The effect of cognitive behavioral group therapy for depression: a meta-analysis 2000-2010.
The goals of the meta-analysis were to investigate the overall effectiveness of cognitive behavioral group therapy (CBGT) for depression and relapse prevention in depression from 2000 to 2010, and to investigate how the variables (episode, residual symptoms, group size, control group, group manual, therapist experience, therapy frequency, session length, and take-home assignment) of a CBGT study could affect the effect size. This study collected actual study designs sought of CBGT for depression published from 2000 to 2010. These studies were then cross-referenced using Medical Subject Headings (MeSH) with the following keywords: group therapy, cognitive therapy, cognitive behavioral therapy, cognitive behavioral group therapy, psychotherapy, depression, relapse, and recurrence. The quality of the studies was evaluated using Cochrane Collaboration Guidelines. The effect size of CBGT on depression and relapse prevention in depression used the formula devised by Hedges and Olkin (1985). The study investigated the results of 32 studies on the effect of CBGT for depression. The CBGT had an immediate (g=-0.40) and continuous effect over 6 months (g=-0.38), but no continuous effect after 6 months (g=-0.06). The CBGT lowered the relapse rate of depression (RD = 0.16). Variables significantly different from each other in terms of immediate effect were: CBGT versus usual care, therapy sessions lasting longer than 1 hour, and take-home assignments. Preintervention severity of depression and patient turnover rate were found to be significantly related to the size of the immediate effect. The relapse rate after 6 months was significantly related only to "participants have no residual symptoms/participants did not mention residual symptoms." Researchers and clinicians should take note that CBGT had a moderate effect on the level of depression and a small effect on the relapse rate of depression. The results of this study suggest that the patient should receive a course of therapy at least every 6 months.


Virulence and biofilms as promising targets in developing antipathogenic drugs against candidiasis.
Candida albicans has remained the main etiological agent of candidiasis, challenges clinicians with high mortality and morbidity. The emergence of resistance to antifungal drugs, toxicity and lower efficacy have all contributed to an urgent need to develop alternative drugs aiming at novel targets in C. albicans. Targeting the production of virulence factors, which are essential processes for infectious agents, represents an attractive substitute for the development of newer anti-infectives. The present review highlights the recent developments made in the understanding of the pathogenicity of C. albicans. Production of hydrolytic enzymes, morphogenesis and biofilm formation, along with their molecular and metabolic regulation in Candida are discussed with regard to the development of novel antipathogenic drugs against candidiasis.


Is childhood vaccination associated with asthma? A meta-analysis of observational studies.
The possible link between immunization and atopic diseases has been under intense debate in the last decade. The aim of this study was to systematically review the available evidence on the association of whole-cell pertussis and BCG vaccination with the risk of asthma in childhood and adolescence. The major medical electronic databases (Medline, National Library of Medicine Gateway, and Cochrane Library) were searched, and reference lists of the relevant publications were reviewed for relevant birth-cohort studies and randomized, controlled trials from 1966 to March 2006. Only studies that directly compared vaccinated and unvaccinated children, validated vaccination status by medical charts, and used preset criteria to define asthma were included. Data were abstracted by using a standardized protocol and computerized report form. Results were analyzed by applying a fixed-effect or random-effect model, according to the heterogeneity of the studies. Sensitivity analyses by scoring criteria were performed. Seven studies of pertussis vaccination (with a total of 186,663 patients) and 5 studies of BCG vaccination (with a total of 41,479 patients) met our inclusion criteria. No statistically significant association was detected between either whole-cell pertussis or BCG vaccination and incidence rates of asthma during childhood and adolescence. This lack of a significant association proved to be robust on sensitivity analyses for BCG but not for pertussis vaccine. Currently available data, based on observational studies, do not support an association, provocative or protective, between receipt of the BCG or whole-cell pertussis vaccine and risk of asthma in childhood and adolescence.


Pyroxasulfone-Resistant Annual Ryegrass (Lolium rigidum) Has Enhanced Capacity for Glutathione Transferase-Mediated Pyroxasulfone Conjugation.
The herbicide pyroxasulfone was widely introduced in 2012, and cases of evolved resistance in weeds such as annual ryegrass (Lolium rigidum Gaud.) and tall waterhemp [Amaranthus tuberculatus (Moq.) Sauer] have started to emerge. Pyroxasulfone is detoxified by tolerant crops, and by annual ryegrass that has been recurrently selected with pyroxasulfone, in a pathway that is hypothesized to involve glutathione conjugation. In the current study, it was confirmed that pyroxasulfone is conjugated to glutathione in vitro by glutathione transferases (GSTs) purified from susceptible and resistant annual ryegrass populations and from a tolerant crop species, wheat. The extent of conjugation corresponded to the pyroxasulfone resistance level. Pyroxasulfone-conjugating activity was higher in radicles, roots, and seeds compared to coleoptiles or expanded leaves. Among the GSTs purified from annual ryegrass radicles and seeds, an orthologue of Brachypodium distachyon GSTF13 was >20-fold more abundant in the pyroxasulfone-resistant population, suggesting that this protein could be responsible for pyroxasulfone conjugation.


Rapid determination of the tumour stroma ratio in squamous cell carcinomas with desorption electrospray ionization mass spectrometry (DESI-MS): a proof-of-concept demonstration.
Squamous cell carcinomas constitute a major class of head & neck cancers, where the tumour stroma ratio (TSR) carries prognostic information. Patients affected by stroma-rich tumours exhibit a poor prognosis and a higher chance of relapse. As such, there is a need for a technology platform that allows rapid determination of the tumour stroma ratio. In this work, we provide a proof-of-principle demonstration that Desorption Electrospray Ionization Mass Spectrometry (DESI-MS) can be used to determine tumour stroma ratios. Slices from three independent mouse xenograft tumours from the human FaDu cell line were subjected to DESI-MS imaging, staining and detailed analysis using digital pathology methods. Using multivariate statistical methods we compared the MS profiles with those of isolated stromal cells. We found that m/z 773.53 [PG(18:1)(18:1) - H]-, m/z 835.53 [PI(34:1) - H]- and m/z 863.56 [PI(18:1)(18:0) - H]- are biomarker ions that can distinguish FaDu cancer from cancer associated fibroblast (CAF) cells. A comparison with DESI-MS analysis of controlled mixtures of the CAF and FaDu cells showed that the abundance of the biomarker ions above can be used to determine, with an error margin of close to 5% compared with quantitative pathology estimates, TSR values. This proof-of-principle demonstration is encouraging and must be further validated using human samples and a larger sample base. At maturity, DESI-MS thus may become a stand-alone molecular pathology tool providing an alternative rapid cancer assessment without the need for time-consuming staining and microscopy methods, potentially further conserving human resources.


Histone Deacetylase Inhibitors Enhance CD4 T Cell Susceptibility to NK Cell Killing but Reduce NK Cell Function.
In the search for a cure for HIV-1 infection, histone deacetylase inhibitors (HDACi) are being investigated as activators of latently infected CD4 T cells to promote their targeting by cytotoxic T-lymphocytes (CTL). However, HDACi may also inhibit CTL function, suggesting different immunotherapy approaches may need to be explored. Here, we study the impact of different HDACi on both Natural Killer (NK) and CTL targeting of HIV-1 infected cells. We found HDACi down-regulated HLA class I expression independently of HIV-1 Nef which, without significantly compromising CTL function, led to enhanced targeting by NK cells. HDACi-treated HIV-1-infected CD4 T cells were also more effectively cleared than untreated controls during NK co-culture. However, HDACi impaired NK function, reducing degranulation and killing capacity. Depending on the HDACi and dose, this impairment could counteract the benefit gained by treating infected target cells. These data suggest that following HDACi-induced HLA class I down-regulation NK cells kill HIV-1-infected cells, although HDACi-mediated NK cell inhibition may negate this effect. Our data emphasize the importance of studying the effects of potential interventions on both targets and effectors.


Glucagon-like peptide-1 increases myocardial glucose uptake via p38alpha MAP kinase-mediated, nitric oxide-dependent mechanisms in conscious dogs with dilated cardiomyopathy.
We have shown that glucagon-like peptide-1 (GLP-1[7-36] amide) stimulates myocardial glucose uptake in dilated cardiomyopathy (DCM) independent of an insulinotropic effect. The cellular mechanisms of GLP-1-induced myocardial glucose uptake are unknown. Myocardial substrates and glucoregulatory hormones were measured in conscious, chronically instrumented dogs at control (n=6), DCM (n=9) and DCM after treatment with a 48-hour infusion of GLP-1 (7-36) amide (n=9) or vehicle (n=6). GLP-1 receptors and cellular pathways implicated in myocardial glucose uptake were measured in sarcolemmal membranes harvested from the 4 groups. GLP-1 stimulated myocardial glucose uptake (DCM: 20+/-7 nmol/min/g; DCM+GLP-1: 61+/-12 nmol/min/g; P=0.001) independent of increased plasma insulin levels. The GLP-1 receptors were upregulated in the sarcolemmal membranes (control: 98+/-2 density units; DCM: 256+/-58 density units; P=0.046) and were expressed in their activated (65 kDa) form in DCM. The GLP-1-induced increases in myocardial glucose uptake did not involve adenylyl cyclase or Akt activation but was associated with marked increases in p38alpha MAP kinase activity (DCM+vehicle: 97+/-22 pmol ATP/mg/min; DCM+GLP-1: 170+/-36 pmol ATP/mg/min; P=0.051), induction of nitric oxide synthase 2 (DCM+vehicle: 151+/-13 density units; DCM+GLP-1: 306+/-12 density units; P=0.001), and GLUT-1 translocation (DCM+vehicle: 21+/-3% membrane bound; DCM+GLP-1: 39+/-3% membrane bound; P=0.005). The effects of GLP-1 on myocardial glucose uptake were blocked by pretreatment with the p38alpha MAP kinase inhibitor or the nonspecific nitric oxide synthase inhibitor nitro-l-arginine. GLP-1 stimulates myocardial glucose uptake through a non-Akt-1-dependent mechanism by activating cellular pathways that have been identified in mediating chronic hibernation and the late phase of ischemic preconditioning.


