An expert opinion on safinamide in Parkinson's disease.
Dopamine replacement therapies (levodopa, dopamine receptor agonists, anticholinergics, monoamine oxidase B inhibitors, and catechol-O-methyltransferase inhibitors) remain the cornerstones of therapeutic interventions for Parkinson's disease (PD). Despite the treatment options for PD symptoms, a cure remains elusive. An optimal treatment would be one that combined relief in both motor and nonmotor symptoms with neuroprotective properties. Safinamide is an investigational drug for PD currently in development as add-on therapy to both dopamine agonists and levodopa. Safinamide is a unique molecule with a novel mode of action, targeting both dopaminergic and glutaminergic systems, and potentially provides motor symptom control. Preliminary results from experimental models suggest potential neuroprotective effects. Studies on the potential effects on nonmotor symptoms are ongoing. To review the mechanism of action and pharmacokinetics, and to evaluate the available clinical safety and efficacy results of safinamide. A search of the electronic database MEDLINE (PubMed, no time limits) was performed on 14 December 2007. The full text of all citations was obtained for review. Furthermore, two abstracts on safinamide published as proceedings of a European conference were reviewed. Safinamide is a promising investigational drug for PD with a novel mode of action. Early reports confirm the potential efficacy of safinamide in PD. Further studies on potential effects on cognition and neuroprotection are needed.


A rabbit model for capsular contracture: development and clinical implications.
Capsular contracture remains one of the most common complications involving aesthetic and reconstructive breast surgery; however, its cause, prevention, and treatment remain to be fully elucidated. Presently, there is no accurate and reproducible pathologic in vitro or in vivo model examining capsular contracture. The purpose of this study was to establish an effective pathologic capsular contracture animal model that mimics the formation of capsular contracture response in humans. New Zealand White rabbits (n = 32) were subdivided into experimental (n = 16) and control groups (n = 16). Each subgroup underwent placement of smooth saline mini implants (30 cc) beneath the panniculus carnosus in the dorsal region of the back. In addition, the experimental group underwent instillation of fibrin glue into the implant pocket as a capsular contracture-inducing agent. Rabbits were euthanized from 2 to 8 weeks after the procedure. Before the animals were euthanized, each implant was serially inflated with saline and a pressure-volume curve was developed using a Stryker device to assess the degree of contracture. Representative capsule samples were collected and histologically examined. Normal and contracted human capsular tissue samples were also collected from patients undergoing breast implant revision and replacement procedures. Tissue samples were assessed histologically. Pressure-volume curves demonstrated a statistically significantly increased intracapsular pressure in the experimental group compared with the control group. The experimental subgroup had thicker, less transparent capsules than the control group. Histologic evaluation of the rabbit capsule was similar to that of the human capsule for the control and experimental subgroups. The authors conclude that pathologic capsular contracture can be reliably induced in the rabbit. This animal model provides the framework for future investigations testing the effects of various systemic or local agents on reduction of capsular contracture.


Acoustic trapping for bacteria identification in positive blood cultures with MALDI-TOF MS.
Matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) is currently changing the clinical routine for identification of microbial pathogens. One important application is the rapid identification of bacteria for the diagnosis of bloodstream infections (BSI). A novel approach based on acoustic trapping and an integrated selective enrichment target (ISET) microchip that improves the sample preparation step for this type of analysis is presented. The method is evaluated on clinically relevant samples in the form of Escherichia coli infected blood cultures. It is shown that noncontact acoustic trapping enables capture, enrichment, and washing of bacteria directly from the complex background of crude blood cultures. The technology replaces centrifugation-based separation with a faster and highly automated sample preparation method that minimizes manual handling of hazardous pathogens. The presented method includes a solid phase extraction step that was optimized for enrichment of the bacterial proteins and peptides that are used for bacterial identification. The acoustic trapping-based assay provided correct identification in 12 out 12 cases of E. coli positive blood cultures with an average score of 2.19 ± 0.09 compared to 1.98 ± 0.08 when using the standard assay. This new technology opens up the possibility to automate and speed up an important and widely used diagnostic assay for bloodstream infections.


Serum total bilirubin level and prevalent lower-extremity peripheral arterial disease: National Health and Nutrition Examination Survey (NHANES) 1999 to 2004.
Bilirubin, with recently recognized antioxidant and antiinflammatory activity, has emerged as a candidate for atheroprotection. We hypothesized that higher levels of bilirubin would reduce susceptibility to peripheral arterial disease (PAD). We analyzed 7075 adults with data available on the ankle brachial index, serum total bilirubin level, and PAD risk factors in the National Health and Nutrition Examination Survey (1999 to 2004), a nationally representative cross-sectional examination of the United States population. A 0.1 mg/dL increase in bilirubin level was associated with a 6% reduction in the odds of PAD (OR 0.94 [95% CI 0.90 to 0.98]) after adjustment for age, gender, race/ethnicity, smoking status, diabetes, hypertension, hypercholesterolemia, chronic kidney disease, CRP, and homocysteine. This result was not dependent on bilirubin levels above the reference range, liver disease, or alcohol intake. The inverse association of bilirubin with PAD tended to be stronger among men (OR 0.90 [95% CI 0.85 to 0.96]) compared with women (OR 0.97 [95% CI 0.91 to 1.04]; P(interaction)=0.05), and was stronger among active smokers (OR 0.81 [95% CI 0.73 to 0.90]) compared with nonsmokers (OR 0.97 [95% CI 0.93 to 1.02]; P(interaction)<0.01). Increased serum total bilirubin level is associated with reduced PAD prevalence. This result is consistent with the hypothesis that bilirubin is protective from PAD.


Pluripotent stem cells and their niches.
The ability of stem cells to self-renew and to replace mature cells is fundamental to ontogeny and tissue regeneration. Stem cells of the adult organism can be categorized as mono-, bi-, or multipotent, based on the number of mature cell types to which they can give rise. In contrast, pluripotent stem cells of the early embryo have the ability to form every cell type of the adult body. Permanent lines of pluripotent stem cells have been derived from preimplantation embryos (embryonic stem cells), fetal primordial germ cells (embryonic germ cells), and malignant teratocarcinomas (embryonal carcinoma cells). Cultured pluripotent stem cells can easily be manipulated genetically, and they can be matured into adult-type stem cells and terminally differentiated cell types in vitro, thereby, providing powerful model systems for the study of mammalian embryogenesis and disease processes. In addition, human embryonic stem cell lines hold great promise for the development of novel regenerative therapies. To fully utilize the potential of these cells, we must first understand the mechanisms that control pluripotent stem cell fate and function. In recent decades, the microenvironment or niche has emerged as particularly critical for stem cell regulation. In this article, we review how pluripotent stem cell signal transduction mechanisms and transcription factor circuitries integrate information provided by the microenvironment. In addition, we consider the potential existence and location of adult pluripotent stem cell niches, based on the notion that a revealing feature indicating the presence of stem cells in a given tissue is the occurrence of tumors whose characteristics reflect the normal developmental potential of the cognate stem cells.


Leaky wave analysis of an optical grating coupler with a large grating period.
Results of a rigorous leaky wave analysis of an optical grating coupler having a large grating period are presented. The coupler is designed so that most of the guided-wave power is transferred to a substrate beam progressing in the forward direction with the first-order air beam made evanescent. It is found that a large power partition into the substrate beam can readily be obtained in spite of the presence of a number of higherorder propagating space harmonics. Validity of the approximate perturbation method for the case of the long grating period is also examined.


Serial prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure.
To find out whether changes in the daily prothrombin time are of prognostic importance in patients with paracetamol induced fulminant hepatic failure. Retrospective study. The Liver Unit, King's College Hospital, London. 150 Consecutive patients with paracetamol induced fulminant hepatic failure admitted between October 1986 and February 1989. Death. Of the 150 patients, 72 (48%) died. In all, 34 of the 37 (92%) patients with a peak prothrombin time of greater than or equal to 180 seconds died as did 20 of the 41 (49%) with a time of 130-179 seconds, nine of the 25 (36%) with a time of 90-129 seconds, and nine of the 47 (19%) with a time of less than 90 seconds. Of the 42 patients with a continuing rise in prothrombin time between days 3 and 4 after overdose, 39 died (93%) compared with 21 of the 96 (22%) in whom the prothrombin time fell. These data indicate that a continued increase in prothrombin time on day 4 after overdose and a peak prothrombin time of greater than or equal to 180 seconds identify at an early stage those patients with a less than 8% chance of survival. Liver transplantation should be considered in patients meeting either of these criteria.


Mesenteric Castleman's disease.
We report here a rare case of mesenteric Castleman's disease presenting as a mesenteric mass. A 13-year-old female child was admitted to our hospital complaining of intermittent vague abdominal pain. She had hypochromic anemia, thrombocytosis and an elevated erythrocyte sedimentation rate (ESR). Ultrasonography and computed tomography indicated an intra- abdominal mass might represent a lymphoma or gastrointestinal stromal tumor or leiomyoma, but the definitive preoperative diagnosis couldn't be confirmed. The surgical resection of the mass revealed the mesenteric hyaline vascular-type Castleman's disease.


Laparoscopic treatment of ovarian granulosa cells tumor developed in the pelvic anterior preperitoneal space 20 years after laparotomic salpingo-oophorectomy: case report and review of literature.
Granulosa cells (GC) tumors are rare tumors which account for approximately 2-3% of all ovarian malignancies with a favorable prognosis. We report a case of a 54-year-old postmenopausal woman who developed an ovarian GC tumor in the pelvic anterior preperitoneal space 20 years after laparotomic salpingo-oophorectomy due to small part of the cyst could drop or remain entrapped into the abdominal wound during the closure of laparotomy 20 years before. Then, the patient underwent a second laparoscopic procedure with peritoneal washing, a type A radical hysterectomy, omentectomy, appendectomy, and pelvic and para-aortic lymphadenectomy. This rare case of ovarian GC tumor developing in the site of previous laparotomy demonstrates the importance of a correct and clean surgical procedure to avoid the risk of leaving even small portions of the cyst exposing the patients to either the risk of malignancy or additional surgical procedures.Precis: This rare case of ovarian granulosa cells tumor developed from residual ovarian tissue intrapped into the abdominal wound 20 years after laparotomic ovariectomy.


