Outcome prediction models in AQP4-IgG positive neuromyelitis optica spectrum disorders.
Pathogenic antibodies targeting the aquaporin-4 water channel on astrocytes are associated with relapsing inflammatory neuromyelitis optica spectrum disorders. The clinical phenotype is characterized by recurrent episodes of optic neuritis, longitudinally extensive transverse myelitis, area postrema attacks and less common brainstem and cerebral events. Patients often develop major residual disability from these attacks, so early diagnosis and initiation of attackpreventing medications is important. Accurate prediction of relapse would assist physicians in counselling patients, planning treatment and designing clinical trials. We used a large multicentre dataset of 441 patients from the UK, USA, Japan and Martinique who collectively experienced 1976 attacks, and applied sophisticated mathematical modelling to predict likelihood of relapse and disability at different time points. We found that Japanese patients had a lower risk of subsequent attacks except for brainstem and cerebral events, with an overall relative relapse risk of 0.681 (P = 0.001) compared to Caucasians and African patients, who had a higher likelihood of cerebral attacks, with a relative relapse risk of 3.309 (P = 0.009) compared to Caucasians. Female patients had a higher chance of relapse than male patients (P = 0.009), and patients with younger age of onset were more likely to have optic neuritis relapses (P < 0.001). Immunosuppressant drugs reduced and multiple sclerosis disease-modifying agents increased the likelihood of relapse (P < 0.001). Patients with optic neuritis at onset were more likely to develop blindness (P < 0.001), and those with older age of onset were more likely to develop ambulatory disability. Only 25% of long-term disability was related to initial onset attack, indicating the importance of early attack prevention. With respect to selection of patients for clinical trial design, there would be no gain in power by selecting recent onset patients and only a small gain by selecting patients with recent high disease activity. We provide risk estimates of relapse and disability for patients diagnosed and treated with immunosuppressive treatments over the subsequent 2, 3, 5 and 10 years according to type of attack at onset or the first 2-year course, ethnicity, sex and onset age. This study supports significant effects of onset age, onset phenotype and ethnicity on neuromyelitis optica spectrum disorders outcomes. Our results suggest that powering clinical treatment trials based upon relapse activity in the preceding 2 years may offer little benefit in the way of attack risk yet severely hamper clinical trial success.


Flow motion in peripheral diabetic neuropathy.
1. Flow motion is the cyclical variation in blood flow owing to the rhythmical opening and closing of arterioles. Previous studies have suggested that cutaneous flow motion may be altered in diabetic neuropathy but have not been consistent in their findings. 2. In order to assess the effect of diabetic peripheral neuropathy on flow motion, we have examined the frequency and amplitude of flow motion in 12 patients with diabetic peripheral neuropathy, 10 age-matched diabetic patients without peripheral neuropathy and 10 age-matched non-diabetic controls. 3. Peripheral neuropathy was diagnosed by a history of foot ulceration or chronic painful neuropathy, clinical examination and abnormal peroneal nerve conduction velocities. Blood flow, using laser Doppler flowmetry, was measured at four sites on the dorsum of both hands and feet. Flow motion was analysed using fast Fourier transform analysis, between 0.05 and 0.2 Hz, and displayed on a power spectral density graph. Predominant frequency and relative amplitude of flow motion were calculated. 4. Relative amplitude and frequency of flow motion were similar in the hands of all three groups, as was the frequency in the feet of the three groups. Relative amplitude was significantly smaller in the feet of diabetic patients with neuropathy (median 7.2%, 95% confidence interval 4.9-9.4%) than in diabetic patients without neuropathy (median 13.5%, 95% confidence interval 6.3-21.5%, P < 0.02) or in non-diabetic control subjects (median 10.3%, 95% confidence interval 6.9-27.4%, P < 0.02). 5. Flow motion amplitude is reduced in diabetic peripheral neuropathy. The control of flow motion amplitude appears to be at least partly under neurological control.


Towards semi-automated curation: using text mining to recreate the HIV-1, human protein interaction database.
Manual curation has long been used for extracting key information found within the primary literature for input into biological databases. The human immunodeficiency virus type 1 (HIV-1), human protein interaction database (HHPID), for example, contains 2589 manually extracted interactions, linked to 14,312 mentions in 3090 articles. The advancement of text-mining (TM) techniques has offered a possibility to rapidly retrieve such data from large volumes of text to a high degree of accuracy. Here, we present a recreation of the HHPID using the current state of the art in TM. To retrieve interactions, we performed gene/protein named entity recognition (NER) and applied two molecular event extraction tools on all abstracts and titles cited in the HHPID. Our best NER scores for precision, recall and F-score were 87.5%, 90.0% and 88.6%, respectively, while event extraction achieved 76.4%, 84.2% and 80.1%, respectively. We demonstrate that over 50% of the HHPID interactions can be recreated from abstracts and titles. Furthermore, from 49 available open-access full-text articles, we extracted a total of 237 unique HIV-1-human interactions, as opposed to 187 interactions recorded in the HHPID from the same articles. On average, we extracted 23 times more mentions of interactions and events from a full-text article than from an abstract and title, with a 6-fold increase in the number of unique interactions. We further demonstrated that more frequently occurring interactions extracted by TM are more likely to be true positives. Overall, the results demonstrate that TM was able to recover a large proportion of interactions, many of which were found within the HHPID, making TM a useful assistant in the manual curation process. Finally, we also retrieved other types of interactions in the context of HIV-1 that are not currently present in the HHPID, thus, expanding the scope of this data set. All data is available at http://gnode1.mib.man.ac.uk/HIV1-text-mining.


Early detection of COPD in primary care: screening by invitation of smokers aged 40 to 55 years.
The incidence of chronic obstructive pulmonary disease (COPD) is increasing in developed countries, as is the mortality rate. The main cause of COPD is smoking, and COPD is usually diagnosed at a late stage. To evaluate a method to detect COPD at an early stage in smokers in a young age group (40-55 years). Prospective descriptive study. The city of Motala (45,000 inhabitants) and its surrounding rural areas (43,000 inhabitants) in south-east Sweden. Nineteen thousand, seven hundred and fifty subjects were between 40 and 55 years of age. According to Swedish statistics, approximately 27% of this population are smokers. Smokers aged between 40 and 55 years were invited to have free spirometry testing in primary healthcare centres. Placards were placed in pharmacies and health centres and advertising was carried out locally twice a year. A total of 512 smokers responded. The prevalence of COPD was 27% (n = 141). The COPD was classified as mild obstruction in 85% (n = 120), moderate in 13% (n = 18) and severe in 2% (n = 3) according to the European Respiratory Society classification. Knowledge of the disease COPD was acknowledged by 39% of the responders to the questionnaire. Logistic regression analysis showed that age, male sex, number of pack years, dyspnoea and symptoms of chronic bronchitis significantly increased the odds of having COPD. The adjusted odds ratio was significant for having > 30 pack years. This method of inviting relatively young smokers selected a population of smokers with a high incidence of COPD, and may be one way of identifying smokers with COPD in the early stages.


Progression of Plasmodium berghei through Anopheles stephensi is density-dependent.
It is well documented that the density of Plasmodium in its vertebrate host modulates the physiological response induced; this in turn regulates parasite survival and transmission. It is less clear that parasite density in the mosquito regulates survival and transmission of this important pathogen. Numerous studies have described conversion rates of Plasmodium from one life stage to the next within the mosquito, yet few have considered that these rates might vary with parasite density. Here we establish infections with defined numbers of the rodent malaria parasite Plasmodium berghei to examine how parasite density at each stage of development (gametocytes; ookinetes; oocysts and sporozoites) influences development to the ensuing stage in Anopheles stephensi, and thus the delivery of infectious sporozoites to the vertebrate host. We show that every developmental transition exhibits strong density dependence, with numbers of the ensuing stages saturating at high density. We further show that when fed ookinetes at very low densities, oocyst development is facilitated by increasing ookinete number (i.e., the efficiency of ookinete-oocyst transformation follows a sigmoid relationship). We discuss how observations on this model system generate important hypotheses for the understanding of malaria biology, and how these might guide the rational analysis of interventions against the transmission of the malaria parasites of humans by their diverse vector species.


Progression of chronic pain and associated health-related quality of life and healthcare resource use over 5 years after total knee replacement: evidence from a cohort study.
As part of the STAR Programme, a comprehensive study exploring long-term pain after surgery, we investigated how pain and function, health-related quality of life (HRQL), and healthcare resource use evolved over 5 years after total knee replacement (TKR) for those with and without chronic pain 1 year after their primary surgery. We used data from the Clinical Outcomes in Arthroplasty Study prospective cohort study, which followed patients undergoing TKR from two English hospitals for 5 years. Chronic pain was defined using the Oxford Knee Score Pain Subscale (OKS-PS) where participants reporting a score of 14 or lower were classified as having chronic pain 1-year postsurgery. Pain and function were measured with the OKS, HRQL using the EuroQoL-5 Dimension, resource use from yearly questionnaires, and costs estimated from a healthcare system perspective. We analysed the changes in OKS-PS, HRQL and resource use over a 5-year follow-up period. Multiple imputation accounted for missing data. Chronic pain was reported in 70/552 operated knees (12.7%) 1 year after surgery. The chronic pain group had worse pain, function and HRQL presurgery and postsurgery than the non-chronic pain group. Those without chronic pain markedly improved right after surgery, then plateaued. Those with chronic pain improved slowly but steadily. Participants with chronic pain reported greater healthcare resource use and costs than those without, especially 1 year after surgery, and mostly from hospital readmissions. 64.7% of those in chronic pain recovered during the following 4 years, while 30.9% fluctuated in and out of chronic pain. Although TKR is often highly beneficial, some patients experienced chronic pain postsurgery. Although many fluctuated in their pain levels and most recovered over time, identifying people most likely to have chronic pain and supporting their recovery would benefit patients and healthcare systems.