Accessory cell populations in the cornea.
According to the "classical" doctrine, resident cells of the cornea include the stratified epithelial cells, quiescent keratocytes, and a single layer of nondividing endothelial cells. However, it has become increasingly evident that other cell types are involved in the homeostasis of the cornea. The presence of various cell types from different lineages has raised concern among researchers as to what we are actually "seeing" in the cornea. Although definitive conclusions cannot yet be drawn, this review attempts to clarify the various accessory cell types reported in the human and murine cornea. The epithelial layer of the limbal area includes melanocytes, as well as antigen-presenting cells that are also present in the peripheral clear cornea. The most debated tissue currently is perhaps the corneal stroma, where resident keratocytes are not as large a population as was previously believed. Bone marrow-derived cells are found in the cornea, and these may not express the typical HLA molecules usually found on the surface of antigen-presenting cells. Nerve fibers extend though the superficial stroma to form a plexus beneath the epithelium. Although the cell body of the neuron itself is not in the cornea, neural glial cells, such as Schwann cells, are present in the stroma. The use of specific molecular markers and high-quality imaging techniques will be required to fully elucidate the various accessory cells of the cornea and their function.


Simulation Training for Residents Focused on Mechanical Ventilation: A Randomized Trial Using Mannequin-Based Versus Computer-Based Simulation.
Advances in knowledge regarding mechanical ventilation (MV), in particular lung-protective ventilation strategies, have been shown to reduce mortality. However, the translation of these advances in knowledge into better therapeutic performance in real-life clinical settings continues to lag. High-fidelity simulation with a mannequin allows students to interact in lifelike situations; this may be a valuable addition to traditional didactic teaching. The purpose of this study is to compare computer-based and mannequin-based approaches for training residents on MV. This prospective randomized single-blind trial involved 50 residents. All participants attended the same didactic lecture on respiratory pathophysiology and were subsequently randomized into two groups: the mannequin group (n = 25) and the computer screen-based simulator group (n = 25). One week later, each underwent a training assessment using five different scenarios of acute respiratory failure of different etiologies. Later, both groups underwent further testing of patient management, using in situ high-fidelity simulation of a patient with acute respiratory distress syndrome. Baseline knowledge was not significantly different between the two groups (P = 0.72). Regarding the training assessment, no significant differences were detected between the groups. In the final assessment, the scores of only the mannequin group significantly improved between the training and final session in terms of either global rating score [3.0 (2.5-4.0) vs. 2.0 (2.0-3.0), P = 0.005] or percentage of key score (82% vs. 71%, P = 0.001). Mannequin-based simulation has the potential to improve skills in managing MV.


Oligonucleotide fingerprinting detects genetic diversity among Ascochyta rabiei isolates from a single chickpea field in Tunisia.
Fifty isolates of Ascochyta rabiei (Pass.) Labr. were hierarchically sampled from four well-separated locations of a single chickpea field in Beja (Tunisia), and single-spored. DNA was isolated from in-vitro-grown mycelia, digested with HinfI or RsaI, and hybridized to a set of synthetic oligonucleotides complementary to simple repetitive sequences. According to the fingerprint patterns derived from the probes (CA)8, (CAA)5, (CAT)5 and (GATA)4, 12 different fungal haplotypes were found at various frequencies within the investigated field. Seven haplotypes were confined to one location only, four occurred at two, one at three, and none at all four locations. Most of the genetic variability originated from diversity within, rather than between, locations. In some cases, more than one haplotype was isolated from the same lesion of a single host plant. Genetic distances between isolates, as calculated from band-sharing data, varied between 0.05 and 0.22. Relatedness between the different haplotypes was evaluated by cluster analysis using UPGMA.


Multi-marker strategy of natriuretic peptide with either conventional or high-sensitivity troponin-T for acute coronary syndrome diagnosis in emergency department patients with chest pain: from the "Rule Out Myocardial Infarction using Computer Assisted Tomography" (ROMICAT) trial.
Compared to troponin alone, a dual-marker strategy with natriuretic peptides may improve acute coronary syndrome (ACS) diagnosis with a single blood draw and provide physiologic information regarding underlying heart disease. We evaluate the value of adding natriuretic peptides (myocyte stress markers) to troponins (myocardial injury markers) for diagnosing ACS in emergency department patients with chest pain. In 328 patients (53 ± 12 years, 63% men) with an initially negative conventional troponin and nonischemic electrocardiogram who underwent 64-slice cardiac computed tomography (CT), we measured conventional troponin-T (cTnT), high-sensitivity troponin-T (hsTnT), N-terminal pro-B type natriuretic peptide, and mid-regional pro-atrial natriuretic peptide. ACS was defined as myocardial infarction or unstable angina. CT was evaluated for coronary plaque, stenosis, and regional wall motion abnormality. Patients with ACS (n = 29, 9%) had higher concentrations of each biomarker compared to those without (all P < .01). Adding natriuretic peptides, especially N-terminal pro-B type natriuretic peptide, to both cTnT or hsTnT improved the C-statistics and net reclassification index for ACS, largely driven by correctly reclassifying events. Dual-negative marker results improved sensitivity (cTnT 38% to 83%-86%, hsTnT 59% to 86%-90%; all P < .01) and negative predictive value (cTnT 94% to 97%-98%, hsTnT 96% to 97%-98%) for ACS. Patients with dual-negative markers had the lowest percentage of CT coronary plaque, stenosis, and regional wall motion abnormality (all P-trend <.001). Among emergency department patients with low-intermediate likelihood of ACS, combining natriuretic peptides with either conventional or highly-sensitive troponin improved discriminatory capacity and allowed for better reclassification of ACS, findings supported by structural and functional CT results.


Deletion of pro-angiogenic factor vasohibin-2 ameliorates glomerular alterations in a mouse diabetic nephropathy model.
Angiogenesis has been implicated in glomerular alterations in the early stage of diabetic nephropathy. We previously reported the renoprotective effects of vasohibin-1 (VASH1), which is a novel angiogenesis inhibitor derived from endothelial cells, on diabetic nephropathy progression. Vasohibin-2 (VASH2) was originally identified as a VASH1 homolog and possesses pro-angiogenic activity in contrast to VASH1. In addition, VASH2 was recently shown to promote epithelial-to-mesenchymal transition via enhanced transforming growth factor (TGF)-β signaling in cancer cells. Herein, we investigated the pathogenic roles of VASH2 in diabetic nephropathy using VAHS2-deficient mice. The type 1 diabetes model was induced by intraperitoneal injections of streptozotocin in VASH2 homozygous knockout (VASH2LacZ/LacZ) or wild-type mice. These mice were euthanized 16 weeks after inducing hyperglycemia. Increased urine albumin excretion and creatinine clearance observed in diabetic wild-type mice were significantly prevented in diabetic VASH2-deficient mice. Accordingly, diabetes-induced increase in glomerular volume and reduction in glomerular slit-diaphragm density were significantly improved in VASH2 knockout mice. Increased glomerular endothelial area was also suppressed in VASH2-deficient mice, in association with inhibition of enhanced vascular endothelial growth factor (VEGF) receptor 2 (VEGFR2), but not VEGF level. Furthermore, glomerular accumulation of mesangial matrix, including type IV collagen, and increased expression of TGF-β were improved in diabetic VASH2 knockout mice compared with diabetic wild-type mice. Based on the immunofluorescence findings, endogenous VASH2 localization in glomeruli was consistent with mesangial cells. Human mesangial cells (HMCs) were cultured under high glucose condition in in vitro experiments. Transfection of VASH2 small interfering RNA (siRNA) into the HMCs resulted in the suppression of type IV collagen production induced by high glucose compared with control siRNA. These results indicate that VASH2 may be involved in diabetes-induced glomerular alterations, particularly impaired filtration barrier and mesangial expansion. Therefore, VASH2 is likely to represent a promising therapeutic target for diabetic nephropathy.


Intra-articular corticosteroids versus intra-articular corticosteroids plus methotrexate in oligoarticular juvenile idiopathic arthritis: a multicentre, prospective, randomised, open-label trial.
Little evidence-based information is available to guide the treatment of oligoarticular juvenile idiopathic arthritis. We aimed to investigate whether oral methotrexate increases the efficacy of intra-articular corticosteroid therapy. We did this prospective, open-label, randomised trial at ten hospitals in Italy. Using a concealed computer-generated list, children younger than 18 years with oligoarticular-onset disease were randomly assigned (1:1) to intra-articular corticosteroids alone or in combination with oral methotrexate (15 mg/m2; maximum 20 mg). Corticosteroids used were triamcinolone hexacetonide (shoulder, elbow, wrist, knee, and tibiotalar joints) or methylprednisolone acetate (ie, subtalar and tarsal joints). We did not mask patients or investigators to treatment assignments. Our primary outcome was the proportion of patients in the intention-to-treat population who had remission of arthritis in all injected joints at 12 months. This trial is registered with European Union Clinical Trials Register, EudraCT number 2008-006741-70. Between July 7, 2009, and March 31, 2013, we screened 226 participants and randomly assigned 102 to intra-articular corticosteroids alone and 105 to intra-articular corticosteroids plus methotrexate. 33 (32%) patients assigned to intra-articular corticosteroids alone and 39 (37%) assigned to intra-articular corticosteroids and methotrexate therapy had remission of arthritis in all injected joints (p=0·48). Adverse events were recorded for 20 (17%) patients who received methotrexate, which led to permanent treatment discontinuation in two patients (one due to increased liver transaminases and one due to gastrointestinal discomfort). No patient had a serious adverse event. Concomitant administration of methotrexate did not augment the effectiveness of intra-articular corticosteroid therapy. Future studies are needed to define the optimal therapeutic strategies for oligoarticular juvenile idiopathic arthritis. Italian Agency of Drug Evaluation.