The Need for an Evidence-Based Encyclopaedia in Health Services Research in Pharmacy.
Pharmacy practice research (PPR) is a specialty field within the wider area of health services research and it focuses on studies of how and why people access pharmacy services. This stream of research is also referred to as more universally recognized term such as health services research in pharmacy. The health services research in pharmacy has increased manifold; however, the impact of this research is not visible at the global level. The editorial explains several issues on quality and quantity of evidence produced including how evidence produced could contribute to improve quality of care and patients' health outcomes. It also narrates examples from the UK and Australia showing how health services research in pharmacy has made an impact on healthcare service delivery. The editorial argues that building an encyclopaedia in health services research in pharmacy is vital to enhance the visibility and impact of this research.


Toxicological evaluation of hydroethanol leaf extract of Pupalia lappacea (Linn.) Juss. (Amaranthaceae) in rodents.
Several studies have established the ethnobotanical benefits of Pupalia lappacea (PL) in laboratory animals without extensive toxicological evaluation of its safety profiles. Thus, an extensive toxicological investigation of sub-chronic oral administration of the hydroethanol leaf extract of P. lappacea in rodents was carried out in this study. Different groups of rats were treated orally with the extract (10, 50 and 250 mg/kg) daily for 90 consecutive days. The control group received distilled water (10 mL/kg). After 90 days, some rats were left for additional 30 days without treatment for reversibility study. Blood and organs samples were collected for different evaluations at the end of study periods. The extract decreased the bodyweights, feeding and water intakes in female rats. PL increased the weights of the liver and kidney in male rats. PL increased the red blood cell (RBC), packed cell volume (PCV), hemoglobin (Hb), triglycerides (TRIG), cholesterol and high density lipoprotein (HDL) contents in rats. PL (250 mg/kg) significantly reduced the sperm motility and serum testosterone level. Cyto-architectural distortions of the testes, liver and spleen were visible. The findings showed that P. lappacea is relatively safe at lower doses but cautions should be taken at higher dose.


Design and Application of Magnetic-based Theranostic Nanoparticle Systems.
Recently, magnetic-based theranostic nanoparticle (MBTN) systems have been studied, researched, and applied extensively to detect and treat various diseases including cancer. Theranostic nanoparticles are advantageous in that the diagnosis and treatment of a disease can be performed in a single setting using combinational strategies of targeting, imaging, and/or therapy. Of these theranostic strategies, magnetic-based systems containing magnetic nanoparticles (MNPs) have gained popularity because of their unique ability to be used in magnetic resonance imaging, magnetic targeting, hyperthermia, and controlled drug release. To increase their effectiveness, MNPs have been decorated with a wide variety of materials to improve their biocompatibility, carry therapeutic payloads, encapsulate/bind imaging agents, and provide functional groups for conjugation of biomolecules that provide receptor-mediated targeting of the disease. This review summarizes recent patents involving various polymer coatings, imaging agents, therapeutic agents, targeting mechanisms, and applications along with the major requirements and challenges faced in using MBTN for disease management.


Cross-drug resistance to sunitinib induced by doxorubicin in endothelial cells.
Multiple drug resistance remains an unsolved problem in cancer therapy. A previous study has demonstrated that the chemotherapeutic drug doxorubicin (Dox) induced upregulation of P-glycoprotein in endothelial cells, resulting in a 20-fold increase in drug resistance and reduced efficiency of doxorubicin treatment in a mouse tumor model. In the present study, the cross-resistance and sensitivity of HMECd1 and HMECd2 established cell lines to anti-angiogenic drugs, particularly sunitinib, was explored. The results revealed that Dox treatment induced a significant increase in the breast cancer resistance protein (ABCG2) gene transcription and protein expression. This increase gave rise to a 4- to 5-fold increase in the half maximal inhibitory concentration of the HMECd1 and HMECd2 cells in response to sunitinib treatment in vitro. Functionally, the role of ABCG2 in the resistance to sunitinib was confirmed by the use of the ABCG2 inhibitors fumitremorgin C and diethylstilbestrol, which blocked cell resistance. The present study indicates that endothelial cells exhibit cross-resistance between cytotoxic drugs and anti-angiogenic drugs. This suggests that multiple drug resistance induced by chemotherapy in endothelial cells may affect the efficiency of anti-angiogenic drugs.


Donor-Site Complications and Remnant of Rectus Abdominis Muscle Status after Transverse Rectus Abdominis Myocutaneous Flap Reconstruction.
Transverse rectus abdominis myocutaneous (TRAM) flap reconstruction after mastectomy in breast cancer patients has become one of the milestones in breast reconstruction. There are several techniques that have been used in an attempt to minimize untoward complications. We present the whole muscle with partial sheath-sparing technique that focuses on the anatomy of arcuate line and the closure of the anterior abdominal wall techniques with mesh and determine factors associated with its complications and outcomes. We retrospectively and prospectively review the results of 30 pedicled TRAM flaps that were performed between November 2013 and March 2016, focusing on outcomes and complications. Among the 30 pedicled TRAM flap procedures in 30 patients, there were complications in 5 patients (17%). Most common complications were surgical-site infection (7%). After a median follow-up time of 15 months, no patient developed abdominal wall hernia or bulging in daily activities in our study, but 6 patients (20%) had asymptomatic abdominal wall bulging when exercised. Significant factors related to asymptomatic exercised abdominal wall bulging included having a body mass index of more than 23 kg/m2. Pedicled TRAM flap by using the technique of the whole muscle with partial sheath-sparing technique combined with reinforcement above the arcuate line with mesh can reduce the occurrence of abdominal bulging and hernia.


Expression of glucagon-like Peptide 1 receptor and its effects on biologic behavior in pancreatic neuroendocrine tumors.
Glucagon-like peptide 1 (GLP-1) interacts with its specific high-affinity receptor, glucagon-like peptide 1 receptor (GLP-1R), and induces cellular growth and inhibition of apoptosis in pancreatic β cells. The aim of this study was to investigate the significance of GLP-1R expression in pancreatic neuroendocrine tumors (PNETs). Glucagon-like peptide 1 receptor expression was semiquantitatively evaluated by immunohistochemical staining in 50 resected PNETs, and the correlation between the GLP-1R expression and clinicopathologic features was investigated. There were 23 PNETs with positive expression and 27 PNETs with negative expression of GLP-1R. Positive expression of GLP-1R was more frequently observed in insulinoma than in gastrinoma and nonfunctioning tumor (P < 0.05). Although expression status of GLP-1R did not affect the prognosis of the patients with PNETs (P = 0.82), most of the metastatic sites such as lymph node and liver showed positive staining for GLP-1R (8 of 11 PNETs, 73%). Glucagon-like peptide 1 receptor would be a diagnostic marker of insulinoma and might become a molecular target for treatment of metastatic PNETs and hormonal regulation of insulin.


Iron particles enhance visualization of experimental gliomas with high-resolution sonography.
Intraoperative MR imaging and sonography are used for navigation during neurosurgical procedures. The purpose of this experimental study was to evaluate the potential of high-resolution sonography using superparamagnetic iron oxide (SPIO) particles as a contrast medium to delineate brain tumors and to relate these findings with those of MR imaging. C6 gliomas were implanted in 36 rats. Eleven days after tumor implantation, the animals underwent MR imaging with a 1.5-T MR imaging unit. Twelve animals received gadopentetate dimeglumine immediately before the MR examination, 12 animals were injected with SPIO particles 24 hours before MR imaging, and 12 animals received no contrast agent. Immediately after MR imaging, the animals were sacrificed and their brains were removed and placed in saline. Sonography was performed instantly after brain removal. Brains were embedded in paraffin, and sections were stained for iron with Perl's stain and for macrophages with ED-1 immunohistochemistry. At MR imaging, the tumors appeared hyperintense on T2-weighted and gadolinium-enhanced T1-weighted images. After application of SPIO particles, they became markedly hypointense on T2-weighted images and hypo- to hyperintense on T1-weighted images. On sonograms, gliomas were iso- to slightly hyperechoic to normal brain parenchyma on nonenhanced and on gadolinium-enhanced images. After application of SPIO particles, tumors became markedly hyperechoic and were distinctly demarcated from the surrounding brain tissue. SPIO particles improved the detection and demarcation of the experimental gliomas on sonograms, which may improve intraoperative neuronavigation with sonography.


[Thermal and Lighting Housing Environments and Circadian Blood Pressure Variability: Findings from the HEIJO-KYO Cohort].
The purpose of this short review is to describe the influence of housing environment temperature and lighting on circadian blood pressure (BP) variability using data from the HEIJO-KYO cohort, a community-based cohort study launched in 2010. Increased excess mortality from cardiovascular disease in winter is a worldwide problem. Previous studies showed higher conventional BP and higher daytime ambulatory BP in winter; however, the relationship between indoor cold exposure and circadian BP variability remained unknown. In our cohort, we found a significant inverse relationship between indoor temperature and morning BP surge, independent of potential confounding factors. In addition, we found the tertile group with the lowest daytime indoor temperatures showed significantly higher urinary sodium excretion than the tertile group with the highest daytime indoor temperatures. Higher sodium intake caused by indoor cold exposure may partly explain the higher BP in winter. Physiologically, light exposure is the most important environmental cue for the circadian timing system and melatonin secretion. In our cohort, we observed that an increase in nighttime short-wave length light exposure and a decrease in daytime light exposure were significantly associated with lower melatonin secretion. Furthermore, lower melatonin levels were significantly related to higher nighttime BPs and parameters of atherosclerosis, which are predictors of cardiovascular disease incidence. Further longitudinal studies of the influence of housing environment temperature and lighting on cardiovascular disease incidence are required.


Performance of an enzymatic extract in Botrycoccus braunii cell wall disruption.
Microalgae can produce and contain lipids, proteins and carbohydrates, which can be extracted and marketed as potential novel added-value bio-products. However, microalgae cell wall disruption is one of the most important challenges involved while processing this type of biomass. In this context, white-rot fungi, responsible for the biodegradation of lignin present in wood due to non-specific extracellular enzymes, could be applied for promoting microalgae cell wall degradation. Therefore, the aim of this study was to evaluate the use of an enzymatic extract produced by the white-rot fungi Anthracophyllum discolor as a biotechnological tool for Botryococcus braunii cell wall disruption. The fungus was inoculated in wheat grains and manganese peroxidase (MnP) activity was monitored while obtaining the enzymatic extract. Then, cell wall disruption trials with different MnP activity were evaluated by the biochemical methane potential (BMP). In relation to cell wall disruption, it was observed that the optimal value was obtained with enzymatic concentration of 1000 U/L with a BMP of 521 mL CH4/g VS. Under these conditions almost 90% of biomass biodegradability was observed, increasing in 62% compared to the microalgae without treatment. Therefore, the results indicate that enzymes secreted by A. discolor promoted the attack of the different cell wall components finally weakening it. Therefore, the application of this treatment could be a promissory biotechnological approach to decrease the energetic input required for the cell wall disruption step.