Muscle fiber type distribution and architecture of the cat diaphragm.
Three types of diaphragmatic muscle fibers were identified histochemically in the sternal, costal, and crural regions of the cat diaphragm. Differences in the proportion of each muscle fiber type were observed between the abdominal and thoracic surfaces of the diaphragm but not among the different regions. A higher percentage of slow-twitch oxidative fibers was noted on the abdominal surface, whereas more fast-twitch fibers (fast-twitch oxidative-glycolytic and fast-twitch glycolytic) were found on the thoracic surface. Differences in muscle architecture were observed between diaphragmatic regions, but not between abdominal and thoracic sides. Overall, muscle fibers were longer in the crural regions, with the longest fibers being found in the crossing-band area of the crura. In the costal regions, fibers were longest in the center and became shorter toward the ventral and dorsal extent of these regions. Fiber lengths were similar throughout the sternal region. In each diaphragmatic region, the length of fibers extended from the origin of the muscle to its insertion. We conclude that functional differences between diaphragmatic regions could be attributed to fiber length and/or orientation, but not to differences in fiber-type composition.


A simple and rapid approach for screening of SARS-coronavirus genotypes: an evaluation study.
The Severe Acute Respiratory Syndrome (SARS) was a newly emerged infectious disease which caused a global epidemic in 2002-2003. Sequence analysis of SARS-coronavirus isolates revealed that specific genotypes predominated at different periods of the epidemic. This information can be used as a footprint for tracing the epidemiology of infections and monitor viral evolution. However, direct sequencing analysis of a large number of clinical samples is cumbersome and time consuming. We present here a simple and rapid assay for the screening of SARS-coronavirus genotypes based on the use of fluorogenic oligonucleotide probes for allelic discrimination. Thirty SARS patients were recruited. Allelic discrimination assays were developed based on the use of fluorogenic oligonucleotide probes (TaqMan). Genotyping of the SARS-coronavirus isolates obtained from these patients were carried out by the allelic discrimination assays and confirmed by direct sequencing. Genotyping based on the allelic discrimination assays were fully concordant with direct sequencing. All of the 30 SARS-coronavirus genotypes studied were characteristic of genotypes previously documented to be associated with the latter part of the epidemic. Seven of the isolates contained a previously reported major deletion but in patients not epidemiologically related to the previously studied cohort. We have developed a simple and accurate method for the characterization and screening of SARS-coronavirus genotypes. It is a promising tool for the study of epidemiological relationships between documented cases during an outbreak.


Reduction of Dacarbazine cytogenetic effects on somatic cells in male mice using bee glue (Propolis) to manifest the scientific miracles in the Quran.
This study was carried out to investigate the ability of Propolis to ameliorate the adverse cytogenetic effects of Dacarbazine on bone marrow cells. In this experimental in vivo study, 18 mice were used, divided into four groups: control group; Propolis-treated group (treated with 50mg/kg Propolis); and Dacarbazine-treated group (treated with 3.5mg/kg Dacarbazine). The fourth, fifth, and sixth were treated with Dacarbazine and Propolis as pre 2h, post 2h, and concomitant treatment. After five days, the Bone Marrow (BM) samples were obtained for cytogenetic investigation. The in vivo studies revealed that Dacarbazine induced an abnormalities in polychromatic erythrocytes cells (PECs) as increase of cell with micronuclei, while the dual treatment accompanied with improvement of this abnormalities. It could be concluded that there are protective effects of Propolis against the adverse effects of Dacarbazine. It could be recommended to use Propolis as an adjuvant with chemotherapeutic agents.


Defect in the membrane expression of high affinity 72-kD Fc gamma receptors on phagocytic cells in four healthy subjects.
Three different receptors for the Fc portion of IgG (FcR) have been characterized on human leukocytes. We have identified four healthy members of one family, whose blood phagocytic cells lack functional 72 kD high-affinity FcRI. Their monocytes were unable to bind the Fc portion of mouse (m)-IgG2a and of monomeric human IgG, and they were unreactive with two anti-FcRI monoclonal antibodies. Thus, FcRI is either absent, expressed at very low density, or is so structurally altered as to be unable to bind both its ligand and the anti-FcRI antibodies. The failure to bind the Fc portion of mIgG2a underlies the previously reported inability of these monocytes to support T cell mitogenesis on OKT3 stimulation. FcRI was not inducible upon incubation of their monocytes or neutrophils in gamma interferon. However, their monocytes were able to bind aggregated human IgG, and to phagocytose IgG-coated particles in vitro. Both functions could be blocked with a monoclonal antibody to the 40-kD low-affinity FcRII and therefore apparently were mediated exclusively through FcRII. This also demonstrates that FcRII can mediate phagocytosis independently. Despite the FcRI defect, these subjects had no circulating immune complexes, no evidence of autoimmune pathology and no increased susceptibility to infections.


Reduced hamster usage and stress in propagating Leishmania chagasi promastigotes using cryopreservation and saphenous vein inoculation.
Leishmania chagasi, a causal agent of visceral leishmaniasis, requires passage through lab animals such as hamsters to maintain its virulence. Hamster infection is typically accomplished via cardiac puncture or intraperitoneal injection, procedures accompanied by risks of increased animal stress and death. The use of the hamster model also necessitates a regular supply of infected animals, because L. chagasi parasites newly isolated from an infected hamster can be grown in culture for only several weeks before loss of function/phenotype occurs. In an effort to decrease animal usage and animal stress, experiments were performed to assess a more gentle inoculation procedure (saphenous vein inoculation) and the use of cryopreserved parasite cells for research experiments. Of 81 hamsters inoculated by the saphenous vein, 80 became infected as determined ante mortem, by display of clinical symptoms of leishmaniasis (onset of symptoms at 105 +/- 22 days post-inoculation), and postmortem by the presence of parasites within the spleen. Splenic parasite load calculated for a subset (n = 34) of infected hamsters was 124 to 26,177 Leishmania donovani infection units. Cryopreserved, and never-stored, cells were equivalent in all properties evaluated, including developmental changes in morphology during culture, culture growth rates, parasite resistance to serum-mediated lysis, and expression of developmentally regulated surface proteins major surface protease and promastigote surface antigen.


Racial/Ethnic Differences in Inpatient Palliative Care Consultation for Patients With Advanced Cancer.
Inpatient palliative care consultation (IPCC) may help address barriers that limit the use of hospice and the receipt of symptom-focused care for racial/ethnic minorities, yet little is known about disparities in the rates of IPCC. We evaluated the association between race/ethnicity and rates of IPCC for patients with advanced cancer. Patients with metastatic cancer who were hospitalized between January 1, 2009, and December 31, 2010, at an urban academic medical center participated in the study. Patient-level multivariable logistic regression was used to evaluate the association between race/ethnicity and IPCC. A total of 6,288 patients (69% non-Hispanic white, 19% African American, and 6% Hispanic) were eligible. Of these patients, 16% of whites, 22% of African Americans, and 20% of Hispanics had an IPCC (overall P < .001). Compared with whites, African Americans had a greater likelihood of receiving an IPCC (odds ratio, 1.21; 95% CI, 1.01 to 1.44), even after adjusting for insurance, hospitalizations, marital status, and illness severity. Among patients who received an IPCC, African Americans had a higher median number of days from IPCC to death compared with whites (25 v 17 days; P = .006), and were more likely than Hispanics (59% v 41%; P = .006), but not whites, to be referred to hospice. Inpatient settings may neutralize some racial/ethnic differences in access to hospice and palliative care services; however, irrespective of race/ethnicity, rates of IPCC remain low and occur close to death. Additional research is needed to identify interventions to improve access to palliative care in the hospital for all patients with advanced cancer.


DIANA-microT web server: elucidating microRNA functions through target prediction.
Computational microRNA (miRNA) target prediction is one of the key means for deciphering the role of miRNAs in development and disease. Here, we present the DIANA-microT web server as the user interface to the DIANA-microT 3.0 miRNA target prediction algorithm. The web server provides extensive information for predicted miRNA:target gene interactions with a user-friendly interface, providing extensive connectivity to online biological resources. Target gene and miRNA functions may be elucidated through automated bibliographic searches and functional information is accessible through Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The web server offers links to nomenclature, sequence and protein databases, and users are facilitated by being able to search for targeted genes using different nomenclatures or functional features, such as the genes possible involvement in biological pathways. The target prediction algorithm supports parameters calculated individually for each miRNA:target gene interaction and provides a signal-to-noise ratio and a precision score that helps in the evaluation of the significance of the predicted results. Using a set of miRNA targets recently identified through the pSILAC method, the performance of several computational target prediction programs was assessed. DIANA-microT 3.0 achieved there with 66% the highest ratio of correctly predicted targets over all predicted targets. The DIANA-microT web server is freely available at www.microrna.gr/microT.


Supporting the provision of palliative care in the home environment: a proof-of-concept single-arm trial of a PalliativE Carers Education Package (PrECEPt).
Practical educational interventions for palliative carers are needed. Current supports frequently rely on carers travelling to a central venue to receive education. A substantial gap therefore exists around determining how high-quality relevant information can be delivered nationally, with limited cost implications, using educational methods that are acceptable to carers in palliative care. This study seeks to design and assess feasibility and acceptability of a distance-learning approach to educating carers. This is an embedded mixed-method feasibility and acceptability study. It embeds an unblinded 1-arm pilot test, with subsequent qualitative interviews which will be used to inform the assessment of the intervention's acceptability and feasibility. The theoretical framework is self-efficacy theory, whereby we seek to impact carers' beliefs in their ability to carry out and succeed in caring tasks and situations. The educational materials focused on pain and nutrition/hydration will be developed in phase 1 with former carers (n=8) providing input into the content and style of materials. The educational package privileges adult-learning styles, recognising and responding to the learner's context including their learning needs, prior knowledge and motivations for engaging in education. The materials will be tested with up to 24 current carers. Analysis will focus on determining recruitment processes for a full-scale study, data collection procedures/completion rates, queries directed to the hospice from carers involved in the feasibility work, mode of delivery and content of the materials. The primary outcome measure is self-efficacy, with other measures focused on caregiver preparedness and caregiving tasks, consequences and needs questionnaire. Adherence to educational components will also be collected and reported. Ethical approval has been provided by the participating site, Calvary Healthcare, Canberra, reference 02-2016, and the Australian Catholic University. Results will be published in peer-reviewed journals, presented at conferences and a lay summary sent to participants. ACTRN12616000601437; Pre-results.