From the concrete to the intangible: understanding the diverse experiences and impacts of new transport infrastructure.
Changes to the environment that support active travel have the potential to increase population physical activity. The Cambridgeshire Guided Busway is an example of such an intervention that provides new traffic-free infrastructure for walking, cycling and public transport. This qualitative investigation explored the diverse experiences of new transport infrastructure and its impacts on active travel behaviours. Thirty-eight adult participants from the Commuting and Health in Cambridge natural experimental study were purposively selected according to their demographic and travel behaviour change characteristics and invited to participate in semi-structured interviews between February and June 2013. A mixed-method, following-a-thread approach was used to construct two contrasting vignettes (stories) to which the participants were asked to respond as part of the interviews. Inductive thematic qualitative analysis of the interview data was performed with the aid of QSR NVivo8. Perceptions of the busway's attributes were important in shaping responses to it. Some participants rarely considered the new transport infrastructure or described it as unappealing because of its inaccessibility or inconvenient routing. Others located more conveniently for access points experienced the new infrastructure as an attractive travel option. Likewise, the guided buses and adjacent path presented ambiguous spaces which were received in different ways, depending on travel preferences. While new features such as on board internet access or off-road cycling were appreciated, shortcomings such as overcrowded buses or a lack of path lighting were barriers to use. The process of adapting to the environmental change was discussed in terms of planning and trialling new behaviours. The establishment of the busway in commuting patterns appeared to be influenced by whether the anticipated benefits of change were realised. This study examined the diverse responses to an environmental intervention that may help to explain small or conflicting aggregate effects in quantitative outcome evaluation studies. Place and space features, including accessibility, convenience, pleasantness and safety relative to the alternative options were important for the acceptance of the busway. Our findings show how environmental change supporting active travel and public transport can encourage behaviour change for some people in certain circumstances.


Addressing the Challenge of Pain Education in Low-Resource Countries: Essential Pain Management in Papua New Guinea.
Papua New Guinea (PNG) is a low-resource country in the South-West Pacific with considerable health care challenges, including a high burden of painful disease. The Essential Pain Management (EPM) educational program was developed to address the challenge of inadequate pain education in PNG and the first workshop was held in 2010. The aims of EPM are to improve pain knowledge, teach a simple system for managing pain, and address local pain management barriers. It is usually delivered as an interactive, multidisciplinary 1-day workshop with an emphasis on developing local solutions to local problems. The program includes an instructor workshop to encourage early handover to local health care workers. Between 2010 and 2018, a total of 42 one-day workshops and 6 instructor workshops were held throughout PNG, and 783 health care workers were trained, as well as 60 instructors. Over two-thirds of the 1-day workshops were taught entirely by local instructors. A shorter version of the workshop, called EPM Lite, was used to train 109 medical and nursing students. Program evaluation has included participant feedback (reaction) and preworkshop and postworkshop tests (knowledge) since inception. Evaluation of behavioral and organizational change has proved more challenging; however, a survey of past participants suggests some important behavioral changes and points to areas for formal research. The uptake of the EPM program in PNG is encouraging and suggests that there is a need for a pain management education program that is simple and easily adopted by local health care workers. There are still significant challenges, including a lack of funding, limited uptake at undergraduate level, the need for more formal evaluation of clinical impact, and the requirement for an all-of-system approach to improve pain management in PNG. Worldwide, EPM has now been taught in more than 60 countries. Our priorities for coming years include support for embedding EPM into health care systems and teaching programs, increased mentorship for instructors, assistance with overcoming local pain management barriers, and development of specific projects that will assess the impact of EPM education on patient outcomes.


The relationship between obesity and hypoferraemia in adults: a systematic review.
A growing number of studies suggest a potential link between obesity and altered iron metabolism. The purpose of this systematic review was to examine existing literature on iron status in obese populations. A comprehensive literature search was conducted. Included studies recruited participants ≥ 18 years with a body mass index ≥ 30 kg m(-2) and provided descriptive statistics for haemoglobin or ferritin at a minimum. There were 25 studies meeting all eligibility criteria, of these 10 examined iron status in free-living obese individuals and 15 reported baseline iron biomarkers from bariatric surgery candidates. Non-obese comparison groups were used by 10 (40%) articles. In these, seven obese groups reported higher mean haemoglobin concentration; six reported significantly higher ferritin concentration; and four significantly lower transferrin saturation. Due to insufficient data, it was not possible to make conclusions regarding mean differences for soluble transferrin receptor (sTfR), hepcidin or C-reactive protein. Existing evidence suggests a tendency for higher haemoglobin and ferritin concentration and lower transferrin saturation in obesity. Alternation of iron biomarkers in obese populations may be a result of obesity-related inflammation and/or related comorbidities. Further research incorporating measurement of inflammatory cytokines, sTfR and hepcidin is required to confirm the impact of obesity on iron status.


Maternal C-Reactive Protein Concentration in Early Pregnancy and Child Autistic Traits in the General Population.
Exposure to elevated levels of inflammatory markers during pregnancy has been suggested as possible aetiologic factor in the occurrence of autism spectrum disorder (ASD). In this study, we investigated the prospective relation between maternal C-reactive protein (CRP) during early pregnancy and children's autistic traits in the general population. In a large population-based cohort in the Netherlands, we measured maternal CRP levels before 18 weeks of gestation (N = 4165). Parents reported on their children's autistic traits at age 6 years using the Social Responsiveness Scale, and the Pervasive Developmental Problem scale. Regression models were used to examine the relation between maternal CRP levels and autistic traits in children. Compared with the reference group (CRP < 2.3 mg/L), elevated levels of CRP (>7.8 mg/L) in pregnant women were associated with higher Social Responsiveness Scale scores in children [β = 0.055, 95% confidence interval (CI) 0.033, 0.078]; however, the effect was strongly attenuated after adjustment for several socioeconomic factors and in particular by maternal health-related factors including body mass index (fully adjusted model β = 0.018, 95% CI -0.005, 0.042). We found no relation between maternal CRP levels and pervasive developmental problem. Our results suggest that the association between elevated levels of maternal CRP in pregnancy and autistic traits in children is confounded by maternal health-related and socioeconomic factors. Further studies are needed to explore whether other maternal inflammatory markers during pregnancy, as a response to maternal inflammation, are associated with the development of autistic traits in the offspring.


Outcome measurement for treated and untreated TMD patients using the TMJ scale.
Changes in symptom profiles of two groups of treated and untreated temporomandibular disorders (TMD) patients were measured using the TMJ Scale. Forty-nine consecutive TMD patients were included in the study. Of these, 29 patients were treated using splint therapy, physical therapy, counseling, and non-steroidal anti-inflammatory (NSAID) medications. Patients completed the TMJ Scale questionnaire prior to treatment and at completion of the TMD therapy. Sixty-five patients were not treated in any manner, having completed the questionnaire during an initial diagnostic study and having declined treatment. They were contacted by mail at least four months later and asked to complete the second questionnaire if they had not received any treatment. Twenty untreated patients returned the completed questionnaire. The initial scale scores for the two groups were similar. Comparison of the two tests of both groups revealed the treated group improved significantly, while the untreated group remained unchanged, except for a statistically non-significant increase of scale scores (increased symptom severity) for joint dysfunction and range of motion limitation. Younger patients responded more favorably to therapy than older patients. The findings do not support the conclusions of the few previous studies that found TMD are often self-limiting and rarely progress to chronic intracapsular derangement. The findings strongly support the hypothesis that symptom improvement was related to treatment and not solely to the passage of time.


Mycosis fungoides: management with topical nitrogen mustard.
The technique of treatment, response rate, freedom from relapse, survival, and complications of therapy in 123 patients treated with topical nitrogen mustard (HN2) for cutaneous mycosis fungoides (MF) at Stanford University Medical Center are reviewed. Patients were treated with HN2 in an aqueous or ointment base with equal efficacy. Response rates depended on the extent of skin involvement. In limited plaque (T1) disease, complete and overall response rates were 51% and 88%, respectively, while in generalized plaque (T2) disease they were 26% and 69%. No patients with tumorous involvement (T3) achieved complete skin clearance and all 13 of these patients developed progression of disease. Only two of nine patients with erythrodema (T4) achieved a complete response (CR), and both later relapsed. After achieving a CR, 40% of patients with T1 disease and 60% with T2 disease later relapsed; however, subsequent therapies, including repeat courses of topical HN2, often were successful in achieving later skin clearance. Overall, 42% of T1 patients and 31% of T2 patients were without evidence of MF at last follow-up. When death occurred, it was usually unrelated to MF in the T1 group. However, half of the deaths of patients with T2 disease were attributable to MF. Among the 22 patients with T3 or T4 disease, 80% of deaths were attributable to MF. The most common complication observed was a cutaneous hypersensitivity reaction, which occurred much more commonly with the aqueous than the ointment preparation. Fourteen patients (11%) developed subsequent cutaneous malignancies.


Aerobic workout and bone mass in females.
This cross-sectional study aimed to investigate bone mass in females participating in aerobic workout. Twenty-three females (age 24.1 +/- 2.7 years), participating in aerobic workout for about 3 hours/week, were compared with 23 age-, weight- and height-matched non-active females. Areal bone mineral density (BMD) was measured in total body, head, whole dominant humerus, lumbar spine, right femoral neck, Ward's triangle, trochanter femoris, in specific sites in right femur diaphysis, distal femur, proximal tibia and tibial diaphysis, and bone mineral content (BMC) was measured in the whole dominant arm and right leg, using dual energy X-ray absorptiometry. The aerobic workout group had significantly (P < 0.05-0.01) higher BMD in total body (3.7%), lumbar spine (7.8%), femoral neck (11.6%), Ward's triangle (11.7%), trochanter femoris (9.6%), proximal tibia (6.8%) and tibia diaphysis (5.9%) compared to the non-active controls. There were no differences between the groups concerning BMD of the whole dominant humerus, femoral diaphysis, distal femur and BMC and lean mass of the whole dominant arm and right leg. Leaness of the whole dominant arm and leg was correlated to BMC of the whole dominant arm and right leg in both groups. In young females, aerobic workout containing alternating high and low impact movements for the lower body is associated with a higher bone mass in clinically important sites like the lumbar spine and hip, but muscle strengthening exercises like push-ups and soft-glove boxing are not associated with a higher bone mass in the dominant humerus. It appears that there is a skeletal adaptation to the loads of the activity.


Sleep disturbance, distress, and quality of life in ovarian cancer patients during the first year after diagnosis.
Sleep disturbance is a common clinical complaint of oncology patients and contributes to substantial morbidity. However, because most sleep studies have been cross-sectional, associations between sleep quality and distress in patients with ovarian cancer over time remain unclear. This prospective longitudinal study examined rates of sleep disturbance; contributions of depression, anxiety, and medication use in sleep disturbance; and associations between sleep quality and quality of life (QOL) during the first year after diagnosis among women with ovarian cancer. Women with a pelvic mass completed measures of sleep quality, depression, anxiety, and QOL before surgery. Those diagnosed with primary epithelial ovarian, fallopian tube, or peritoneal cancer repeated surveys at 6 months and 1 year after diagnosis. Mixed modeling was used to examine trajectories of psychosocial measures over time, as well as associations between changes in distress and sleep quality. Relationships between changes in sleep and QOL were also examined. The majority of patients reported disturbed global sleep (Pittsburgh Sleep Quality Index > 5) at all 3 time points. Medications for sleep and pain were associated with worse sleep at all time points. Greater increases in depression were associated with increased disturbances in sleep quality over time (P < .04). Worsening sleep was also associated with declines in QOL over time (P < .001). Sleep disturbance is common and persistent in women with ovarian cancer, and is linked to depressive symptoms and QOL. Pharmacologic treatment does not appear to adequately address this problem. Results highlight the need for ongoing screening and intervention for sleep disturbance in this population.


