Meningiomas in children and adolescents: a meta-analysis of individual patient data.
The epidemiological, prognostic, and therapeutic features of child and adolescent meningioma are poorly defined. Clinical knowledge has been drawn from small case series and extrapolation from adult studies. This study was done to pool and analyse the clinical evidence on child and adolescent meningioma. Searches of PubMed, Medline, and Embase identified 35 case series of child and adolescent meningioma completed over the past 21 years. Individual patient data were obtained from 30 studies via direct communication with investigators. Primary outcomes were relapse-free survival (RFS) and overall survival. Prognostic variables were extent of initial surgery, use of upfront radiotherapy, age, sex, presence of neurofibromatosis, tumour location, and tumour grade. RFS and overall survival were analysed using Kaplan-Meier survival curves and multivariable Cox regression models. From a total of 677 children and adolescents with meningioma, 518 were eligible for RFS analysis and 547 for overall survival analysis. Multivariable analysis showed that patients who underwent initial gross-total resection had better RFS (hazard ratio 0·16, 95% CI 0·10-0·25; p<0·0001) and overall survival (0·21, 0·11-0·39; p<0·0001) than those who had subtotal resection. No significant benefit was seen for upfront radiotherapy in terms of RFS (0·59, 0·30-1·16; p=0·128) or overall survival (1·10, 0·53-2·28; p=0·791). Patients with neurofibromatosis type 2 (NF2) had worse RFS than those without neurofibromatosis (2·36, 1·23-4·51; p=0·010). There was a significant change in overall survival with time between patients with NF2 compared with those without neurofibromatosis (1·45, 1·09-1·92; p=0·011); although overall survival was initially better for patients with NF2 than for those without neurofibromatosis, overall survival at 10 years was worse for patients with NF2. Patients with WHO grade III tumours had worse RFS than those with WHO grade I (3·90, 2·10-7·26; p<0·0001) and grade II tumours (2·49, 1·11-5·56; p=0·027). Extent of initial surgical resection is the strongest independent prognostic factor for child and adolescent meningioma. No benefit for upfront radiotherapy was noted. Hence, aggressive surgical management, to achieve gross-total resection, is the initial treatment of choice. In the event of a subtotal resection, repeat resection is recommended to achieve maximum extirpation. Close observation is warranted for patients who have a subtotal resection or who have WHO grade III tumours. Patients without neurofibromatosis should have a minimum 10-year follow-up, whereas patients with NF2 should be considered a special risk category, necessitating life-long follow-up. None.


Calcifications in the cuff: take it or leave it?
The aim of this study was to evaluate whether removing the calcifications in the rotator cuff tendons during surgical subacromial decompression improves outcome in patients with calcific tendonitis. Two groups of 20 patients with a subacromial impingement syndrome and cuff calcifications were operated on. In group A, patients had an anterolateral acromioplasty according to Neer with excision of calcifications. In group B, the same procedure was performed without additional excision of calcifications. After a minimum follow-up of 3 years the patients were assessed with the disabilities of arm, shoulder and hand score (DASH), the visual analogue scale (VAS) for pain, measurements of range of motion (ROM) in all planes, and satisfaction with treatment. The results for the DASH score, ROM, VAS and satisfaction with treatment showed no significant difference between the two groups. The results of our study suggest that removal of calcific deposits with anterolateral acromioplasty does not influence patient outcome. Further prospective studies are needed to determine the optimal surgical treatment for calcific tendonitis.


The California Verbal Learning Test-Children's Version: relation to factor indices of the Wechsler Intelligence Scale for Children-Third Edition.
The California Verbal Learning Test-Children's Version (CVLT-C) provides clinicians with a method of assessing various aspects of children's verbal memory and has been found to be sensitive to memory deficits resulting from a variety of neurological conditions. Intuitively, the CVLT-C would be expected to be highly related to a child's verbal cognitive abilities; however, with only a few exceptions, the relationship of this test to various domains of cognitive function has not been broadly studied empirically. To examine this issue, we evaluated the amount of unique variance in CVLT-C scores that could be predicted by the Verbal Comprehension, Perceptual Organization, Freedom from Distractibility, and Processing Speed indices of the Wechsler Intelligence Scale for Children, Third Edition (WISC-III) beyond that accounted for by age and gender in a sample of 62 children referred to an outpatient psychiatry clinic for neuropsychological evaluation. While the Processing Speed Index predicted a significant amount of variance for both short and long delay free and cued recall, the Verbal Comprehension Index was a poor predictor of CVLT-C performance on all outcome variables, accounting for only 1.5 to 4.5% additional variance above age and gender. These findings indicate that while the CVLT-C may be relatively independent of influences of verbal intelligence and abstract verbal reasoning, general speed and efficiency of processing play an important role in successful encoding for later retrieval on the CVLT-C.