Principles of Pediatric Patient Safety: Reducing Harm Due to Medical Care.
Pediatricians render care in an increasingly complex environment, which results in multiple opportunities to cause unintended harm. National awareness of patient safety risks has grown since the National Academy of Medicine (formerly the Institute of Medicine) published its report "To Err Is Human: Building a Safer Health System" in 1999. Patients and society as a whole continue to challenge health care providers to examine their practices and implement safety solutions. The depth and breadth of harm incurred by the practice of medicine is still being defined as reports continue to reveal a variety of avoidable errors, from those that involve specific high-risk medications to those that are more generalizable, such as patient misidentification and diagnostic error. Pediatric health care providers in all practice environments benefit from having a working knowledge of patient safety language. Pediatric providers should serve as advocates for best practices and policies with the goal of attending to risks that are unique to children, identifying and supporting a culture of safety, and leading efforts to eliminate avoidable harm in any setting in which medical care is rendered to children. In this Policy Statement, we provide an update to the 2011 Policy Statement "Principles of Pediatric Patient Safety: Reducing Harm Due to Medical Care."


A typology of reviews: an analysis of 14 review types and associated methodologies.
The expansion of evidence-based practice across sectors has lead to an increasing variety of review types. However, the diversity of terminology used means that the full potential of these review types may be lost amongst a confusion of indistinct and misapplied terms. The objective of this study is to provide descriptive insight into the most common types of reviews, with illustrative examples from health and health information domains. Following scoping searches, an examination was made of the vocabulary associated with the literature of review and synthesis (literary warrant). A simple analytical framework -- Search, AppraisaL, Synthesis and Analysis (SALSA) -- was used to examine the main review types. Fourteen review types and associated methodologies were analysed against the SALSA framework, illustrating the inputs and processes of each review type. A description of the key characteristics is given, together with perceived strengths and weaknesses. A limited number of review types are currently utilized within the health information domain. Few review types possess prescribed and explicit methodologies and many fall short of being mutually exclusive. Notwithstanding such limitations, this typology provides a valuable reference point for those commissioning, conducting, supporting or interpreting reviews, both within health information and the wider health care domain.


Isolation and characterization of two pigment-dispersing hormones from the whiteleg shrimp, Litopenaeus vannamei.
In crustaceans, the pigment-dispersing hormone (PDH) is released from the X-organ/sinus gland complex located in the eyestalks, and controls pigment dispersion in the chromatophores. Knowledge concerning the structure and activity of PDH in penaeid shrimps is remains limited, since natural PDH has been purified from only the Kuruma prawn, Marsupenaeus japonicus. In this study, two PDHs (Liv-PDH-A and -B) were purified from the sinus gland extracts of another penaeid species, the whiteleg shrimp, Litopenaeus vannamei, by two steps of reversed-phase HPLC, and their amino acid sequences were determined. They both consist of 18 amino acid residues, with a free N-terminus and an amidated C-terminus, the sequences of Liv-PDH-A and -B being NSELINSLLGIPKVMNDAamide and NSELINSLLGLPKVMNDAamide, respectively. These sequences are identical to those of mature PDHs deduced from cDNAs encoding L. vannamei PDH precursors cloned previously by other workers. Liv-PDH-A and -B showed significant pigment-dispersing activity in melanophores by in vivo bioassay.


Colicins exploit native disorder to gain cell entry: a hitchhiker's guide to translocation.
The translocation of protein toxins into a cell relies on a myriad of protein-protein interactions. One such group of toxins are enzymatic E colicins, protein antibiotics produced by Escherichia coli in times of stress. These proteins subvert ordinary nutrient uptake mechanisms to enter the cell and unleash nuclease activity. We, and others, have previously shown that uptake of ColE9 (colicin E9) is dependent on engagement of the OM (outer membrane) receptors BtuB and OmpF as well as recruitment of the periplasmic protein TolB, forming a large supramolecular complex. Intriguingly, colicins bind TolB using a natively disordered region to mimic the interaction of TolB with Pal (peptidoglycan-associated lipoprotein). This is thought to trigger OM instability and prime the system for translocation. Here, we review key interactions in the assembly of this 'colicin translocon' and discuss the key role disorder plays in achieving uptake.


A parallel mixture of SVMs for very large scale problems.
Support vector machines (SVMs) are the state-of-the-art models for many classification problems, but they suffer from the complexity of their training algorithm, which is at least quadratic with respect to the number of examples. Hence, it is hopeless to try to solve real-life problems having more than a few hundred thousand examples with SVMs. This article proposes a new mixture of SVMs that can be easily implemented in parallel and where each SVM is trained on a small subset of the whole data set. Experiments on a large benchmark data set (Forest) yielded significant time improvement (time complexity appears empirically to locally grow linearly with the number of examples). In addition, and surprisingly, a significant improvement in generalization was observed.


Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women.
A positive relationship has generally been observed between plasma estrogen levels and breast cancer risk in postmenopausal women, but most of these studies have been small and few have evaluated specific estrogen fractions (such as percent bioavailable estradiol). In addition, few studies have evaluated plasma androgen levels in relation to breast cancer risk, and their results have been inconsistent. We prospectively evaluated relationships between sex steroid hormone levels in plasma and risk of breast cancer in postmenopausal women by use of a case-control study nested within the Nurses' Health Study. Blood samples were collected during the period from 1989 through 1990. Among postmenopausal women not using hormone replacement therapy at blood collection (n = 11,169 women), 156 women were diagnosed with breast cancer after blood collection but before June 1, 1994. Two control subjects were selected per case subject and matched with respect to age, menopausal status, month and time of day of blood collection, and fasting status at the time of blood collection. From comparisons of highest and lowest (reference) quartiles, we observed statistically significant positive associations with risk of breast cancer for circulating levels of estradiol (multivariate relative risk [RR] = 1.91; 95% confidence interval [CI] = 1.06-3.46), estrone (multivariate RR = 1.96; 95% CI = 1.05-3.65), estrone sulfate (multivariate RR = 2.25; 95% CI = 1.23-4.12), and dehydroepiandrosterone sulfate (multivariate RR = 2.15; 95% CI = 1.11-4.17). We found no substantial associations with percent free or percent bioavailable estradiol, androstenedione, testosterone, or dehydroepiandrosterone. The positive relationships were substantially stronger among women with no previous hormone replacement therapy. Our data, in conjunction with past epidemiologic and animal studies, provide strong evidence for a causal relationship between postmenopausal estrogen levels and the risk of breast cancer.


Undefined and unpredictable responsibility: a focus group study of the experiences of informal caregiver spouses of patients with severe COPD.
To explore how spouses of patients with severe chronic obstructive pulmonary disease experience their role as informal caregiver. Informal caregiver spouses are of pivotal importance in the way that patients with chronic obstructive pulmonary disease cope with their daily life, including their opportunity to stay at home and avoid hospitalisations in the last stages of the disease. However, caregiving is associated with increased morbidity and mortality among caregivers. Further understanding of the role as an informal caregiver spouse of patients with severe chronic obstructive pulmonary disease is needed to develop supportive interventions aimed at reducing the caregiver burden. The study had a qualitative exploratory design. The data collection and analysis were based on framework method. Framework method is a thematic methodology and consists of five key stages: familiarisation, identifying a thematic framework, indexing, charting and mapping & interpretation. Three focus groups were conducted in November 2013 with 22 spouses of patients with severe chronic obstructive pulmonary disease. Undefined and unpredictable responsibility was found to be the overarching theme describing the informal caregiver role. Underlying themes were: being constantly in a state of alertness, social life modified, maintaining normality, ambivalence in the relationship and a willingness to be involved. The informal caregiver spouses experienced ambiguity about expectations from their private and the health professionals' surroundings. The informal caregiver spouses wanted to provide meaningful care for their partners, but sought knowledge and support from the health professionals. We recommend that nurses take on the responsibility for including the informal caregiver spouses in those aspects of decision-making that involve the common life of the patients and their spouses.


Influence of the substituent on the phosphine ligand in novel rhenium(i) aldehydes. Synthesis, computational studies and first insights into the antiproliferative activity.
Cyrhetrenyl aldehyde derivatives [(η5-C5H4CHO)Re(CO)2PR3] with R = methyl (Me, 2a), phenyl (Ph, 2b), and cyclohexyl (Cy, 2c) were synthesized by a photochemical reaction from the starting material [(η5-C5H4CHO)Re(CO)3] (1) and the corresponding phosphines. The complexes were fully characterized by FT-IR, 1H, 13C and 31P NMR spectroscopy, elemental analysis and mass spectrometry. The molecular structures of 2a-c have also been determined. Electronic structure calculations by TD-DFT and electrochemical studies are in sound agreement with the effect of the substitution of one carbonyl group by a phosphine ligand. Additionally, the antiproliferative activity of complexes 1 and 2a-c was studied on the human cancer cell lines HT-29 and PT-45 using an MTT assay. Out of all new compounds, only the triphenylphosphine derivative 2b exhibited pronounced cytotoxic effects on both cell lines, being ca. 1.5 times more potent than cisplatin.


Co-transmission of dopamine and GABA in periglomerular cells.
Most central neurons package and release a single transmitter. However co-transmission of fast-acting and modulatory transmitters has been observed in vertebrate and invertebrate systems. Here we describe a population of periglomerular cells in mouse brain slices (PND14-21) that co-release dopamine and GABA. We made whole cell recordings from periglomerular cells that expressed enhanced green fluorescent protein (EGFP) under the control of the tyrosine hyrdoxylase (TH) promoter. Immunolabeling confirmed that EGFP+ periglomerular cells synthesized TH as well as glutamic acid decarboxylase (GAD). Stimulation of olfactory receptor neuron (ORN) afferent input evoked excitatory postsynaptic currents (EPSCs) in EGFP+ cells that were inhibited by cocaine, which blocks dopamine transport. These effects were reversed by the D2 receptor antagonist sulpiride. Cocaine also increased the paired-pulse ratio of ORN-evoked EPSCs. These results demonstrate that TH+ periglomerular cells spontaneously release dopamine. In addition to dopamine, TH-EGFP+ cells also released GABA. Brief depolarizing voltage steps in labeled cells evoked a tail current that was completely blocked by the GABA(A) receptor antagonist gabazine and by cadmium, indicative of calcium-dependent self-inhibition in periglomerular cells. However, similar voltage steps were insufficient to cause D2-receptor mediated inhibition of ORN terminals. Our results indicate that TH+ periglomerular cells are directly activated by ORN input and release both dopamine and GABA. We suggest that concerted activation of multiple periglomerular cells may be required to detect dopamine release under normal physiological conditions.