Structure-activity studies on high affinity NOP-active hexapeptides.
Nociceptin/orphanin FQ (N/OFQ) is a 17 amino acid peptide that is the endogenous ligand for the G-protein coupled receptor ORL1 (NOP), a member of the opioid receptor family. Although it is clear that this receptor system is involved in a variety of physiologic functions, including analgesia, the precise actions of N/OFQ remain largely uncharacterized. One reason for this has been limited number of high-affinity ligands to NOP, and particularly the lack of availability of useful specific antagonists. Herein, we describe the pharmacologic activity of a series of modified amino acid containing modifications of the hexapeptide Ac-RYYRWR-NH2, with high affinity for NOP. These compounds were tested for binding affinity using [3H]N/OFQ binding to human NOP in CHO cells, and functional activity by measuring stimulation of [35S]GTPgammaS-binding in CHO cell membranes. These studies suggest that each Arg of the hexapeptide is required to maintain high-binding affinity. The peptide maintains high affinity if the Tyr2 or Tyr3 are modified, but at least one of these residues must maintain its hydroxyl group or there is a large decrease in intrinsic activity of the peptide.


[Initial experience with high-resolution computer tomography in diffuse pulmonary diseases].
The authors describe their initial experience with the use of high resolution computed tomography (HRCT) in diffuse lung diseases. They analyze in detail the examination technique, different parameters of the visualization modus, aiming of the scan and the standard procedure in HRCT examinations. They demonstrate also the picture of normal anatomical structures on HRCT pictures and morphological types of changes reflecting pathological processes in the pulmonary parenchyma. In a group of 21 patients the most frequent disease was idiopathic pulmonary fibrosis or suspected fibrosis, suspected carcinomatous lymphopathy, pulmonary emphysema incl. the vanishing lung syndrome, exogenous allergic alveolitis and alveolar microlithiasis, diffuse pulmonary affections in collagenoses and Crohn's disease. When the clinical findings are considered concurrently, the HRCT picture is fairly pathognomic and contributes to the establishment of the final diagnosis. In idiopathic pulmonary fibrosis CT and HRCT give a more accurate idea of the extent, grade and frequently also stage of the disease, and as compared with a simple X-ray of the chest, it is a more accurate and more sensitive method. It may be assumed that gradually it will become a standard examination method in diffuse pulmonary diseases.


False-positive diagnosis of pulmonary hypertension by Doppler echocardiography.
A 37-yr-old female presented with a history of several months of exertional dyspnoea. A diagnosis of primary pulmonary hypertension was suspected on the basis of a negative extensive cardiorespiratory work-up with a systolic pulmonary artery pressure of 41-46 mmHg calculated from repeated measurement of the maximum velocity of tricuspid regurgitation jets at 2.8-3 m x s(-1) by continuous-wave Doppler echocardiography. However, a right heart catheterization with a high-fidelity transducer-tipped catheter revealed pulmonary artery pressures of 22/8 mmHg at rest, which remained within normal limits at exercise. This case indicates a possible misleading overestimation of pulmonary artery pressures from Doppler echocardiographic studies of tricuspid regurgitation.


Underrepresented faculty play a disproportionate role in advancing diversity and inclusion.
A diverse and inclusive scientific community is more productive, innovative and impactful, yet ecology and evolutionary biology continues to be dominated by white male faculty. We quantify faculty engagement in activities related to diversity and inclusion and identify factors that either facilitate or hinder participation. Through a nationwide survey, we show that faculty with underrepresented identities disproportionally engage in diversity and inclusion activities, yet such engagement was not considered important for tenure. Faculty perceived time and funding as major limitations, which suggests that institutions should reallocate resources and reconsider how faculty are evaluated to promote shared responsibility in advancing diversity and inclusion.


Infant feeding: emerging concepts to prevent HIV transmission.
HIV screening in pregnancy, universal suppressive antiretroviral therapy (ART) and breastfeeding avoidance can almost completely prevent vertical transmission of HIV. Breastfeeding is associated with an additional risk of transmission, although this risk is extremely low with suppressive maternal ART. This minimal risk must be balanced with the benefits of breastfeeding for women living with HIV (WLHIV) and their infants. Guidance in high-income countries has evolved, moving towards supported breast feeding for women on suppressive ART. Breastmilk transmission accounts for an increasing proportion of new infant infections globally. The majority of transmission data comes from studies including women not on suppressive ART. Breastmilk transmissions in the context of undetectable viral load have rarely occurred, although risk factors remain unclear. Outcome data on supported breastfeeding are accumulating, providing evidence for guidelines and informing infant feeding decisions. Long-acting ART for maternal preexposure prophylaxis or treatment, and infant postnatal prophylaxis are promising future options. Breastfeeding on suppressive ART has a very low risk of vertical transmission and can have multiple benefits for WLHIV and their infants. However, caution is advised with relaxation of breastfeeding guidance so as not to jeopardise the global goal of elimination of vertical transmission by 2030.


3D Retinal Vessel Density Mapping With OCT-Angiography.
Optical Coherence Tomography Angiography (OCTA) is a novel, non-invasive imaging modality of retinal capillaries at micron resolution. Recent studies have correlated macular OCTA vascular measures with retinal disease severity and supported their use as a diagnostic tool. However, these measurements mostly rely on a few summary statistics in retinal layers or regions of interest in the two-dimensional (2D) en face projection images. To enable 3D and localized comparisons of retinal vasculature between longitudinal scans and across populations, we develop a novel approach for mapping retinal vessel density from OCTA images. We first obtain a high-quality 3D representation of OCTA-based vessel networks via curvelet-based denoising and optimally oriented flux (OOF). Then, an effective 3D retinal vessel density mapping method is proposed. In this framework, a vessel density image (VDI) is constructed by diffusing the vessel mask derived from OOF-based analysis to the entire image volume. Subsequently, we utilize a non-linear, 3D OCT image registration method to provide localized comparisons of retinal vasculature across subjects. In our experimental results, we demonstrate an application of our method for longitudinal qualitative analysis of two pathological subjects with edema during the course of clinical care. Additionally, we quantitatively validate our method on synthetic data with simulated capillary dropout, a dataset obtained from a normal control (NC) population divided into two age groups and a dataset obtained from patients with diabetic retinopathy (DR). Our results show that we can successfully detect localized vascular changes caused by simulated capillary loss, normal aging, and DR pathology even in presence of edema. These results demonstrate the potential of the proposed framework in localized detection of microvascular changes and monitoring retinal disease progression.


Causal superseding.
When agents violate norms, they are typically judged to be more of a cause of resulting outcomes. In this paper, we suggest that norm violations also affect the causality attributed to other agents, a phenomenon we refer to as "causal superseding." We propose and test a counterfactual reasoning model of this phenomenon in four experiments. Experiments 1 and 2 provide an initial demonstration of the causal superseding effect and distinguish it from previously studied effects. Experiment 3 shows that this causal superseding effect is dependent on a particular event structure, following a prediction of our counterfactual model. Experiment 4 demonstrates that causal superseding can occur with violations of non-moral norms. We propose a model of the superseding effect based on the idea of counterfactual sufficiency.


Nuclear entry of the circadian regulator mPER1 is controlled by mammalian casein kinase I epsilon.
The molecular oscillator that keeps circadian time is generated by a negative feedback loop. Nuclear entry of circadian regulatory proteins that inhibit transcription from E-box-containing promoters appears to be a critical component of this loop in both Drosophila and mammals. The Drosophila double-time gene product, a casein kinase I epsilon (CKIepsilon) homolog, has been reported to interact with dPER and regulate circadian cycle length. We find that mammalian CKIepsilon binds to and phosphorylates the murine circadian regulator mPER1. Unlike both dPER and mPER2, mPER1 expressed alone in HEK 293 cells is predominantly a nuclear protein. Two distinct mechanisms appear to retard mPER1 nuclear entry. First, coexpression of mPER2 leads to mPER1-mPER2 heterodimer formation and cytoplasmic colocalization. Second, coexpression of CKIepsilon leads to masking of the mPER1 nuclear localization signal and phosphorylation-dependent cytoplasmic retention of both proteins. CKIepsilon may regulate mammalian circadian rhythm by controlling the rate at which mPER1 enters the nucleus.


Selective killing of Fc-receptor-bearing tumor cells through endocytosis of a drug-carrying immune complex.
A soluble immune complex was used as a drug carrier targeted to Fc-receptor-positive cells. Two receptor-positive tumor cell lines, WEHI-3 and M5076, were exposed to methotrexate-human serum albumin conjugate (MTX-HSA) in the presence and absence of anti-HSA antiserum. Both cell types were killed by 30 nM MTX when the drug conjugate was given in the presence of antiserum but were totally unaffected in the absence of antiserum. Drug-free HSA given with antiserum had no effect. Both cell lines responded similarly despite their marked difference in phagocytotic activity. One of the two lines, M5076, is defective in MTX transport and hence resistant to free MTX. Since this line would not be affected by MTX released extracellularly from MTX-HSA, its susceptibility implies that MTX is released inside cells, after endocytosis of the complex, and that endocytosis circumvents the transport defect. Two cell lines lacking Fc receptors (CHO and L929) were not influenced by the drug complex. The pharmacologic effect is mediated by a specific ligand-receptor interaction, since Fc receptor-positive cells are protected by an excess of unconjugated HSA and by the addition of a small amount of staphylococcal protein A, which binds to the Fc portion of IgG. These data demonstrate that Fc receptors can be exploited for cellular drug delivery using a common antigen-antibody complex as a drug carrier.