Improving on-line information for potential living kidney donors.
Individuals who consider becoming living kidney donors often search the internet for reliable information before contacting the transplant center. The quality of such information requires due consideration. Using the search engines Google and Yahoo and the WebMD information portal, two reviewers independently abstracted data on the classification, readability, and general quality of websites. The coverage and accuracy of each site's discussion of the risks, benefits, and process of living donation was also assessed against a checklist of recommended information. Eighty-six unique websites on living kidney donation were found. Most were created by transplant programs and transplant organizations. Although the content of most sites was accurate, almost all (98%) were written above the recommended patient reading level (i.e., fifth grade). On average, each site covered 38% of the recommended information on living donation (range 8-76%). Educational topics of potential long-term medical risks, psychological risks, and expected benefits to the donor were often missing. The most visited websites were often not ranked among the best sites to provide information. By better understanding the nature of on-line information, transplant professionals can direct their patients to the best available websites. Local educational efforts, including the effective use of internet resources, will ensure living donation and complete understanding of the risks by potential donors and recipients.


Effects of neonatal enucleation on receptive-field properties of visual neurons in superior colliculus of the golden hamster.
1. Monocular enucleation in infant hamsters results in a marked expansion of the normally very limited ipsilateral retinotectal projection (13). In 34 hamsters subjected to removal of one eye within 12 h of birth, the receptive-field characteristics of superior collicular neurons ipsilateral and contralateral to the remaining eye were investigated quantitatively and compared to those of normal animals. In six additional neonatal enucleates, the density of the expanded retinotectal projection was studied with the autoradiographic method and an attempt was made to relate the anatomical reorganization with the electrophysiological findings, 2. The response characteristics of visual cells in the colliculus contralateral to the remaining eye were not significantly different from those observed in normal animals. In the ipsilateral tectum, however, numerous changes were observed. Visual receptive fields were abnormally large. The incidence of directional selectivity was markedly reduced, as were the magnitudes of the discharges elicited by either flashed or moving stimuli. Fewer cells were activated by small flashed spots and most of the units that were responsive to such stimulation failed to exhibit the surround suppression typical for the majority of tectal neurons in normal hamsters. Most cells in the ipsilateral colliculus responded only to relatively low (less than 50 degrees/s) stimulus velocities and response decrements resulting from repeated stimulation also occurred much more readily for the neurons tested on this side. 3. The results of additional experiments in neonatal enucleates (n = 8), which were also subjected to acute bilateral removal of the visual cortex, demonstrated that such damage resulted in a marked reduction in the incidence of directional selectivity in the colliculus contralateral to the remaining eye but had no effect on the responses of cells innervated by the aberrant ipsilateral pathway. 4. A correlation between the relative density of the ipsilateral retinal projection at different points in the colliculus, as demonstrated by the autroradiography and the nature of the visual responses obtained in different portions of the structure, indicated that receptive-field size was negatively correlated with the density of the aberrant retinotectal projection and that absolute responsivity (number of impulses elicited by an optimal stimulus) was positively correlated with autoradiographic grain density. 5. These findings demonstrate that while the aberrant retinocollicular projection can, along with the other visual inputs to the tectum, result in the organization of normal response properties for a small number of tectal neurons, the majority of the visual cells innervated by this pathway have responses that are appreciably different from normal.


Inflammatory Markers and Fatigue in Individuals With Moderate to Severe Chronic Obstructive Pulmonary Disease.
Fatigue, a prevalent complex symptom among patients with chronic obstructive pulmonary disease (COPD), is considered an important clinical indicator of disease severity. However, the underlying mechanisms of COPD-related fatigue are not fully understood. This analysis explored the relationships between peripheral inflammatory markers and COPD-related fatigue in people with moderate to severe COPD. This is a secondary analysis of a longitudinal observational study of individuals with COPD examining the biological causes and functional consequences of depression. The data used in this study were collected at baseline. Systemic inflammation markers included C-reactive protein (CRP) and three pro-inflammatory cytokines consisting of interleukin-6 (IL-6), IL-8, and tumor necrosis factor-α. COPD-related fatigue was self-reported using the Chronic Respiratory Questionnaire. Covariates included age; gender; smoking status; disease severity; symptoms of depression, anxiety, and pain; and social support. Multivariable linear regression analyses were conducted. The sample included 300 adults living with COPD; 80% were male, and the average age was 67.6 years. Modest correlations were found between two systemic inflammatory markers (CRP and IL-8) and COPD-related fatigue. CRP was the only inflammatory marker significantly associated with fatigue symptoms after adjusting for covariates in multivariable analyses. Depression, pain, and education level were also significant predictors of COPD-related fatigue. The findings suggest that altered immune response based on CRP may contribute to COPD-related fatigue. Management of depression and pain may work as an effective treatment strategy for COPD-related fatigue. Further longitudinal studies with a broader range of inflammatory markers and multidimensional measures of fatigue symptoms are warranted.


The level of CD4 expression limits infection of primary rhesus monkey macrophages by a T-tropic simian immunodeficiency virus and macrophagetropic human immunodeficiency viruses.
The entry of primate immunodeficiency viruses into cells is dependent on the interaction of the viral envelope glycoproteins with receptors, CD4, and specific members of the chemokine receptor family. Although in many cases the tropism of these viruses is explained by the qualitative pattern of coreceptor expression, several instances have been observed where the expression of a coreceptor on the cell surface is not sufficient to allow infection by a virus that successfully utilizes the coreceptor in a different context. For example, both the T-tropic simian immunodeficiency virus (SIV) SIVmac239 and the macrophagetropic (M-tropic) SIVmac316 can utilize CD4 and CCR5 as coreceptors, and both viruses can infect primary T lymphocytes, yet only SIVmac316 can efficiently infect CCR5-expressing primary macrophages from rhesus monkeys. Likewise, M-tropic strains of human immunodeficiency virus type 1 (HIV-1) do not infect primary rhesus monkey macrophages efficiently. Here we show that the basis of this restriction is the low level of CD4 on the surface of these cells. Overexpression of human or rhesus monkey CD4 in primary rhesus monkey macrophages allowed infection by both T-tropic and M-tropic SIV and by primary M-tropic HIV-1. By contrast, CCR5 overexpression did not specifically compensate for the inefficient infection of primary monkey macrophages by T-tropic SIV or M-tropic HIV-1. Apparently, the limited ability of these viruses to utilize a low density of CD4 for target cell entry accounts for the restriction of these viruses in primary rhesus monkey macrophages.


Seasonal Succession and Spatial Patterns of Synechococcus Microdiversity in a Salt Marsh Estuary Revealed through 16S rRNA Gene Oligotyping.
Synechococcus are ubiquitous and cosmopolitan cyanobacteria that play important roles in global productivity and biogeochemical cycles. This study investigated the fine scale microdiversity, seasonal patterns, and spatial distributions of Synechococcus in estuarine waters of Little Sippewissett salt marsh (LSM) on Cape Cod, MA. The proportion of Synechococcus reads was higher in the summer than winter, and higher in coastal waters than within the estuary. Variations in the V4-V6 region of the bacterial 16S rRNA gene revealed 12 unique Synechococcus oligotypes. Two distinct communities emerged in early and late summer, each comprising a different set of statistically co-occurring Synechococcus oligotypes from different clades. The early summer community included clades I and IV, which correlated with lower temperature and higher dissolved oxygen levels. The late summer community included clades CB5, I, IV, and VI, which correlated with higher temperatures and higher salinity levels. Four rare oligotypes occurred in the late summer community, and their relative abundances more strongly correlated with high salinity than did other co-occurring oligotypes. The analysis revealed that multiple, closely related oligotypes comprised certain abundant clades (e.g., clade 1 in the early summer and clade CB5 in the late summer), but the correlations between these oligotypes varied from pair to pair, suggesting they had slightly different niches despite being closely related at the clade level. Lack of tidal water exchange between sampling stations gave rise to a unique oligotype not abundant at other locations in the estuary, suggesting physical isolation plays a role in generating additional microdiversity within the community. Together, these results contribute to our understanding of the environmental and ecological factors that influence patterns of Synechococcus microbial community composition over space and time in salt marsh estuarine waters.


Systems biology beyond networks: generating order from disorder through self-organization.
Erwin Schrödinger pointed out in his 1944 book "What is Life" that one defining attribute of biological systems seems to be their tendency to generate order from disorder defying the second law of thermodynamics. Almost parallel to his findings, the science of complex systems was founded based on observations on physical and chemical systems showing that inanimate matter can exhibit complex structures although their interacting parts follow simple rules. This is explained by a process known as self-organization and it is now widely accepted that multi-cellular biological organisms are themselves self-organizing complex systems in which the relations among their parts are dynamic, contextual and interdependent. In order to fully understand such systems, we are required to computationally and mathematically model their interactions as promulgated in systems biology. The preponderance of network models in the practice of systems biology inspired by a reductionist, bottom-up view, seems to neglect, however, the importance of bidirectional interactions across spatial scales and domains. This approach introduces a shortcoming that may hinder research on emergent phenomena such as those of tissue morphogenesis and related diseases, such as cancer. Another hindrance of current modeling attempts is that those systems operate in a parameter space that seems far removed from biological reality. This misperception calls for more tightly coupled mathematical and computational models to biological experiments by creating and designing biological model systems that are accessible to a wide range of experimental manipulations. In this way, a comprehensive understanding of fundamental processes in normal development or of aberrations, like cancer, will be generated.


