[MASK (Mobile Airways Sentinel networK) in Turkey-the ARIA integrated mobile solution for allergic rhinitis and asthma multimorbidity].
mHealth, such as apps running on consumer smart devices is becoming increasingly popular and has the potential to profoundly affect healthcare and health outcomes. Allergic Rhinitis and its impact on asthma (ARIA) has evolved from a guideline using the best evidence-based approach to care pathways suited to real-life using mobile technology in allergic rhinitis (AR) and asthma multimorbidity MASK-rhinitis (Mobile Airways Sentinel networK), the Phase 3 ARIA initiative, is based on the freely available app. The Allergy Diary is used by people who were informed by physicians, searched the internet, Apple App Store, Google Play. Turkish Validation has been available and currently in use.


COMT Val158Met polymorphism is associated with post-traumatic stress disorder and functional outcome following mild traumatic brain injury.
Mild traumatic brain injury (mTBI) results in variable clinical trajectories and outcomes. The source of variability remains unclear, but may involve genetic variations, such as single nucleotide polymorphisms (SNPs). A SNP in catechol-o-methyltransferase (COMT) is suggested to influence development of post-traumatic stress disorder (PTSD), but its role in TBI remains unclear. Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether the COMT Val158Met polymorphism is associated with PTSD and global functional outcome as measured by the PTSD Checklist - Civilian Version and Glasgow Outcome Scale Extended (GOSE), respectively. Results in 93 predominately Caucasian subjects with mTBI show that the COMT Met158 allele is associated with lower incidence of PTSD (univariate odds ratio (OR) of 0.25, 95% CI [0.09-0.69]) and higher GOSE scores (univariate OR 2.87, 95% CI [1.20-6.86]) 6-months following injury. The COMT Val158Met genotype and PTSD association persists after controlling for race (multivariable OR of 0.29, 95% CI [0.10-0.83]) and pre-existing psychiatric disorders/substance abuse (multivariable OR of 0.32, 95% CI [0.11-0.97]). PTSD emerged as a strong predictor of poorer outcome on GOSE (multivariable OR 0.09, 95% CI [0.03-0.26]), which persists after controlling for age, GCS, and race. When accounting for PTSD in multivariable analysis, the association of COMT genotype and GOSE did not remain significant (multivariable OR 1.73, 95% CI [0.69-4.35]). Whether COMT genotype indirectly influences global functional outcome through PTSD remains to be determined and larger studies in more diverse populations are needed to confirm these findings.


Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement.
A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment. Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force. We reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non-levothyroxine-based thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones. We concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine-liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes. Some examples of future research needs include the development of superior biomarkers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine levels (including effects of age and disease status, relationship with tissue concentrations, as well as potential therapeutic targeting), and long-term outcome clinical trials testing combination therapy or thyroid extracts (including subgroup effects). Additional research is also needed to develop thyroid hormone analogs with a favorable benefit to risk profile.


CT-X antigen expression in human breast cancer.
Cancer/testis (CT) genes are predominantly expressed in human germ line cells, but not somatic tissues, and frequently become activated in different cancer types. Several CT antigens have already proved to be useful biomarkers and are promising targets for therapeutic cancer vaccines. The aim of the present study was to investigate the expression of CT antigens in breast cancer. Using previously generated massively parallel signature sequencing (MPSS) data, together with 9 publicly available gene expression datasets, the expression pattern of CT antigens located on the X chromosome (CT-X) was interrogated. Whereas a minority of unselected breast cancers was found to contain CT-X transcripts, a significantly higher expression frequency was detected in estrogen and progesterone receptor (ER) negative breast cancer cell lines and primary breast carcinomas. A coordinated pattern of CT-X antigen expression was observed, with MAGEA and NY-ESO-1/CTAG1B being the most prevalent antigens. Immunohistochemical staining confirmed the correlation of CT-X antigen expression and ER negativity in breast tumors and demonstrated a trend for their coexpression with basal cell markers. Because of the limited therapeutic options for ER-negative breast cancers, vaccines based on CT-X antigens might prove to be useful.


The incidence and aetiology of stroke in the Caerphilly and Speedwell Collaborative Studies I: methods and incidence of events.
Stroke mortality and morbidity remain high despite downward trends in incidence and case fatality. Population-based longitudinal studies which include collection of risk factor data are required for a better understanding of stroke aetiology. From a representative cohort of men from South Wales and South-west England, followed up for a median of 17 y, details of possible cerebrovascular events were collected from questionnaires, hospital admission data, general practitioner records, death certificates, radiology records and post-mortem reports. Radiology records, and strokes and transient ischaemic attacks were independently validated. There were 433 strokes and 163 transient ischaemic attacks identified during follow-up. Of these, 333 were the first ever in a lifetime strokes of which 139 were definite ischaemic, 20 were haemorrhagic and 168 were probable ischaemic strokes. The crude incidence rate for stroke was 445 (95% confidence interval 398-493) per 100 000 person years. The age-standardised rates for 10 y age-bands were: 45-54 y 91 (10-172); 55-64 y 351 (269-432) and 65-74 y 855 (669-1040). The 30 d case-fatality rate was 21.0% (70/333) for all strokes and 19.2% (60/312) for ischaemic strokes. For transient ischaemic attacks the age-standardised incidence rates for the same 10 y age bands were 92 (4-179), 111 (64-157), and 273 (167-80), respectively. These rates for stroke transient ischaemic attack are likely to be accurate given the high ascertainment of events in this representative population of middle-aged men. Such studies, reporting reliable measures of cerebrovascular events, are important for measuring burden of disease, and for analysis of risk factor associations to help improve understanding of stroke aetiology and inform preventive efforts.


Comparison between low cost USB nailfold capillaroscopy and videocapillaroscopy: a pilot study.
Universal serial bus (USB) microscopy (capillaroscopy) could provide all rheumatologists with an easy-to-use, low-cost tool to examine the nailfold capillaries to facilitate early diagnosis of SSc. The objectives of this pilot study were to examine the feasibility of acquiring and analysing images using USB microscopy and to compare results to videocapillaroscopy. Videocapillaroscopy and USB microscope images were obtained from the right and left ring fingers of 20 patients with SSc and 20 healthy control subjects. In addition to generating panoramic capillary mosaics from across the whole nailbed, custom software made fully automated measurements of vessel structure including capillary width and density. The area under the receiver operating characteristic curve (AZ) was used to measure separation between the SSc and healthy control groups. High quality images could be generated from the USB microscope, with reconstructed USB images comparing very favourably with those obtained using videocapillaroscopy. Using USB microscope images, the receiver operating characteristic curve AZ for group separation based on mean width was 0.81 (standard error 0.120) compared with 0.81 (standard error 0.095) for the (gold standard) videocapillaroscopy. The receiver operating characteristic curve AZ for group separation using capillary density was 0.48 (standard error 0.16) for USB microscope images, compared with 0.70 (standard error 0.10) for videocapillaroscopy. In this pilot study, USB capillaroscopy was able to discriminate between patients with SSc and controls as well as videocapillaroscopy on the basis of capillary width. This finding, together with the high-quality images obtained, highlights the potential of USB capillaroscopy as a low-cost, easily accessible clinical and research tool.


Prevalence, expenditures, utilization, and payment for persons with MS in insured populations.
To determine the prevalence, expenditures, and utilization of enrollees with MS relative to all enrollees in privately insured, Medicare, and Medicaid populations. The authors used insurer administrative billing data to identify persons with MS, their insured medical expenditures and utilization, and benchmark general insured population expenditures and utilization. Three samples of insurer billing data were analyzed: nationally representative samples for the privately insured (1994 through 1995) and Medicare (1996 though 1997) populations, and Medicaid data for disabled (1991 through 1996) populations from six states. Using 2 years of diagnoses on claims, the prevalence of MS in the privately insured population was 24 per 10,000, 36 per 10,000 in the Medicare population, and 71 per 10,000 in the Medicaid disabled population. Annual insured expenditures were $7,677 per privately insured enrollee with MS vs $2,394 for all privately insured enrollees, $13,048 per Medicare beneficiary with MS compared with $6,006 for all Medicare beneficiaries, and $7,352 per Medicaid disabled recipient with MS vs $4,088 per disabled recipient without MS. Home health expenditures were very high for Medicare beneficiaries with MS and nursing facility expenditures were very high for Medicaid disabled recipients with MS. A small proportion of enrollees with MS accounted for most expenditures. Insured enrollees with MS are two to three times more expensive than average insured enrollees. If the premiums that employers or governments pay health insurers and the capitation amounts that insurers pay health care providers do not account for these higher costs, a disincentive is created for the enrollment and care of persons with MS.


Cisplatin plus vinorelbine as first-line treatment for advanced non-small-cell lung cancer: Is a hemogram on day 8 essential?
One of the standard treatments for metastatic non-small-cell lung cancer patients is the combination of cisplatin plus vinorelbine. This regimen is associated with a high rate of severe neutropenia, and a hemogram is therefore routinely performed on day 8 before the administration of vinorelbine. However, no study has ever examined the rate of neutropenia detected in this hemogram or the rate of discontinuation of chemotherapy as a result. Since one of the objectives in the treatment of advanced lung cancer is to maintain quality of life, we have retrospectively analyzed a Spanish Lung Cancer Group study of cisplatin plus vinorelbine to address the question of whether this hemogram on day 8 could be avoided, thus eliminating unnecessary venipunctures without endangering patient safety. Between April 2004 and January 2006, 180 chemotherapy-naïve, advanced NSCLC patients were included from 35 centers. They received intravenous doses of cisplatin 75mg/m(2) on day 1 plus vinorelbine 25mg/m(2) on days 1 and 8, every 3 weeks, for a maximum of six cycles. Median age was 62.5 years; 87.2% were males; 80.6% were smokers; 48.2% were adenocarcinomas and 36% were squamous cell carcinomas; 17.2% were stage IIIB and 82.8% stage IV. Of 750 cycles analyzed, vinorelbine was administered on day 8 in 661 (88.1%), and the dose was reduced or canceled in 15 (2%) due to hematological toxicity. Among patients aged<70 with no dose modification in previous cycles, the likelihood of observing hematological toxicity at day 8 was only 0.8% (95% CI, 0.1-3%). We speculate that the hemogram on day 8 could potentially be avoided in this subgroup of patients while still maintaining an acceptable safety margin. Prospective clinical studies to further examine this hypothesis are warranted.