Anthocyanin-rich purple corn extract inhibit diabetes-associated glomerular angiogenesis.
Diabetic nephropathy (DN) is one of the major diabetic complications and the leading cause of end-stage renal disease. Abnormal angiogenesis results in new vessels that are often immature and play a pathological role in DN, contributing to renal fibrosis and disrupting glomerular failure. Purple corn has been utilized as a daily food and exerts disease-preventive activities. This study was designed to investigate whether anthocyanin-rich purple corn extract (PCE) prevented glomerular angiogenesis under hyperglycemic conditions. Human endothelial cells were cultured in conditioned media of mesangial cells exposed to 33 mM high glucose (HG-HRMC-CM). PCE decreased endothelial expression of vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF)-1α induced by HG-HRMC-CM. Additionally, PCE attenuated the induction of the endothelial marker of platelet endothelial cell adhesion molecule (PECAM)-1 and integrin β3 enhanced in HG-HRMC-CM. Endothelial tube formation promoted by HG-HRMC-CM was disrupted in the presence of PCE. In the in vivo study employing db/db mice treated with 10 mg/kg PCE for 8 weeks, PCE alleviated glomerular angiogenesis of diabetic kidneys by attenuating the induction of VEGF and HIF-1α. Oral administration of PCE retarded the endothelial proliferation in db/db mouse kidneys, evidenced by its inhibition of the induction of vascular endothelium-cadherin, PECAM-1 and Ki-67. PCE diminished the mesangial and endothelial induction of angiopoietin (Angpt) proteins under hypeglycemic conditions. The induction and activation of VEGF receptor 2 (VEGFR2) were dampened by treating PCE to db/db mice. These results demonstrate that PCE antagonized glomerular angiogenesis due to chronic hyperglycemia and diabetes through disturbing the Angpt-Tie-2 ligand-receptor system linked to renal VEGFR2 signaling pathway. Therefore, PCE may be a potent therapeutic agent targeting abnormal angiogenesis in DN leading to kidney failure.


Intensive mutagenesis of the nisin hinge leads to the rational design of enhanced derivatives.
Nisin A is the most extensively studied lantibiotic and has been used as a preservative by the food industry since 1953. This 34 amino acid peptide contains three dehydrated amino acids and five thioether rings. These rings, resulting from one lanthionine and four methyllanthionine bridges, confer the peptide with its unique structure. Nisin A has two mechanisms of action, with the N-terminal domain of the peptide inhibiting cell wall synthesis through lipid II binding and the C-terminal domain responsible for pore-formation. The focus of this study is the three amino acid 'hinge' region (N 20, M 21 and K 22) which separates these two domains and allows for conformational flexibility. As all lantibiotics are gene encoded, novel variants can be generated through manipulation of the corresponding gene. A number of derivatives in which the hinge region was altered have previously been shown to possess enhanced antimicrobial activity. Here we take this approach further by employing simultaneous, indiscriminate site-saturation mutagenesis of all three hinge residues to create a novel bank of nisin derivative producers. Screening of this bank revealed that producers of peptides with hinge regions consisting of AAK, NAI and SLS displayed enhanced bioactivity against a variety of targets. These and other results suggested a preference for small, chiral amino acids within the hinge region, leading to the design and creation of producers of peptides with hinges consisting of AAA and SAA. These producers, and the corresponding peptides, exhibited enhanced bioactivity against Lactococcus lactis HP, Streptococcus agalactiae ATCC 13813, Mycobacterium smegmatis MC2155 and Staphylococcus aureus RF122 and thus represent the first example of nisin derivatives that possess enhanced activity as a consequence of rational design.


Rosmarinus officinalis extract inhibits human melanoma cell growth.
Rosmarinus officinalis L. is receiving increasing attention due to its anti-inflammatory and antioxidative constituents. Our recent studies showed that R. officinalis extract, containing 31.7% of carnosic acid, was able to counteract the deleterious effects of UV-R, by protecting plasmid DNA from hydroxyl radicals generated by UV-A. In this work, we evaluated the effects of this extract on pBR322 DNA cleavage induced by nitric oxide, and the growth inhibitory activity against two human melanoma cell lines, M14 and A375. The extract showed a protective effect on plasmid DNA damage, and at concentrations of 10-80 microg/mL was able to reduce significantly (p<0.001) the growth (MTT assay) of both melanoma cell lines. In addition, our results indicate that apoptotic cell demise is induced in M14 and A375 cells. No statistically significant increase in LDH release was observed in melanoma cells, correlated to a fragmentation of genomic DNA, determined by COMET assay.


Inference or enaction? The impact of genre on the narrative processing of other minds.
Do narratives shape how humans process other minds or do they presuppose an existing theory of mind? This study experimentally investigated this problem by assessing subject responses to systematic alterations in the genre, levels of intentionality, and linguistic complexity of narratives. It showed that the interaction of genre and intentionality level are crucial in determining how narratives are cognitively processed. Specifically, genres that deployed evolutionarily familiar scenarios (relationship stories) were rated as being higher in quality when levels of intentionality were increased; conversely, stories that lacked evolutionary familiarity (espionage stories) were rated as being lower in quality with increases in intentionality level. Overall, the study showed that narrative is not solely either the origin or the product of our intuitions about other minds; instead, different genres will have different-even opposite-effects on how we understand the mind states of others.


The impact of the ART approach on the treatment profile in a mobile dental system (MDS) in South Africa.
The changing profile of oral care rendered through the Mobile Dental System (MDS), after the introduction of the Atraumatic Restorative Treatment (ART) approach is described. During the first year of introduction of ART, the percentages of amalgam restorations and tooth extractions decreased significantly (P < 0.0001). This is partly ascribed to a change in choice of treatment by dental operators in favour of ART and also due to an increase in acceptance by patients because of the reduced fear, and the patient-friendly nature of the ART approach. The reduction in amalgam restorations was 16.0 per cent for permanent and 1.4 per cent for primary posterior teeth. Extraction of posterior teeth was reduced by 17.4 per cent in the permanent and 35.7 per cent in the primary dentitions. The restorative component of oral care increased by 33.4 per cent in the permanent and 37.1 per cent in primary posterior teeth. The one-year survival of one-surface ART restorations using Fuji IX and KetacMolar was 93.6 per cent. Full and partial (more than 90 per cent) retention of the sealant part of the ART restoration was obtained in 75 per cent of the cases after one-year. During the one-year period, infection control was made more simple and this facilitated easier maintenance of mobile dental equipment. The introduction of the ART approach reduced extraction, restored more teeth and made oral care in the MDS more preventive, less threatening and thus more patient-friendly.