Implementing quality improvement in small, autonomous primary care practices: implications for the patient-centred medical home.
Implementing improvement programmes to enhance quality of care in primary care clinics is complex. Understanding how improvement strategies can be implemented in primary care is timely given the recent national movement towards transforming primary care into patient centred medical homes (PCMH). This study examined practice members' perceptions of the opportunities and challenges associated with implementing changes in their practice. Semi-structured interviews were conducted with a sample of 56 individuals working in 16 small, community based primary care practices. The interviews consisted of open-ended questions focused on participants' perceptions of: (1) practice vision, (2) perceived need for practice improvement and (3) barriers that hinder practice improvement. The interviews were conducted at the participating clinics and were tape-recorded, transcribed, and content analysed. Content analysis identified two main domains for practice improvement related to: (1) the process of care, and (2) patients' involvement in their disease management. Examples of desired process of care changes included improvement in patient tracking and follow-up, standardisation of processes of care and overall clinic documentation. Changes related to patients' involvement in their care included improving (a) health education, and (b) self-care management. Among the internal barriers were: staff readiness for change, poor communication and relationship difficulties among team members. External barriers were insurance regulations, finances and patient health literacy. Transforming practices to more patient-centred models of care will be a priority for primary care providers. Identifying opportunities and challenges associated with implementing change is critical for successful improvement programmes. Successful strategies for enhancing the adoption and uptake of PCMH elements should leverage areas of concordance between practice members' perceived needs and planned improvement efforts.


Primary in vitro cytotoxic T cell response to non-major histocompatibility complex alloantigens in normal mice.
We have shown for the first time that it is possible to consistently generate a primary in vitro cytotoxic T cell (Tc) response to non-major histocompatibility complex alloantigens using responder cells from a normal mouse strain. This was achieved by carrying out, in the generating phase, a limiting dilution procedure in which it appears that suppressor cells that inhibit Tc activation or expansion are too dilute to manifest their effect. Moreover, the response was observed in mouse serum-(MS) as well as fetal calf serum- (FCS) supplemented media, an important finding in the light of the anomalous nonspecific effects induced by FCS. The cytotoxic response produced in MS-supplemented media was shown to be highly specific in both the generating and effector phases, whereas the responses in FCS had a strong nonspecific component.


Community knowledge, attitude and practices regarding sexually transmitted infections in a rural district of Pakistan.
To determine knowledge, attitude and practices regarding sexually transmitted infections in district Khairpur, Sindh, Pakistan. A needs assessment study employing a community based survey, key informant interviews and focus group discussions was conducted in all seven sub-districts of the district. This paper is based on the results of the key informant interviews and the focus group discussions. Thirty interviews and six group discussions were held with members of the community and with the health care providers. There was little awareness regarding causes and prevention of sexually transmitted infections in the community. The situation was slightly better among health care providers. While health care providers believed that the prevalence of sexually transmitted infections is high, the community did not consider themselves at risk. The community believed that these diseases are a problem among a sub-population of male adolescents, especially those who have homosexual relations. However, due to social norms, they rarely discussed such health problems with other family members or elders. Adolescents with any sexual health problems visit hakims and quacks. The community was aware about aetiology and some of the risk factors associated with AIDS and hepatitis, most probably due to the recent public health campaigns against both diseases. Considering the suspected high prevalence of sexually transmitted infections and the relative lack of knowledge, it is imperative that a public health intervention be initiated. This must include educating not only the community but also the health workers. The governments' initiative to train community workers in reproductive health is a step in the right direction (JPMA 52:21, 2002).


Electromagnetic Funnel: Reflectionless Transmission and Guiding of Waves through Subwavelength Apertures.
Confining and controlling electromagnetic energy typically involves a highly resonant phenomenon, especially when subwavelength confinement is desired. Here, we present a class of nonresonant, self-dual planar metastructures capable of protected energy transmission from one side to the other, through arbitrarily narrow apertures. It is shown that the transmission is in the form of matched propagating modes and is independent of the thickness and specific composition of the surface. We analytically prove that the self-dual condition is sufficient to guarantee 100% transmission that is robust to the presence of discontinuities along the propagation path. The results are confirmed numerically through study of various scenarios. The operation is broadband and subject only to the bandwidth of the constituent materials. The polarization of the internal field can also be independently controlled with respect to the incident one. Our structures are promising for applications in sensing, particle trapping, near-field imaging, and wide scan antenna arrays.


Substitution between Formal and Informal Care for Persons with Severe Mental Illness and Substance Use Disorders.
BACKGROUND: Persons with severe mental illness (SMI) often get extensive informal care from family members and friends as well as substantial amounts of formal treatment from paid professionals. Both sources of care are well documented, but very little is known about how one affects the other. AIMS OF THE STUDY: This analysis estimates the extent of substitution between direct care provided by family and friends and formal treatment for people with severe mental illness and substance use disorders. Separate estimates are generated for short-term and long-term effects. METHODS: Data are from a randomized clinical trial conducted at seven mental health centers in New Hampshire between 1989 and 1995. The study includes detailed data for 193 persons with dual disorders measured at study entry and every six months for three years. Hours of informal care were compared with total treatment costs within each six-month period to measure short-term effects. Average amount of informal care over three years represented long-term caregiving practices. Measures of informal care are from interviews with informal caregivers. Treatment costs are based on combined data from management information systems, Medicaid claims, hospital records, and self reports. We used mixed effects repeated measures regression to estimate longitudinal effects and a multiple imputation technique to test the sensitivity of results to missing data. RESULTS: In the short-term, persons with bipolar disorder used significantly more formal care as informal care increased (complementarity). The relationship between short-term informal and formal care was significantly weaker for persons with schizophrenia. For both diagnostic groups there was a long-term substitution effect; a 4-6% increase in informal care hours was associated with an approximate 1% decrease in formal care costs. DISCUSSION: Although they must be confirmed by further research, these findings suggest that there is a significant and strong relationship between care given by family and friends and that supplied by formal treatment providers. The analysis indicates that the short-term relationship between informal care and formal treatment tends to be complementary, but differs according to diagnosis. Long-term effects, which are possibly related to changing role perceptions, show substitution between the two forms of care. Missing data for family care hours in some time periods was a concern in this study. However, the consistency in results between the analyses that used imputed data and the model using only original data increase our confidence in the findings. Although there may be some endogeneity between formal and informal care in other treatment settings we believe the unique characteristics of the service-rich environment in which this study was conducted limit that concern here. IMPLICATIONS FOR HEALTH CARE PROVISION AND USE: The amount of care provided by informal caregivers has a significant impact on formal treatment costs. Models of care that explicitly acknowledge the interplay between the two types of care are needed to ensure efficient combinations of formal and informal care. IMPLICATIONS FOR HEALTH POLICY FORMULATION: How to best to encourage informal support, without overburdening caregivers, is a key challenge facing policy makers and providers of mental health services. The merits of various approaches to reducing caregiver burden is a subject that needs more attention from researchers. In the interim, the demands on informal caregivers may mount as efforts to reduce health care spending continue. IMPLICATIONS FOR FURTHER RESEARCH: Informal care is not often included in economic evaluations of mental health treatment. Although additional research is needed to understand better the mechanisms by which informal care and formal treatment are related, we believe our results offer a strong argument for including measures of informal care in future economic evaluations.


Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells.
We have defined the mechanism of action of lurbinectedin, a marine-derived drug exhibiting a potent antitumor activity across several cancer cell lines and tumor xenografts. This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis. The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair. Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism. Mol Cancer Ther; 15(10); 2399-412. ©2016 AACR.


Fatty acid reesterification but not oxidation is increased by oral contraceptive use in women.
We evaluated the hypothesis that fatty acid reesterification would be increased during rest and exercise in the midluteal menstrual cycle phase and during oral contraceptive use, when ovarian hormone concentrations are high, compared with the early follicular phase. Subjects were eight moderately active, weight-stable, eumenorrheic women (24.8 +/- 1.2 yr, peak oxygen consumption = 42.0 +/- 2.3 ml.kg(-1).min(-1)) who had not taken oral contraceptives for at least 6 mo. Plasma free fatty acid (FFA) kinetics were assessed in the 3-h postprandial state by continuous infusion of [1-(13)C]palmitate and [1,1,2,3,3-(2)H]glycerol during 90 min of rest and 60 min of exercise at 45% and 65% peak oxygen consumption in the early follicular and midluteal menstrual cycle phases and during the inactive- and high-dose phases following 4 mo of oral contraceptive use. Plasma FFA rates of appearance, disappearance, and oxidation increased significantly from rest to exercise with no differences noted between menstrual cycle or oral contraceptive phases or exercise intensities. Compared with either menstrual cycle phase, oral contraceptive use resulted in an increase in plasma-derived fatty acid reesterification and a decrease in the proportion of plasma FFA rate of disappearance that was oxidized at rest and during exercise. Endogenous and exogenous synthetic ovarian hormones do not exert a measurable influence on plasma FFA turnover or oxidation at rest or during moderate-intensity exercise in the 3-h postprandial state when carbohydrate use predominates. The increase in whole body lipolytic rate during exercise noted previously with oral contraceptive use is not matched by an increase in fatty acid oxidation and results in an increase in reesterification. Synthetic ovarian hormones contained in oral contraceptives increase lipolytic rate, but fatty acid oxidation during exercise is determined by exercise intensity and its metabolic and endocrine consequences.