Whole blood assay as a model for in vitro evaluation of inflammasome activation and subsequent caspase-mediated interleukin-1 beta release.
Processing of pro-interleukin (IL)-1β and IL-18 is regulated by multiprotein complexes, known as inflammasomes. Inflammasome activation results in generation of bioactive IL-1β and IL-18, which can exert potent pro-inflammatory effects. Our aim was to develop a whole blood-based assay to study the inflammasome in vitro and that also can be used as an assay in clinical studies. We show whole blood is a suitable milieu to study inflammasome activation in primary human monocytes. We demonstrated that unprocessed human blood cells can be stimulated to activate the inflammasome by the addition of adenosine 5'-triphosphate (ATP) within a narrow timeframe following lipopolysaccharide (LPS) priming. Stimulation with LPS resulted in IL-1β release; however, addition of ATP is necessary for "full-blown" inflammasome stimulation resulting in high IL-1β and IL-18 release. Intracellular cytokine staining demonstrated monocytes are the major producers of IL-1β in human whole blood cultures, and this was associated with activation of caspase-1/4/5, as detected by a fluorescently labelled caspase-1/4/5 probe. By applying caspase inhibitors, we show that both the canonical inflammasome pathway (via caspase-1) as well as the non-canonical inflammasome pathway (via caspases-4 and 5) can be studied using this whole blood-based model.


The Association of Prehospital Intravenous Fluids and Mortality in Patients with Penetrating Trauma.
The optimal approach to prehospital care of trauma patients is controversial, and thought to require balancing advanced field interventions with rapid transport to definitive care. We sought principally to examine any association between the amount of prehospital IV fluid (IVF) administered and mortality. We conducted a retrospective cohort analysis of trauma registry data patients who sustained penetrating trauma between January 2008 and February 2011, as identified in the Pennsylvania Trauma Systems Foundation registry with corresponding prehospital records from the Philadelphia Fire Department. Analyses were conducted with logistic regression models and instrumental variable analysis, adjusted for injury severity using scene vital signs before the intervention was delivered. There were 1966 patients identified. Overall mortality was 22.60%. Approximately two-thirds received fluids and one-third did not. Both cohorts had similar Trauma and Injury Severity Score-predicted mortality. Mortality was similar in those who received IVF (23.43%) and those who did not (21.30%) (p = 0.212). Patients who received IVF had longer mean scene times (10.82 min) than those who did not (9.18 min) (p < 0.0001), although call times were similar in those who received IVF (24.14 min) and those who did not (23.83 min) (p = 0.637). Adjusted analysis of 1722 patients demonstrated no benefit or harm associated with prehospital fluid (odds ratio [OR] 0.905, 95% confidence interval [CI] 0.47-1.75). Instrumental variable analysis utilizing variations in use of IVF across different Emergency Medical Services (EMS) units also found no association between the unit's percentage of patients that were provided fluids and mortality (OR 1.02, 95% CI 0.96-1.08). We found no significant difference in mortality or EMS call time between patients who did or did not receive prehospital IVF after penetrating trauma.


Inverse relationship between vertebral fractures and spine osteoarthritis in postmenopausal women with osteoporosis.
Although the coexistence of osteoarthritis and osteoporosis is considered as uncommon, it has been suggested that, in postmenopausal women, disc space narrowing increases the risk of vertebral fracture. The aim of this study was to check this hypothesis in postmenopausal women with osteoporosis. We analysed the relationship between vertebral fractures and spine osteoarthritis in 410 postmenopausal women with osteoporosis: in this population both disc space narrowing and osteophytes are inversely related to vertebral fractures. This study is based on baseline data collected in a multicentre, prospective and 6-month longitudinal observational study. 410 postmenopausal women (74+/-5 years) were enrolled who had consulted for back pain, and had osteoporosis (according to WHO definition). Spine x-rays were performed according to standardised procedures. Vertebral fractures were evaluated from T4 to L4 using the Genant's semiquantitative method; osteoarthritis was evaluated by scoring osteophytes and disc space narrowing at all levels of the thoracic and lumbar spine, and by a qualitative assessment of facet joint arthritis. The prevalence of vertebral fractures was 52.4%. At least one osteophyte, one disc space narrowing and one facet arthritis were present in 90.2, 64.6 and 77.8% of patients respectively. There was an inverse association between vertebral fractures and osteoarthritis: odds ratios adjusted for age and weight (95% CI) were 0.38 (0.17-0.86), p = 0.02 and 0.27 (0.16-0.46), p<10(-4) for the presence of at least one osteophyte, and of at least three disc space narrowings respectively. In a cluster analysis, it was possible to identify a subgroup of patients without any disc space narrowing, and another subgroup with all patients having at least one disc space narrowing; the proportion of patients having more than three vertebral fractures was 25.2 and 15.9% in these two clusters respectively. Disc space narrowing and osteophytes are associated with a decreased vertebral fracture prevalence in postmenopausal women with osteoporosis.


Social network analysis of patient sharing among hospitals in Orange County, California.
We applied social network analyses to determine how hospitals within Orange County, California, are interconnected by patient sharing, a system which may have numerous public health implications. Our analyses considered 2 general patient-sharing networks: uninterrupted patient sharing (UPS; i.e., direct interhospital transfers) and total patient sharing (TPS; i.e., all interhospital patient sharing, including patients with intervening nonhospital stays). We considered these networks at 3 thresholds of patient sharing: at least 1, at least 10, and at least 100 patients shared. Geographically proximate hospitals were somewhat more likely to share patients, but many hospitals shared patients with distant hospitals. Number of patient admissions and percentage of cancer patients were associated with greater connectivity across the system. The TPS network revealed numerous connections not seen in the UPS network, meaning that direct transfers only accounted for a fraction of total patient sharing. Our analysis demonstrated that Orange County's 32 hospitals were highly and heterogeneously interconnected by patient sharing. Different hospital populations had different levels of influence over the patient-sharing network.


Influences and policies that affect immunisation coverage-a summary review of literature.
Effective national immunisation programmes require a high proportion of the population to be immunised. Although New Zealand has made significant progress towards immunisation goals over the last two decades, immunisation coverage remains inadequate to prevent intermittent outbreaks of disease, and immunisation inequities persist between geographic, ethnic and socioeconomic groups. Here we summarise a recent literature review that was conducted to identify and examine key factors that influence immunisation coverage, timeliness of vaccinations and the core drivers that affect vaccine uptake. We conclude that well designed systems, taking a holistic approach with multiple components, gain broader community acceptance and trust; early and continual engagement with well-informed healthcare professionals builds trust and improves uptake; the family's experience during vaccination events is important; community-led vaccine advocacy is required to target specific populations to help to promote and improve access to immunisation. Coercive approaches can be marginally effective, but risk disproportionately penalising those already experiencing mistrust and hardship.


Docetaxel combined with irinotecan or 5-fluorouracil in patients with advanced oesophago-gastric cancer: a randomised phase II study.
Docetaxel and irinotecan chemotherapy have shown good efficacy in the treatment of advanced oesophago-gastric cancer. This randomised phase II study evaluated the efficacy and toxicity profile of two non-platinum docetaxel-based doublet regimens in advanced oesophago-gastric cancer. Chemotherapy-naïve patients with advanced oesophago-gastric cancer were randomised to receive either 3-weekly DI (docetaxel 60 mg m(-2) plus irinotecan 250 mg m(-2) (Day 1)) or 3-weekly DF (docetaxel 85 mg m(-2) (Day 1) followed by 5-fluorouracil 750 mg m(-2) per day as a continuous infusion (Days 1-5)). A total of 85 patients received DI (n=42) or DF (n=43). The primary endpoint was overall response rate (ORR). The ORR and time to progression (TTP) in the evaluable population (n=65) were 37.5% (DI) vs 33.3% (DF), and 4.2 months vs 4.4 months, respectively. In the intent-to-treat population, the observed ORR, TTP and median overall survival were similar between the two groups. Grade 3-4 neutropenia, febrile neutropenia and diarrhoea were more frequent in the DI arm as compared with the DF arm (83.3% vs 69.8%, 40.5% vs 18.6%, and 42.9% vs 16.3%, respectively). Both docetaxel-based doublet regimens show comparable efficacy; however, the DF regimen was associated with a better toxicity profile and is an alternative treatment option for patients in whom platinum-based regimens are unsuitable.


A Rare Vehicle-Assisted Ligature Hanging: Suicide at the Wheel.
Suicide by hanging inside a motor vehicle is a rare occurrence. A 48-year-old woman suffering from major depression was found having agonal breathing inside her automobile. A 20-mm diameter blue nylon rope was wrapped tightly around her neck, with its other end tied to a nearby wooden fence post. Despite resuscitation attempts, she was declared deceased after several minutes. The vehicle was located in an area with a slight downward slope. The motor was off. It was in neutral gear, with the parking brake disengaged. Consequently, the gravitational forces, attributable to the mass of the vehicle and the declivity of the terrain, caused the rope to tighten.The dynamics fulfill the criteria for a partial hanging, given the difference in height between the point at which the rope was secured to the post and woman's neck, which in turn presented the typical oblique upward groove.This case, thus, represents a unique mode of partial hanging inside a passenger vehicle, rarely reported in the literature. The relative lack of internal injury is also noteworthy, along with the fact that the victim was discovered while still alive. The latter feature can be explained by the absence of the sudden or violent acceleration forces that can be generated with the engine on.


A whole-genome assembly of Drosophila.
We report on the quality of a whole-genome assembly of Drosophila melanogaster and the nature of the computer algorithms that accomplished it. Three independent external data sources essentially agree with and support the assembly's sequence and ordering of contigs across the euchromatic portion of the genome. In addition, there are isolated contigs that we believe represent nonrepetitive pockets within the heterochromatin of the centromeres. Comparison with a previously sequenced 2.9- megabase region indicates that sequencing accuracy within nonrepetitive segments is greater than 99. 99% without manual curation. As such, this initial reconstruction of the Drosophila sequence should be of substantial value to the scientific community.