Attenuation of osteoclastogenesis and osteoclast function by apigenin.
The physiological effects of the flavone, apigenin on bone cells were studied. We first show that apigenin inhibits tumor necrosis factor alpha (TNFalpha)- and interferon gamma (IFNgamma)-induced secretion of several osteoclastogenic cytokines from MC3T3-E1 mouse calvarial osteoblast cell line. Ligands of the TNF receptor family constitute the most potent osteoclastic cytokines. In MC3T3-E1 cells, apigenin dose-dependently (from 5 to 20 microM) inhibits TNFalpha-induced production of the osteoclastogenic cytokines, IL-6 (interleukin-6), RANTES (regulated upon activation, normal T cell-expressed and -secreted), monocyte chemoattractant protein-1 (MCP-1) and MCP-3. In addition, apigenin inhibits IFNgamma-stimulated secretion of monokines, CXCL-9, and -10 in MC3T3-E1 cells. Next, we show that apigenin strongly inhibits differentiation of 3T3-L1 preadipocytes to adipocytes with attendant inhibition of adipocyte differentiation-induced IL-6, MCP-1, and leptin production. Inhibition of adipogenic differentiation by apigenin could be due to induction of osteogensis as it robustly upregulates mRNA levels of bone morphogenetic protein-6 (BMP-6). Finally, the presence of apigenin inhibited osteoclast differentiation from the RAW 264.7 cell line by reducing receptor activator of nuclear factor kappa ligand (RANKL)-induced expression of tartrate-resistant acid phosphatase (TRAP), RANK, and calcitonin receptor but not CCR1, resulting in the inhibition of multinucleated osteoclast formation. Similarly, apigenin inhibited expression of the osteoclast differentiation markers TRAP, RANK, and c-Fms in osteoclast precursor cells obtained from mouse bone marrow following treatment with RANKL and macrophage colony stimulating factor (MCSF). Furthermore, apigenin induced apoptosis of mature osteoclasts obtained from rabbit long bone and inhibited bone resorption. In all instances, a structurally related compound, flavone had no significant effect. These data suggest that apigenin has multiple effects on all three bone cells that could prevent bone loss in vivo.


Improved digital holographic reconstruction algorithm for depth error reduction and elimination of out-of-focus particles.
The digital holography has immense potential related to many applications of science and engineering. It has many advantages compared to conventional holography i.e. characterization of online dynamic phenomena and imaging in small scale microscopic systems. However, its primary limitation is the size of sensors and number of sensors compared to the conventional holographic plate. The critical issue of digital holography is the numerical reconstruction procedure. The present study proposes a new reconstruction algorithm known as 'Within Depth Intensity Averaging (WDIA)'. The effectiveness of the WDIA algorithm is demonstrated using both experiment and simulation for single particle, 2D and 3D distribution of particles. The 3D distribution of particles is experimentally simulated by using gelatin film on the glass slide. The particle images from digital holography compare well with that of microscopic images demonstrating the success of the proposed algorithm compared to the existing reconstruction procedure. The depth error significantly reduces (maximum 100%) and particles of any size can be characterized by the WDIA reconstruction algorithm contrary to the existing reconstruction algorithm available in literature. The effect of particle number density, particle size and sample volume depth on reconstruction effectiveness using the WDIA algorithm has been investigated and compared with the literature demonstrating its superiority in performance.


Contractile mechanisms of action of gastroprokinetic agents: cisapride, metoclopramide, and domperidone.
We investigated the contractile mechanisms of action of three putative gastroprokinetic agents (cisapride, metoclopramide, and domperidone) on the linear phase of gastroduodenal emptying of solid meals in six healthy conscious dogs. The spatial and temporal parameters of gastric, pyloric, and duodenal contractions during the entire period of gastroduodenal emptying, during the 60-min period of drug infusion (ti), and during the postdrug infusion period (tpi) were analyzed by a computer method. Cisapride accelerated the total gastroduodenal emptying time (tfull), metoclopramide had no significant effect, and domperidone delayed the tfull. None of the drugs had a significant effect on gastroduodenal emptying during ti. Both cisapride and metoclopramide enhanced the rate of gastroduodenal emptying during tpi. Cisapride enhanced pyloric and duodenal motor activity but had no significant effect on antropyloroduodenal coordination during tfull and ti. During tpi, cisapride significantly enhanced both the pyloric and duodenal motor activity and antropyloroduodenal coordination. Metoclopramide exhibited only a few significant effects on the frequency, amplitude, duration, and area under contractions in the antrum, pylorus, and duodenum, but it enhanced antropyloroduodenal coordination during tfull and tpi. Domperidone decreased the frequency of corporeal, pyloric, and duodenal contractions and deteriorated antropyloroduodenal coordination by decreasing the frequency of contractions propagating from the antrum or the pylorus to the duodenum. Cisapride and metoclopramide, but not domperidone, increased the mean distance of propagation of duodenal contractions during tfull, ti, and tpi. We conclude that cisapride is more effective in accelerating gastroduodenal emptying because it stimulates the largest number of parameters of gastropyloroduodenal contractions that enhance gastric emptying. Most enhancement of gastric emptying rate with both cisapride and metoclopramide occurs during tpi.


Clinical- and cost-effectiveness of the STAR care pathway compared to usual care for patients with chronic pain after total knee replacement: study protocol for a UK randomised controlled trial.
Approximately 20% of patients experience chronic pain after total knee replacement. There is little evidence for effective interventions for the management of this pain, and current healthcare provision is patchy and inconsistent. Given the complexity of this condition, multimodal and individualised interventions matched to pain characteristics are needed. We have undertaken a comprehensive programme of work to develop a care pathway for patients with chronic pain after total knee replacement. This protocol describes the design of a randomised controlled trial to evaluate the clinical- and cost-effectiveness of a complex intervention care pathway compared with usual care. This is a pragmatic two-armed, open, multi-centred randomised controlled trial conducted within secondary care in the UK. Patients will be screened at 2 months after total knee replacement and 381 patients with chronic pain at 3 months postoperatively will be recruited. Recruitment processes will be optimised through qualitative research during a 6-month internal pilot phase. Patients are randomised using a 2:1 intervention:control allocation ratio. All participants receive usual care as provided by their hospital. The intervention comprises an assessment clinic appointment at 3 months postoperatively with an Extended Scope Practitioner and up to six telephone follow-up calls over 12 months. In the assessment clinic, a standardised protocol is followed to identify potential underlying causes for the chronic pain and enable appropriate onward referrals to existing services for targeted and individualised treatment. Outcomes are assessed by questionnaires at 6 and 12 months after randomisation. The co-primary outcomes are pain severity and pain interference assessed using the Brief Pain Inventory at 12 months after randomisation. Secondary outcomes relate to resource use, function, neuropathic pain, mental well-being, use of pain medications, satisfaction with pain relief, pain frequency, capability, health-related quality of life and bodily pain. After trial completion, up to 30 patients in the intervention group will be interviewed about their experiences of the care pathway. If shown to be clinically and cost-effective, this care pathway intervention could improve the management of chronic pain after total knee replacement. ISRCTN registry ( ISRCTN92545361 ), prospectively registered on 30 August 2016.


Functional anatomy of obsessive-compulsive phenomena.
Regional cerebral blood flow was measured with H2 15O positron emission tomography in four patients with obsessive-compulsive disorder. Patients were scanned on 12 occasions in the same session, with each scan paired with brief exposure to one of a hierarchy of contaminants that elicited increasingly intense urges to ritualise. The relationship between symptom intensity and regional cerebral blood flow (rCBF; an index of neural activity) was subsequently examined in the group and in individual patients. The group showed significant positive correlations between symptom intensity and blood flow in the right inferior frontal gyrus, caudate nucleus, putamen, globus pallidus and thalamus, and the left hippocampus and posterior cingulate gyrus. Negative correlations were evident in the right superior prefrontal cortex, and the temporoparietal junction, particularly on the right side. The pattern in single subjects was broadly similar, although individual differences in neural response were also observed. A graded relationship between symptom intensity and regional brain activity can thus be identified in obsessive-compulsive disorder. It is hypothesised that the increases in rCBF in the orbitofrontal cortex, neostriatum, global pallidus and thalamus were related to urges to perform compulsive movements, while those in the hippocampus and posterior cingulate cortex corresponded to the anxiety that accompanied them.


RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis.
Myeloproliferative neoplasms (MPNs) frequently have an activating mutation in the gene encoding Janus kinase 2 (JAK2). Thus, targeting the pathway mediated by JAK and its downstream substrate, signal transducer and activator of transcription (STAT), may yield clinical benefit for patients with MPNs containing the JAK2(V617F) mutation. Although JAK inhibitor therapy reduces splenomegaly and improves systemic symptoms in patients, this treatment does not appreciably reduce the number of neoplastic cells. To identify potential mechanisms underlying this inherent resistance phenomenon, we performed pathway-centric, gain-of-function screens in JAK2(V617F) hematopoietic cells and found that the activation of the guanosine triphosphatase (GTPase) RAS or its effector pathways [mediated by the kinases AKT and ERK (extracellular signal-regulated kinase)] renders cells insensitive to JAK inhibition. Resistant MPN cells became sensitized to JAK inhibitors when also exposed to inhibitors of the AKT or ERK pathways. Mechanistically, in JAK2(V617F) cells, a JAK2-mediated inactivating phosphorylation of the proapoptotic protein BAD [B cell lymphoma 2 (BCL-2)-associated death promoter] promoted cell survival. In sensitive cells, exposure to a JAK inhibitor resulted in dephosphorylation of BAD, enabling BAD to bind and sequester the prosurvival protein BCL-XL (BCL-2-like 1), thereby triggering apoptosis. In resistant cells, RAS effector pathways maintained BAD phosphorylation in the presence of JAK inhibitors, yielding a specific dependence on BCL-XL for survival. In patients with MPNs, activating mutations in RAS co-occur with the JAK2(V617F) mutation in the malignant cells, suggesting that RAS effector pathways likely play an important role in clinically observed resistance.