Protective effect of astaxanthin on liver fibrosis through modulation of TGF-β1 expression and autophagy.
Liver fibrosis is a common pathway leading to cirrhosis and a worldwide clinical issue. Astaxanthin is a red carotenoid pigment with antioxidant, anticancer, and anti-inflammatory properties. The aim of this study was to investigate the effect of astaxanthin on liver fibrosis and its potential protective mechanisms. Liver fibrosis was induced in a mouse model using CCL4 (intraperitoneal injection, three times a week for 8 weeks), and astaxanthin was administered everyday at three doses (20, 40, and 80 mg/kg). Pathological results indicated that astaxanthin significantly improved the pathological lesions of liver fibrosis. The levels of alanine aminotransferase aspartate aminotransferase and hydroxyproline were also significantly decreased by astaxanthin. The same results were confirmed in bile duct liagtion, (BDL) model. In addition, astaxanthin inhibited hepatic stellate cells (HSCs) activation and formation of extracellular matrix (ECM) by decreasing the expression of NF-κB and TGF-β1 and maintaining the balance between MMP2 and TIMP1. In addition, astaxanthin reduced energy production in HSCs by downregulating the level of autophagy. These results were simultaneously confirmed in vivo and in vitro. In conclusion, our study showed that 80 mg/kg astaxanthin had a significant protective effect on liver fibrosis by suppressing multiple profibrogenic factors.


Comparison of the effects of topical and systemic atropine sulfate on intraocular pressure and pupil diameter in the normal canine eye.
To compare the effects of topical 1% atropine sulfate and systemic 0.1% atropine sulfate on the intraocular pressure (IOP) and horizontal pupil diameter (HPD) in the canine eye. Four groups, each containing 10 dogs of varying age, breed, and sex were treated as follows: (i) One 30 μL drop of topical 1% atropine sulfate was applied unilaterally in each dog, (ii) A control group, one drop of 0.9% saline was used, (iii) 0.06 mg/kg atropine sulfate was given by intramuscular injection, and (iv) Control with saline injected intramuscularly. In all groups, IOP and HPD were measured every 5 min over 60 min. Topical atropine significantly increased IOP in the treated eye with no change in the untreated eye. A maximum increase in IOP from 17.7 ± 3.1 to 20.3 ± 3.1 mmHg (14.7% increase) was obtained 23.0 ± 14.3 min post-treatment. Maximal HPD of 12.1 ± 1.7 mm in the treated eye occurred 46.5 ± 6.3 min after treatment, with no increase in the untreated eye. Systemic atropine caused an increase in IOP in both eyes, showing a maximum at 15.5 ± 10.6 min post-treatment with an IOP of 17.3 ± 4.6 mmHg in the right eye and 17.1 ± 5.2 mmHg in the left eye (21.8% increase in the right eye and 21.6% in the left eye). Maximal HPD was noted in both eyes 30.0 ± 11.6 min after treatment. Atropine sulfate causes a significant increase in IOP when given both topically and by intramuscular injection. It should be used with caution, or indeed avoided entirely, in dogs with glaucoma or in those with a predisposition to the condition.


Inhibition of the STAT3 Protein by a Dinuclear Macrocyclic Complex.
A new diethylenetriamine-derived macrocycle bearing 2-methylpyridyl arms and containing m-xylyl spacers, L, was prepared, and its dinuclear copper(II) and zinc(II) complexes were used as receptors for the recognition in aqueous solution of a phosphorylated peptide derived from a sequence of the STAT3 protein. A detailed study of the acid-base behavior of L and of its complexation properties as well as of the association of the phosphorylated peptide to the receptor was carried out by potentiometry in aqueous solution at 298.2 K and I = 0.10 M in KNO3. The data revealed that the receptor forms stable associations with several protonated forms of the substrate, with constant values ranging from 3.32 to 4.25 log units. The affinity of the receptor for the phosphorylated substrate studied is higher at a pH value where the receptor is mainly in the [Cu2L](4+) form and the pY residue of the substrate is in the dianionic form (pH 6.55). These results, also supported by (31)P NMR studies, showed that the phosphopeptide is bound through the phosphoryl group in a bridging mode. Additionally, the receptor inhibited binding between active (phosphorylated) STAT3 and its target DNA sequence in a dose-dependent manner (IC50 63 ± 3.4 μM) in human nuclear extracts in vitro. Treatment of whole cells with the inhibitor revealed that it is bioactive in living cells and has oncostatic properties that could be interesting for the fight against cancer and other pathologies involving the STAT3 protein.


MicroRNA-128 governs neuronal excitability and motor behavior in mice.
The control of motor behavior in animals and humans requires constant adaptation of neuronal networks to signals of various types and strengths. We found that microRNA-128 (miR-128), which is expressed in adult neurons, regulates motor behavior by modulating neuronal signaling networks and excitability. miR-128 governs motor activity by suppressing the expression of various ion channels and signaling components of the extracellular signal-regulated kinase ERK2 network that regulate neuronal excitability. In mice, a reduction of miR-128 expression in postnatal neurons causes increased motor activity and fatal epilepsy. Overexpression of miR-128 attenuates neuronal responsiveness, suppresses motor activity, and alleviates motor abnormalities associated with Parkinson's-like disease and seizures in mice. These data suggest a therapeutic potential for miR-128 in the treatment of epilepsy and movement disorders.


[Effect of preparations on the intracellular cAMP and prostaglandin E content and on the functional activity of antigen-induced B-suppressors].
Not adhering to a plastic, B-cells of intact or immunized with the suboptimal dose of ram erythrocytes mice were treated in vitro with several agonists and antagonists of cAMP and prostaglandins E and then were transferred to syngenic or allogenic unirradiated recipients. Afterwards the number of the antibody-forming cells against ram erythrocytes was determined. It was shown that a decrease of cAMP and prostaglandin E contents in the intact B-cells results in the appearance of the ability to stimulate the immune response. An increase of cAMP content in the immune B-cells is followed by a reduction of their suppressing activity. The absence of the relationship between this activity and prostaglandin E content in the immune cells is suggested.


Low fasting serum triglyceride level as a precocious marker of autoimmune disorders.
The authors recently reported the occurrence of low fasting serum triglyceride (TG) and high free fatty acid (FFA) levels in idiopathic pulmonary fibrosis. TG estimation in diverse groups of patients with autoimmune disease or hyperactive immune response confirmed the occurrence of a similar decrease of TG. In some patients, serum FFA level was also evaluated. TG value in lean and obese patients was compared with that in lean (n = 108) and obese (n = 208) control subjects without autoimmune disease. In patients affected by autoimmune chronic thyroiditis with enhanced concentration of antithyroglobulin antibodies and without thyroidal failure (n = 24), lean and obese patients had reduced TG (-69/%, P < .01 and -52%, P < .0001, respectively). Both lean and obese patients affected by chronic active B or C hepatitis (n = 26), with autoantibodies and without signs of hepatic insufficiency or cirrhosis, presented reduced TG (-57%, P < .01 and -61%, P < .001, respectively). A marked TG decrease (-73%, P < .001) was observed in the lean patients affected by lupus-like syndrome (n = 7). The lean and obese patients with systemic lupus erythematosus or rheumatoid arthritis (n = 11) showed TG decrease (-66%, P < .01 and -55%, P < .05, respectively). In patients affected by anamnestic allergy or atopic dermatitis/asthma (n = 66), both lean and obese, TGs were reduced (-67%, P < .0001 and -62%, P < .001, respectively). In isolated cases of diverse autoimmune diseases (scleroderma, APECED [autoimmune polyendocrinopathy, candidiasis, and ectodermal dystrophy], urticaria or urticarial vasculitis, Reiter or Sjogren syndromes, ulcerative colitis or Crohn's disease, multiple sclerosis or Guillain-Barré syndrome) (n = 14), decreased TG was also observed both in the lean and obese subjects (-59%, P < .01 and -57%, P < .01, respectively). Concerning FFA (n = 69), value in lean patients (n = 22) vs that in lean controls (n = 18) was increased (520 +/- 31 vs 299 +/- 30 mcEq/L, +74%, P < .001), whereas value in obese patients (n = 18) vs that in obese control subjects (n = 11) was decreased (542 +/- 34 vs 774 +/- 62, -30%, P < .01). This opposite behavior of FFA in lean and obese patients needs to be confirmed. Data in this study seem to indicate that low TG value may be a precocious marker of autoimmunity or immune system hyperreactivity.


Bacteriophage ZCSE2 is a Potent Antimicrobial Against Salmonella enterica Serovars: Ultrastructure, Genomics and Efficacy.
Developing novel antimicrobials capable of controlling multidrug-resistant bacterial pathogens is essential to restrict the use of antibiotics. Bacteriophages (phages) constitute a major resource that can be harnessed as an alternative to traditional antimicrobial therapies. Phage ZCSE2 was isolated among several others from raw sewage but was distinguished by broad-spectrum activity against Salmonella serovars considered pathogenic to humans and animals. Lytic profiles of ZCSE2 against a panel of Salmonella were determined together with low temperature activity and pH stability. The morphological features of the phage and host infection processes were characterized using a combination of transmission electron and atomic force microscopies. Whole genome sequencing of ZCSE2 produced a complete DNA sequence of 53,965 bp. No known virulence genes were identified in the sequence data, making ZCSE2 a good candidate for phage-mediated biological control purposes. ZCSE2 was further tested against S. Enteritidis in liquid culture and was observed to reduce the target bacterium to below the limits of detection from initial concentrations of 107-108 Colony Forming Units (CFU)/mL. With a broad host-range against pathogenic Salmonella serovars, phage ZCSE2 constitutes a potential tool against a major cause of human and animal disease.


Treatment and justice.
Support for the belief that criminal behaviour was amenable to treatment served different purposes: for developing psychiatry it offered a module of power to be exploited whereas for the State it was a convenient disguise for the infliction of pain which was the real intention of punishment. Having served its purpose the treatment approach is being abandoned in favour of a philosophy of just deserts which is more acceptable in the present political climate.