Prognostic influence of diabetes mellitus on long-term clinical outcomes and stent thrombosis after drug-eluting stent implantation in asian patients.
Diabetes mellitus has been associated with an increased risk of mortality and stent thrombosis after implantation of drug-eluting stents (DES). Little is known about the prognostic impact of diabetes on clinical outcomes in an Asian population treated with DES. We compared adverse outcomes between 865 patients with diabetes and 2,295 patients without diabetes treated with DES after adjustment for differences in baseline risk factors in the patients. The primary outcome was the composite of death, nonfatal myocardial infarction, or target-vessel revascularization (TVR). The 3-year unadjusted rates of death (5.8% vs 3.5%, p = 0.002) and TVR (12.2% vs 8.6%, p = 0.003) were significantly higher in patients with diabetes. After adjustment for baseline differences, the risk of TVR remained higher in patients with diabetes (hazard ratio 1.37, 95% confidence interval [CI] 1.04 to 1.81, p = 0.03), but the risk of death did not (hazard ratio 1.35, 95% CI 0.89 to 2.05, p = 0.16). The 3-year adjusted risk of the primary composite outcome was significantly higher in patients with diabetes compared with patients without diabetes (23.3% vs 16.1%, hazard ratio 1.24, 95% CI 1.02 to 1.51, p = 0.03). Insulin use was an independent predictor for each outcome (death, TVR, and composite outcome). After adjustment by baseline risk profile and for propensity, diabetes was not associated with an increased risk of stent thrombosis (multivariable-adjusted hazard ratio 0.87, 95% CI 0.36 to 2.15, p = 0.77 and propensity-adjusted hazard ratio 0.87, 95% CI 0.37 to 2.06, p = 0.76). In conclusion, diabetic status was associated with increased TVR without a significantly increased rate of death. A diabetes-associated excess risk of stent thrombosis was not observed in Asian patients.


Expression and biologic characterization of the murine chemokine KC.
KC, the product of an immediate early gene induced in mouse fibroblasts by platelet-derived growth factor, was expressed in Escherichia coli by using a maltose binding protein vector and biochemically characterized as a ligand for both murine and human polymorphonuclear neutrophils (PMN). On murine PMN, KC is both a potent chemoattractant and up-regulator of Mac-1 cell surface expression. On human PMN, in contrast, KC exhibits dissociation of its chemoattractant and Mac-1 up-regulatory activities. Although KC strongly increases Mac-1 expression on human PMN, it does not induce chemotaxis in vitro. 125I-KC-Tyr binds to both mouse and human PMN with two classes of binding sites, including high affinity sites of 0.8 and 2 nM, with approximately 9,000 and 10,000 sites per cell, respectively. On mouse PMN, human macrophage inflammatory protein (MIP)-2 alpha and MIP-2 beta compete for 125I-KC-Tyr binding with high affinity, whereas the murine beta-chemokine TCA-3 does not compete. KC binds to human PMN by the IL-8 type B receptor and to murine PMN by a murine IL-8 type B receptor homologue. 125I-KC-Tyr also binds to human RBC with a single class of high affinity sites. KC mRNA is constitutively expressed in multiple murine tissues. With human IL-8 and KC cDNA as probes, a mouse neutrophil exudate library was screened: KC and MIP-2 were the dominant chemokine species found. Thus, KC appears to be intimately involved in murine inflammation and its constitutive expression may have a role in the basal trafficking of neutrophils.


Unexpected bird-feather mite associations revealed by DNA metabarcoding uncovers a dynamic ecoevolutionary scenario.
The high relevance of host-switching for the diversification of highly host-specific symbionts (i.e., those commonly inhabiting a single host species) demands a better understanding of host-switching dynamics at an ecological scale. Here, we used DNA metabarcoding to study feather mites on passerine birds in Spain, sequencing mtDNA (COI) for 25,540 individual mites (representing 64 species) from 1,130 birds (representing 71 species). Surprisingly, 1,228 (4.8%) mites from 84 (7.4%) birds were found on host species that were not the expected to be a host according to a recent bird-feather mite associations catalog. Unexpected associations were widespread across studied mite (40.6%) and bird (43.7%) species and showed smaller average infrapopulation sizes than typical associations. Unexpected mite species colonized hosts being distantly related to the set of their usual hosts, but with similar body size. The network of bird-mite associations was modular (i.e., some groups of bird and mite species tended to be more associated with each other than with the others), with 75.9% of the unexpected associations appearing within the module of the typical hosts of the mite species. Lastly, 68.4% of mite species found on unexpected hosts showed signatures of genetic differentiation, and we found evidence for reproduction or the potential for it in many of the unexpected associations. Results show host colonization as a common phenomenon even for these putatively highly host-specific symbionts. Thus, host-switching by feather mites, rather than a rare phenomenon, appears as a relatively frequent phenomenon shaped by ecological filters such as host morphology and is revealed as a fundamental component for a dynamic coevolutionary and codiversification scenario.