Impact of moral injury on the lives of UK military veterans: a pilot study.
Research suggests that moral injury (MI) in US veterans is associated with poor psychological outcomes and disruption in functioning. However, little is known about how MI may impact UK Armed Forces (AF) veterans. This study aimed to explore the impact of MI on veteran psychological well-being and functioning. Six veterans identified as having had exposure to MI and four clinicians who treated veterans with MI were recruited from a UK charitable organisation which provides psychological care for veterans. Data were analysed using thematic analysis. MI was perceived to cause substantial psychological distress in this sample. Our data suggest that some veterans held extremely negative self-appraisals which appeared to contribute towards and maintain their distress. Issues relating to spirituality following MI were thought to be infrequent; however, a loss of faith was perceived by clinicians to be more common in morally injured veterans than heightened spiritual/religious views. Several difficulties relating to employment were described, including increased trouble coping with occupational stress and authority figures. Interpersonal difficulties were frequently reported, with withdrawal from others often leading to relationship breakdown with spouses and children. This study provides some of the first evidence of the impact of MI on UK AF veterans' psychological, spiritual, social and day-to-day functioning all of which would pose challenges to clinicians aiming to manage such difficulties. These findings highlight several gaps in existing care provision for morally injured veterans, including addressing issues related to spirituality, employment and family functioning, which could ultimately improve veteran well-being.


Characterization of the multiple-copy host-selective toxin gene, ToxB, in pathogenic and nonpathogenic isolates of Pyrenophora tritici-repentis.
ToxB, a gene that encodes a 6.6-kDa host-selective toxin (HST), is present in several races of the wheat pathogen Pyrenophora tritici-repentis. To learn more about the multiple ToxB open reading frames (ORFs), six of the estimated nine copies from a race 5 isolate were cloned and analyzed. All six copies of ToxB have identical 261-bp ORFs and thus encode the same form of Ptr ToxB. Sequence analysis of regions flanking the cloned ToxB loci revealed that the majority of loci are associated with portions of retrotransposons and a transposon-like sequence. Data indicate that ToxB loci reside on two chromosomes, 3.5 and 2.7 Mb, with the majority of copies located on the 2.7 Mb chromosome. A related gene, referred to as toxb, from a nonpathogenic race 4 isolate was also cloned and characterized. This is interesting because, until now, HST genes have only been found in toxin-producing, pathogenic isolates of plant pathogenic fungi. The toxb gene from nonpathogenic isolates is 86% similar to ToxB, and data suggest that toxb is a single-copy gene. No toxb transcript was detected under culture conditions that favor the expression of ToxB; therefore, these genes differ in their transcriptional regulation.


The quartet theory of human emotions: An integrative and neurofunctional model.
Despite an explosion of research in the affective sciences during the last few decades, interdisciplinary theories of human emotions are lacking. Here we present a neurobiological theory of emotions that includes emotions which are uniquely human (such as complex moral emotions), considers the role of language for emotions, advances the understanding of neural correlates of attachment-related emotions, and integrates emotion theories from different disciplines. We propose that four classes of emotions originate from four neuroanatomically distinct cerebral systems. These emotional core systems constitute a quartet of affect systems: the brainstem-, diencephalon-, hippocampus-, and orbitofrontal-centred affect systems. The affect systems were increasingly differentiated during the course of evolution, and each of these systems generates a specific class of affects (e.g., ascending activation, pain/pleasure, attachment-related affects, and moral affects). The affect systems interact with each other, and activity of the affect systems has effects on - and interacts with - biological systems denoted here as emotional effector systems. These effector systems include motor systems (which produce actions, action tendencies, and motoric expression of emotion), peripheral physiological arousal, as well as attentional and memory systems. Activity of affect systems and effector systems is synthesized into an emotion percept (pre-verbal subjective feeling), which can be transformed (or reconfigured) into a symbolic code such as language. Moreover, conscious cognitive appraisal (involving rational thought, logic, and usually language) can regulate, modulate, and partly initiate, activity of affect systems and effector systems. Our emotion theory integrates psychological, neurobiological, sociological, anthropological, and psycholinguistic perspectives on emotions in an interdisciplinary manner, aiming to advance the understanding of human emotions and their neural correlates.


Perceived prevalence and risks for human papillomavirus (HPV) infection among women who have sex with women.
Previous research shows that perceptions of disease prevalence, particularly infectious diseases, are also related to health behaviors, but the association between perceived disease prevalence and risk perceptions is unknown. We chose to survey women who have sex with women (WSW) because they are an understudied population who are at risk for human papillomavirus (HPV). Prevalence rate of HPV infection among WSW is around 13%. We sought to test the relationship between having had an abnormal Pap smear and perceived risk for HPV. Perceived prevalence was also hypothesized as being a mediator and moderator of the relationship between abnormal Pap smear and perceived risk of HPV. Participants were approached at a gay pride festival and asked if they would like to complete a survey concerning same-sex relationships. Regression analyses, including moderation and mediation testing, were used to examine women who have and have not had an abnormal Pap smear. Participants (n = 275) completed anonymous surveys. Eighty-four (27%) women had a history of abnormal Pap smears, and 16 (5%) women had been diagnosed with HPV. Women with a history of abnormal Pap smears perceived themselves at greater risk for and greater prevalence of HPV. The association between history of abnormal Pap smears and risk perceptions was mediated by perceived disease prevalence. The association between perceived disease prevalence and perceived risk was significant only among women with a history of abnormal Pap smears. Perceived local disease prevalence is important for understanding risk perceptions in relation to health behaviors and health outcomes. Interventions can use local disease prevalence as a means for motivating behavior change.


Defining the economic scope for ecosystem-based fishery management.
The emergence of ecosystem-based fisheries management (EBFM) has broadened the policy scope of fisheries management by accounting for the biological and ecological connectivity of fisheries. Less attention, however, has been given to the economic connectivity of fisheries. If fishers consider multiple fisheries when deciding where, when, and how much to fish, then management changes in one fishery can generate spillover impacts in other fisheries. Catch-share programs are a popular fisheries management framework that may be particularly prone to generating spillovers given that they typically change fishers' incentives and their subsequent actions. We use data from Alaska fisheries to examine spillovers from each of the main catch-share programs in Alaska. We evaluate changes in participation-a traditional indicator in fisheries economics-in both the catch-share and non-catch-share fisheries. Using network analysis, we also investigate whether catch-share programs change the economic connectivity of fisheries, which can have implications for the socioeconomic resilience and robustness of the ecosystem, and empirically identify the set of fisheries impacted by each Alaska catch-share program. We find that cross-fishery participation spillovers and changes in economic connectivity coincide with some, but not all, catch-share programs. Our findings suggest that economic connectivity and the potential for cross-fishery spillovers deserve serious consideration, especially when designing and evaluating EBFM policies.


Unrealistic fatalism in U.S. youth ages 14 to 22: prevalence and characteristics.
To estimate the proportion of U.S. youth that exhibits unrealistic fatalism about its future (not expecting to live past age 30), and to test predictions about risk factors for this expectation. Four waves of a nationally representative telephone survey from 2002 to 2005 with youth ages 14 to 22 (N = 4201) were analyzed using logistic regression to identify correlates and predictors of unrealistic fatalism. Approximately 1 out of every 15 youth interviewed (6.7%, 95% confidence interval [CI] = 5.9%, 7.5%) responded that they agreed they would not live much past the age of 30. Compared to other youth, fatalists were significantly more likely to be older, male, to identify as Hispanic, and have completed the interview in Spanish. As predicted, recent experience of hopelessness was a strong predictor of fatalism. In addition, nonwhite youth who had experienced hopelessness reported increasing rates of fatalism as they aged. Fatalistic youth engaged in greater suicidal planning, had more accepting attitudes toward suicide, were less attached to religion, and were more impulsive than other youth. Approximately 43% of fatalists forecast a likely death by suicide, whereas the rest anticipated death by an outside source. Fatalists were also more likely not to stay in school. Because youth exhibiting fatalism are at risk for not staying in school and suicidal planning, they should be identified at an early age for referral to programs that are effective in treating youth with hopelessness and suicidal tendencies.


[Irradiation of lymph nodes areas in breast cancer].
Postoperative radiotherapy after breast surgery increases overall survival by decreasing the local relapse rate. The main site of relapse is the breast or the chest wall. The value of irradiation of the nodal basins is still discussed. It must be emphasized that nodal areas were systematically irradiated in the postmastectomy randomized trials demonstrating a benefit in survival for adjuvant radiotherapy. Axillary relapses are infrequent in case of complete axillary dissection; complementary irradiation could be proposed if the axillary dissection is incomplete or if there is a massive pathologic involvement of the axilla. Its main complication is lymphoedema, which remains the most frequent sequellae of the treatment of breast cancer. Supraclavicular irradiation is logical in case of axillary involvement. Internal mammary nodes are involved in 20 to 40% of the patients, depending of the axillary involvement and location of the tumor inside the breast. Irradiation of the internal mammary basin is difficult: optimal dosimetry required a CT-based simulation. Its benefit remains to be proved. Internal mammary nodes irradiation probably increased cardiovascular mortality. Sophisticated techniques are needed to spare the heart from irradiation. Two large randomized trials (French group, European Organization for Research and Treatment of Cancer [EORTC]) are currently evaluating the possible benefit of internal mammary irradiation.


A sensing array of radically coupled genetic 'biopixels'.
Although there has been considerable progress in the development of engineering principles for synthetic biology, a substantial challenge is the construction of robust circuits in a noisy cellular environment. Such an environment leads to considerable intercellular variability in circuit behaviour, which can hinder functionality at the colony level. Here we engineer the synchronization of thousands of oscillating colony 'biopixels' over centimetre-length scales through the use of synergistic intercellular coupling involving quorum sensing within a colony and gas-phase redox signalling between colonies. We use this platform to construct a liquid crystal display (LCD)-like macroscopic clock that can be used to sense arsenic via modulation of the oscillatory period. Given the repertoire of sensing capabilities of bacteria such as Escherichia coli, the ability to coordinate their behaviour over large length scales sets the stage for the construction of low cost genetic biosensors that are capable of detecting heavy metals and pathogens in the field.