Prevention of early islet graft failure by selective inducible nitric oxide synthase inhibitors after pig to nude rat intraportal islet transplantation.
Clinical and experimental data indicate that early failure of intraportally grafted islets is caused by inflammation including secretion of cytokines and nitric oxide. Direct inducible nitric oxide synthase suppression may avoid detrimental effects associated with steroid administration. We compared the efficiency of selective and unselective inducible nitric oxide synthase inhibitors with dexamethasone to suppress nitric oxide generation after intraportal islet xenotransplantation into nude rats. Nonfasting serum glucose levels were daily evaluated after intraportal transplantation of 4000 freshly isolated pig islets into diabetic nude rats (85 mg/kg streptozotocin) either sham-treated with saline (n=21) or continuously infused for 7 days with L-NG-monomethyl-arginine (n=7), S-methyl-isothiourea (n=15), or S-(2-aminoethyl)-isothiourea (n=19) in a dosage of 240, 100, or 50 mg/kg/day, respectively. Dexamethasone was injected i.p. twice as a daily bolus of 20 mg/kg (n=10) starting 1 day pretransplant. The nitrate/nitrite serum level was quantified colorimetrically 0, 24, and 48 hr posttransplant. Saline treatment partially resulted in graft function (4/21) throughout the observation period (21 days). L-NG-monomethyl-arginine-treated rats showed sustained hyperglycemia (0/7) not different from diabetic controls. Normoglycemia was observed after treatment with dexamethasone (6/10, P<0.05 versus saline and L-NG-monomethyl-arginine), S-methyl-isothiourea (10/15, P<0.01), or S-(2-aminoethyl)-isothiourea (15/19, P<0.001). Graft function was associated with complete suppression of nitric oxide generation after S-methyl-isothiourea and S-(2-aminoethyl)-isothiourea treatment (P<0.001 versus saline) and partial suppression after dexamethasone treatment (P<0.05). Our observation of long-term function of xenogeneic islets in an inflammatory environment without interference of reactive T cells revealed the potency of highly selective isothioureas to completely suppress inducible nitric oxide synthase making reduction of islet-toxic immunosuppression feasible.


Time for a paradigm shift with computerized adaptive testing of general physical function outcomes measurements.
Patient-reported outcomes (PRO) are critical to understanding the value of orthopedic treatments. We hypothesized that use of the computerized adaptive testing from a well-characterized physical function item bank would show superiority in assessing all levels of physical function compared to current standard generic physical function outcomes instruments for foot and ankle patients. In a population of 126 foot and ankle patients we compared the psychometric properties for three PROs: the Physical Function subscale of the Medical Outcomes General Health Survey (SF-36 PF) version 2, the Patient-Reported Outcomes Measurement Information System (PROMIS) Physical Function (PF) Computerized Adaptive Test (CAT), and the Lower Extremity (LE) CAT. A Rasch item response theory (IRT) model was applied to assess and compare the fit, dimensionality, reliability, validity, and coverage. The unexplained variance for the PF CAT was 3.9% and the LE CAT was 2.1%, suggesting each instrument explained a single concept. The SF-36 PF had more concerning unexplained variance of 7.6%. We found no floor or ceiling effects for the PF CAT, a minimal floor effect (1.6%) but no ceiling effect for the LE CAT, and an 11.1% floor effect and 9.5% ceiling effect for the SF-36 PF. Foot and ankle clinicians and researchers interested in measuring patient perceived functional outcomes with a generic instrument should consider using either the PF CAT or the LE CAT rather than the SF-36 PF. Further studies comparing these CATs to anatomic specific instruments are needed. Level I, diagnostic study.


The burdens of age-related and occupational noise-induced hearing loss in the United States.
Aging and noise are generally considered the most common causes of adult hearing loss in developed countries. This study estimates the contributions of aging and occupational noise in the United States. A model of hearing loss burden in American adults was constructed using data from the Census Bureau, from an international standard that predicts age-related and noise-induced hearing loss (ISO-1999), from the American Medical Association method of determining hearing impairment, and from sources estimating the distribution of occupational noise exposure in different age and sex groups. Occupational noise exposure probably accounts for less than 10% of the burden of adult hearing loss in the United States; most of the rest is age-related. Most of the occupational noise burden is attributable to unprotected exposures above 95 dBA, and becomes apparent in middle age, when occupational noise exposure has ceased but age-related threshold shifts are added to prior noise-induced shifts, resulting in clinically significant impairment. In our current state of knowledge, noise-induced hearing loss is still the most important preventable cause of hearing loss in the United States. The burden of occupational noise-induced hearing loss could probably be reduced by stricter enforcement of existing regulations. Longer lifespans in developed countries and migration of manufacturing jobs to developing countries will continue to reduce the relative contribution of occupational hearing loss in countries like the United States. Preventive interventions for age-related hearing loss, even if only partially effective, could potentially reduce the burden of adult hearing loss more than elimination of occupational noise.


Archiving next generation sequencing data.
Next generation sequencing platforms are producing biological sequencing data in unprecedented amounts. The partners of the International Nucleotide Sequencing Database Collaboration, which includes the National Center for Biotechnology Information (NCBI), the European Bioinformatics Institute (EBI), and the DNA Data Bank of Japan (DDBJ), have established the Sequence Read Archive (SRA) to provide the scientific community with an archival destination for next generation data sets. The SRA is now accessible at http://www.ncbi.nlm.nih.gov/Traces/sra from NCBI, at http://www.ebi.ac.uk/ena from EBI and at http://www.ddbj.nig.ac.jp/sub/trace_sra-e.html from DDBJ. Users of these resources can obtain data sets deposited in any of the three SRA instances. Links and submission instructions are provided.


Plastid encoded RNA polymerase activity and expression of photosynthesis genes required for embryo and seed development in Arabidopsis.
Chloroplast biogenesis and function is essential for proper plant embryo and seed development but the molecular mechanisms underlying the role of plastids during embryogenesis are poorly understood. Expression of plastid encoded genes is dependent on two different transcription machineries; a plastid-encoded bacterial-type RNA polymerase (PEP) and a nuclear-encoded phage-type RNA polymerase (NEP), which recognize distinct types of promoters. However, the division of labor between PEP and NEP during plastid development and in mature chloroplasts is unclear. We show here that PLASTID REDOX INSENSITIVE 2 (PRIN2) and CHLOROPLAST STEM-LOOP BINDING PROTEIN 41 kDa (CSP41b), two proteins identified in plastid nucleoid preparations, are essential for proper plant embryo development. Using Co-IP assays and native PAGE we have shown a direct physical interaction between PRIN2 and CSP41b. Moreover, PRIN2 and CSP41b form a distinct protein complex in vitro that binds DNA. The prin2.2 and csp41b-2 single mutants displayed pale phenotypes, abnormal chloroplasts with reduced transcript levels of photosynthesis genes and defects in embryo development. The respective csp41b-2prin2.2 homo/heterozygote double mutants produced abnormal white colored ovules and shrunken seeds. Thus, the csp41b-2prin2.2 double mutant is embryo lethal. In silico analysis of available array data showed that a large number of genes traditionally classified as PEP dependent genes are transcribed during early embryo development from the pre-globular stage to the mature-green-stage. Taken together, our results suggest that PEP activity and consequently the switch from NEP to PEP activity, is essential during embryo development and that the PRIN2-CSP41b DNA binding protein complex possibly is important for full PEP activity during this process.


Is genu varum a risk factor for the prevalence and severity of achilles tendinopathy? A cross-sectional study of Nigerian elite track and field athletes.
Achilles tendinopathy (AT) is one of the most frequently reported ankle and foot overuse injuries. Prior studies have reported altered biomechanical variables of the lower limb as risk factors for the prevalence and severity of AT in athletes, especially in Caucasians, but there are few reports on African elite athletes. Because it is established that anthropometric and biomechanical values vary with racial disposition, this study was designed to investigate the association between selected physical and biomechanical variables of the lower limb and the prevalence and severity of AT in Nigerian elite track and field athletes. Eighty-five elite Nigerian track and field athletes participated in this cross-sectional study. Biomechanical variables of Q-angle, tibial torsion, limb-length discrepancy (LLD) and foot posture index (FPI) were evaluated using standard procedures. The presence of AT was confirmed with ultrasonography and clinical assessments, whereas the severity was evaluated with VISA-A questionnaire. Inferential statistics of Chi-square was used to determine the association between prevalence of AT and the biomechanical variables. The prevalence of AT was 15.3%, made up of participants who tested positive to both clinical test and ultrasound scan. There was no significant association between AT and LLD, tibial torsion and FPI. Most of the participants with AT had genu varum, which was significantly associated with both the prevalence and severity of AT. It was concluded that genu varum had a significant association with both the prevalence and severity of AT in elite Nigerian track and field athletes.


Using a partial sum method and GPS tracking data to identify area restricted search by artisanal fishers at moored fish aggregating devices in the Commonwealth of Dominica.
Foragers must often travel from a central place to exploit aggregations of prey. These patches can be identified behaviorally when a forager shifts from travel to area restricted search, identified by a decrease in speed and an increase in sinuosity of movement. Faster, more directed movement is associated with travel. Differentiating foraging behavior at patches from travel to patches is important for a variety of research questions and has now been made easier by the advent of small, GPS devices that can track forager movement with high resolution. In the summer and fall of 2012, movement data were collected from GPS devices placed on foraging trips originating in the artisanal fishing village of Desa Ikan (pseudonym), on the east coast of the Caribbean island nation of the Commonwealth Dominica. Moored FADs are human-made structures anchored to the ocean floor with fish attraction material on or near the surface designed to effectively create a resource patch. The ultimate goal of the research is to understand how property rights are emerging after the introduction of fish aggregating device (FAD) technology at the site in 1999. This paper reports on research to identify area-restricted search foraging behavior at FAD patches. For 22 foraging trips simultaneous behavioral observations were made to ground-truth the GPS movement data. Using a cumulative sum method, area restricted search was identified as negative deviations from the mean travel speed and the method was able to correctly identify FAD patches in every case.


Recovery of Elemental Tellurium Nanoparticles by the Reduction of Tellurium Oxyanions in a Methanogenic Microbial Consortium.
This research focuses on the microbial recovery of elemental tellurium (Te(0)) from aqueous streams containing soluble tellurium oxyanions, tellurate (Te(VI)), and tellurite (Te(IV)). An anaerobic mixed microbial culture occurring in methanogenic granular sludge was able to biocatalyze the reduction of both Te oxyanions to produce Te(0) nanoparticles (NPs) in sulfur-free medium. Te(IV) reduction was seven times faster than that of Te(VI), such that Te(IV) did not accumulate to a great extent during Te(VI) reduction. Endogenous substrates in the granular sludge provided the electron equivalents required to reduce Te oxyanions; however, the reduction rates were modestly increased with an exogenous electron donor such as H2. The effect of four redox mediators (anthraquinone-2,6-disulfonate, hydroxocobalamin, riboflavin, and lawsone) was also tested. Riboflavin increased the rate of Te(IV) reduction eleven-fold and also enhanced the fraction Te recovered as extracellular Te(0) NPs from 21% to 64%. Lawsone increased the rate of Te(VI) reduction five-fold, and the fraction of Te recovered as extracellular material increased from 49% to 83%. The redox mediators and electron donors also impacted the morphologies and localization of Te(0) NPs, suggesting that NP production can be tailored for a particular application.