Elevated serum levels of circulating immunoinflammation-related protein complexes are associated with cancer.
Disease-specific immune response-related protein complexes in the bloodstream are associated with disease status. We used proteomic technologies to screen novel circulating immunoinflammation-related protein complexes (IIRPCs) and to evaluate their diagnostic accuracy. The discovery study included 96 gastric cancer patients and 83 healthy controls and was designed to isolate and identify the IIRPCs. Then an independent validation study including 1366 patients with lung, colorectal, pancreatic, gastric, or thyroid cancer, 141 patients with other types of cancer, 376 patients with benign lung, colorectal, pancreatic, gastric, or thyroid diseases, and 3707 healthy controls was performed. We observed seven major patterns of the IIRPCs and confirmed the IIRPCs as personalized biomarkers of cancers. The levels of the IIRPCs were significantly increased in cancer patients compared with controls and benign patients (p < 0.0001). Each of the IIRPCs (a2 to a4, a6, a7, and b3 to b5) shows excellent discriminating power for lung, colorectal, pancreatic, and gastric cancer, with the areas under the receiver operating characteristic curves (AUCs) from 0.95 to 0.99 (95% CIs 0.91-1.00), and for thyroid cancer, with the AUCs from 0.87 to 0.96 (95% CIs 0.80-0.98). The IIRPCs can be used as a novel type of broad-spectrum and supramolecular biomarker for personalized cancer diagnosis.


Do all ischemic stroke subtypes benefit from organized inpatient stroke care?
There are limited data on the effectiveness of organized stroke care in different ischemic stroke subtypes in the real-world setting. We analyzed the effect of organized stroke care in all stroke subtypes in a longitudinal cohort study using data from the Registry of the Canadian Stroke Network. Between July 2003 and September 2007, there were 6,223 consecutive patients with ischemic stroke subtype information by Trial of Org 10172 in Acute Stroke Treatment criteria. Subtypes were categorized as large artery atherosclerotic disease, lacunar, cardioembolic, or other. The amount of organized stroke care was quantified using the previously published organized care index (OCI), graded 0-3 based on the presence or absence of occupational therapy or physiotherapy, stroke team assessment, and admission to a stroke unit. Mortality at 30 days was associated with both stroke subtype and OCI. Higher OCI (defined as score 2-3 compared to 0-1) was strongly associated with lower odds of 30-day mortality in each ischemic stroke subtype (adjusted odds ratio estimates ranged from 0.16 to 0.43, p < 0.001, controlling for age, gender, stroke severity, and medical comorbidities by logistic regression). These estimates were essentially unchanged after excluding patients treated with palliative care. Numbers needed to treat, to prevent 1 death at 30 days, ranged from 4 to 9 across the subtypes. A strong association between higher OCI and lower 30-day mortality was apparent in each ischemic stroke subtype. These data suggest that organized stroke care should be provided to stroke patients regardless of stroke subtype.


Six-year change in high-sensitivity C-reactive protein and risk of diabetes, cardiovascular disease, and mortality.
Single measurements of elevated high-sensitivity C-reactive protein (hs-CRP) are associated with increased risk of diabetes, cardiovascular disease, and mortality. Large increases or sustained elevations in hs-CRP may be associated with even greater risk of these outcomes. The objective of this study was to characterize the association of 6-year change in hs-CRP with incident diabetes, incident cardiovascular events (heart disease, stroke, and heart failure), and mortality. We included 10,160 ARIC participants with hs-CRP measured at visits 2 (1990-1992) and 4 (1996-1998). Change in hs-CRP was categorized as sustained low/moderate (<3 mg/L at both visits), decreased (≥3 mg/L at visit 2 and <3 mg/L at visit 4), increased (<3 mg/L at visit 2 and ≥3 mg/L at visit 4), and sustained elevated (≥3 mg/L at both visits). Cox proportional hazards models were used to assess the association of 6-year change in hs-CRP with incident diabetes, cardiovascular events, and death during ~15 years after visit 4. Compared with persons with sustained low/moderate hs-CRP, those with increased or sustained elevated hs-CRP had an increased risk of incident diabetes (hazard ratios [95% CIs] 1.56 [1.38-1.76] and 1.39 [1.25-1.56], respectively), whereas those with deceased hs-CRP did not. Persons with sustained elevated hs-CRP had an increased risk of coronary heart disease, ischemic stroke, heart failure, and mortality (hazard ratios [95% CIs] 1.51 [1.23-1.85], 1.70 [1.32-2.20], 1.60 [1.35-1.89], and 1.52 [1.37-1.69], respectively) compared with those with sustained low/moderate hs-CRP. Associations for sustained elevated hs-CRP were greater than for those with increased hs-CRP over 6 years. Large increases or sustained elevations in hs-CRP over a 6-year period were associated with a subsequent increased risk of diabetes, and persons with sustained elevations in hs-CRP were at the highest risk for cardiovascular disease and mortality. Two measurements of hs-CRP are better than one for characterizing risk, and large increases are particularly prognostic.