Revisiting a 'simple' fungal metabolic pathway reveals redundancy, complexity and diversity.
Next to d-glucose, the pentoses l-arabinose and d-xylose are the main monosaccharide components of plant cell wall polysaccharides and are therefore of major importance in biotechnological applications that use plant biomass as a substrate. Pentose catabolism is one of the best-studied pathways of primary metabolism of Aspergillus niger, and an initial outline of this pathway with individual enzymes covering each step of the pathway has been previously established. However, although growth on l-arabinose and/or d-xylose of most pentose catabolic pathway (PCP) single deletion mutants of A. niger has been shown to be negatively affected, it was not abolished, suggesting the involvement of additional enzymes. Detailed analysis of the single deletion mutants of the known A. niger PCP genes led to the identification of additional genes involved in the pathway. These results reveal a high level of complexity and redundancy in this pathway, emphasizing the need for a comprehensive understanding of metabolic pathways before entering metabolic engineering of such pathways for the generation of more efficient fungal cell factories.


Novel organophosphorus aminopyrimidines as unique structural DNA-targeting membrane active inhibitors towards drug-resistant methicillin-resistant Staphylococcus aureus.
A series of novel unique structural organophosphorus aminopyrimidines were developed as potential DNA-targeting membrane active inhibitors through an efficient one-pot procedure from aldehydes, phosphonate and aminopyrimidine. The biological assay revealed that some of the prepared compounds displayed antibacterial activities. In particular, imidazole derivative 2c exhibited more potent inhibitory activity against MRSA with an MIC value of 4 μg mL-1 in comparison with the clinical drugs chloromycin and norfloxacin. Experiments revealed that the active molecule 2c had the ability to rapidly kill the tested strains without obviously triggering the development of bacterial resistance, showed low toxicity to L929 cells and could disturb the cell membrane. The molecular docking study discovered that compound 2c could bind with DNA gyrase via hydrogen bonds and other weak interactions. Further exploration disclosed that the active molecule 2c could also effectively intercalate into MRSA DNA and form a steady 2c-DNA supramolecular complex, which might further block DNA replication to exert powerful antibacterial effects.


Expression of MUC2 epithelial mucin in breast carcinoma.
To examine the expression of the MUC2 epithelial mucin in breast carcinoma; to relate this to patient survival. Sections from 210 breast carcinomas were stained with the anti-MUC2 core protein monoclonal antibody, 4F1, using an immunoperoxidase technique. The proportion of tumour cells positively stained and the localisation and intensity of any staining were recorded. Expression of MUC2 was compared with histological type and grade, tumour size, presence of nodal metastases, presence of oestrogen receptors, and menopausal status. The prognostic value of MUC2 expression was examined using Kaplan-Meier survival analysis. MUC2 mucin was detected in 19% of cases of invasive carcinoma, in 11% of cases of carcinoma in situ, where present, but very rarely in adjacent normal breast epithelium. Presence of MUC2 was significantly associated with a shorter disease free interval (p < 0.05), although the observed difference in duration of overall survival was not significant. The MUC2 detected in breast carcinoma may be underglycosylated or staining may represent detection of the protein core before the completion of glycosylation. The virtual absence of 4F1 reactivity in normal breast epithelium suggests that, unlike the MUC1 mucin, the MUC2 mucin is not highly expressed by these cells. The mechanism by which expression of MUC2 affects the biology of breast tumours is unclear, although expression may be a reflection of general derepression of genes during tumour progression.


Fasting Intervention for Children With Unilateral Renal Tumors to Reduce Toxicity.
Childhood renal tumors account for around 6% of all childhood cancers and 90% of these cases are Wilms tumor. In Europe, the SIOP-RTSG approach is considered standard of care and has resulted in five-year survival rates of over 90%. Efforts to decrease toxicity are now being pursued. Short-term fasting (STF), a short but strong reduction in calorie-intake, is associated with improved fitness, enhanced coping with acute physical stress and a lower risk of age-associated diseases. STF temporarily reduces growth to boost resilience, maintenance, and defense-mechanisms, by which toxic side-effects of (oxidative) damage and inflammation are largely prevented. Renal surgery for Wilms tumor carries a risk of acute kidney injury (AKI) and pediatric patients that had an episode of AKI are at increased risk for developing chronic renal disease. STF could mitigate surgery-induced stress and could further improve outcomes. We aim to investigate the effect of STF on renal function recovery after renal tumor surgery by conducting a single-center, prospective, randomized, non-blinded, intervention study. Children diagnosed with a unilateral renal tumor and opting for curative treatment are eligible for inclusion. The main study objective is to investigate the potential decrease in occurrence of AKI due to STF. Secondary objectives include renal function recovery, child's wellbeing, physical functioning, and feasibility of and adherence to STF in children with cancer.


Fever, thrombocytopenia, and AKI-A profile of malaria, dengue, and leptospirosis with renal failure in a South Indian tertiary-care hospital.
In the tropics, the triad of fever, thrombocytopenia, and AKI portends a grim prognosis with high mortality and a severe strain on already-stretched resources. Malaria, dengue, and leptospirosis account for most cases. We undertook a review of cases to determine factors accounting for adverse prognosis. All patients presenting to the emergency room (ER) with a history of fever, thrombocytopenia, and renal failure were included in the study. Patients were followed until discharge or death, and end points looked at were 1-week and 30-day mortality, and renal function upon discharge. Parameters like liver function test (LFT), renal function, and platelet count upon discharge were also documented. A total of 43 patients was included in the study. Mean age was 42.5 years with 86% males. Mean APACHE and SOFA scores on admission were 23.89 and 15.42, respectively. Mean admission platelet counts were 41,000. Mean serum creatinine was 4.1, and bilirubin was 9.94. A platelet count of < 34,000, serum creatinine of > 4, albumin of > 2.3, SOFA score of > 20, and APACHE score of > 32.2 were significantly predictive of 1 week mortality. Need for mechanical ventilation, oliguria on admission, and need for dialysis all were highly predictive of 30-day mortality. In addition, a serum bicarbonate of < 12, INR of > 1.5, hemoglobin of < 9.5 were highly predictive of higher 30 day mortality. Overall, 1-week mortality was 16.3%, of which 48% was accounted for by patients with leptospirosis. Factors like low platelet count, oliguria, need for dialysis, high APACHE and SOFA scores on admission, need for mechanical ventilation, and low serum albumin portend a grave prognosis. There is need for randomized control trials (RCT) to further determine adverse prognostic factors in this subsect of patients.


Changing Patterns of Tobacco and Alcohol Co-Use by Gender in the United States, 1976-2010.
Smoking is a serious health concern both globally and in the U.S. Because drinking amplifies the negative health effects of smoking, the high association of these behaviors is an additional source of population morbidity. However, very little is known about trends in the co-use of smoking and drinking over time. To describe trends in tobacco use, alcohol use, and their co-use among U.S. youth, and to separate out trends in the association of smoking and drinking from trends in their marginal distributions. We use data on the smoking and drinking behaviors of 12th graders from 1976 to 2010 in the Monitoring the Future study to examine trends in smoking, drinking, and co-use separately by gender. In each year we estimate the degree of co-use attributable to tobacco and alcohol use probabilities as well as the association between tobacco and alcohol use. Although the prevalence of tobacco and alcohol co-use has declined over time, the association of the two has increased. This association accounts for an increasing proportion of the co-use of tobacco and alcohol. We conclude that co-users of tobacco and alcohol are an increasingly select subpopulation. This suggests that continued decreases in the contribution of substance use to population health and mortality may not continue apace.


MAPKAPK-2-mediated LIM-kinase activation is critical for VEGF-induced actin remodeling and cell migration.
Vascular endothelial growth factor-A (VEGF-A) induces actin reorganization and migration of endothelial cells through a p38 mitogen-activated protein kinase (MAPK) pathway. LIM-kinase 1 (LIMK1) induces actin remodeling by phosphorylating and inactivating cofilin, an actin-depolymerizing factor. In this study, we demonstrate that activation of LIMK1 by MAPKAPK-2 (MK2; a downstream kinase of p38 MAPK) represents a novel signaling pathway in VEGF-A-induced cell migration. VEGF-A induced LIMK1 activation and cofilin phosphorylation, and this was inhibited by the p38 MAPK inhibitor SB203580. Although p38 phosphorylated LIMK1 at Ser-310, it failed to activate LIMK1 directly; however, MK2 activated LIMK1 by phosphorylation at Ser-323. Expression of a Ser-323-non-phosphorylatable mutant of LIMK1 suppressed VEGF-A-induced stress fiber formation and cell migration; however, expression of a Ser-323-phosphorylation-mimic mutant enhanced these processes. Knockdown of MK2 by siRNA suppressed VEGF-A-induced LIMK1 activation, stress fiber formation, and cell migration. Expression of kinase-dead LIMK1 suppressed VEGF-A-induced tubule formation. These findings suggest that MK2-mediated LIMK1 phosphorylation/activation plays an essential role in VEGF-A-induced actin reorganization, migration, and tubule formation of endothelial cells.


Anxiolytic effect of saponins from Panax quinquefolium in mice.
The anxiolytic effect of the saponins from Aniliaeea Panax quinquefolium L. (PQS) was studied in male mice by using a number of experimental paradigms of anxiety and compared with that of the known anxiolytic compound diazepam. Use of the elevated plus-maze test revealed that PQS (50 mg/kg, p.o.) and diazepam (2.5 mg/kg, p.o.) increased the percentage of time and entries spent in open arms. In the light/dark test, PQS (50 and 100 mg/kg, p.o.) and diazepam (2.5 mg/kg, p.o.) prolonged the time spent in the light area. In the hole-board test, PQS (50 and 100 mg/kg, p.o.) and diazepam (2.5 mg/kg, p.o.) significantly increased both head-dip counts and head-dip duration. Both PQS (50 and 100 mg/kg, p.o.) and diazepam (2.5 mg/kg, p.o.) decreased the total fighting time in the isolation-induced aggressive test. Since PQS, in contrast to diazepam, had no effect on locomotion in these tests, its side-effect profile might be considered superior to the benzodiazepines. Thus, the present findings suggest that PQS might be a potential candidate for use as an anxiolytic drug.


1-[3-(4-Fluoro-phen-yl)-5-phenyl-4,5-dihydro-1H-pyrazol-1-yl]ethanone.
In the title compound, C(17)H(15)FN(2)O, the pyrazoline ring adopts a flattened envelope conformation. The dihedral angle between the fluoro-substituted benzene ring and the phenyl ring is 69.20 (5)°. In the crystal, a pair of C-H⋯O hydrogen bonds link neighbouring mol-ecules, forming an inversion dimer. The crystal structure is further consolidated by C-H⋯π inter-actions and by a π-π inter-action with a centroid-centroid distance of 3.7379 (6) Å.