Improving the Nutritional, Structural, and Sensory Properties of Gluten-Free Bread with Different Species of Microalgae.
Microalgae are an enormous source of nutrients that can be utilized to enrich common food of inherently low nutritional value, such as gluten-free (GF) bread. Addition of the algae species: Tetraselmis chuii (Tc), Chlorella vulgaris (Cv), and Nannochloropsis gaditana (Ng) biomass led to a significant increase in proteins, lipids, minerals (Ca, Mg, K, P, S, Fe, Cu, Zn, Mn), and antioxidant activity. Although, a compromise on dough rheology and consequential sensory properties was observed. To address this, ethanol treatment of the biomass was necessary to eliminate pigments and odor compounds, which resulted in the bread receiving a similar score as the control during sensory trials. Ethanol treatment also resulted in increased dough strength depicted by creep/recovery tests. Due to the stronger dough structure, more air bubbles were trapped in the dough resulting in softer breads (23-65%) of high volume (12-27%) vs. the native algae biomass bread. Breads baked with Ng and Cv resulted in higher protein-enrichment than the Tc, while Tc enrichment led to an elevated mineral content, especially the Ca, which was six times higher than the other algae species. Overall, Ng, in combination with ethanol treatment, yielded a highly nutritious bread of improved technological and sensory properties, indicating that this species might be a candidate for functional GF bread development.


Identification and analysis of sugar transporters capable of co-transporting glucose and xylose simultaneously.
Simultaneous co-fermentation of glucose and xylose is a key desired trait of engineered Saccharomyces cerevisiae for efficient and rapid production of biofuels and chemicals. However, glucose strongly inhibits xylose transport by endogenous hexose transporters of S. cerevisiae. We identified structurally distant sugar transporters (Lipomyces starkeyi LST1_205437 and Arabidopsis thaliana AtSWEET7) capable of co-transporting glucose and xylose from previously unexplored oleaginous yeasts and plants. Kinetic analysis showed that LST1_205437 had lenient glucose inhibition on xylose transport and AtSWEET7 transported glucose and xylose simultaneously with no inhibition. Modelling studies of LST1_205437 revealed that Ala335 residue at sugar binding site can accommodates both glucose and xylose. Docking studies with AtSWEET7 revealed that Trp59, Trp183, Asn145, and Asn179 residues stabilized the interactions with sugars, allowing both xylose and glucose to be co-transported. In addition, we altered sugar preference of LST1_205437 by single amino acid mutation at Asn365. Our findings provide a new mechanistic insight on glucose and xylose transport mechanism of sugar transporters and the identified sugar transporters can be employed to develop engineered yeast strains for producing cellulosic biofuels and chemicals.


Repair between dose fractions: a simpler method of analyzing and reporting apparently biexponential repair.
Increasing numbers of animal experiments in situ are reporting that repair of sublethal radiation damage in vivo slows down with time, usually described as two components of (monoexponential) repair. For repair of DNA strand breaks, plotting the reciprocal of proportion unrepaired as a function of time yielded straight lines. Two processes have been suggested as causing this: (1) a second-order process (bimolecular) instead of first-order (exponential) and (2) a skewed distribution of monoexponential rates. The present paper investigates whether such plots of hyperbolic or reciprocal repair are relevant for laboratory animal tissue results. Published repair data were reanalyzed from laboratory animal experiments that employed split doses or two fractions per day. Graphs are presented of the reciprocal proportion of damage remaining as a function of the interval between the two doses. If the reciprocal model applies, the graphs would be straight lines. Different animal data showed no inconsistency with straight reciprocal plots. These reciprocal plots describe well with one parameter tau, the first half-time, repair curves previously thought to be "biexponential", and to require three parameters. Straight reciprocal plots mean that in a constant time interval tau the unrepaired damage falls from 1 to (1/2), then from (1/2) to (1/3), then (1/3) to (1/4), etc. A much larger proportion of damage would therefore remain unrepaired at several half-times than is estimated by current mono- or biexponential models. The practical implications for clinical radiotherapy are important.


The level of Internet access and ICT training for health information professionals in sub-Saharan Africa.
Information and Communication Technologies (ICTs) are important tools for development. Despite its significant growth on a global scale, Internet access is limited in sub-Saharan Africa (SSA). Few studies have explored Internet access, use of electronic resources and ICT training among health information professionals in Africa. The study assessed Internet access, use of electronic resources and ICT training among health information professionals in SSA. A 26-item self-administered questionnaire in English and French was used for data collection. The questionnaire was completed by health information professionals from five Listservs and delegates at the 10th biannual Congress of the Association of Health Information and Libraries in Africa (AHILA). A total of 121 respondents participated in the study and, of those, 68% lived in their countries' capital. The majority (85.1%) had Internet access at work and 40.8% used cybercafes as alternative access points. Slightly less than two-thirds (61.2%) first learned to use ICT through self-teaching, whilst 70.2% had not received any formal training in the previous year. Eighty-eight per cent of respondents required further ICT training. In SSA, freely available digital information resources are underutilized by health information professionals. ICT training is recommended to optimize use of digital resources. To harness these resources, intergovernmental and non-governmental organizations must play a key role.


Oxidation-reduction potentials and ionization states of extracellular peroxidases from the lignin-degrading fungus Phanerochaete chrysosporium.
The oxidation-reduction potentials of lignin peroxidase isozymes H1, H2, H8, and H10 as well as the Mn-dependent peroxidase isozymes H3 and H4 are reported. The potentiometric titrations involving the ferrous and ferric states of the enzyme had Nernst plots indicating single-electron transfer. The Em7 values of lignin peroxidase isozymes H1, H2, H8, and H10 are -142, -135, -137, and -127 mV versus standard hydrogen electrode, respectively. The Em7 values for the Mn-dependent peroxidase isozymes H3 and H4 are -88 and -93 mV versus standard hydrogen electrode, respectively. The midpoint potential of H1, H8, and H4 remained unchanged in the presence of their respective substrates, veratryl alcohol and Mn(II). The midpoint potential between the ferric and ferrous forms of isozymes H1 and H4 exhibited a pH-dependent change between pH 3.5 and pH 6.5. These results indicate that the reductive half-reaction of the enzymes is the following: ferric peroxidase + le- + H+----ferrous peroxidase. Above pH 6.5, the effect of pH on the midpoint potential is diminished and indicates that an ionization with an apparent pKa equal to approximately 6.6-6.7 occurs in the reduced form of the enzymes. A heme-linked ionization group in the ferrous form of the enzymes was confirmed by studying the effect of pH on the absorption spectra of isozymes H1 and H4. These spectrophotometric pH titration experiments confirmed the electrochemical results indicating pKa values of 6.59 and 6.69 for reduced isozymes H1 and H4, respectively. These results indicate the presence of a heme-linked ionization of an amino acid in the reduced form of the lignin peroxidase isozymes similar to that of other plant peroxidases.


[Preoperative prophylactic pacemakers: apropos of their indication in a disputed case].
The criteria for preoperative use of pacemakers are not unanimously agreed upon. Certain cases require careful assessment to weigh potential benefits against inherent risks in placing the device. Although external transcutaneous pacemakers, whose use circumvents the risks of transvenous insertion, have been available for years, such devices are not always appropriate, depending on the flow disorder involved or the type of surgery that will be performed. We report the case of a 75-year-old woman who was a candidate for surgery requiring general anesthesia (lumboperitoneal shunt due to chronic adult hydrocephaly). Although her condition did not initially call for prophylactic use of a pacemaker before surgery, changes soon developed that necessitated insertion of a temporary transvenous device for surgery and insertion of a permanent pacemaker the day after surgery.


Homonucleotide expansion and contraction mutations of PAX2 and inclusion of Chiari 1 malformation as part of renal-coloboma syndrome.
Renal-Coloboma syndrome, an autosomal dominant disorder characterized by colobomatous eye defects, vesicoureteral reflux, and abnormal kidneys, results from mutations in PAX2. The purpose of this study was to identify mutations in PAX2 and understand the associated patient phenotypes. We report a severely affected girl and a mildly affected mother and daughter, all of whom have PAX2 homoguanine tract (7 G) missense mutations. The mother and daughter have optic nerve colobomas and the daughter has vesicoureteral reflux. The severely affected girl developed renal failure and has bilateral colobomatous eye defects. Additionally, this girl developed hydrocephalus associated with platybasia and a Chiari 1 malformation. We examined genomic DNA from these individuals by SSCP and sequencing. The mother and daughter had a novel mutation: a contraction in a string of 7 G's to 6 G's in one allele of PAX2, leading to a premature stop codon two amino acids downstream. The severely affected girl had an expansion to 8 G's, leading to a premature stop codon 27 amino acids downstream. The 8 G expansion has been found in other patients without brain anomalies and has occurred spontaneously in a mouse model, PAX2(1Neu). We expand the known phenotype associated with mutations in PAX2 to include brain malformations. The homoguanine tract in PAX2 is a hot spot for spontaneous expansion or contraction mutations and demonstrates the importance of homonucleotide tract mutations in human malformation syndromes.


Pharmacokinetic analysis of polyamide nucleic-acid-cell penetrating peptide conjugates targeted against HIV-1 transactivation response element.
We have demonstrated that polyamide nucleic acids complementary to the transactivation response (TAR) element of HIV-1 LTR inhibit HIV-1 production when transfected in HIV-1 infected cells. We have further shown that anti-TAR PNA (PNA(TAR)) conjugated with cell-penetrating peptide (CPP) is rapidly taken up by cells and exhibits strong antiviral and anti-HIV-1 virucidal activities. Here, we pharmacokinetically analyzed (125)I-labeled PNA(TAR) conjugated with two CPPs: a 16-mer penetratin derived from antennapedia and a 13-mer Tat peptide derived from HIV-1 Tat. We administered the (125)I-labeled PNA(TAR)-CPP conjugates to male Balb/C mice through intraperitoneal or gavage routes. The naked (125)I-labeled PNA(TAR) was used as a control. Following a single administration of the labeled compounds, their distribution and retention in various organs were monitored at various time points. Regardless of the administration route, a significant accumulation of each PNA(TAR)-CPP conjugate was found in different mouse organs and tissues. The clearance profile of the accumulated radioactivity from different organs displayed a biphasic exponential pathway whereby part of the radioactivity cleared rapidly, but a significant portion of it was slowly released over a prolonged period. The kinetics of clearance of individual PNA(TAR)-CPP conjugates slightly varied in different organs, while the overall biphasic clearance pattern remained unaltered regardless of the administration route. Surprisingly, unconjugated naked PNA(TAR) displayed a similar distribution and clearance profile in most organs studied although extent of its uptake was lower than the PNA(TAR)-CPP conjugates.