Mannose-binding lectin in chronic hepatitis B virus infection.
Mannose binding lectin (MBL) is a pattern-recognition molecule of the innate immune system. The roles of MBL and its gene (mbl2) polymorphisms, -221X/Y and codon 54A/B, in hepatitis B virus (HBV) infection were investigated in this study. We recruited 320 nonprogressed hepatitis B surface antigen (HBsAg) carriers; 199 progressed HBsAg carriers with hepatocellular carcinoma or cirrhosis; 87 spontaneously recovered individuals who were HBsAg negative and anti-HBs and anti HBc positive; and 484 controls who were naïve to HBV. There was no significant difference between nonprogressed carriers, spontaneously recovered individuals, and controls in terms of serum MBL levels and mbl2 polymorphisms distributions. However, the low MBL genotypes had a dose-dependent correlation with the cirrhosis and hepatocellular carcinoma in progressed carriers with odds ratios of 1.36 and 3.21 for the low and extremely low MBL genotypes, respectively (P = .01). The low-expression promoter haplotype XA (OR = 1.97) and the mutant haplotype YB (OR = 1.90) were also associated with the cirrhosis and hepatocellular carcinoma (P = .002). As expected, the lower serum MBL levels in progressed carriers as compared with nonprogressed carriers were due to an overrepresentation of low and extremely low MBL genotypes. Moreover, MBL could bind HBsAg in a dose- and calcium-dependent and mannan-inhibitable manner in vitro, suggesting that binding occurs via the carbohydrate recognition domains. This binding also enhanced C4 deposition. In conclusion, these results suggest that low MBL genotypes associate with the occurrence of cirrhosis and hepatocellular carcinoma in progressed HBsAg carriers, and MBL can bind HBsAg.


Multiplex PCR detection of vanA, vanB, vanC-1, and vanC-2/3 genes in enterococci.
Vancomycin-resistant enterococci (VRE) are increasingly isolated from clinical specimens. One hundred clinical isolates of enterococci (E. casseliflavus/E. flavescens [n = 10], E. faecalis [n = 34], E. faecium [n = 43], E. avium [n = 1], E. gallinarum [n = 11], and E. raffinosus [n = 1]) were examined for the presence of vanA, vanB, vanC-1, and vanC-2/3 genes by a single multiplex PCR performed directly with colonies from blood agar plates. Six previously characterized VRE strains which carry either vanA, vanB, vanC-1, or vanC-2 genes were used as controls. To discriminate among van genes, the PCR amplicons were digested with MspI and were electrophoresed on agarose gels. Because of significant sequence homology between vanC-2 and vanC-3 genes, this assay is unable to discriminate these genes from each other; therefore, these are referred to as vanC-2/3 genes. PCR products were detected in 63 of the 100 clinical isolates. The restriction fragment length patterns were consistent with vanA for 10 strains, vanB for 30 strains, vanC-1 for 12 strains, vanC-2 for 6 strains, and vanA and vanC-1 for 1 strain. The vancomycin MICs for the isolates with restriction fragment length patterns consistent with vanA and vanB were all > and = 64 micrograms/ml. The vancomycin MICs for the isolates with restriction fragment length patterns consistent with vanC-1 or vanC-2 were 4 to 8 micrograms/ml. The vancomycin MICs for the isolates from which no PCR amplicons were produced were 2 to 4 micrograms/ml. A PCR product was produced in four isolates (vancomycin MICs, 4 to > 256 micrograms/ml) with restriction fragment length patterns differing from those for the control vanA, vanB, vanC-1, and vanC-2 isolates. DNA sequencing of these amplicons revealed that two of the four isolates had nucleic acid sequences which were closely related to the published sequence for the vanB gene and two had nucleic acid sequences which were closely related to the published sequence for the vanC-2 and vanC-3 genes. Multiplex PCR-restriction fragment length polymorphism appears to be a useful and convenient method for rapidly detecting and discriminating genotypes for vancomycin-resistant Enterococcus spp. in the clinical laboratory. In instances in which unusual restriction fragment patterns of PCR amplicons occur, DNA sequencing can be performed to discriminate van genotypes.


Patient participation and associated factors in the discussions on do-not-attempt-resuscitation and end-of-life disclosure: a retrospective chart review study.
Patient participation is a key foundation of advance care planning (ACP). However, a patient himself/herself may be left out from sensitive conversations such as end-of-life (EOL) care discussions. The objectives of this study were to investigate patients' participation rate in the discussion of Cardiopulmonary Resuscitation (CPR) / Do-Not-Attempt-Resuscitation (DNAR) order, and in the discussion that the patient is at his/her EOL stage (EOL disclosure), and to explore their associated factors. This is a retrospective chart review study. The participants were all the patients who were hospitalized and died in a university-affiliated teaching hospital (tertiary medical facility) in central Tokyo, Japan during the period from April 2018 to March 2019. The following patients were excluded: (1) cardiopulmonary arrest on arrival; (2) stillbirth; (3) under 18 years old at the time of death; and (4) refusal by their bereaved family. Presence or absence of CPR/DNAR discussion and EOL disclosure, patients' involvement in those discussions, and their associated factors were investigated. CPR/DNAR discussions were observed in 336 out of the 358 patients (93.9%). However, 224 of these discussions were carried out without a patient (patient participation rate 33.3%). Male gender (odds ratio (OR) = 2.37 [95% confidence interval (CI) 1.32-4.25]), living alone (OR = 2.51 [1.34-4.71]), and 1 year or more from the date of diagnosis (OR = 1.78 [1.03-3.10]) were associated with higher patient's participation in CPR/DNAR discussions. The EOL disclosure was observed in 341 out of the 358 patients (95.3%). However, 170 of the discussions were carried out without the patient (patient participation rate 50.1%). Patients who died of cancer (OR = 2.41[1.45-4.03]) and patients without mental illness (OR=2.41 [1.11-5.25]) were more likely to participate in EOL disclosure. In this clinical sample, only up to half of the patients participated in CPR/DNAR discussions and EOL disclosure. Female, living with family, a shorter period from the diagnosis, non-cancer, and mental illness presence are risk factors for lack of patients' participation in CPR/DNAR or EOL discussions. Further attempts to facilitate patients' participation, based on their preference, are warranted.


The effect of posture and a mandibular protruding device on pharyngeal dimensions: a cephalometric study.
The objectives were to evaluate the impact of body posture on cephalometric measures and the level and the extent to which treatment with a mandibular protruding device (MPD) affects pharyngeal width. The study was composed of 77 patients: 50 were diagnosed with obstructive sleep apnea (OSA) and 27 snored. After each patient underwent a baseline medical (including a somnographic registration), dental and stomatognathic examination, an MPD that would protrude the mandible 75% of the maximal protrusion range was fabricated. In a radiographic examination, four cephalograms were taken: two in the upright position with and without the MPD and two in the supine position with and without the MPD. The cephalometric measures focused on the pharyngeal structures. MPD treatment significantly increased the relative pharyngeal area (at the level of the oropharynx and the hypopharynx) by a mean of +89.6 mm2 (P < 0.01) in the upright posture. The relative pharyngeal area, however, was reduced by more than 50% in the supine position compared with the upright position, independent of MPD treatment. In the supine position, compared with upright, most pharyngeal measures decreased significantly; the hyoid was significantly lower and displaced posteriorly, and the area of the velum increased by a mean of +201.2 mm2 (P < 0.001). We conclude that the MPD significantly increased most pharyngeal measures except the linear distance between the hyoid bone and the third vertebra and decreased the area of the velum.


Early nuclear factor-kappaB activation and inducible nitric oxide synthase expression in injured spinal cord neurons correlating with a diffuse reduction of constitutive nitric oxide synthase activity.
Because of toxicity at high concentrations, nitric oxide (NO) contributes to spinal cord injury (SCI) secondary lesions. At low concentrations NO modulates nuclear factor-kappaB (NF-kappaB) activation. The authors investigated the activity of neuronal and endothelial NO synthase (nNOS and eNOS) to determine correlations with NF-kappaB activation and inducible NOS (iNOS) expression soon after SCI. In 48 adult male Wistar rats clip-based (50 g/mm2/10 seconds) SCI was induced, and spinal cords were removed at different intervals for the following evaluations: 1) assaying specific activity of nNOS and eNOS; 2) electrophoresis mobility shift assay for activated NF-kappaB; 3) Northern blotting for iNOS; 4) immunohistochemistry for iNOS and NF-kappaB; and 5) immunofluorescence for iNOS and NF-kappaB. At 15 minutes postinjury, eNOS activity decreased significantly (p < 0.001), as did nNOS activity at 1 hour compared with these levels in control animals and rats killed at 15 and 30 minutes after SCI (p < 0.001). Basal NF-kappaB levels were variable in controls and at 15 and 30 minutes after injury. One hour postinjury, NF-kappaB activation was diffuse. Inducible NOS messenger RNA localized diffusely, peaking 6 hours after injury and remaining stable until 24 hours postinjury. Immunohistochemical analysis showed diffuse iNOS and NF-kappaB staining, especially in neurons inside and around the lesion. Immunofluorescence demonstrated that injured neurons were a source of NF-kappaB and iNOS soon after injury. Both nNOS and eNOS exhibited different regulation and roles soon after injury: nNOS correlated with NF-kappaB activation, whereas eNOS may have participated in vascular changes of the injured spinal cord. Neurons seemed to play a pivotal role in modulating and amplifying the inflammatory response in the injured spinal cord.


CNS Response to Osimertinib Versus Standard Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients With Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer.
Purpose We report CNS efficacy of osimertinib versus standard epidermal growth factor receptor ( EGFR) tyrosine kinase inhibitors (TKIs) in patients with untreated EGFR-mutated advanced non-small-cell lung cancer from the phase III FLAURA study. Patients and Methods Patients (N = 556) were randomly assigned to osimertinib or standard EGFR-TKIs (gefitinib or erlotinib); brain scans were not mandated unless clinically indicated. Patients with asymptomatic or stable CNS metastases were included. In patients with symptomatic CNS metastases, neurologic status was required to be stable for ≥ 2 weeks after completion of definitive therapy and corticosteroids. A preplanned subgroup analysis with CNS progression-free survival as primary objective was conducted in patients with measurable and/or nonmeasurable CNS lesions on baseline brain scan by blinded independent central neuroradiologic review. The CNS evaluable-for-response set included patients with ≥ one measurable CNS lesion. Results Of 200 patients with available brain scans at baseline, 128 (osimertinib, n = 61; standard EGFR-TKIs, n = 67) had measurable and/or nonmeasurable CNS lesions, including 41 patients (osimertinib, n = 22; standard EGFR-TKIs, n = 19) with ≥ one measurable CNS lesion. Median CNS progression-free survival in patients with measurable and/or nonmeasurable CNS lesions was not reached with osimertinib (95% CI, 16.5 months to not calculable) and 13.9 months (95% CI, 8.3 months to not calculable) with standard EGFR-TKIs (hazard ratio, 0.48; 95% CI, 0.26 to 0.86; P = .014 [nominally statistically significant]). CNS objective response rates were 91% and 68% in patients with ≥ one measurable CNS lesion (odds ratio, 4.6; 95% CI, 0.9 to 34.9; P = .066) and 66% and 43% in patients with measurable and/or nonmeasurable CNS lesions (odds ratio, 2.5; 95% CI, 1.2 to 5.2; P = .011) treated with osimertinib and standard EGFR-TKIs, respectively. Probability of experiencing a CNS progression event was consistently lower with osimertinib versus standard EGFR-TKIs. Conclusion Osimertinib has CNS efficacy in patients with untreated EGFR-mutated non-small-cell lung cancer. These results suggest a reduced risk of CNS progression with osimertinib versus standard EGFR-TKIs.