Potent inhibition of mandelate racemase by a fluorinated substrate-product analogue with a novel binding mode.
Mandelate racemase (MR) from Pseudomonas putida catalyzes the Mg(2+)-dependent 1,1-proton transfer that interconverts the enantiomers of mandelate. Because trifluorolactate is also a substrate of MR, we anticipated that replacing the phenyl rings of the competitive, substrate-product analogue inhibitor benzilate (Ki = 0.7 mM) with trifluoromethyl groups might furnish an inhibitor. Surprisingly, the substrate-product analogue 3,3,3-trifluoro-2-hydroxy-2-(trifluoromethyl)propanoate (TFHTP) was a potent competitive inhibitor [Ki = 27 ± 4 μM; cf. Km = 1.2 mM for both (R)-mandelate and (R)-trifluorolactate]. To understand the origins of this high binding affinity, we determined the X-ray crystal structure of the MR-TFHTP complex to 1.68 Å resolution. Rather than chelating the active site Mg(2+) with its glycolate moiety, like other ground state analogues, TFHTP exhibited a novel binding mode with the two trifluoromethyl groups closely packed against the 20s loop and the carboxylate bridging the two active site Brønsted acid-base catalysts Lys 166 and His 297. Recognizing that positioning a carboxylate between the Brønsted acid-base catalysts could yield an inhibitor, we showed that tartronate was a competitive inhibitor of MR (Ki = 1.8 ± 0.1 mM). The X-ray crystal structure of the MR-tartronate complex (1.80 Å resolution) revealed that the glycolate moiety of tartronate chelated the Mg(2+) and that the carboxylate bridged Lys 166 and His 297. Models of tartronate in monomers A and B of the crystal structure mimicked the binding orientations of (S)-mandelate and that anticipated for (R)-mandelate, respectively. For the latter monomer, the 20s loop appeared to be disordered, as it also did in the X-ray structure of the MR triple mutant (C92S/C264S/K166C) complexed with benzilate, which was determined to 1.89 Å resolution. These observations indicate that the 20s loop likely undergoes a significant conformational change upon binding (R)-mandelate. In general, our observations suggest that inhibitors of other enolase superfamily enzymes may be designed to capitalize on the recognition of the active site Brønsted acid-base catalysts as binding determinants.


Binocular rivalry in children on the autism spectrum.
When different images are presented to the eyes, the brain is faced with ambiguity, causing perceptual bistability: visual perception continuously alternates between the monocular images, a phenomenon called binocular rivalry. Many models of rivalry suggest that its temporal dynamics depend on mutual inhibition among neurons representing competing images. These models predict that rivalry should be different in autism, which has been proposed to present an atypical ratio of excitation and inhibition [the E/I imbalance hypothesis; Rubenstein & Merzenich, 2003]. In line with this prediction, some recent studies have provided evidence for atypical binocular rivalry dynamics in autistic adults. In this study, we examined if these findings generalize to autistic children. We developed a child-friendly binocular rivalry paradigm, which included two types of stimuli, low- and high-complexity, and compared rivalry dynamics in groups of autistic and age- and intellectual ability-matched typical children. Unexpectedly, the two groups of children presented the same number of perceptual transitions and the same mean phase durations (times perceiving one of the two stimuli). Yet autistic children reported mixed percepts for a shorter proportion of time (a difference which was in the opposite direction to previous adult studies), while elevated autistic symptomatology was associated with shorter mixed perception periods. Rivalry in the two groups was affected similarly by stimulus type, and consistent with previous findings. Our results suggest that rivalry dynamics are differentially affected in adults and developing autistic children and could be accounted for by hierarchical models of binocular rivalry, including both inhibition and top-down influences. Autism Res 2017. ©2017 The Authors Autism Research published by Wiley Periodicals, Inc. on behalf of International Society for Autism Research Autism Res 2017, 10: 1096-1106. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.


Retinoic acid is a cofactor for translational regulation of vascular endothelial growth factor in human endometrial stromal cells.
Vascular endothelial growth factor (VEGF) and endometrial angiogenesis play a critical role in successful embryonic implantation. Despite many studies of the effects of estrogen and progesterone on VEGF expression, its focal regulation at the site of implantation is unknown. Retinoic acid (RA) has been reported to regulate VEGF in a variety of cell types. Because localized RA synthesis occurs within the periimplantation endometrium, we tested the possibility that RA regulates VEGF production in endometrial stromal cells. Using primary and telomerase-immortalized human endometrial stromal cells, we determined that RA alone did not alter constitutive levels of VEGF production, but markedly amplified secretion when the cells were cotreated with activators of VEGF gene transcription (12-O-tetradecanoyl phorbol-13-acetate, TPA; TGF-beta; and IL-1beta). Whereas TPA or TGF-beta alone stimulated VEGF promoter activity and up-regulated mRNA levels, significant protein secretion was detected only after RA was added to the culture systems. Analysis of retinoids in secretory phase endometrial biopsies indicated that endogenous RA accumulated at concentrations sufficient to induce VEGF secretion. Polyribosome profile analysis showed that the addition of RA to transcriptional activators of VEGF shifted the translational suppressed VEGF mRNA transcripts into larger polyribosome complexes engaged in active translation. Although the precise mechanism(s) of the RA effect remains to be defined, it appears to be mediated by reactive oxygen species; the antioxidant N-acetylcysteine inhibited RA+TPA-stimulated secretion of VEGF by more than 80%. Together, our results demonstrate that in human endometrial stromal cells, RA can combine with transcriptional activators of VEGF to augment VEGF secretion through a translational mechanism of action mediated by reactive oxygen species. These findings suggest a link between the spatiotemporal changes of retinoid synthesis in the periimplantation stroma and the capacity to quickly up-regulate focal VEGF secretion needed to induce early angiogenic events of pregnancy.


Hormone-specific inhibitory influence of alpha-subunit Asn56 oligosaccharide on in vitro subunit association and follicle-stimulating hormone receptor binding of equine gonadotropins.
Hybrid hormones were created using combinations of equine (e) LH, eFSH, and eCG alpha- and beta-subunit preparations. The efficiency of eFSH beta association was highest with eLH alpha (64-72%) and was lowest with eCG alpha (37-50%). Selective removal of alphaAsn56 oligosaccharide increased heterodimerization efficiency by 9-20% for eLH alpha, by 21-28% for eFSH alpha, and by 28-41% for eCG alpha. Both alpha and beta subunits contributed significantly to FSH receptor-binding activities of the hybrids. Purified hybrid hormone preparations consisting of either eFSH beta or eLH beta combined with eLH alpha, eFSH alpha, or eCG alpha were prepared. Equine FSH beta hybrids were more active in the FSH radioreceptor assay than eLH beta hybrids; within each beta-subunit group the eLH alpha hybrids were the most active, followed by eFSH alpha hybrids, while the least active were eCG alpha hybrids. A truncated, des(121-149) eLH beta derivative (eLH beta t) combined with native alpha-subunit preparations exhibited the same effect of alpha-subunit type on FSH receptor binding. Hybrids combining the eLH beta t derivative with Asn56-deglycosylated (N56dg-)eLH alpha, N56dg-eFSH alpha, and N56dg-eCG alpha preparations possessed 2.2- to 4.3-fold increased FSH receptor-binding activities as compared with the same hybrid preparations possessing the Asn56 carbohydrate. Granulosa cell bioassay of purified native eFSH beta and eLH beta hybrid hormones indicated no significant effect of the alpha-subunit carbohydrate differences on progesterone production. The alpha-subunit Asn56 oligosaccharide exerts a hormone-specific inhibitory influence on in vitro subunit reassociation and FSH receptor binding related to the size of its Man(alpha1-6)Man antenna.


The Endocrine Disruptor Bisphenol A (BPA) Exerts a Wide Range of Effects in Carcinogenesis and Response to Therapy.
Bisphenol A (BPA) is a synthetic plasticizer that is commonly used in the production of polycarbonate plastics and epoxy resins. Human exposure occurs when BPA migrates from food and beverage containers into the contents when heated or even under normal conditions of use. BPA exerts endocrine disruptor action due to its weak binding affinity for the estrogen receptors ERα and ERβ. BPA exerts other effects by activating the membrane receptor GPER (GPR30) and/or other receptors such as the estrogen-related receptors (ERRs). This review summarizes emerging data on BPA and cancer. These include data linking exposure to BPA with an increased risk of hormone-related cancers such as those of the ovary, breast, prostate, and even colon cancer. BPA can also induce resistance to various chemotherapeutics such as doxorubicin, cisplatin, and vinblastine in vitro. The development of chemoresistance to available therapeutics is an emerging significant aspect of BPA toxicity because it worsens the prognosis of many tumors. Recent findings support a causal role of BPA at low levels in the development of cancers and in dictating their response to cytotoxic therapy. Accurate knowledge and consideration of these issues would be highly beneficial to cancer prevention and management.