Erratum: Differential expressed genes in ECV304 Endothelial-like Cells infected with Human Cytomegalovirus.
Human cytomegalovirus (HCMV) is a virus which has the potential to alter cellular gene expression through multiple mechanisms. With the application of DNA microarrays, we could monitor the effects of pathogens on host-cell gene expression programmes in great depth and on a broad scale. Changes in mRNA expression levels of human endothelial-like ECV304 cells following infection with human cytomegalovirus AD169 strain was analyzed by a microarray system comprising 21073 60-mer oligonucleotide probes which represent 18716 human genes or transcripts. The results from cDNA microarray showed that there were 559 differential expressed genes consisted of 471 upregulated genes and 88 down-regulated genes. Real-time qPCR was performed to validate the expression of 6 selected genes (RPS24, MGC8721, SLC27A3, MST4, TRAF2 and LRRC28), and the results of which were consistent with those from the microarray. Among 237 biology processes, 39 biology processes were found to be related significantly to HCMV-infection. The signal transduction is the most significant biological process with the lowest p value (p=0.005) among all biological process which involved in response to HCMV infection. Several of these gene products might play key roles in virus-induced pathogenesis. These findings may help to elucidate the pathogenic mechanisms of HCMV caused diseases. [This corrects the article on p. 243 in vol. 13, PMID: 24235919.].


[Gustatory disorders during multiple sclerosis relapse].
Gustatory dysfunction is a known but uncommon element in the course of multiple sclerosis. Gustatory dysfunction has been described during the chronic progressive phase and during the relapse phase. We report five patients with clinically definite multiple sclerosis who developed transient gustatory disorders during the relapse phase of their disease. Agueusia occurred as one of the first symptoms in three patients, revealing the disease. Symptoms generally improved with remission or corticosteroid administration. These disorders are due to demyelinating lesions of the gustatory pathways in the thalamus or brainstem. MRI studies were not performed during the relapse phase and no clinical neuroimaging correlations could be established. Agueusia may be accompanied by olfactory dysfunction which is due to plaque demyelinization of the olfactory pathways, particularly in the temporal and inferior frontal lobes. Taste anomalies can also be observed in other diseases, including systemic diseases such as sarcoidosis or Sjogrën's syndrome. Drug-induced gustatory disorders are also reported.


Comparison of clozapine in nail and hair of psychiatric patients determined with LC-MS/MS.
As a keratinized material, nail recently has attracting researchers' attention in the pharmaceuticals analysis. There are comparatively limited studies concerning nail's xenobiotic determination and its mechanism. This article reported the development of a sensitive, specific and reproducible LC-MS/MS method, which could be as a foundation of other studies on drug determination in nail. It can also be regarded as the first report on organic drug in mainland China. Sixteen nail samples from volunteers, who were ingested clozapine for more than nine months, are confirmed positive after being analyzed by the method. It is found that contents of clozapine in the patients' nails are above the nanogram level. Besides, a comparative study of clozapine concentration in nails and hair was made, with a result that there exists a correlation between the two materials in terms of clozapine concentration.


Resolution enhancement of monochrome and color video using motion compensation.
We propose an iterative algorithm for enhancing the resolution of monochrome and color image sequences. Various approaches toward motion estimation are investigated and compared. Improving the spatial resolution of an image sequence critically depends upon the accuracy of the motion estimator. The problem is complicated by the fact that the motion field is prone to significant errors since the original high-resolution images are not available. Improved motion estimates may be obtained by using a more robust and accurate motion estimator, such as a pel-recursive scheme instead of block matching, in processing color image sequences, there is the added advantage of having more flexibility in how the final motion estimates are obtained, and further improvement in the accuracy of the motion field is therefore possible. This is because there are three different intensity fields (channels) conveying the same motion information. In this paper, the choice of which motion estimator to use versus how the final estimates are obtained is weighed to see which issue is more critical in improving the estimated high-resolution sequences. Toward this end, an iterative algorithm is proposed, and two sets of experiments are presented. First, several different experiments using the same motion estimator but three different data fusion approaches to merge the individual motion fields were performed. Second, estimated high-resolution images using the block matching estimator were compared to those obtained by employing a pel-recursive scheme. Experiments were performed on a real color image sequence, and performance was measured by the peak signal to noise ratio (PSNR).


Anatomical changes in the East Asian midface skeleton with aging.
Understanding the aging process of the midface skeleton is considered crucial for correct facial rejuvenation. However, the canine fossa, an important morphological feature of the midface skeleton, has not yet been observed in connection with aging, despite the fact that it is the most main part of the maxillary bone. Here, the authors focus on the depression of the canine fossa to evaluate the Asian midface skeleton. Computed tomography (CT) scans of the facial skeleton of 114 Koreans (59 males and 55 females) were reconstructed to three-dimensional (3D) images using a 3D analysis software programme. The study subjects included 27 young males, 32 old males, 28 young females and 27 old females. The angular measurements of three bony regions were measured for each 3D model: the canine fossa angle (assessing depth of the canine fossa), the maxillary angle (assessing orientation of the lateral maxilla) and the piriform angle (assessing orientation of the medial maxilla). The canine fossa angle showed a statistically significant decrease with aging in both sexes, indicating the canine fossa actually becomes more concave with age. In contrast, the maxillary and piriform angle showed statistically insignificant changes with aging in female subjects. These results suggest that the canine fossa may be one of the effective markers to evaluate the anatomical changes to the facial skeleton with midface aging. (.


Microscopy based methods for characterization, drug delivery, and understanding the dynamics of nanoparticles.
Nanomedicine is an emerging field that exploits nanotechnology for the development of novel therapeutic and diagnostic modalities. Researches are been focussed in nanoimaging to develop noninvasive, highly sensitive, and reliable tools for diagnosis and visualization in nanomedical field. The application of nanomedicine in healthcare requires in-depth understanding of their structural, physical and morphological properties, internalization inside living system, biodistribution and localization, stability, mode of action and possible toxic health effects. Microscopic techniques including fluorescence-based confocal laser scanning microscopy, super-resolution fluorescence microscopy and multiphoton microscopy; optical-based Raman microscopy, photoacoustic microscopy and optical coherence tomography; photothermal microscopy; electron microscopy (transmission electron microscope and scanning electron microscope); atomic force microscopy; X-ray microscopy and, correlative multimodal imaging are recognized as an indispensable tool in material research and aided in numerous discoveries. Microscopy holds great promise in detecting the fundamental structures of nanoparticles (NPs) that determines their performance and applications. Moreover, the intricate details that allows assessment of chemical composition, surface topology and interfacial properties, molecular, microstructure, and micromechanical properties are also elucidated. With plethora of applications, microscopy-based techniques have been used to characterize novel NPs alongwith their proficient designing and adoption of safe strategies to be exploited in nanomedicine. Consequently, microscopic techniques have been extensively used in the characterization of fabricated NPs, and their biomedical application in diagnostics and therapeutics. The present review provides an overview of the microscopy-based techniques for in vitro and in vivo application in nanomedical investigation alongwith their challenges and advancement to meet the limitations of conventional methods.


Musculoskeletal Ultrasound in Early Rheumatoid Arthritis - Correlations with Disease Activity Score.
to assess synovial inflammation using musculoskeletal ultrasonography, in a cohort of patients with early rheumatoid arthritis, and establish the correlations with disease activity score. We enrolled 29 patients diagnosed with early RA, according to ACR-EULAR 2010 classification criteria, in Rheumatology Clinic, Emergency County Hospital Craiova, between September 2013-August 2014. We performed clinical evaluation, assessed laboratory tests and performed US for all the patients. Musculoskeletal ultrasonography was performed using an ESAOTE MyLab 25 ultrasound, by the same examiner, with multi-frequency linear array transducers (7-12Mh). The presence of synovitis was assessed both in grey scale (GSUS) and power-Doppler (PDUS), according to OMERACT-EULAR consent. Assessment of synovial inflammatory activity by ultrasound examination, using both grey scale and PDUS, has shown active synovitis in all patients, with a mean number of joints with active synovitis of 5. Evaluating the grade, using PDUS, we found grade 1 in all patients, 2 in 14 and grade 3 in 3 patients. Inflammatory markers correlated significant with both GSUS and PDUS. Analysis of correlation between GSUS examination parameters and disease activity score, found a positive, moderate inter-relation, results found also for PD score. our results sustain the role of US for detecting inflammatory activity in early RA patients, and, in addition with clinical and biological assessment, represents a sensitive, reliable and reproducible method, easily approached, that should be included in our routine evaluation.


Differentiating Cardiac Troponin Levels During Cardiac Myosin Inhibition or Cardiac Myosin Activation Treatments: Drug Effect or the Canary in the Coal Mine?
Cardiac myosin inhibitors (CMIs) and activators are emerging therapies for hypertrophic cardiomyopathy (HCM) and heart failure with reduced ejection fraction (HFrEF), respectively. However, their effects on cardiac troponin levels, a biomarker of myocardial injury, are incompletely understood. In patients with HCM, CMIs cause substantial reductions in cardiac troponin levels which are reversible after stopping treatment. In patients with HFrEF, cardiac myosin activator (omecamtiv mecarbil) therapy cause modest increases in cardiac troponin levels which are reversible following treatment cessation and not associated with myocardial ischaemia or infarction. Transient changes in cardiac troponin levels might reflect alterations in cardiac contractility and mechanical stress. Such transient changes might not indicate cardiac injury and do not appear to be associated with adverse outcomes in the short to intermediate term. Longitudinal changes in troponin levels vary depending on the population and treatment. Further research is needed to elucidate mechanisms underlying changes in troponin levels.