Microvascular decompression for hemifacial spasm: long-term outcome and prognostic factors, with emphasis on delayed cure.
The postoperative course of microvascular decompression (MVD) for hemifacial spasm (HFS) is variable, and the optimal time for assessing the results is unclear. From April 1997 to October 2007, MVD for HFS was performed in 801 patients. Patients were divided into two groups (cured or failed) according to subjective patient assessments over a 3-year period. We analyzed patient characteristics and surgical findings to determine prognostic factors. Medical records were analyzed retrospectively over the 3-year follow-up period. Of the 801 patients who underwent surgery, 743 (92.8 %) appeared to be cured, 70 (8.7 %) had residual or recurrent spasms more than 1 year after surgery, 11 (1.3 %) had gradual improvement over 3 years, and 1 (0.1 %) had delayed improvement more than 3 years after surgery. Fifty-eight patients (7.2 %) had residual or recurrent spasms more than 3 years after surgery, of which 19 (2.4 %) had recurrence after initial relief. The mean time to spasm recurrence was 18.9 months. Intraoperative resolution of the lateral spread response (LSR) after decompression (p = 0.048) and severe indentation (p = 0.038) were significant predictors of good long-term outcome after MVD for HFS. In our series, 70 patients (8.7 %) had residual or recurrent spasms more than 1 year after surgery, of which 12 (17.1 %) improved gradually after 1 year. If the surgeon can confirm intraoperative resolution of the LSR and severe indentation, reoperation can be delayed until 3 years after MVD.


Thyroid Function Within the Normal Range, Subclinical Hypothyroidism, and the Risk of Atrial Fibrillation.
Atrial fibrillation (AF) is a highly prevalent disorder leading to heart failure, stroke, and death. Enhanced understanding of modifiable risk factors may yield opportunities for prevention. The risk of AF is increased in subclinical hyperthyroidism, but it is uncertain whether variations in thyroid function within the normal range or subclinical hypothyroidism are also associated with AF. We conducted a systematic review and obtained individual participant data from prospective cohort studies that measured thyroid function at baseline and assessed incident AF. Studies were identified from MEDLINE and EMBASE databases from inception to July 27, 2016. The euthyroid state was defined as thyroid-stimulating hormone (TSH) 0.45 to 4.49 mIU/L, and subclinical hypothyroidism as TSH 4.5 to 19.9 mIU/L with free thyroxine (fT4) levels within reference range. The association of TSH levels in the euthyroid and subclinical hypothyroid range with incident AF was examined by using Cox proportional hazards models. In euthyroid participants, we additionally examined the association between fT4 levels and incident AF. Of 30 085 participants from 11 cohorts (278 955 person-years of follow-up), 1958 (6.5%) had subclinical hypothyroidism and 2574 individuals (8.6%) developed AF during follow-up. TSH at baseline was not significantly associated with incident AF in euthyroid participants or those with subclinical hypothyroidism. Higher fT4 levels at baseline in euthyroid individuals were associated with increased AF risk in age- and sex-adjusted analyses (hazard ratio, 1.45; 95% confidence interval, 1.26-1.66, for the highest quartile versus the lowest quartile of fT4; P for trend ≤0.001 across quartiles). Estimates did not substantially differ after further adjustment for preexisting cardiovascular disease. In euthyroid individuals, higher circulating fT4 levels, but not TSH levels, are associated with increased risk of incident AF.


Comparing media and family predictors of alcohol use: a cohort study of US adolescents.
To compare media/marketing exposures and family factors in predicting adolescent alcohol use. Cohort study. Confidential telephone survey of adolescents in their homes. Representative sample of 6522 US adolescents, aged 10-14 years at baseline and surveyed four times over 2 years. Time to alcohol onset and progression to binge drinking were assessed with two survival models. Predictors were movie alcohol exposure (MAE), ownership of alcohol-branded merchandise and characteristics of the family (parental alcohol use, home availability of alcohol and parenting). Covariates included sociodemographics, peer drinking and personality factors. Over the study period, the prevalence of adolescent ever use and binge drinking increased from 11% to 25% and from 4% to 13%, respectively. At baseline, the median estimated MAE from a population of 532 movies was 4.5 h and 11% owned alcohol-branded merchandise at time 2. Parental alcohol use (greater than or equal to weekly) was reported by 23% and 29% of adolescents could obtain alcohol from home. Peer drinking, MAE, alcohol-branded merchandise, age and rebelliousness were associated with both alcohol onset and progression to binge drinking. The adjusted hazard ratios for alcohol onset and binge drinking transition for high versus low MAE exposure were 2.13 (95% CI 1.76 to 2.57) and 1.63 (1.20 to 2.21), respectively, and MAE accounted for 28% and 20% of these transitions, respectively. Characteristics of the family were associated with alcohol onset but not with progression. The results suggest that family focused interventions would have a larger impact on alcohol onset while limiting media and marketing exposure could help prevent both onset and progression.


Simulated climate change causes immune suppression and protein damage in the crustacean Nephrops norvegicus.
Rising atmospheric carbon dioxide concentration is causing global warming, which affects oceans by elevating water temperature and reducing pH. Crustaceans have been considered tolerant to ocean acidification because of their retained capacity to calcify during subnormal pH. However, we report here that significant immune suppression of the Norway lobster, Nephrops norvegicus, occurs after a 4-month exposure to ocean acidification (OA) at a level predicted for the year 2100 (hypercapnic seawater with a pH lowered by 0.4 units). Experiments carried out at different temperatures (5, 10, 12, 14, 16, and 18°C) demonstrated that the temperature within this range alone did not affect lobster immune responses. In the OA-treatment, hemocyte numbers were reduced by almost 50% and the phagocytic capacity of the remaining hemocytes was inhibited by 60%. The reduction in hemocyte numbers was not due to increased apoptosis in hematopoetic tissue. Cellular responses to stress were investigated through evaluating advanced glycation end products (AGE) and lipid oxidation in lobster hepatopancreata, and OA-treatment was shown to significantly increase AGEs', indicating stress-induced protein alterations. Furthermore, the extracellular pH of lobster hemolymph was reduced by approximately 0.2 units in the OA-treatment group, indicating either limited pH compensation or buffering capacity. The negative effects of OA-treatment on the nephropidae immune response and tissue homeostasis were more pronounced at higher temperatures (12-18°C versus 5°C), which may potentially affect disease severity and spread. Our results signify that ocean acidification may have adverse effects on the physiology of lobsters, which previously had been overlooked in studies of basic parameters such as lobster growth or calcification.


Cruciferous vegetables intake is associated with lower risk of renal cell carcinoma: evidence from a meta-analysis of observational studies.
Epidemiologic studies have evaluated the association between cruciferous vegetables(CV) intake and the risk of renal cell carcinoma(RCC); however, the existing results are controversial. The aim of this meta-analysis was to investigate the association between CV intake and RCC risk. A literature search was carried out using PUBMED and EMBASE database between January 1966 and March 2013. Fixed-effect and random-effect models were used to estimate summary relative risks (RR) and the corresponding 95% confidence intervals (CIs). Potential sources of heterogeneity were detected by meta-regression. Subgroup analyses, sensitivity analysis and cumulative meta-analysis were also performed. A total of 12 studies (six cohorts, six case-control) contributed to the analysis, involving 1,228,518 participants and 5,773 RCC cases. When all studies were pooled, we observed a significantly inverse association between CV intake and RCC risk (RR = 0.81, 95% CI [0.72, 0.91]). This association was also significant when analyses were restricted to six high-quality studies (RR = 0.89, 95% CI [0.82, 0.98]). In subgroup analyses, CV intake was significantly associated with reduced RCC risk among studies conducted in America (RR = 0.77, 95%CI [0.70, 0.86]); however, CV intake had no significant association with RCC risk among studies conducted in Europe (RR = 0.87, 95%CI [0.71, 1.07]). Furthermore, sensitivity analysis confirmed the stability of results. The findings of this meta-analysis suggested that high intake of CV was inversely associated with RCC risk among Americans. More studies, especially high quality cohort studies with larger sample size, well controlled confounding factors are warranted to confirm this association.


Proximity (Mis)perception: Public Awareness of Nuclear, Refinery, and Fracking Sites.
Whether on grounds of perceived safety, aesthetics, or overall quality of life, residents may wish to be aware of nearby energy sites such as nuclear reactors, refineries, and fracking wells. Yet people are not always accurate in their impressions of proximity. Indeed, our data show that only 54% of Americans living within 25 miles of a nuclear site say they do, and even fewer fracking-proximal (30%) and refinery-proximal (24%) residents respond accurately. In this article, we analyze factors that could either help people form more accurate perceptions or distort their impressions of proximity. We evaluate these hypotheses using a large national survey sample and corresponding geographic information system (GIS) data. Results show that among those living in close proximity to energy sites, those who perceive greater risk are less likely to report living nearby. Conversely, social contact with employees of these industries increases perceived proximity regardless of actual distance. These relationships are consistent across each site type we examine. Other potential factors-such as local news use-may play a role in proximity perception on a case-by-case basis. Our findings are an important step toward a more generalizable understanding of how the public forms perceptions of proximity to risk sites, showing multiple potential mechanisms of bias.


Concentration-dependent effects of carbon nanoparticles in gram-negative bacteria determined by infrared spectroscopy with multivariate analysis.
With increasing production of carbon nanoparticles (CNPs), environmental release of these entities becomes an ever-greater inevitability. However, many questions remain regarding their impact on soil microorganisms. This study examined the effects of long or short multiwalled carbon nanotubes (MWCNTs), C60 fullerene and fullerene soot in Gram-negative bacteria. Attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy was applied to derive signature spectral fingerprints of effects. A concentration-dependent response in spectral alterations was observed for each nanoparticle type. Long or short MWCNTs and fullerene soot gave rise to similar alterations to lipids, Amide II and DNA. The extent of alteration varies with nanoparticle size, with smaller short MWCNTs resulting in greater toxicity than long MWCNTs. Fullerene soot was the least toxic. C60 results in the most distinct and largest overall alterations, notably in extensive protein alteration. This work demonstrates a novel approach for assaying and discriminating the effects of CNPs in target systems.