Etanercept and infliximab for the treatment of psoriatic arthritis: a systematic review and economic evaluation.
To evaluate the clinical effectiveness, safety, tolerability and cost-effectiveness of etanercept and infliximab for the treatment of active and progressive psoriatic arthritis (PsA) in patients who have inadequate response to standard treatment, including disease-modifying antirheumatic drug (DMARD) therapy. Electronic databases were searched up to July 2004. A systematic review evaluated the clinical efficacy and adverse effects of etanercept and infliximab. The efficacy of DMARDs in the treatment of PsA was also reviewed and treatments were compared using Bayesian evidence synthesis methods. Following evaluation of existing economic evaluations of etanercept and infliximab in PsA, a new economic model was developed (the York Model). This utilised the results from the evidence synthesis and data from a range of other sources. Across the two trials, at 12 weeks, around 65% of patients treated with etanercept achieved an American College of Rheumatology (ACR) 20 {pooled relative risk (RR) 4.19 [95% confidence interval (CI) 2.74 to 6.42]}, demonstrating a basic degree of efficacy in terms of arthritis-related symptoms. In addition, around 45% of patients treated with etanercept achieved an ACR 50 [pooled RR 10.84 (95% CI 4.47 to 26.28)] and around 12% achieved an ACR 70 [pooled RR 16.28 (95% CI 2.20 to 120.54)], demonstrating a good level of efficacy. The subgroup analyses conducted in one trial revealed that the effect of etanercept was not dependent upon patients' concomitant use of methotrexate. In addition, almost 85% of patients treated with etanercept achieved a Psoriatic Arthritis Response Criteria (PsARC) [pooled RR 2.60 (95% CI 1.96 to 3.45). The Psoriatic Area and Severity Index (PASI) results indicate some beneficial effect on psoriasis at 12 weeks; however, the data are sparse. The statistically significant reduction (improvement) in Health Assessment Questionnaire (HAQ) score with etanercept compared with placebo indicates a beneficial effect of etanercept on function. Similar results were seen at 24 weeks, except that the results for PASI 75 and PASI 50 now achieved statistical significance and data for Total Sharp Score annualised rate of progression were available; this was statistically significantly lower in etanercept-treated patients than in placebo-treated patients. Uncontrolled follow-up of patients indicates that treatment benefit may be maintained for at least 50 weeks. At 16 weeks, 65% of patients treated with infliximab achieved an ACR 20 [RR 6.80 (95% CI 2.89 to 16.01)], demonstrating a basic degree of efficacy in terms of arthritis-related symptoms. This level of efficacy was not dependent upon patients' concomitant use of methotrexate. Almost half the patients treated with infliximab achieved an ACR 50 [RR 49.00 (95% CI 3.06 to 785.06)] and over one-quarter achieved an ACR 70 [RR 31.00 (95% CI 1.90 to 504.86)] compared with none of the placebo group, demonstrating a good level of efficacy. In addition, 75% of patients treated with infliximab achieved a PsARC [RR 3.55 (95% CI 2.05 to 6.13)]. The beneficial treatment effect on psoriasis was also statistically significant with a mean difference in percentage change from baseline in PASI of -5 (95% CI -6.8 to -3.3), as was the percentage improvement from baseline in HAQ score with infliximab compared with placebo [mean difference 51.4 (95% CI 48.08 to 54.72)], indicating a beneficial effect of infliximab on functional status. Uncontrolled data from all measures of joint disease, psoriasis and HAQ collected up to 50 weeks of follow-up reflect those at 16 weeks. There were no radiographic assessments, so nothing can be determined about the potential or otherwise of infliximab to delay the progression of joint disease. Using the York cost-effectiveness model, infliximab was consistently dominated by etanercept because of its higher acquisition and administration costs without superior effectiveness. The incremental cost per quality-adjusted life-year (QALY) gained of etanercept compared with palliative care ranged from 14,818 pounds (females, 40-year time horizon) to 49,374 pounds (males, 1-year time horizon) if it is assumed that, when patients eventually fail on biological therapy, their disability (in terms of HAQ score) deteriorates by the same amount as it improved when they initially respond to treatment (rebound equal to gain). Results for etanercept ranged from 25,443 pounds (females, 40-year time horizon) to 49,441 pounds (males, 1-year time horizon) per QALY gained under the assumption that, when patients fail on therapy, their disability level returns to what it would have been had they never responded (rebound equal to natural history). The limited data available indicated that etanercept and infliximab are efficacious in the treatment of PsA with beneficial effects on both joint and psoriasis symptoms and on functional status. Short-term data indicated that etanercept can delay joint disease progression, but long-term data are needed. There are no controlled data as yet to indicate that infliximab can delay joint disease progression. Treatment with both etanercept and infliximab for 12 weeks demonstrated a significant degree of efficacy, with no statistically significant difference between them. For both drugs, adverse events were common with mild injection/infusion reactions being the main treatment-related effect. The York model indicated that etanercept is more cost-effective than infliximab as it has a lower cost with little difference in outcomes. The cost-effectiveness of etanercept is also sensitive to assumptions made about the extent of disease progression when patients are responding to therapy. The number of years for which a patient can be safely on biologicals is uncertain so these results should be considered with caution. Further research should include long-term controlled trials to confirm benefits, review adverse events and to explore further the implications of biologic therapy.


Development of monoclonal gammopathy precedes the development of Epstein-Barr virus-induced posttransplant lymphoproliferative disorder.
Epstein-Barr virus (EBV)-induced posttransplant lymphoproliferative disorder (PTLD) develops in 3% to 10% of solid organ transplant recipients with a resultant mortality of up to 70%. Unfortunately, there is no current marker which identifies patients who will develop this disease. We therefore conducted a risk factor analysis of variables that might predict the development of PTLD. Specifically, since EBV may cause both PTLD and the development of monoclonal proteins (M protein), we sought to determine if the development of an M protein preceded and therefore might serve as a predictive marker of subsequent PTLD. Before and after liver transplantation, 201 patients were evaluated for the presence of urine and serum M proteins. Patients were followed to monitor the development of PTLD for a mean of 1,733 days. PTLD developed in seven patients (3.5%), three (43%) of whom died from disseminated PTLD. PTLD was classified as polymorphous in six patients and monomorphous in one patient. Fifty-seven patients (28%) developed an M protein after transplantation: five of seven patients (71%) with PTLD and 52/194 (27%) of patients without PTLD. Multivariate risk factor analysis for the development of an M protein after transplantation identified cytomegalovirus (CMV) donor seropositivity (P = 0.0002) and postoperative symptomatic CMV infection (P = 0.019) as risk factors. Whereas EBV serostatus of either the donor or recipient was not found to be a risk factor for the occurrence of either an M protein or PTLD, the development of a serum immunoglobulin M (IgM) M protein (P = 0.04) and of any urine M protein (P = 0.01) was identified by univariate analysis as being associated with the development of PTLD. Further studies are needed to determine the predictive value of M proteins as a marker for PTLD. Until such time, the development of serum or urine M protein should heighten the suspicion of developing PTLD.


N-/C-terminal deleted mutant of human endostatin efficiently acts as an anti-angiogenic and anti-tumorigenic agent.
Non-collagenous (NC-1) fragments at the C-terminus of basement membrane collagen IV, XV and XIII have been implicated as negative regulators of angiogenesis. Endostatin is an endogenous carboxyl-terminal fragment of collagen XVIII/NC-1, suppressing endothelial cell proliferation, migration in vitro and tumor growth in mouse models. Endostatin can bind zinc through N- and C-terminal residues. Here we demonstrate that N-/C-terminal deleted derivative of human endostatin, H5, effectively inhibited the proliferation of human umbilical vein endothelial cells (HUVECs). Also, tube formation in vitro was comparably inhibited either by H5 or endostatin. The anti-angiogenic and anti-tumorigenic activities of H5 and endostatin were confirmed by an in vivo assay using chick chorioallantoic membrane (CAM) and mouse models, respectively. Treatment of 30 ng of H5 inhibited the capillary formation in CAM by 50%. In addition, H5 exhibited more potent anti-tumor activity than wild-type endostatin in in vivo mouse metastasis assay. These results indicate that the N-/C-terminal deletion mutant would be a strong candidate of anti-cancer agent against spontaneous tumor development and growth.


Biophysical studies of the membrane location of the voltage-gated sensors in the HsapBK and KvAP K(+) channels.
The membrane location of two fragments in two different K(+)-channels, the KvAP (from Aeropyrum pernix) and the HsapBK (human) corresponding to the putative "paddle" domains, has been investigated by CD, fluorescence and NMR spectroscopy. Both domains interact with q = 0.5 phospholipid bicelles, DHPC micelles and with POPC vesicles. CD spectra demonstrate that both peptides become largely helical in the presence of phospholipid bicelles. Fluorescence quenching studies using soluble acrylamide or lipid-attached doxyl-groups show that the arginine-rich domains are located within the bilayered region in phospholipid bicelles. Nuclear magnetic relaxation parameters, T(1) and (13)C-(1)H NOE, for DMPC in DMPC/DHPC bicelles and for DHPC in micelles showed that the lipid acyl chains in the bicelles become less flexible in the presence of either of the fragments. An even more pronounced effect is seen on the glycerol carbons. (2)H NMR spectra of magnetically aligned bicelles showed that the peptide derived from KvAP had no or little effect on bilayer order, while the peptide derived from HsapBK had the effect of lowering the order of the bilayer. The present study demonstrates that the fragments derived from the full-length proteins interact with the bilayered interior of model membranes, and that they affect both the local mobility and lipid order of model membrane systems.


The Charlie Gard Case, and the Ethics of Obstructing International Transfer of Seriously Ill Children.
In 2017, the court case over medical treatment of UK infant, Charlie Gard, reached global attention. In this article, I will analyze one of the more distinctive elements of the case. The UK courts concluded that treatment of Charlie Gard was not in his best interests and that it would be permissible to withdraw life-sustaining treatment. However, in addition, the court ruled that Charlie should not be transferred overseas for the treatment that his parents sought, even though specialists in Italy and the US were willing to provide that treatment. Is it ethical to prevent parents from pursuing life-prolonging treatment overseas for their children? If so, when is it ethical to do this? I will outline arguments in defense of obstructing transfer in some situations. I will argue, however, that this is only justified if there is good reason to think that the proposed treatment would cause harm.


Evaluation of the effects of Iranian propolis on the severity of post operational-induced peritoneal adhesion in rats.
Peritoneal adhesion is a major complication of surgery that can lead to serious problems such as bowel obstruction, pain, infertility and even mortality. Propolis is a honey bee product with anti-inflammatory and anti-oxidant activities that could potentially protect against adhesive surgical complications. Forty 8-weeks-old rats (275 ± 25 g) were divided into five groups: normal group without any surgical procedure, and experimental groups treated with normal saline, 50 mg/kg, 100 mg/kg and 200 mg/kg of propolis. Peritoneal adhesions were examined macroscopically and also, the levels of inflammatory factors (IL-6, IL-1β and TNF-α), growth factors (TGF-β1 and VEGF) were evaluated in the study groups using ELISA. Biochemical indices of oxidative status including Nitric Oxide (NO), Malondialdehyde (MDA) and Glutathione (GSH) were also measured. Peritoneal adhesion scores, IL-1β, IL-6, TNF-α, TGF-β1, VEGF, NO, GSH and MDA levels were significantly different between the study groups (p < 0.001). Propolis treatment reduced peritoneal adhesion (p < 0.001), TNF-α (p < 0.001), IL-1β (p < 0.001), IL-6 (p < 0.001), TGF-β1 (p < 0.001), VEGF (p < 0.001), NO (p < 0.001) and MDA (p < 0.001), while GSH levels were increased (p < 0.001) compared with the vehicle group. Our results showed that higher dose of propolis was associated with significantly greater reductions in peritoneal adhesion (p < 0.001), TNF-α (p < 0.001), IL-1β (p < 0.001), IL-6 (p < 0.001), VEGF (p < 0.001), NO (p < 0.001) and MDA (p < 0.001), a greater increase in GSH levels (p < 0.001) compared with the lower dose. Propolis treatment can dose-dependently reduce peritoneal adhesion through its anti-inflammatory, anti-angiogenic and antioxidant properties. Therefore, propolis might serve as a protective agent against post-surgical adhesive complications.


