlying memory deficits in AD that might be amenable to novel therapeutic strategies.