Enterococcus gallinarum Causing Native Valve Endocarditis.
Endocarditis due to Enterococcus gallinarum is a rare condition, usually affecting older patients. The most frequent source of infection is the gastrointestinal or genitourinary tracts; it frequently involves the aortic valve and tends to produce heart failure. We present a case of Enterococcus gallinarum endocarditis developing on a normal native heart valve. Enterococcus gallinarum is intrinsically resistant to vancomycin. Antibiotic susceptibility patterns indicate that most isolates are penicillin and ampicillin-susceptible. Endocarditis due to Enterococcus gallinarum is rare.Enterococcus gallinarum is intrinsically resistant to vancomycin.Most isolates are penicillin and ampicillin-susceptible.


Validation of the SF-6D Health State Utilities Measure in Lower Extremity Sarcoma.
Aim. Health state utilities measures are preference-weighted patient-reported outcome (PRO) instruments that facilitate comparative effectiveness research. One such measure, the SF-6D, is generated from the Short Form 36 (SF-36). This report describes a psychometric evaluation of the SF-6D in a cross-sectional population of lower extremity sarcoma patients. Methods. Patients with lower extremity sarcoma from a prospective database who had completed the SF-36 and Toronto Extremity Salvage Score (TESS) were eligible for inclusion. Computed SF-6D health states were given preference weights based on a prior valuation. The primary outcome was correlation between the SF-6D and TESS. Results. In 63 pairs of surveys in a lower extremity sarcoma population, the mean preference-weighted SF-6D score was 0.59 (95% CI 0.4-0.81). The distribution of SF-6D scores approximated a normal curve (skewness = 0.11). There was a positive correlation between the SF-6D and TESS (r = 0.75, P < 0.01). Respondents who reported walking aid use had lower SF-6D scores (0.53 versus 0.61, P = 0.03). Five respondents underwent amputation, with lower SF-6D scores that approached significance (0.48 versus 0.6, P = 0.06). Conclusions. The SF-6D health state utilities measure demonstrated convergent validity without evidence of ceiling or floor effects. The SF-6D is a health state utilities measure suitable for further research in sarcoma patients.


Use of cone beam computed tomography in implant dentistry: the International Congress of Oral Implantologists consensus report.
The International Congress of Oral Implantologists has supported the development of this consensus report involving the use of Cone Beam Computed Tomography (CBCT) in implant dentistry with the intent of providing scientifically based guidance to clinicians regarding its use as an adjunct to traditional imaging modalities. The literature regarding CBCT and implant dentistry was systematically reviewed. A PubMed search that included studies published between January 1, 2000, and July 31, 2011, was conducted. Oral presentations, in conjunction with these studies, were given by Dr. Erika Benavides, Dr. Scott Ganz, Dr. James Mah, Dr. Myung-Jin Kim, and Dr. David Hatcher at a meeting of the International Congress of Oral Implantologists in Seoul, Korea, on October 6-8, 2011. The studies published could be divided into four main groups: diagnostics, implant planning, surgical guidance, and postimplant evaluation. The literature supports the use of CBCT in dental implant treatment planning particularly in regards to linear measurements, three-dimensional evaluation of alveolar ridge topography, proximity to vital anatomical structures, and fabrication of surgical guides. Areas such as CBCT-derived bone density measurements, CBCT-aided surgical navigation, and postimplant CBCT artifacts need further research. ICOI RECOMMENDATIONS: All CBCT examinations, as all other radiographic examinations, must be justified on an individualized needs basis. The benefits to the patient for each CBCT scan must outweigh the potential risks. CBCT scans should not be taken without initially obtaining thorough medical and dental histories and performing a comprehensive clinical examination. CBCT should be considered as an imaging alternative in cases where the projected implant receptor or bone augmentation site(s) are suspect, and conventional radiography may not be able to assess the true regional three-dimensional anatomical presentation. The smallest possible field of view should be used, and the entire image volume should be interpreted.


Utility of the SEER-Medicare data to identify chemotherapy use.
Medicare claims include codes for chemotherapy administration and specific drugs given, and researchers are increasingly using these data to measure the use of chemotherapy. However, the validity and completeness of these data as a source of information has not been established. This analysis is intended to assess the utility of the Medicare claims to capture chemotherapy use. Persons with breast, colorectal, and ovarian cancer were identified from the linked SEER-Medicare data. Their Medicare claims were reviewed to determine if there were any bills for chemotherapy, and if so, if there were claims for specific agents. This information was compared with data on the first course of treatment obtained from hospitals and treating physicians by the SEER registries through an NCI-supported Patterns of Care Studies (POC). Agreement was measured using kappa statistics. The sensitivity of the Medicare claims to capture chemotherapy, as reported from the POC data, was also measured. An additional comparison assessed the agreement between the two data sources concerning which specific drugs had been given. For all of the cancers, there was a high level of agreement between the Medicare claims and the POC data regarding whether or not the patient had received chemotherapy (kappa >or=0.73). The sensitivity of the Medicare data to determine if a person had received chemotherapy was high (>or=88%). In cases where the Medicare claim included a code for a specific drug, there high agreement between Medicare and POC about the specific drug given in breast and colorectal cancers, although the agreement was lower for ovarian cancers. The sensitivity of the Medicare claims to identify specific agents varies by cancer type. The Medicare claims can be used to identify which persons are receiving chemotherapy. The utility of Medicare data to measure treatment with specific agents varies by cancer type and specific agent. For some cancers, it is possible to use these claims to assess use of specific drugs, while for other drugs the data are limited.


"We Tie Up the Loose Ends": Homecare Nursing in a Changing Health Care Landscape.
During the last decades, the work of homecare nurses has been affected by several changes, including an aging population, the decentralization of health care, nursing recruitment crises and the scarcity of public resources. Few scholars have analyzed how these changes have impacted homecare nursing. In this article, we describe and discuss aspects of homecare nurses' work, with specific focus on nurses "organising work." We outline three phenomena that are increasingly occurring: (a) homecare nurses are frequently involved in negotiating care level and, consequently, what kind of care the patient will receive; (b) homecare nurses' clinical practice has become increasingly advanced; and (c) and homecare nurses play an important role in coordinating care among interdependent actors. The article draws on material from participant observation and interviews with homecare nurses in two Norwegian studies. Changes in work practice increase the demand for nurses to be competent and have excellent organizational and collaborative skills.


The Relationship Between Intuitive Eating and Postpartum Weight Loss.
Objective Postpartum weight loss is challenging for new mothers who report limited time and difficulties following traditional weight loss methods. Intuitive eating (IE) is a behavior that includes eating based on physical hunger and fullness and may have a role in encouraging weight loss. The purpose of this study was to examine the relationship between IE and postpartum weight loss. Methods Women 12-18 months postpartum completed a questionnaire regarding weight changes surrounding pregnancy, exercise, breastfeeding and intuitive eating using the Intuitive Eating Scale. Latent growth curve modeling was utilized to determine the relationship between IE, breastfeeding, weight gain during pregnancy, and postpartum weight trajectories. Results Participants (n = 50) were 28.5 ± 4.9 years old, had an average pre-pregnancy BMI of 26.4 ± 6.8 and the majority were married, and non-Hispanic white. The conditional model revealed that more intuitive eating practices predicted greater postpartum BMI decreases (Est. = -0.10, p < .05) when controlling for breastfeeding duration, exercise duration, and initial BMI and pregnancy BMI changes. Greater pregnancy BMI increases were associated with more rapid postpartum BMI decreases (Est. = -0.34, p < .001) while breastfeeding duration, exercise and initial BMI were not related. Conclusions for Practice Postpartum weight retention is a challenge for many women. Following a more intuitive eating approach to food consumption may encourage postpartum weight loss without the required weighing, measuring, recording and assessing dietary intake that is required of traditional weight loss programs. IE could offer an alternative approach that may be less arduous for new mothers.


External Validation of Prediction Models for Pneumonia in Primary Care Patients with Lower Respiratory Tract Infection: An Individual Patient Data Meta-Analysis.
Pneumonia remains difficult to diagnose in primary care. Prediction models based on signs and symptoms (S&S) serve to minimize the diagnostic uncertainty. External validation of these models is essential before implementation into routine practice. In this study all published S&S models for prediction of pneumonia in primary care were externally validated in the individual patient data (IPD) of previously performed diagnostic studies. S&S models for diagnosing pneumonia in adults presenting to primary care with lower respiratory tract infection and IPD for validation were identified through a systematical search. Six prediction models and IPD of eight diagnostic studies (N total = 5308, prevalence pneumonia 12%) were included. Models were assessed on discrimination and calibration. Discrimination was measured using the pooled Area Under the Curve (AUC) and delta AUC, representing the performance of an individual model relative to the average dataset performance. Prediction models by van Vugt et al. and Heckerling et al. demonstrated the highest pooled AUC of 0.79 (95% CI 0.74-0.85) and 0.72 (0.68-0.76), respectively. Other models by Diehr et al., Singal et al., Melbye et al., and Hopstaken et al. demonstrated pooled AUCs of 0.65 (0.61-0.68), 0.64 (0.61-0.67), 0.56 (0.49-0.63) and 0.53 (0.5-0.56), respectively. A similar ranking was present based on the delta AUCs of the models. Calibration demonstrated close agreement of observed and predicted probabilities in the models by van Vugt et al. and Singal et al., other models lacked such correspondence. The absence of predictors in the IPD on dataset level hampered a systematical comparison of model performance and could be a limitation to the study. The model by van Vugt et al. demonstrated the highest discriminative accuracy coupled with reasonable to good calibration across the IPD of different study populations. This model is therefore the main candidate for primary care use.