The Remedial Efficacy of Spirulina platensis versus Chromium-Induced Nephrotoxicity in Male Sprague-Dawley Rats.
This study was conducted to investigate the possible protective effect of Spirulina platensis against chromium-induced nephrotoxicity. A total of 36 adult male Sprague-Dawley rats were divided into 4 equal groups (Gps). Gp1 served as control, rats of Gps 2, 3, and 4 were exposed to Spirulina platensis (300 mg/kg b.wt per os) and sodium dichromate dihydrate (SDD) via drinking water at concentration of 520 mg /l respectively. Chromium administration caused alterations in the renal function markers as evidenced by significant increase of blood urea and creatinine levels accompanied with significant increase in kidney's chromium residues and MDA level as well as decreased catalase activity and glutathion content in kidney tissue. Histologically, Cr provoked deleterious changes including: vascular congestion, wide spread tubular epithelium necrobiotic changes, atrophy of glomerular tuft and proliferative hyperplasia. The latter was accompanied with positive PCNA expression in kidney tissues as well as DNA ploidy interpretation of major cellular population of degenerated cells, appearance of tetraploid cells, high proliferation index and high DNA index. Morphometrical measurements revealed marked glomerular and tubular lumen alterations. On contrary, spirulina co-treatment with Cr significantly restored the histopathological changes, antioxidants and renal function markers and all the previously mentioned changes as well.


Evidence for histidyl and carboxy groups at the active site of the human placental Na+-H+ exchanger.
The Na+-H+ exchanger of the human placental brush-border membrane was inhibited by pretreatment of the membrane vesicles with a histidyl-group-specific reagent, diethyl pyrocarbonate and with a carboxy-group-specific reagent, N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. In both cases the inhibition was irreversible and non-competitive in nature. But, if the membrane vesicles were treated with these reagents in the presence of amiloride, cimetidine or clonidine, there was no inhibition. Since amiloride, cimetidine and clonidine all interact with the active site of the exchanger in a mutually exclusive manner, the findings provide evidence for the presence of essential histidyl and carboxy groups at or near the active site of the human placental Na+-H+ exchanger. This conclusion was further substantiated by the findings that Rose Bengal-catalysed photo-oxidation of histidine residues as well as covalent modification of carboxy residues with NN'-dicyclohexylcarbodi-imide irreversibly inhibited the Na+-H+ exchanger and that amiloride protected the exchanger from inhibition caused by NN'-dicyclohexylcarbodi-imide.


Anaphylaxis Complicated by Acute Respiratory Distress and Fatal Outcome in A Nigerian Family.
Reports on hypersensitivity diseases in Nigerians are rare. We report the incidence of anaphylaxis in three siblings following fatal outcome in their mother. Urticarial rashes were noticed in three siblings' resident in a South Western Nigerian town, one week before presentation at our facility. All the three siblings developed respiratory distress four days after the rash was noticed. Onset of respiratory distress made the family seek care at a private hospital, where they were admitted and treated with intravenous aminophylline and ceftriaxone. The mother of the children had experienced the same symptoms earlier also. She took treatment and died in the same private hospital, where her children received care. Death of the mother and worsening respiratory distress in the children made the father effect transfer of the children to the paediatric emergency unit of Ladoke Akintola University of Technology Teaching Hospital, Osogbo. The three children made a slow but uneventful recovery after instituting appropriate management for anaphylaxis and acute respiratory distress syndrome. The cases are discussed with a view to create awareness amongst health practitioners about the occurrence of anaphylaxis in our society. The need for prompt recognition and appropriate management, when confronted with this disease is also underscored.


Responses of Different Cancer Cells to White Tea Aqueous Extract.
White tea from the eastern Chinese province of Fujian is a unique tea variety. Although the health effects of various teas have been investigated in recent years, most studies focused exclusively on green tea varieties. In order to study effects exerted by white tea from eastern Fujian on the viability of cancer cells, we analyzed its main bioactive ingredients. We also evaluated the antioxidant activity of white tea aqueous extract (WTAE) and employed MTT assay to evaluate effects of WTAE on viabilities of Hela and BEL-7402 cancer cell lines. Apoptosis rate detection was also applied to estimate efficacy of cellular apoptotic induction by WTAE in these two cells types. Results revealed that WTAE exhibited high antioxidant activity and inhibited effectively the proliferation of Hela and BEL-7402 cells. The half maximal inhibitory concentration (IC50) of WTAE for Hela cells (0.05 mg/mL) was lower than that for BEL-7402 cells (0.1 mg/mL). Although WTAE induced apoptosis in both cell lines, pro-apoptotic effects were markedly more apparent in Hela cells. Our study demonstrated that WTAE inhibited proliferation of cancer cells via induction of apoptosis and that Hela cells were more sensitive to WTAE than BEL-7402 cells. The aim of this study is to provide a new approach toward cancer prevention by consuming white tea, the properties of which may also be helpful in formulating novel anticancer therapeutics.


Evidence-based appraisal of two guidelines for the diagnosis of suspected, uncomplicated urinary tract infections in primary care: a diagnostic accuracy validation study.
Given the lack of accurate rapid diagnostics for urinary tract infection (UTI) in women, many countries have developed guidelines aiming to support appropriate antibiotic prescribing, but some guidelines have not been validated. We performed a diagnostic accuracy validation study of two guidelines: Public Health England (GW-1263) and Scottish Intercollegiate Guidelines Network (SIGN160). We used data from women with symptoms suggestive of uncomplicated UTI from a randomized controlled trial comparing urine collection devices. Symptom information was recorded via baseline questionnaire and primary care assessment. Women provided urine samples for dipstick testing and culture. We calculated the number within each risk category of diagnostic flowcharts who had positive/mixed growth/no significant growth urine culture. Results were presented as positive/negative predictive values, with 95% CIs. Of women aged under 65 years, 311/509 (61.1%, 95% CI 56.7%-65.3%) classified to the highest risk category (recommended to consider immediate antibiotic prescribing) and 80/199 (40.2%, 95% CI 33.4%-47.4%) classified to the lowest risk category (recommended to reassure that UTI is less likely) by the GW-1263 guideline (n = 810) had positive culture. For the SIGN160 guideline (n = 814), the proportion with positive culture ranged from 60/82 (73.2%, 95% CI 62.1%-82.1%) in those for whom immediate treatment was indicated to 33/76 (43.4%, 95% CI 32.3%-55.3%) in those recommended a self-care/waiting strategy. Clinicians should be aware of the potential for diagnostic error when using diagnostic guidelines for managing uncomplicated UTI and making antimicrobial prescribing decisions. Infection cannot be excluded on the basis of symptoms and dipstick testing alone.


A widely tunable dual-wavelength CW Ti:sapphire laser with collinear output.
We report a collinear output and tunable dual-wavelength CW Ti:sapphire laser with a simple cavity configuration. The wavelength splitting range is easily tuned from 10 nm to 110 nm, which provides 56 THz bandwidth for terahertz generation. The total output power of two colors with the spatial mode of TEM(00) is between 700 mW and 300 mW, for small and large wavelength splittings, respectively, under 5 W argon-ion laser pumping.


Cerebral abnormalities in Friedreich ataxia: A review.
Friedreich ataxia (FRDA) is an inherited degenerative disorder affecting multiple systems of the body and resulting in symptoms which include progressive ataxia, dysarthria, and cardiomyopathy. Central nervous system pathology has been traditionally ascribed to the spinal cord and dentate nucleus of the cerebellum. However, cerebral abnormalities in FRDA are being increasingly documented via multiple neuroimaging techniques. Understanding the nature and implications of cerebral abnormalities in FRDA provides more comprehensive knowledge of nervous system involvement in this disorder and increases the prospects of identifying effective treatment targets. We review the cerebellar and the cerebral involvement with a focus on the emerging in vivo human neuroimaging findings suggesting wide-spread cerebral involvement, including aberrant cerebellar-cerebral connectivity. We synthesise the findings by proposing potential mechanisms that may drive these effects. Finally, we identify future research directions which, we argue, will lead to a better understanding of the extent and potential mechanisms of cerebral aberrations in FRDA.


Potential unsatisfiability of cyclic constraints on stochastic biological networks biases selection towards hierarchical architectures.
Constraints placed upon the phenotypes of organisms result from their interactions with the environment. Over evolutionary time scales, these constraints feed back onto smaller molecular subnetworks comprising the organism. The evolution of biological networks is studied by considering a network of a few nodes embedded in a larger context. Taking into account this fact that any network under study is actually embedded in a larger context, we define network architecture, not on the basis of physical interactions alone, but rather as a specification of the manner in which constraints are placed upon the states of its nodes. We show that such network architectures possessing cycles in their topology, in contrast to those that do not, may be subjected to unsatisfiable constraints. This may be a significant factor leading to selection biased against those network architectures where such inconsistent constraints are more likely to arise. We proceed to quantify the likelihood of inconsistency arising as a function of network architecture finding that, in the absence of sampling bias over the space of possible constraints and for a given network size, networks with a larger number of cycles are more likely to have unsatisfiable constraints placed upon them. Our results identify a constraint that, at least in isolation, would contribute to a bias in the evolutionary process towards more hierarchical -modular versus completely connected network architectures. Together, these results highlight the context dependence of the functionality of biological networks.