How Do Women Learn They Are Pregnant? The Introduction of Clinics and Pregnancy Awareness in Nepal.
The earlier a woman learns about her pregnancy status, the sooner she can make decisions about her own and infant's health. This paper examines how women learn about their pregnancy status and measures how access to pregnancy tests affects earlier pregnancy knowledge. Using 10 years of individual-level monthly panel data in Nepal, we find that, on average, women learn they are pregnant in their 4.6th month of pregnancy. Living approximately a mile further from a clinic offering pregnancy tests increases the time a woman knows she is pregnant by one week (5 percent increase) and decreases the likelihood of knowing in the first trimester by 4.5 percentage points (16 percent decrease). Women with prior pregnancies experience the most substantial effects of distance within the first two trimesters, while, for women experiencing their first pregnancy, distance does not affect knowledge. These results suggest that, while access to clinics can increase pregnancy awareness for women who recognize pregnancy symptoms, other complementary policies are needed to increase pregnancy awareness of women in their first pregnancy.


Therapists' roles in pressure ulcer management in persons with spinal cord injury.
Among veterans with spinal cord injury (SCI), severe pressure ulcers (PrU) are treated by interdisciplinary rehabilitation teams in SCI units. Cross-sectional survey administered to therapists attending a conference of the Therapy Leadership Council in SCI. Respondents included physical therapists (PTs; n=24) and occupational therapists (OTs; n=15). Wound care practices as indicated by 75% or more of participants as "usual practice". In general, therapist involvement with wound care was initiated by physician order (e.g., electrical stimulation) or postsurgery protocols. "Usual practice" after tissue healing included progressive range of motion; initial remobilization (first sitting after wound healing); progression of sitting time including assessment of skin tolerance; instruction in pressure relief maneuvers/techniques; and instruction in safe transfers. Practices in prevention of a new ulcer included education and evaluation of seating posture/positioning. Results indicate that centers may delegate responsibilities for management of ulcers differentially by discipline. A limitation was that we were unable to determine whether these centers were the same or different for OT and PT respondents. Although sample size was small and some sites had multiple respondents, the survey showed a growing role for OTs and PTs in PrU treatment. Because 75% of each discipline reported that there were usual practices, including patient education and remobilization protocols, this area requires further study to determine the clinical outcomes in terms of preventing PrUs and recurrence.


Intimate partner violence in the family: considerations for children's safety.
Children's exposure to intimate partner violence (IPV) is increasingly recognized as a type of child maltreatment that has a level of impairment similar to other types of abuse and neglect. Despite advances in the area of IPV, the safety planning strategies recommended as part of the overall response to IPV need to be examined in terms of their implications for children. This article discusses these strategies within the context of child safety, comparing IPV safety planning with approaches aimed at reducing exposure to other types of violence such as child sexual abuse, as well as general child safety strategies. Despite the emphasis on safety planning in information available on responding to IPV, the actual effectiveness of such planning in improving safety and reducing violence is unknown. Safety planning provided to children by a parent experiencing IPV, especially when IPV is ongoing and not recognized by anyone outside the home, may lead to confusing messages for children, particularly if there is an emphasis on secrecy. While awaiting evidence about the effectiveness of specific safety planning strategies for children, we suggest basic principles and general strategies that emphasize universality in terms of education about any type of violence or abuse in the home being unacceptable, as well as the need to focus on safety in general.


Differentiation of functional constipation and constipation predominant irritable bowel syndrome based on Rome III criteria: a population-based study.
While the Rome III classification recognises functional constipation (FC) and constipation predominant IBS (IBS-C) as distinct disorders, recent evidence has suggested that these disorders are difficult to separate in clinical practice. To identify whether clinical and lifestyle factors differentiate Rome III-defined IBS-C from FC based on gastrointestinal symptoms and lifestyle characteristics. 3260 people randomly selected from the Australian population returned a postal survey. FC and IBS-C were defined according to Rome III. The first model used logistic regression to differentiate IBS-C from FC based on lifestyle, quality-of-life and psychological characteristics. The second approach was data-driven employing latent class analysis (LCA) to identify naturally occurring clusters in the data considering all symptoms involved in the Rome III criteria for IBS-C and FC. We found n = 206 (6.5%; 95% CI 5.7-7.4%) people met strict Rome III FC whereas n = 109 (3.5%; 95% CI 2.8-4.1%) met strict Rome III IBS-C. The case-control approach indicated that FC patients reported an older age at onset of constipation, were less likely to exercise, had higher mental QoL and less health care seeking than IBS-C. LCA yielded one latent class that was predominantly (75%) FC, while the other class was approximately half IBS-C and half FC. The FC-dominated latent class had clearly lower levels of symptoms used to classify IBS (pain-related symptoms) and was more likely to be male (P = 0.046) but was otherwise similar in distribution of lifestyle factors to the mixed class. The latent class analysis approach suggests a differentiation based more on symptom severity rather than the Rome III view.


PU.1 is linking the glycolytic enzyme HK3 in neutrophil differentiation and survival of APL cells.
The transcription factor PU.1 is a master regulator of myeloid differentiation and function. On the other hand, only scarce information is available on PU.1-regulated genes involved in cell survival. We now identified the glycolytic enzyme hexokinase 3 (HK3), a gene with cytoprotective functions, as transcriptional target of PU.1. Interestingly, HK3 expression is highly associated with the myeloid lineage and was significantly decreased in acute myeloid leukemia patients compared with normal granulocytes. Moreover, HK3 expression was significantly lower in acute promyelocytic leukemia (APL) compared with non-APL patient samples. In line with the observations in primary APL patient samples, we observed significantly higher HK3 expression during neutrophil differentiation of APL cell lines. Moreover, knocking down PU.1 impaired HK3 induction during neutrophil differentiation. In vivo binding of PU.1 and PML-RARA to the HK3 promoter was found, and PML-RARA attenuated PU.1 activation of the HK3 promoter. Next, inhibiting HK3 in APL cell lines resulted in significantly reduced neutrophil differentiation and viability compared with control cells. Our findings strongly suggest that HK3 is: (1) directly activated by PU.1, (2) repressed by PML-RARA, and (3) functionally involved in neutrophil differentiation and cell viability of APL cells.