Moiré patterns between aperiodic layers: quantitative analysis and synthesis.
Moiré effects that occur in the superposition of aperiodic layers such as random dot screens are known as Glass patterns. Unlike classical moiré effects between periodic layers, which are periodically repeated throughout the superposition, a Glass pattern is concentrated around a certain point in the superposition, and farther away from this point it fades out and disappears. I show that Glass patterns between aperiodic layers can be analyzed by using an extension of the Fourier-based theory that governs the classical moiré patterns between periodic layers. Surprisingly, even spectral-domain considerations can be extended in a natural way to aperiodic cases, with some straightforward adaptations. These new results allow us to predict quantitatively the intensity profile of Glass patterns; furthermore, they open the way to the synthesis of Glass patterns that have any desired shapes and intensity profiles.


Improving outcomes for patients with chronic hepatitis B.
A focused meeting on hepatitis B virus (HBV) infection was held at the United States National Institutes of Health in Washington, DC, in April 2006. This meeting focused on new and historical data and served as a review for basic scientists and clinicians, as well as representatives from the pharmaceutical industry. Understanding HBV disease must include up-to-date information concerning virology, immunology, animal models, natural history, prevalence, and transmission risk, as well as an understanding of the evolving therapies for this life-threatening infection. Serious outcomes such as advanced fibrosis, cirrhosis, liver failure and hepatocellular carcinoma from hepatitis B infection appear to be closely tied to both historical and current serum levels of HBV DNA, and elevated serum levels of liver enzymes. Decreasing risk events and vaccinating susceptible individuals are key steps in managing this global scourge. New oral treatments for patients withchronic hepatitis B infection characterized by more potent antiviral effects, less toxicity, and minimal or no risk of resistance were reviewed and emphasized. Entecavir and pegylated interferons have recently been approved for treatment of chronic hepatitis B. Further expansion of our information about lamivudine and adefovir were highlighted. Several other new anti-HBV agents are also in phase II or III clinical trials or have been submitted for licensing including LdT (telbivudine). The NIH review meeting is summarized in this review and new and emerging areas of information are highlighted.


FXR-induced secretion of FGF15/19 inhibits CYP27 expression in cholangiocytes through p38 kinase pathway.
Cholangiocytes, bile duct lining cells, actively adjust the amount of cholesterol and bile acids in bile through expression of enzymes and channels involved in transportation and metabolism of the cholesterol and bile acids. Herein, we report molecular mechanisms regulating bile acid biosynthesis in cholangiocytes. Among the cytochrome p450 (Cyp) enzymes involved in bile acid biosynthesis, sterol 27-hydroxylase (Cyp27) that is the rate-limiting enzyme for the acidic pathway of bile acid biosynthesis expressed in cholangiocytes. Expression of other Cyp enzymes for the basic bile acid biosynthesis was hardly detected. The Cyp27 expression was negatively regulated by a hydrophobic bile acid through farnesoid X receptor (FXR), a nuclear receptor activated by bile acid ligands. Activated FXR exerted the negative effects by inducing an expression of fibroblast growth factor 15/19 (FGF15/19). Similar to its repressive function against cholesterol 7α-hydroxylase (Cyp7a1) expression in hepatocytes, secreted FGF15/19 triggered Cyp27 repression in cholangiocytes through interaction with its cognate receptor fibroblast growth factor receptor 4 (FGFR4). The involvements of FXR and FGFR4 for the bile acid-induced Cyp27 repression were confirmed in vivo using knockout mouse models. Different from the signaling in hepatocytes, wherein the FGF15/19-induced repression signaling is mediated by c-Jun N-terminal kinase (JNK), FGF15/19-induced Cyp27 repression in cholangiocytes was mediated by p38 kinase. Thus, the results collectively suggest that cholangiocytes may be able to actively regulate bile acid biosynthesis in cholangiocytes and even hepatocyte by secreting FGF15/19. We suggest the presence of cholangiocyte-mediated intrahepatic feedback loop in addition to the enterohepatic feedback loop against bile acid biosynthesis in the liver.


Pentanuclear Lanthanide Mono-organophosphates: Synthesis, Structure, and Magnetism.
Research on rare-earth phosphates has recently received substantial interest because of their unique physical and chemical properties. In recent years, because of their low solubility, research interest has been built on developing methodologies to prepare nanostructures and grow single crystals of inorganic rare-earth phosphates. The chemistry of rare-earth organophosphates, however, is still at a latent stage. Contrary to the traditional hydrothermal route, we report rare examples of discrete pentanuclear lanthanide(III) organophosphate clusters assembled from a sterically encumbered monoester of phosphoric acid under mild reaction conditions. Single-crystal X-ray analysis revealed that all of the compounds possess a similar core structure, [Ln5(μ3-OH)(dipp)6(NO3)x(CH3OH)y(H2O)z]2+ [Ln = Nd (1), Sm (2), Eu (3), Gd (4), Tb (5), Dy (6), Ho (7), Er (8), Tm (9); dipp = 2,6-diisopropylphenylphosphate], where the anionic charge balance is maintained by the presence of chelating nitrate anions (in the case of 9, x = 0), protonated tmeda, or dipp2- ligands. The vacant coordination sites on the metal ions are satisfied by coordinated methanol or water molecules. The core structure of these clusters is built on a [Ln3(μ3-OH)(dipp)6] triangle where the phosphate ligands bridge to two further Ln(III) ions. The complexes display lanthanide contraction along the series, with Ln(III) ions displaying different coordination environments/geometries as we move along the series. All of the compounds have been characterized by both analytical and spectroscopic techniques. Magnetic studies revealed the presence of weak antiferromagnetic exchange through the bridging μ3-hydroxo moiety and organophosphate groups for the {GdIII5} analogue, with a significant magnetic entropy change (25.8 J kg-1 K-1, ΔH = 7 T). The anisotropic complexes reveal an absence of slow relaxation of magnetization, except for Nd (1), Dy (6), and Er (8), which show slow relaxation in an applied DC field.


Quality assurance for nonradiographic radiotherapy localization and positioning systems: report of Task Group 147.
New technologies continue to be developed to improve the practice of radiation therapy. As several of these technologies have been implemented clinically, the Therapy Committee and the Quality Assurance and Outcomes Improvement Subcommittee of the American Association of Physicists in Medicine commissioned Task Group 147 to review the current nonradiographic technologies used for localization and tracking in radiotherapy. The specific charge of this task group was to make recommendations about the use of nonradiographic methods of localization, specifically; radiofrequency, infrared, laser, and video based patient localization and monitoring systems. The charge of this task group was to review the current use of these technologies and to write quality assurance guidelines for the use of these technologies in the clinical setting. Recommendations include testing of equipment for initial installation as well as ongoing quality assurance. As the equipment included in this task group continues to evolve, both in the type and sophistication of technology and in level of integration with treatment devices, some of the details of how one would conduct such testing will also continue to evolve. This task group, therefore, is focused on providing recommendations on the use of this equipment rather than on the equipment itself, and should be adaptable to each user's situation in helping develop a comprehensive quality assurance program.


Vascular endothelial growth factor-C and C-C chemokine receptor 7 in tumor cell-lymphatic cross-talk promote invasive phenotype.
Most carcinomas spread to distant sites through lymphatic vessels. Several preclinical and clinical studies have shown a positive correlation between the incidence of lymph node metastasis and secretion of the lymphatic growth factor vascular endothelial growth factor-C (VEGF-C) by tumor cells, suggesting tumor lymphangiogenesis as an escape mechanism. However, recent evidence has shown VEGF receptor-3 (VEGFR-3) expression on tumor cells and autocrine signaling, which increase metastatic potential. Furthermore, there is growing evidence implicating lymphatic-homing chemokine receptors, particularly C-C chemokine receptor 7 (CCR7), in lymph node metastasis. We report here that expressions of VEGF-C and CCR7 by tumor cells act synergistically to promote their invasion toward lymphatics. First, VEGF-C acts to increase lymphatic secretion of CCL21, which in turn drives CCR7-dependent tumor chemoinvasion toward lymphatics. Second, VEGF-C acts in an autocrine fashion to increase tumor invasiveness by increasing the proteolytic activity and motility of tumor cells in a three-dimensional matrix. Both of these effects are VEGFR-3 dependent and evident only in three-dimensional environments. We further verified that VEGF-C induces lymphatic CCL21 up-regulation in vivo by direct injection of VEGF-C protein intradermally in the mouse. Taken together, these results bridge the prometastatic functions of CCR7 and VEGF-C in tumors and show that, beyond lymphangiogenesis, VEGF-C promotes tumor invasion toward lymphatics by both autocrine and CCR7-dependent paracrine signaling mechanisms, which may be a significant cause of lymph node metastasis.


Cross cultural validation of the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) and the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS).
The available instruments for cognitive assessment in multiple sclerosis (MS) require considerable time and resources, and are not readily available in all countries. The study aimed to examine validity of the Czech translation of the Minimal Assessment of Cognitive Function in MS (MACFIMS), to validate the Brief International Cognitive Assessment for MS (BICAMS), and to compare their outcomes. We evaluated 367 MS patients and 134 healthy controls with the MACFIMS battery, which comprises the three tests of the BICAMS (Symbol Digit Modalities Test, Brief Visuospatial Memory Test-Revised, California Verbal Learning Test, second edition). The most accurate BICAMS criterion of cognitive deficit was that of at least one of the overall three tests outside the normal range (sensitivity = 94%, specificity = 86%, p = 10(-28)). Outcomes of the Czech translation of the MACFIMS were comparable to its original. The MACFIMS and the BICAMS identified cognitive deficit in 55% and 58% of the MS patients, respectively. Both batteries predicted patient self-reported vocational status. This is the first study to show that the BICAMS is highly sensitive and specific to cognitive impairment in MS as defined by the MACFIMS. This impairment is associated with vocational status. Czech versions of the studied batteries have now been validated.