A method of assessing efficacy of renal arteriography with reference to the space-occupying lesion of the kidney.
A 5 categories classification method has been used for assessing the test efficacy of renal arteriography with reference to suspicion of a space-occupying lesion of the kidney in a urogram. 20 selected intravenous urographies were judged by 7 investigators. Using a diagnostic score the efficacy per patient, per investigator was assessed. The mean of all investigators per patient (= the mean diagnostic score per patient) and the mean of all patients per investigator (= the mean diagnostic score per investigator) were also assessed. The first gives an indication of the difficulty of the case; the second gives an indication of the performance of the investigator.


Factors affecting the risk of brain metastases after definitive chemoradiation for locally advanced non-small-cell lung carcinoma.
As therapy for locally advanced non-small-cell lung carcinoma (NSCLC) improves, brain metastases (BM) may become a greater problem. We analyzed our chemoradiation experience for patients at highest risk for the brain as the first failure site. Records for 150 consecutive patients with stage II/III NSCLC treated definitively with chemoradiation from June 1992 to June 1998 at the University of Pennsylvania were reviewed. Most patients (89%) received cisplatin, paclitaxel, or both. All had negative brain imaging before treatment. Posttreatment brain imaging was performed for suspicious symptoms. Incidence of BM was examined as a function of age, sex, histology, stage, performance status, weight loss, tumor location, surgery, radiation dose, initial radiation field, chemotherapy regimen, and chemotherapy timing. Crude and 2-year actuarial rates of BM were 19% and 30%, respectively. Among pretreatment parameters, stage IIIB was associated with a higher risk of BM (P <.04) versus stage II/IIIA. Histology alone was not significant (P <.12), although patients with IIIB nonsquamous tumors had an exceptionally high 2-year BM rate of 42% (P <.01 v all others). Examining treatment-related parameters, crude and 2-year actuarial risk of BM were 27% and 39%, respectively, in patients receiving chemotherapy before radiotherapy and 15% and 20%, respectively, when radiotherapy was not delayed (P <.05). On multivariate analysis, timing of chemotherapy (P <.01) and stage IIIA versus IIIB (P <.01) remained significant. Patients with later stage, nonsquamous NSCLC, particularly those receiving induction chemotherapy, have sufficiently common BM rates to justify future trials including prophylactic cranial irradiation.


Parasites pitched against nature: Pitch Lake water protects guppies (Poecilia reticulata) from microbial and gyrodactylid infections.
SUMMARY The enemy release hypothesis proposes that in parasite depleted habitats, populations will experience relaxed selection and become more susceptible (or less tolerant) to pathogenic infections. Here, we focus on a population of guppies (Poecilia reticulata) that are found in an extreme environment (the Pitch Lake, Trinidad) and examine whether this habitat represents a refuge from parasites. We investigated the efficacy of pitch in preventing microbial infections in Pitch Lake guppies, by exposing them to dechlorinated water, and reducing gyrodactylid infections on non-Pitch Lake guppies by transferring them to Pitch Lake water. We show that (i) natural prevalence of ectoparasites in the Pitch Lake is low compared to reference populations, (ii) Pitch Lake guppies transferred into aquarium water develop microbial infections, and (iii) experimentally infected guppies are cured of their gyrodactylid infections both by natural Pitch Lake water and by dechlorinated water containing solid pitch. These results indicate a role for Pitch Lake water in the defence of guppies from their parasites and suggest that Pitch Lake guppies might have undergone enemy release in this extreme environment. The Pitch Lake provides an ideal ecosystem for studies on immune gene evolution in the absence of parasites and long-term evolutionary implications of hydrocarbon pollution for vertebrates.


A community hospital experience with total parathyroidectomy and autotransplantation for renal hyperparathyroidism.
This study was undertaken to determine the success of surgical treatment of advanced secondary (renal) hyperparathyroidism. From 1978 to 1985, total parathyroidectomy and autotransplantation (TPA) were performed for secondary hyperparathyroidism in 23 patients who had had dialysis for a mean of 6.5 years preoperatively. Indications for surgery included hypercalcemia, bone pain and pathologic fractures, metastatic calcification, and pruritus. Four glands were found and removed in all patients; 100-150 mg of diced tissue were autotransplanted to one forearm. Two patients died of myocardial infarction in the first postoperative week. Bone pain, present in 19 of 23 patients, was relieved almost immediately postoperatively and relief was sustained to death (of unrelated causes) or most recent follow-up in 13 patients. All fractures healed. All patients had markedly elevated serum parathormone (PTH) preoperatively and 14 of 23 were hypercalcemic. The group mean values of serum calcium, alkaline phosphatase, and PTH all fell to and remained in a normal range by 1 year postoperatively in that subset of patients who did not suffer recurrence. Six patients were reoperated on after 12 to 37 months with partial graft excision for recurrent bone pain and hypercalcemia. Bone pain in two of these patients was due to aluminum-associated bone disease and the diagnosis of recurrent secondary hyperparathyroidism was erroneous. The actual recurrence rate was thus 19 per cent. Consistent technical success, with no late hypocalcemia, was achieved and most patients were restored to medical manageability.(ABSTRACT TRUNCATED AT 250 WORDS)


The prognostic value of various biomarkers in adults with pulmonary hypertension; a multi-biomarker approach.
This study aimed to investigate the prognostic value of six different biomarkers in patients with pulmonary hypertension (PH) and to explore whether a multi-biomarker approach can contribute to a better risk stratification. In this prospective study, patients with PH were included at the day of the diagnostic right heart catheterization between May 2012 and October 2016. Venous blood sampling included; NT-proBNP, high sensitive troponin-T, high sensitive CRP, galectin-3, red blood cell distribution width and eGFR. Associations between biomarker levels and the primary endpoint (death or lung transplantation) and secondary endpoint (death, lung transplantation or heart failure) were assessed with Cox regression, adjusted for age and sex. Additionally, adjustment for the REVEAL risk score was performed. In total, 106 patients were included (median age 58.7 [IQR 47.0-69.2] years, 64% women, 51% pulmonary arterial hypertension). After a median follow-up duration of 23.9 [IQR 15.1-40.0] months, respectively 29 and 37 patients reached the primary and secondary endpoint. All six biomarkers, except eGFR, were significantly associated with the endpoints. A multi-biomarker approach including the number of elevated biomarkers per patient, demonstrated that patients were at higher risk of adverse events as more biomarker levels were elevated (HR for each extra elevated biomarker; 1.33, 95% CI 1.07-1.64, P = .01). However, a single as well as a combination of multiple biomarkers, did not yield prognostic value independent of the REVEAL risk score. Various biomarkers are associated with the event-free survival in adults with PH. However, risk stratification exclusively based on single or a combination of biomarkers seems not superior to existing risk scores.


The closely related Drosophila sry beta and sry delta zinc finger proteins show differential embryonic expression and distinct patterns of binding sites on polytene chromosomes.
Serendipity (sry) beta (beta) and delta (delta) are two finger protein genes resulting from a duplication event. Comparison of their respective protein products shows interspersed blocks of conserved and divergent amino-acid sequences. The most extensively conserved region corresponds to the predicted DNA-binding domain which includes 6 contiguous fingers; no significant sequence conservation is found upstream and downstream of the protein-coding region. We have analysed the evolutionary divergence of the sry beta and delta proteins on two separate levels, their embryonic pattern of expression and their DNA-binding properties in vitro and in vivo. By using specific antibodies and transformant lines containing beta-galactosidase fusion genes, we show that the sry beta and sry delta proteins are maternally inherited and present in embryonic nuclei at the onset of zygotic transcription, suggesting that they are transcription factors involved in this process. Zygotic synthesis of the sry beta protein starts during nuclear division cycles 12-13, prior to cellularisation of the blastoderm, while the zygotic sry delta protein is not detectable before germ band extension (stage 10 embryos). Contrary to sry delta, the zygotic sry beta protein constitutes only a minor fraction of the total embryonic protein. The sry beta and delta proteins made in E. coli bind to DNA, with partly overlapping specificities. Their in vivo patterns of binding to DNA, visualised by immunostaining polytene chromosomes, differ both in the number and position of their binding sites. Thus changes in expression pattern and DNA-binding specificity have contributed to the evolution of the sry beta and delta genes.


The Effects of β-Adrenergic Blockade on the Degrading Effects of Eye Movements on Negative Autobiographical Memories.
Eye movement desensitization and reprocessing (EMDR) is an effective treatment for posttraumatic stress disorder. During EMDR, patients make horizontal eye movements (EMs) while simultaneously recalling a traumatic memory, which renders the memory less vivid and emotional when it is later recalled again. Recalling highly emotional autobiographical memories enhances noradrenergic neurotransmission. Noradrenaline (NA) strengthens memory (re)consolidation. However, memories become less vivid after recall+EMs. Therefore, NA might either play no significant role or serve to strengthen memories that are degraded by EMs. The present study was designed to test the latter hypothesis. We predicted that blocking NA would abolish the memory degrading effects of EMs. Fifty-six healthy participants selected three negative autobiographical memories. One was then recalled while making EMs, one was recalled without EMs, and one was not recalled. Vividness and emotionality of the memories as well as heart rate and skin conductance level during memory retrieval were measured before, directly after, and 24 hours after the EM task. Before the task, participants received a placebo or the noradrenergic β-receptor blocker propranolol (40 mg). There were no effects of EMs on memory emotionality or psychophysiological measures in the propranolol and placebo groups. However, in the placebo group, but not in the propranolol group, memory vividness significantly decreased from pretest to posttest and follow-up after recall+EMs relative to the control conditions. Blocking NA abolished the effects of EMs on the vividness of emotional memories, indicating that NA is crucial for EMDR effectiveness and possibly strengthens the reconsolidation of the degraded memory.


Exploring Evolutionary Relationships Across the Genome Using Topology Weighting.
We introduce the concept of topology weighting, a method for quantifying relationships between taxa that are not necessarily monophyletic, and visualizing how these relationships change across the genome. A given set of taxa can be related in a limited number of ways, but if each taxon is represented by multiple sequences, the number of possible topologies becomes very large. Topology weighting reduces this complexity by quantifying the contribution of each taxon topology to the full tree. We describe our method for topology weighting by iterative sampling of subtrees (Twisst), and test it on both simulated and real genomic data. Overall, we show that this is an informative and versatile approach, suitable for exploring relationships in almost any genomic dataset. Scripts to implement the method described are available at http://github.com/simonhmartin/twisst.