Evolution of science-based uncertainty factors in noncancer risk assessment.
The science behind the use of uncertainty factors has progressed considerably. Increased knowledge of inter- and intraspecies sensitivity, mechanisms of action, and detailed evaluation of data bases can support the use of data-derived uncertainty factors, which ultimately results in a risk assessment with greater confidence. Papers that highlight available data for each of several areas of uncertainty are discussed, indicating that choice of the appropriate factor requires scientific judgement on a case-by-case basis. Case studies from EPA and Health Canada risk values illustrate the use of data in chemical specific risk assessments to support the selection of uncertainty factors other than the default value of 10-fold. In the case studies, the types of data that have been used to support a change in the default value are explicitly reviewed, as well as why the data support a different uncertainty factor, how the uncertainty was reduced, and what assumptions have been satisfied or replaced. Incorporation of all available scientific data into the risk assessment process fosters increased research and ultimately reduces uncertainty. The results of this review support the use of data-derived uncertainty factors when appropriate scientific data are available.


Detection of Clinically Significant Prostate Cancer: Short Dual-Pulse Sequence versus Standard Multiparametric MR Imaging-A Multireader Study.
Purpose To compare the diagnostic performance of a short dual-pulse sequence magnetic resonance (MR) imaging protocol versus a standard six-pulse sequence multiparametric MR imaging protocol for detection of clinically significant prostate cancer. Materials and Methods This HIPAA-compliant study was approved by the regional ethics committee. Between July 2013 and March 2015, 63 patients from a prospectively accrued study population who underwent MR imaging of the prostate including transverse T1-weighted; transverse, coronal, and sagittal T2-weighted; diffusion-weighted; and dynamic contrast material-enhanced MR imaging with a 3-T imager at a single institution were included in this retrospective study. The short MR imaging protocol image set consisted of transverse T2-weighted and diffusion-weighted images only. The standard MR imaging protocol image set contained images from all six pulse sequences. Three expert readers from different institutions assessed the likelihood of prostate cancer on a five-point scale. Diagnostic performance on a quadrant basis was assessed by using areas under the receiver operating characteristic curves, and differences were evaluated by using 83.8% confidence intervals. Intra- and interreader agreement was assessed by using the intraclass correlation coefficient. Transperineal template saturation biopsy served as the standard of reference. Results At histopathologic evaluation, 84 of 252 (33%) quadrants were positive for cancer in 38 of 63 (60%) men. There was no significant difference in detection of tumors larger than or equal to 0.5 mL for any of the readers of the short MR imaging protocol, with areas under the curve in the range of 0.74-0.81 (83.8% confidence interval [CI]: 0.64, 0.89), and for readers of the standard MR imaging protocol, areas under the curve were 0.71-0.77 (83.8% CI: 0.62, 0.86). Ranges for sensitivity were 0.76-0.95 (95% CI: 0.53, 0.99) and 0.76-0.86 (95% CI: 0.53, 0.97) and those for specificity were 0.84-0.90 (95% CI: 0.79, 0.94) and 0.82-0.90 (95% CI: 0.77, 0.94) for the short and standard MR protocols, respectively. Ranges for interreader agreement were 0.48-0.60 (83.8% CI: 0.41, 0.66) and 0.49-0.63 (83.8% CI: 0.42, 0.68) for the short and standard MR imaging protocols. Conclusion For the detection of clinically significant prostate cancer, no difference was found in the diagnostic performance of the short MR imaging protocol consisting of only transverse T2-weighted and diffusion-weighted imaging pulse sequences compared with that of a standard multiparametric MR imaging protocol. © RSNA, 2017 Online supplemental material is available for this article.


Controversy undermines support for state mandates on the human papillomavirus vaccine.
State actions requiring adolescent girls to receive the human papillomavirus (HPV) vaccine created controversy following the vaccine's approval in 2006. Some health professionals worried that the controversy might dampen public support for those state policies and for other school immunizations in general. We fielded an experimental Internet survey to determine how controversy affects attitudes about vaccines. We discovered that public support for the HPV vaccine mandates wanes when the public is informed that the policies are controversial. However, the experimental survey also revealed that exposure to this policy controversy did not spill over and reduce public support for immunizations in general.


Direct analysis of neuropeptides by in situ MALDI-TOF mass spectrometry in the rat brain.
The measure of neuropeptides is an important tool in biology to better define endocrine and neuroendocrine function. Traditionally most methods have relied on the development of specific antibodies. Newer molecular methodologies have used measures of gene expression of neuropeptide precursors, such as Northern blot, PCR or in situ hybridization analysis. Matrix-assisted laser desorption/ionization (MALDI) mass analysis is a novel powerful technique for investigation of neuropeptides. Multiple peptides and peptide forms can be detected simultaneously and with great sensitivity in tissue extracts or partially purified samples. We have now adapted a MALDI methodology for the direct measurement of neuropeptides on fresh tissue sections of rat brains. We have validated the method by examining peptidergic mass profiles of the supraoptic nucleus (SON) and caudate putamen hypothalamic regions. Interestingly, mass profiles showed that vasopressin, which is specifically present in the SON, is modulated when animals are treated with lipopolysaccharides. MALDI-MS on brain slides is a novel complementary technique for neurobiologists and endocrinologists in order to investigate the dynamic and regional distribution of neuropeptides during physiological events.