A survey of the year 2006 literature on applications of isothermal titration calorimetry.
Isothermal titration calorimetry (ITC) is a fast and robust method to determine the energetics of association reactions in solution. The changes in enthalpy, entropy and heat capacity that accompany binding provide unique insights into the balance of forces driving association of molecular entities. ITC is used nowadays on a day-to-day basis in hundreds of laboratories. The method aids projects both in basic and practice-oriented research ranging from medicine and biochemistry to physical chemistry and material sciences. Not surprisingly, the range of studies utilizing ITC data is steadily expanding. In this review, we discuss selected results and ideas that have accumulated in the course of the year 2006, the focus being on biologically relevant systems. Theoretical developments, novel applications and studies that provide a deeper level of understanding of the energetic principles of biological function are primarily considered. Following the appearance of a new generation of titration calorimeters, recent papers provide instructive examples of the synergy between energetic and structural approaches in biomedical and biotechnological research.


Melanopsin: another way of signaling light.
A subset of melanopsin-expressing retinal ganglion cells has been identified to be directly photosensitive (pRGCs), modulating a range of behavioral and physiological responses to light. Recent expression studies of melanopsin have provided compelling evidence that melanopsin is the photopigment of the pRGCs. However, the mechanism by which melanopsin transduces light information remains an open question. This review discusses the signaling pathways that may underlie melanopsin-dependent phototransduction in native pRGCs, as well as the many exciting challenges ahead.


Air quality and emergency pediatric care for symptoms of bronchial obstruction categorized by age bracket in Rio de Janeiro, Brazil.
The objective of this study was to estimate the association between levels of air pollutants and respiratory symptoms in children. An ecological time-series study was conducted between April 2002 and March 2003 with daily data on PM10, SO2, CO, NO2, and O3 and paediatric care in emergency rooms due to symptoms indicating bronchial obstruction. The potential confounding factors considered were: time trend, seasonality, meteorological variables, respiratory infections and the effects of weekends and holidays. A semi-parametric Poisson regression was used to model the time series. Splines (data smoothing functions), indicator variables and cubic polynomials were used to adjust the effects of the confounding variables. A 5% significance level was adopted for the study. A statistically significant increase of 6.7% in paediatric visits of children of less than 2 years of age was associated with PM10. A 3% positive association with O3 showed borderline significance (p < 0.06) in this age bracket. Our findings highlight the existence of an acknowledged public health problem in Rio de Janeiro, Brazil, and also emphasize the need to identify the principal sources of air pollutants.


Public Health Student's Attitudes Toward Research.
Research is able to improve the lives of big populations by investigating effective interventions and then implementing those through public health policies. Whilst research on the inclination of Medical or Science undergraduate and postgraduate students has been conducted, little is known about what students pursuing a Masters degree in Public Health perceive the purpose of research to be. Their perceptions and inclinations will shape their research pursuits and career directions, which impacts the health outcomes of the community. Our findings suggest MPH students see improving the lives of the community as the most important purpose of research. Student's had more inclination to pursue research when influenced by a mentor however, many students still claimed that they either lacked confidence and skills in completing research or had no intention of pursuing research beyond their degrees, which suggests the need for curriculum adjustments.


First Report of Thielaviopsis punctulata Causing Black Scorch Disease on Date Palm in Qatar.
Ceratocystis radicicola (anamorph: Thielaviopsis paradoxa) was reported as an economically important pathogen causing serious diseases on date palm such as rhizosis (2) and black scorch (3) or as an associated pathogen with diseased date palm (1). In this study, we report for the first time that C. radicicola also causes black scorch disease in Qatar. In April to May 2013, we conducted a disease survey in 11 farms located in northern and southern Qatar where three infected farms had an average of 10% disease incidence. Infected trees manifested different disease symptoms such as black scorch of leaves, inflorescence blight, and heart and bud rot. Infected tissues were surface sterilized with 1.0% NaOCl for 60 s, rinsed with distilled water, blotted dry, and then plated on potato dextrose agar (PDA) supplemented with 50 mg/liter Rose Bengal. Single fungal colonies were picked from hyphal tips and grown on PDA for 7 days at 25°C for further examination of the mycological characteristics. Colonies of five C. radicicola isolates on PDA developed aerial mycelium with a light gray color in culture plate, which later changed to black. Both light and scanning electron microscopy were employed to delineate species by spore morphology. Colonies produced ovate aleuroconidia (14 to 17 × 9 to 12 μm) and cylindrical phialoconidia (7 to 9 × 3 to 4 μm) characteristic features of C. radicicola. Phialoconidia (endoconidia) were hyaline to brown in chains produced from endoconidiophore, clamydospores (aleuroconidia), which were single with smooth or slightly rough wall. Additionally, C. radicicola produced single alueroconidia from conidiophores. Amplification of ITS rDNA region from fungal genomic DNA of five isolates, using universal primers ITS1 (5'-TCCGTAGGTGAACCTGCGG-3') and ITS4 (5'-CCTCCGCTTATTGATATGC-3') confirmed the isolated fungus as C. radicicola with no intra-specific variation among the fungal isolates. The length of ITS-rDNA sequence was 534 bp (KJ410228) and had 99 and 93% sequence identity with ITS-rDNA region from C. radicicola (HQ443203) and C. paradoxa (HC415073.1), respectively. A pathogenicity test was conducted using 3-year-old trees from three cultivars (Khalas, Khneezi, and Barhi) growing in sandy loam soil under greenhouse conditions (25 to 29°C and 12/12-h light/dark). Six trees from each cultivar were used for pathogenicity test, where three were inoculated and three other mock-inoculated. Eight millimeter diameter mycelial plugs were obtained from a C. radicicola culture on PDA medium and used to inoculate rachis region and basal petioles of date palm leaves with a 9-mm wound created with a cork borer. Control plants were mock-inoculated with PDA plugs. The inoculated area was covered with wet cotton to prevent dryness and the whole plant was covered for 72 h. Four days post infection (dpi), a rusty black infection appeared on the plants. Fifteen dpi, the whole leaf of inoculated stem showed typical symptoms, from which the fungus was re-isolated and colonies were maintained in PDA for morphological characterization, which were confirmed as C. radicicola. All trees from three cultivars showed symptoms with a variable severity from cultivar to another. To our knowledge, this is the first report of black scorch disease caused by T. punctulata in Qatar. This report highlighted the incidence of black scorch disease in Qatar demanding future research study to control the pathogen. References: (1) Y. M. Al-Raisi et al. New Dis. Rep. 23:23, 2011. (2) C. Linde and W. A. Smit. Plant Dis. 83:880, 1999. (3) P. Suleman et al. Plant Dis. 85:80, 2001.


Sharp and asymmetric transmission response in metal-dielectric-metal plasmonic waveguides containing Kerr nonlinear media.
Based on the excitation of surface plasmon polaritons (SPPs), we analytically and numerically investigate the transmission response in metal-dielectric-metal (MDM) plasmonic waveguides with a side coupled nanocavity (SCNC). By filling the nanocavity with a Kerr nonlinear medium, the position of the resonant dip in the transmission spectrum can be tuned by the incident light intensity. The oscillation of a Fabry-Perot nanocavity formed by incorporating a finite length of the same Kerr nonlinear media into the MDM waveguide acts as a background for the transmission response of the system and induces a sharp and asymmetric response line shape. As a result, the wavelength shift required for the plasmonic device to be switched from the maximum to the minimum transmission can be reduced by half in a structure less than 400 nm long. Such an effect may be potentially applied to constructing SPP-based all-optical switching with low power threshold at nanoscale.


Copper(ii) complexes for cysteine detection using 19F magnetic resonance.
Cysteine plays an essential role in maintaining cellular redox homeostasis and perturbations in cysteine concentration are associated with cardiovascular disease, liver disease, and cancer. 19F MRI is a promising modality for detecting cysteine in biology due to its high tissue penetration and negligible biological background signal. Herein we report fluorinated macrocyclic copper complexes that display a 19F NMR/MRI turn-on response following reduction of the Cu(ii) complexes by cysteine. The reactivity with cysteine was studied by monitoring the appearance of a robust diamagnetic 19F signal following addition of cysteine in conjunction with UV-vis and EPR spectroscopies. Importantly, complexes with -CH2CF3 tags display good water solubility. Studies with this complex in HeLa cells demonstrate the applicability of these probes to detect cysteine in complex biological environments.


Perception of Direction for Applied Tangential Skin Displacement: Effects of Speed, Displacement, and Repetition.
A variety of tasks could benefit from the availability of direction cues that do not rely on vision or sound. The application of tangential skin displacement at the fingertip has been found to be a reliable means of communicating direction and has potential to be rendered by a compact device. Our lab has conducted experiments exploring the use of this type of tactile stimulus to communicate direction. Each subject pressed his/her right index fingertip against a 7 mm rounded rubber cylinder that moved at constant speed, applying shear force to deform the skin of the fingerpad. A range of displacements (0.05-1 mm) and speeds (0.5-4 mm/s) were tested. Subjects were asked to respond with the direction of the skin stretch, choosing from four directions, each separated by 90 degrees. Direction detection accuracy was found to depend upon both the speed and total displacement of the stimulus, with higher speeds and larger displacements resulting in greater accuracy. Accuracy rates greater than 95 percent were observed with as little as 0.2 mm of tangential displacement and at speeds as slow as 1 mm/s. Results were analyzed for direction dependence and temporal trends. Subjects responded most accurately to stimuli in the proximal and distal directions, and least accurately to stimuli in the ulnar direction. Subject performance decreased slightly with prolonged testing but there was no statistically significant learning trend. A second experiment was conducted to evaluate priming effects and the benefit of repeated stimuli. It was found that repeated stimuli do not improve direction communication, but subject responses were found to have a priming effect on future performance. This preliminary information will inform the design and use of a tactile display suitable for use in hand-held electronics.