The effect of depression on stage at diagnosis, treatment, and survival in pancreatic adenocarcinoma.
Depression has been associated with delayed presentation, inadequate treatment, and poor survival in patients with cancer. Using Surveillance, Epidemiology and End Results and Medicare linked data (1992-2005), we identified patients with pancreatic adenocarcinoma (N = 23,745). International classification of diseases, 9th edition, clinical modification codes were used to evaluate depression during the 3 to 27 months before the diagnosis of cancer. The effect of depression on receipt of therapy and survival was evaluated in univariate and multivariate models. Of patients with pancreatic cancer in our study, 7.9% had a diagnosis of depression (N = 1,868). Depression was associated with increased age, female sex, white race, single or widowed status, and advanced stage disease (P < .0001). In an adjusted model, patients with locoregional disease and depression had 37% lower odds of undergoing surgical resection (odds ratio, 0.63; 95% confidence interval, 0.52-0.76). In patients with locoregional disease, depression was associated with lower 2-year survival (hazard ratio, 1.20; 95% confidence interval, 1.09-1.32). After adjusting for surgical resection, this association was attenuated (hazard ratio, 1.14; 95% confidence interval, 1.04-1.26). In patients who underwent surgical resection, depression was a significant predictor of survival (hazard ratio, 1.34; 95% confidence interval, 1.04-1.73). Patients with distant disease and depression had 21% lower odds of receiving chemotherapy (odds ratio, 0.79; 95% confidence interval, 0.70-0.90). After adjusting for chemotherapy for distant disease, depression was no longer a significant predictor of survival (hazard ratio, 1.03; 95% confidence interval, 0.97-1.09). The decreased survival associated with depression appears to be mediated by a lower likelihood of appropriate treatment in depressed patients. Accurate recognition and treatment of pancreatic cancer patients with depression may improve treatment rates and survival.


CHARMM-GUI HMMM Builder for Membrane Simulations with the Highly Mobile Membrane-Mimetic Model.
Slow diffusion of the lipids in conventional all-atom simulations of membrane systems makes it difficult to sample large rearrangements of lipids and protein-lipid interactions. Recently, Tajkhorshid and co-workers developed the highly mobile membrane-mimetic (HMMM) model with accelerated lipid motion by replacing the lipid tails with small organic molecules. The HMMM model provides accelerated lipid diffusion by one to two orders of magnitude, and is particularly useful in studying membrane-protein associations. However, building an HMMM simulation system is not easy, as it requires sophisticated treatment of the lipid tails. In this study, we have developed CHARMM-GUI HMMM Builder (http://www.charmm-gui.org/input/hmmm) to provide users with ready-to-go input files for simulating HMMM membrane systems with/without proteins. Various lipid-only and protein-lipid systems are simulated to validate the qualities of the systems generated by HMMM Builder with focus on the basic properties and advantages of the HMMM model. HMMM Builder supports all lipid types available in CHARMM-GUI and also provides a module to convert back and forth between an HMMM membrane and a full-length membrane. We expect HMMM Builder to be a useful tool in studying membrane systems with enhanced lipid diffusion.


Correlation of circulating immune complexes and complement breakdown products with the severity of the disease in human schistosomiasis mansoni.
Circulating immune complexes and complements compounds were measured in serum and plasma from 66 patients with three different clinical forms of chronic schistosomiasis mansoni: intestinal, hepato-intestinal and hepatosplenic. Three different methods were used: the 125I-C1q-binding assay, conglutinin-binding assay (KgB) and Raji cell-binding assay. Approximately 25% of the patients were positive for circulating immune complexes as measured by the C1q and Raji assays. The levels of complexes increased significantly with the severity of the disease. 60% of the patients were positive for immune complexes as measured by the KgB-assay but the incidence of positive results was not clearly influenced by the stage of the disease. There was no significant correlation between immunoglobulin levels and immune complexes. The complement profile of these patients does not suggest a dramatic activation of the complement system. However, there was a progressive decrease in the plasma levels of C4 and an increase of C3d levels which correlated significantly with the severity of the disease.


Simvastatin induced rhabdomyolysis and an important clinical link with hypothyroidism.
An 85-year-old woman with renal impairment and hypothyroidism was commenced on high dose simvastatin (80 mg) for better lipid control. Shortly after this she developed severe muscular weakness and laboratory evidence of rhabdomyolysis. Despite having hypothyroidism controlled for years with L-thyroxine (100 mcg), her biochemistry now reflected a hypothyroid state with inadequate thyroid replacement. On discontinuing her simvastatin to treat her rhabdomyolysis, the patient's TSH level decreased to normal within 4 weeks without any change in L-thyroxine dosage. To our knowledge this is only the second case reported in the literature of a rare but important interaction between simvastatin and L-thyroxine and the first case reported with associated rhabdomyolysis.


Assessment of the knowledge of United Arab Emirates dentists of Child Maltreatment, protection and safeguarding.
Child safeguarding is society's responsibility. Dentists are uniquely positioned to recognise Child Abuse and Neglect (CAN) in dental practice and the wider society. The United Arab Emirates (UAE) introduced a child protection law in 2016. We aimed to assess the awareness of UAE dentists of child maltreatment, protection and safeguarding. Study Design A cross-sectional survey. We surveyed 381 UAE dentists about the knowledge and practice of CAN and safeguarding issues using a self-administered anonymous questionnaire. Statistical analysis was carried out using Chi-square, t-test, ANOVA and Pearson's correlation test and statistical significance was set as p <0.05. Over 39 % (n=152) of the responders suspected CAN; male dentists suspected more CAN than females (p=0.015). Orthodontists, paediatric dentists (p<0.001) and female dentists (p=0.001) were more knowledgeable about diagnosing CAN. Paediatric dentists attended more CAN-related postgraduate training (p<0.001) than other specialties. Over 90% (n=346) believed that CAN should be addressed, 58.1% (n=224) and 54.1% (n=206) had CAN undergraduate and postgraduate training respectively but 53.5% (n=204) were unaware of local child protection guidelines. Dentists barriers to child protection reporting were; fear of family violence (59.6%, n=227), lack of knowledge of referral process (60.2%, n=228) and lack of diagnosis certainty (54.9%, n=206). UAE dentists qualified in Western and Asian countries had fewer barriers for child protection reporting (p=0.022) than the Arab and Gulf Cooperation Council qualified dentists. A large minority of UAE dentists suspected CAN. Factors influencing child protection reporting were identified. Dentists' gender, specialty, and country of qualification affected their knowledge of CAN and practice of safeguarding. Child protection training is recommended.


Formation and physical stability of the amorphous phase of ranitidine hydrochloride polymorphs prepared by cryo-milling.
The effect of cryo-milling on ranitidine hydrochloride polymorphs form 1 and 2 was investigated with particular interest in the formation and the stability of the amorphous phase. Cryo-milling was carried out using an oscillatory ball mill for periods up to 60 min, with re-cooling of the milling chamber with liquid nitrogen at 15 min intervals. Results showed that both ranitidine hydrochloride form 1 and form 2 could be fully converted to the amorphous form as determined by XRPD within 30 min. Upon 14 days storage, the amorphous samples crystallized back to their original forms. In the stability studies of amorphous drug with seeds, significant polymorphic transformation from form 1 to form 2 was not found when amorphous form prepared from form 1 was seeded with form 2 crystals by gentle physical mixing. In contrast, amorphous form prepared from form 1 seeded with form 2 crystals by ball milling for 1 min and simultaneous cryo-milling methods were found to transform amorphous form prepared from form 1 to crystalline form 2 under some storage conditions. The transformation was thought to be facilitated by interaction between seed crystals and amorphous drug and a storage temperature above the Tg. Amorphous form prepared from form 2 did not transform to crystalline form 1 under any conditions used in this study.


Potential neurotoxicity of prenatal exposure to sevoflurane on offspring: Metabolomics investigation on neurodevelopment and underlying mechanism.
Repeated or prolonged anesthesia to pregnant women disturbs neurodevelopment of developing infants, but its mechanism has not been elaborated absolutely. This study was conducted to investigate the mechanism of potential neurotoxicity on their offspring generation after sevoflurane anesthesia in adult animals during pregnancy based on metabolomics. 16 pregnant rats were equally assigned to sevoflurane group and control group, and serum samples were collected from their 7-day-old offspring for metabolomics analysis using ultra performance liquid chromatography coupled to time-of-flight mass spectrometry. Principal component analysis and partial least squares-discriminate analysis were used for pattern recognition, and pathway analysis was performed by MetaboAnalyst platform. 29 metabolites were discovered as neurotoxicity related-biomarkers, among which S-Adenosylmethioninamine was inhibited dramatically after sevoflurane exposure. Prenatal exposure to sevoflurane led to a significant reduction in S-Adenosylmethionine level, as shown by enzyme-linked immunosorbent assay. Pathway analysis highlighted that prenatal exposure to sevoflurane induced alteration in arginine/proline metabolism, cysteine/methionine metabolism, and so on. The most important altered metabolic pathway was arginine/proline metabolism. This study suggests that abnormal methylation and disturbed arginine/proline metabolism may crucially contribute to the mechanism with neurotoxicity on offspring generation after sevoflurane anesthesia in adult animals during pregnancy, and dietary supplement of S-Adenosylmethionine and modulating arginine/proline metabolism may be the potential therapeutic targets for protecting neurodevelopment from detrimental effects of prenatal exposure to inhalational anesthetics.


Matching-adjusted indirect comparison of bosutinib, dasatinib and nilotinib effect on survival and major cytogenetic response in treatment of second-line chronic phase chronic myeloid leukemia.
Objective: In clinical trials of second-line therapies for chronic phase chronic myeloid leukemia (CP-CML), to date, only single-arm trials have been conducted for the available tyrosine kinase inhibitor treatments (bosutinib, dasatinib and nilotinib). These trials included heterogeneous patient populations in terms of disease and baseline characteristics. These hamper the use of standard network meta-analyses for indirect treatment comparison of relative efficacy. In this situation, a matching-adjusted indirect comparison (MAIC) in second-line CP-CML was performed. The aim was to compare the relative efficacies of bosutinib, dasatinib and nilotinib in second-line CP-CML patients.Methods: The MAIC was preceded by a systematic literature review that ensured inclusion of the underlying data for the analyses. The outcomes were measured in terms of overall survival (OS), progression-free survival (PFS) and major cytogenetic response (MCyR). The treatments were quantitatively compared based on Cox proportional hazard ratio (HR) regressions, on restricted mean survival (RMST, when the proportionality assumption showed evidence of violation) and on odds ratios (for response measures).Results: Comparing with dasatinib, bosutinib resulted in HRs for PFS and OS of 0.63 (0.44-0.90, p < .05) and 0.82 (0.54-1.26, p = .37) respectively, and resulted in an OR for MCyR of 0.78 (0.53-1.16). Although the proportionality of hazards assumption was violated for PFS, the RMST analyses confirmed the findings of the Cox regression. When compared with nilotinib, bosutinib showed a significant HR of 0.54 (0.38-0.76, p < .01) in favor of bosutinib for PFS, a non-significant HR of 0.72 (0.46-1.13, p = .16) for OS and a non-significant OR of 0.98 (0.71-1.35) for MCyR.Conclusions: Bosutinib had a significantly greater PFS than both dasatinib and nilotinib. For OS, the findings were numerically in favor of bosutinib, but not statistically significant. For MCyR, the findings were numerically in favor of dasatinib and nilotinib, but not statistically significant.