Multioracle Coevolutionary Learning of Requirements Specifications from Examples in On-The-Fly Markets.
In software engineering, the imprecise requirements of a user are transformed to a formal requirements specification during the requirements elicitation process. This process is usually guided by requirements engineers interviewing the user. We want to partially automate this first step of the software engineering process in order to enable users to specify a desired software system on their own. With our approach, users are only asked to provide exemplary behavioral descriptions. The problem of synthesizing a requirements specification from examples can partially be reduced to the problem of grammatical inference, to which we apply an active coevolutionary learning approach. However, this approach would usually require many feedback queries to be sent to the user. In this work, we extend and generalize our active learning approach to receive knowledge from multiple oracles, also known as proactive learning. The ``user oracle'' represents input received from the user and the "knowledge oracle" represents available, formalized domain knowledge. We call our two-oracle approach the "first apply knowledge then query" (FAKT/Q) algorithm. We compare FAKT/Q to the active learning approach and provide an extensive benchmark evaluation. As result we find that the number of required user queries is reduced and the inference process is sped up significantly. Finally, with so-called On-The-Fly Markets, we present a motivation and an application of our approach where such knowledge is available.


Acute presentations of syringomyelia. Report of three cases.
Three unusual cases are reported in which communicating syringomyelia presented acutely. The first patient presented with paraplegia, the second with acute respiratory distress secondary to bilateral vocal cord paralysis, and the third with symptoms of acute brain-stem ischemia. Each patient had a communicating spinal cord syrinx associated with a posterior fossa and foramen magnum region anomaly (a huge posterior fossa arachnoid cyst in one and Chiari malformations in two). The mechanisms of craniospinal pressure dissociation and hindbrain herniation are discussed, along with other reported emergency presentations of syringomyelia.


Interaction of hormonal and social environments in understanding body image concerns in adolescent girls.
During adolescence, peer approval becomes increasingly important and may be perceived as contingent upon appearance in girls. Concurrently, girls experience hormonal changes, including an increase in progesterone. Progesterone has been implicated in affiliative behavior but inconsistently associated with body image concerns. The current study sought to examine whether progesterone may moderate the association between perceived social pressures to conform to the thin ideal and body image concerns. Secondary analyses were conducted in cross-sectional data from 813 girls in early puberty and beyond (ages 8-16) who completed assessments of the peer environment, body image concerns, and progesterone. Models for mediation and moderation were examined with BMI, age, and menarcheal status as covariates. Belief that popularity was linked to appearance and the experience of weight-related teasing were both positively associated with greater body image concerns, but neither was associated with progesterone once adjusting for covariates. Progesterone significantly interacted with perceived social pressures in predicting body image concerns. At higher progesterone levels, appearance-popularity beliefs and weight-related teasing were more strongly related to body image concerns than they were at lower progesterone levels. Findings support a moderating role for progesterone in the link between social pressures and body image concerns in girls. This study adds to a growing literature examining how girls' hormonal environments may modulate responses to their social environments. Longitudinal and experimental work is needed to understand temporal relations and mechanisms behind these associations.


HIV prevalence and sexual behaviour changes measured in an antenatal clinic setting in northern Tanzania.
To assess the feasibility of collecting sexual behaviour data during HIV surveillance in antenatal care (ANC) clinics, and to establish whether these data can provide information about the correlates of HIV infection in this population. Sexual behaviour surveys were conducted in the context of two HIV sentinel surveillance rounds in 11 ANC clinics in north west Tanzania between 2000 and 2002. Responses of individual women were anonymously linked to their HIV status. Three clinic catchment areas overlapped with a community based longitudinal study, which provided independent estimates of HIV prevalence and sexual behaviour. Changes between rounds and differentials between clinics were assessed and a two level logistic regression model used to identify behavioural and contextual correlates of HIV in 3689 women under 25 years of age. Women attending clinics were willing to participate in the study. The sexual behaviour data obtained were internally consistent and tallied reasonably well with sexual behaviour data collected in the community overlapping the clinic catchment. Clear relations emerged between HIV infection and measures of sexual exposure: OR 1.20 (95% CL 1.12 to 1.28) for each year of premarital exposure and 1.09 (1.04 to 1.16) for each year after first marriage; background prevalence OR 1.15 (1.04 to 1.26) associated with each percentage point increase in background prevalence at the clinic; and certain partnership variables such as partner's age OR 0.58 (0.45 to 0.76) if partner less than 10 years older. Conducting sexual behaviour surveys in the context of ANC clinics surveillance is feasible and yields useful data.


JunB regulates homeostasis and suppressive functions of effector regulatory T cells.
Foxp3-expressing CD4+ regulatory T (Treg) cells need to differentiate into effector Treg (eTreg) cells to maintain immune homeostasis. T-cell receptor (TCR)-dependent induction of the transcription factor IRF4 is essential for eTreg differentiation, but how IRF4 activity is regulated in Treg cells is still unclear. Here we show that the AP-1 transcription factor, JunB, is expressed in eTreg cells and promotes an IRF4-dependent transcription program. Mice lacking JunB in Treg cells develop multi-organ autoimmunity, concomitant with aberrant activation of T helper cells. JunB promotes expression of Treg effector molecules, such as ICOS and CTLA4, in BATF-dependent and BATF-independent manners, and is also required for homeostasis and suppressive functions of eTreg. Mechanistically, JunB facilitates the accumulation of IRF4 at a subset of IRF4 target sites, including those located near Icos and Ctla4. Thus, JunB is a critical regulator of IRF4-dependent Treg effector programs, highlighting important functions for AP-1 in Treg-mediated immune homeostasis.