Diagnosis-Related Group in Colon Surgery: Identifying Areas of Improvement to Drive High-Value Care.
Diagnosis-related group (DRG) migration is defined as the reassignment of colectomy patients from DRG 331 to 330 based exclusively on postoperative complications. Strategic and comparative application of this metric has the potential to demonstrate baseline and excessive rates of complications related directly to patient care differences across institutions. The aim of this study was to report the variability of DRG migration across United States hospitals and its impact on overall cost and length of stay (LOS). This study investigated the variability of DRG migration rates across United States hospitals polling 5 per cent of the national Medicare data. The study endpoints were total cost, LOS, and DRG migration rate. Hospitals were classified into tertiles for low (0.1-16.6%), moderate (16.7-23.0%), and high (23.1-83.3%) DRG migration rates. The study included 5120 patients from 615 hospitals. DRG migration rates for hospitals ranged from 0.1 per cent to 83.3 per cent, with 157 in the low, 183 in the moderate, and 364 in the high tertile. DRG migration resulted in a progressively increased LOS and hospital costs from the lowest to highest tertile. Several diagnoses were identified which are suggestive of failure to integrate evidence-based processes of care across the tertiles. The data confirm a wide variation in DRG migration rates from DRG 331 to 330 based only on postoperative complications. These ranges allow for the potential definition of both best practice, and opportunities for quality improvement with respect to postoperative complications, identification of hospital outliers, and the economics of care as part of a value-based care program.


MAG-EPA reduces severity of DSS-induced colitis in rats.
Ulcerative colitis (UC) is a chronic disease characterized by diffuse inflammation of the intestinal mucosa of the large bowel. Omega-3 (ω3) fatty acid supplementation has been associated with a decreased production of inflammatory cytokines involved in UC pathogenesis. The aim of this study was to determine the preventive and therapeutic potential of eicosapentaenoic acid monoglyceride (MAG-EPA) in an in vivo rats model of UC induced by dextran sulfate sodium (DSS). DSS rats were untreated or treated per os with MAG-EPA. Morphological, histological, and biochemical analyses were performed following MAG-EPA administrations. Morphological and histological analyses revealed that MAG-EPA pretreatment (12 days pre-DSS) and treatment (6 days post-DSS) exhibited strong activity in reducing severity of disease in DSS rats. Following MAG-EPA administrations, tissue levels of the proinflammatory cytokines TNF-α, IL-1β, and IL-6 were markedly lower compared with rats treated only with DSS. MAG-EPA per os administration decrease neutrophil infiltration in colon tissues, as depicted by myelohyperoxidase activity. Results also revealed a reduced activation of NF-κB pathways correlated with a decreased expression of COX-2 in colon homogenates derived from MAG-EPA-pretreated and treated rats. Tension measurements performed on colon tissues revealed that contractile responses to methacholine and relaxing effect induced by sodium nitroprusside were largely increased following MAG-EPA treatment. The combined treatment of MAG-EPA and vitamin E displayed an antagonistic effect on anti-inflammatory properties of MAG-EPA in DSS rats.


Grades of hypothyroidism.
Seventy-nine patients with hypothyroidism and autoimmune thyroid disease were studied, and allotted to one of four categories on the basis of clinical and biochemical features. Firstly, patients with overt hypothyroidism had obvious clinical features of hypothyroidism and abnormal results from routine tests of thyroid function. Secondly, those with mild hypothyroidism, however, had minor and non-specific symptoms, but the routine measurements of circulating thyroid hormone concentration generally lay within the normal range, although they were significantly lower than those seen in subclinical hypothyroidism or in normal subjects. The serum concentration of thyroid-stimulating hormone (TSH) was raised in this group and their symptoms resolve with treatment. Thirdly, patients with subclinical hypothyroidism were asymptomatic, had a raised serum TSH concentration, but all other measurements of thyroid function are indistinguishable from those recorded in people with autoimmune thyroid disease without disturbance of thyroid function and in normal subjects. Lastly, subjects with circulating thyroid antibodies, normal indices of thyroid function, and a normal serum TSH concentration were indistinguishable biochemically from normal subjects.Thus hypothyroidism is a graded phenomenon, the most valuable features for defining the individual grade being the clinical manifestations, the serum TSH concentration, and the presence of circulating antibodies to thyroid tissue.


Prioritisation criteria for the selection of new diagnostic technologies for evaluation.
Currently there is no framework for those involved in the identification, evaluation and prioritisation of new diagnostic technologies. Therefore we aimed to develop prioritisation criteria for the assessment of new diagnostic technologies, by gaining international consensus on not only which criteria should be used, but also their relative importance. A two-round Delphi process was used to generate consensus amongst an international panel of twenty-six experts on priority criteria for diagnostic health technology assessment. Participants represented a range of health care and related professions, including government, industry, health services and academia. Based on the responses to the first questionnaire 18 criteria were placed into three categories: high, intermediate and moderate priority. For 16 of the 18 criteria, agreement with the categorisation of the criteria into the high, intermediate and moderate categories was high at > or = 70% (10 had agreement > or = 80%). A further questionnaire and panel discussion reduced the criteria to 16 and two categories; seven were classified as high priority and nine intermediate. This study proposes an objective structure of prioritisation criteria to use when assessing new diagnostic technologies, based on an expert consensus process. The value of these criteria is that no one single component should be used as the decisive driver for prioritisation of new diagnostic technologies for adoption in healthcare settings. Future studies should be directed at establishing the value of these prioritisation criteria across a range of healthcare settings.


Metabolomics profiling reveals different patterns in an animal model of asphyxial and dysrhythmic cardiac arrest.
Cardiac arrest (CA) is not a uniform condition and its pathophysiology strongly depends on its cause. In this work we have used a metabolomics approach to study the dynamic metabolic changes occurring in the plasma samples of a swine model following two different causes of CA, namely asphyxia (ACA) and ventricular fibrillation (VFCA). Plasma samples were collected at baseline and every minute during the experimental phases. In order to identify the metabolomics profiles characterizing the two pathological entities, all samples were analysed by 1H NMR spectroscopy and LC-MS/MS spectrometry.The metabolomics fingerprints of ACA and VFCA significantly differed during the peri-arrest period and the resuscitation phase. Major alterations were observed in plasma concentrations of metabolites related to tricarboxylic acid (TCA) cycle, urea cycle, and anaplerotic replenishing of TCA. ACA animals showed significant metabolic disturbances during the asphyxial and CA phases, while for VFCA animals this phenomenon resulted shifted at the resuscitation phase. Interestingly, starting from the asphyxial phase, the ACA animals were stratified in two groups based on their metabolomics profiles that resulted to be correlated with the clinical outcome. Succinate overproduction was observed in the animals with the worse outcome, suggesting a potential prognostic role for this metabolite.


Is smoking a risk factor for collagenous colitis?
The association between smoking and idiopathic inflammatory bowel disease is well known; smoking seems to have a diverse effect. Crohn's disease is associated with smoking, while ulcerative colitis is associated with non-smoking. Data on smoking in microscopic colitis of the collagenous type (CC) are lacking. The aim of this investigation was to study smoking habits in CC and to observe whether smoking had any impact on the course of the disease. 116 patients (92 women) with median age of 62 years (interquartile range 55-73) answered questionnaires covering demographic data, smoking habits and disease activity. As control group we used data from the general population in Sweden retrieved from Statistics Sweden, the central bureau for national socioeconomic information. Of the 116 CC patients, 37% were smokers compared with 17% of controls (p < 0.001, odds ratio (OR) 2.95). In the age group 16-44 years, 75% of CC patients were smokers compared with 15% of controls (p < 0.001, OR 16.54). All CC smoker patients started smoking before the onset of disease. Furthermore, smokers developed the disease earlier than non-smokers--at 42 years of age (median) compared with 56 years in non-smokers (p < 0.003). Although the proportion with active disease did not differ between smokers and non-smokers, there was a trend indicating that more smokers received active treatment (42% vs. 17%, p = 0.078). Smoking is a risk factor for CC. Smokers develop their disease more than 10 years earlier than non-smokers.


Hydrogel-based diffractive optical elements (hDOEs) using rapid digital photopatterning.
Hydrogels, due to their optical transparency and biocompatibility, have emerged as an excellent alternative to conventional optical materials for biomedical applications. Advances in microfabrication techniques have helped convert conventional hydrogels into optically functional materials such as hydrogel-based diffraction optical elements (hDOEs). However, key challenges related to device customization and ease/speed of fabrication need to be addressed to enable widespread utility and acceptance of hDOEs in the field. Here, we report rapid printing of customized hDOEs on polyethylene glycol diacrylate (PEGDA) hydrogel using digital photopatterning; a novel method that combines simulated computer-generated hologram (SCGH) and projection photolithography. To showcase the versatility of this approach, a range of hDOEs are demonstrated, including 1D/2D diffraction gratings, Dammann grating, Fresnel zone plate (FZP) lens, fork-shaped grating and computer-generated hologram (CGH) of arbitrary pattern. Results demonstrate that printed hDOEs exhibit optical performance that is comparable with devices made with conventional materials. This versatile strategy can be potentially implemented with other photosensitive hydrogels to achieve user-defined hDOEs in a time-efficient and cost-effective fashion.


Teratology on the crossroads: historical aspects and modern approaches.
Teratology is the science of congenital developmental disorders (CDDs), overt or latent defects of the organism resulting from the effect of internal and external factors on developmental processes. In this article the significance and position of present-day teratology is discussed in the context of development of this branch of science and related disciplines. The authors present an updated overview of the most important milestones and stages of the development of teratology. Based on the analysis of the historical development of theses and theories that represent a decisive contribution to this field, we present a survey of the fundamental principles of experimental and clinical teratology. The aim of observing these principles is to get insight into developmental relations and to understand mechanisms of action on the level of cell populations (elementary morphogenetic processes), tissues and organs. It is important to realize that any negative intervention into the normal course of these processes, either on genetic or non-genetic basis, inevitably leads to a sequence of subsequent changes resulting in the development of congenital developmental disorders. Despite modern approaches of molecular biology and genetics, along with top diagnostic techniques, we are still not able to identify the actual cause in more than 50% of all congenital defects. One-half of the unidentified cases are referred to as "multifactorial", a term that is rather ambiguous. It either means that some of the basic principles of teratogenesis still escape our attention, or the interpretation of some of the well known principles might be misleading. A third possibility is rather pessimistic. The development of the individual is so sophisticated and dependent on a delicate network of a multitude of factors mutually affecting each other that it is extremely prone to give rise to a plethora of spontaneous errors which are unpredictable and impossible to prevent. Nevertheless, the long and complicated history of scientific endeavour has yielded considerable present-day knowledge on causes and mechanisms of CDDs, a history whose beginnings date back to antiquity.