Lagrangian statistics in weakly forced two-dimensional turbulence.
Measurements of Lagrangian single-point and multiple-point statistics in a quasi-two-dimensional stratified layer system are reported. The system consists of a layer of salt water over an immiscible layer of Fluorinert and is forced electromagnetically so that mean-squared vorticity is injected at a well-defined spatial scale ri. Simultaneous cascades develop in which enstrophy flows predominately to small scales whereas energy cascades, on average, to larger scales. Lagrangian correlations and one- and two-point displacements are measured for random initial conditions and for initial positions within topological centers and saddles. Some of the behavior of these quantities can be understood in terms of the trapping characteristics of long-lived centers, the slow motion near strong saddles, and the rapid fluctuations outside of either centers or saddles. We also present statistics of Lagrangian velocity fluctuations using energy spectra in frequency space and structure functions in real space. We compare with complementary Eulerian velocity statistics. We find that simultaneous inverse energy and enstrophy ranges present in spectra are not directly echoed in real-space moments of velocity difference. Nevertheless, the spectral ranges line up well with features of moment ratios, indicating that although the moments are not exhibiting unambiguous scaling, the behavior of the probability distribution functions is changing over short ranges of length scales. Implications for understanding weakly forced 2D turbulence with simultaneous inverse and direct cascades are discussed.


The epidemiology of regional and widespread musculoskeletal pain in rural versus urban settings in those ≥55 years.
To examine whether the prevalence of regional and chronic widespread pain (CWP) varies with rurality and to determine the characteristics of persons in rural locations in whom pain is found to be in excess. Participants, aged ≥55 years, from participating general practices in seven different geographical locations in Scotland were sent a postal questionnaire. The 1-month prevalence of 10 regional pain conditions plus CWP was identified using body manikins. Differences in the prevalence of pain with differing rurality were examined using Chi(2) test for trend. Thereafter, among the rural population, the relationships between pain and putative risk factors were examined using Poisson regression. Thus, results are described as risk ratios. There was some evidence to suggest that the prevalence of CWP increased with increasing rurality, although the magnitude of this was slight. No large or significant differences were observed with any regional pain conditions. Factors associated with the reporting of CWP included poor general health, feeling downhearted most of the time and selected measures of social contact. Factors independently associated with CWP included female gender (risk ratio: 1.24; 95% confidence interval (CI): 0.997-1.55), poor self-rated health (risk ratio: 3.50; 95% CI: 1.92-6.39) and low mood (risk ratio: 1.54; 95% CI: 1.07-2.20). Also, having fewer than 10 people to turn to in a crisis was associated with a decrease in the risk of CWP - risk ratio: 0.68 (95% CI: 0.50-0.93) and 0.78 (95% CI: 0.60-1.02) for those with 5-10 and <5 people, respectively. This study provides no evidence that the prevalence of regional musculoskeletal pain is increased in rural settings, although there is some evidence of a modest increase in CWP. Risk factors for CWP are similar to those seen in the urban setting, including markers of general health, mental health and also aspects of social contact. It may be, however, that social networks are more difficult to maintain in rural settings, and clinicians should be aware of the negative effect of perceived social isolation on pain in rural areas.


ORAI1 genetic polymorphisms associated with the susceptibility of atopic dermatitis in Japanese and Taiwanese populations.
Atopic dermatitis is a chronic inflammatory skin disease. Multiple genetic and environmental factors are thought to be responsible for susceptibility to AD. In this study, we collected 2,478 DNA samples including 209 AD patients and 729 control subjects from Taiwanese population and 513 AD patients and 1027 control subject from Japanese population for sequencing and genotyping ORAI1. A total of 14 genetic variants including 3 novel single-nucleotide polymorphisms (SNPs) in the ORAI1 gene were identified. Our results indicated that a non-synonymous SNP (rs3741596, Ser218Gly) associated with the susceptibility of AD in the Japanese population but not in the Taiwanese population. However, there is another SNP of ORAI1 (rs3741595) associated with the risk of AD in the Taiwanese population but not in the Japanese population. Taken together, our results indicated that genetic polymorphisms of ORAI1 are very likely to be involved in the susceptibility of AD.


Primary ∆4-3-oxosteroid 5β-reductase deficiency: two cases in China.
Aldo-keto reductase 1D1 (AKR1D1) deficiency, a rare but life-threatening form of bile acid deficiency, has not been previously described in China. Here, we describe the first two primary ∆4-3-oxosteroid 5β-reductase deficiency patients in Mainland China diagnosed by fast atom bombardment-mass spectroscopy of urinary bile acids and confirmed by genetic analysis. A high proportion of atypical 3-oxo-∆4-bile acids in the urine indicated a deficiency in ∆4-3-oxosteroid 5β-reductase. All of the coding exons and adjacent intronic sequence of the AKR1D1 gene were sequenced using peripheral lymphocyte genomic DNA of two patients and one of the patient's parents. One patient exhibited compound heterozygous mutations: c.396C>A and c.722A>T, while the other was heterozygous for the mutation c.797G>A. Based on these mutations, a diagnosis of primary ∆4-3-oxosteroid 5β-reductase deficiency could be confirmed. With ursodeoxycholic acid treatment and fat-soluble vitamin supplements, liver function tests normalized rapidly, and the degree of hepatomegaly was markedly reduced in both patients.


Reflection and peer feedback for augmenting emotional intelligence among undergraduate students: A quasi-experimental study from a rural medical college in central India.
Professionalism is the foundation of the doctor-patient relationship with emotional competency at its core. This competency is based on emotional intelligence (EI), contributing to effective work performance. As EI is reasonably new in health professions education in India, this study was conducted to assess the effect of reflection and peer feedback on EI scores among undergraduate medical students and explore facilitating and hindering factors for augmenting EI. This pre- and post interventional study was conducted among 94 final-year (Part I) medical students from a rural medical college in Central India. Baseline assessment of EI scores was done using a self-reported validated EI scale, and then, a mini-workshop was conducted to sensitize students on EI and to train them in writing reflection and giving peer feedback. Between the pretest and posttest, students were asked to write weekly reflection and take monthly feedback from the "peer" of their choice. Posttest assessment was done at 1 week, 1 month, and 3 months. Force-field analysis was undertaken with 10 students each with highest and lowest EI scores to assess facilitating and hindering factors. There was a significant improvement (P < 0.0001) in the EI scores at each subsequent time point from baseline. Students who were male, from nuclear families and considered themselves spiritual had significantly higher median EI scores. Students reported self-motivation, social support, and openness to learn new things as enabling forces for augmenting EI. Hindering factors were time constraint and lack of mutual trust in the relationship between students. Based on the findings, it can be concluded that personal introspection methods such as self-reflection and peer feedback help to improve the EI of undergraduate students. Therefore, it is imperative that the students are trained in these skills for building their emotional competencies.


Clinical efficacy of zanolimumab (HuMax-CD4): two phase 2 studies in refractory cutaneous T-cell lymphoma.
The efficacy and safety of zanolimumab in patients with refractory cutaneous T-cell lymphoma (CTCL) have been assessed in two phase 2, multicenter, prospective, open-label, uncontrolled clinical studies. Patients with treatment refractory CD4(+) CTCL (mycosis fungoides [MF], n = 38; Sézary syndrome [SS], n = 9) received 17 weekly infusions of zanolimumab (early-stage patients, 280 and 560 mg; advanced-stage patients, 280 and 980 mg). The primary end point was objective response (OR) as assessed by composite assessment of index lesion disease activity score. Secondary end points included physician's global assessment (PGA), time to response, response duration, and time to progression. ORs were recorded for patients in both CTCL types (MF, 13 ORs; SS, 2 ORs). In the high-dose groups (560 and 980 mg dose groups), a response rate of 56% was obtained with a median response of 81 weeks. Adverse events reported most frequently included low-grade infections and eczematous dermatitis. Zanolimumab showed marked clinical efficacy in the treatment of patients with refractory MF, with early onset of response, high response rate, and durable responses. The treatment was well tolerated with no dose-related toxicity other than the targeted depletion of peripheral T cells. A pivotal study has been initiated based on these findings.


Notes on the phlebotomine sand flies from the Peruvian southeast--I. Description of Lutzomyia (Helcocyrtomyia) adamsi n. sp. (Diptera: Psychodidae).
A new species of phlebotomine sand fly, Lutzomyia adamsi n. sp., is described and illustrated from specimens collected during August 1994, in Sandia, Department of Puno-Peru. According to the Oficina Nacional de Evaluacion de Recursos Naturales(ONERN 1976), this locality is situated in the life zone known as humid, mountain, low tropical forest (bh-MBT). Many areas in the northern part of Puno, mainly in the Inambari and Tambopata basins, are endemic to leishmaniasis. These areas are the continuation of others, largely known as "leishmaniasic" in the departments of Cusco and Madre de Dios. The morphological characteristics indicated that this species belongs to the genus Lutzomyia, subgenus Helcocyrtomyia Barretto, 1962.


Sabadinine: a potential non-peptide anti-severe acute-respiratory-syndrome agent identified using structure-aided design.
A novel human coronavirus has been reported to be the causative agent of severe acute respiratory syndrome (SARS). Since replication of HcoVs depends on extensive proteolytic processing, the main proteinase, 3CLpro, is an attractive drug target for anti-SARS agents. We have employed molecular docking of a chemical database into the active site of 3CLpro to search for non-peptidyl inhibitors. One compound was identified to be the natural product sabadinine, isolated from a historical herbal remedy.