Membrane knobs are required for the microcirculatory obstruction induced by Plasmodium falciparum-infected erythrocytes.
We have studied the pathophysiology of the vascular obstruction induced by Plasmodium falciparum-parasitized erythrocytes with the use of an ex vivo microcirculatory preparation perfused with red cells infected with knobless and knobby clones of the FCR-3 strain. We find that parasitized erythrocyte membrane knobs are indispensable for the generation of the circulatory obstruction. Uninfected erythrocytes incubated in culture and erythrocytes infected with early or late forms of the knobless clones or the early forms of the knobby clone all failed to obstruct the microcirculation, although exhibiting various effects on bulk viscosity and peripheral resistance during flow. In contrast, late forms of the knobby clone produced significantly higher peripheral resistance during flow and significant obstruction as detected by changes in time of pressure flow recovery as well as by direct videorecorded microscopic observation. Optical and electron microscopy showed that the adherence of parasitized cells to the endothelium was limited to the venules and involved the knobs in junctions. In addition, we were able to follow the sequence of events during obstruction: initial red-cell adherence to the venular endothelium (sometimes only transitory) followed by progressive recruitment at the venule surface, finally leading to total obstruction that involved parasitized and nonparasitized erythrocytes. Sometimes, retrograde aggregation would extend the obstruction to the capillaries or even precapillary arterioles. These results show that knobs are necessary and sufficient to produce vascular obstruction and that other factors (spleen, immunological, etc.) can only have a modulating role. These results also exclude the possibility that the exclusive adherence to venules is the consequence of "plasma factors" found in the malaric patients.


Fetal central nervous system magnetic resonance imaging at the University Hospital of the West Indies, Jamaica.
Compared with ultrasound, magnetic resonance imaging (MRI) offers superior visualization ofthe fetal brain. It confirms and characterizes brain abnormalities detected by prenatal ultrasound, particularly in late pregnancy when acoustic windows are difficult or fetal position is inaccessible. Prior to July 2008, only two studies were attempted at our institution as local technical expertise was unavailable. Following collaboration with a neuroradiologist at an expert centre, images ofsufficient quality for diagnosis were obtained. The study objective is to evaluate the initial experience with fetal brain MRI and its effects on patient counselling and management in a resource limited healthcare system. In seven fetuses with abnormal ultrasound neuroimaging, fetal MRI was performed with T2-weighted single-shot fast spin-echo (SSFSE) sequences using a 1.5T magnet (GE Medical Systems, Milwaukee, WI). Magnetic resonance imaging did not alter ultrasound diagnosis in two patients (28%); however it changed the diagnosis in three (43%), provided additional information in one (14%) and changed management in two (28%) patients. Magnetic resonance imaging availability further elucidated brain pathology, aided patient counselling, parental decision-making and multidisciplinary management.


Volume-outcome relationship in rectal cancer surgery: a new perspective.
Numerous studies on the volume-outcome relationships in rectal cancer surgery have assessed surgical mortality. However, little is known about the association between hospital/surgeon volumes and postoperative complications, including anastomotic leakage and infection, following rectal cancer surgery. Using a web-based patient registration system, data were collected on inpatients who underwent rectal cancer surgery between November 1, 2006 and February 28, 2007 in Japan. Using multivariate analyses, intraoperative blood loss, postoperative complications and length of stay were independently compared against the provider volumes and covariates. No significant association was identified between the blood loss and hospital volume, while surgeons with the highest volume (> or =500 procedures) were likely to demonstrate a reduced blood loss (odds ratio, 0.67; 95% confidence interval, 0.46-0.99; P = 0.043). No significant relationship was found between the incidence of postoperative complications and the provider volume. A higher hospital volume significantly decreased the length of stay (hazard ratio, 1.41; 95% confidence interval, 1.23-1.62; P < 0.01), but the surgeon volume was not associated with the length of hospital stay. The present study did not find any significant relationship between the volume and postoperative complications. These results do not support the effectiveness of regionalizing rectal cancer surgery to high-volume centers, at least in the Japanese clinical setting.


Identification and genetic analysis of wunen, a gene guiding Drosophila melanogaster germ cell migration.
We describe a novel genetic locus, wunen (wun), required for guidance of germ cell migration in early Drosophila development. Loss of wun function does not abolish movement but disrupts the orientation of the motion causing the germ cells to disperse even though their normal target, the somatic gonad, is well formed. We demonstrate that the product of this gene enables a signal to pass from the soma to the germ line and propose that the function of this signal is to selectively stabilize certain cytoplasmic extensions resulting in oriented movement. To characterize this guidance factor, we have mapped wun to within 100 kb of cloned DNA.


Volumetric MRI-guided, high-intensity focused ultrasound ablation of uterine leiomyomas: ASEAN preliminary experience.
We sought to present our preliminary experience on the effectiveness and safety of magnetic resonance imaging (MRI)-guided, high-intensity focused ultrasound (HIFU) therapy using a volumetric ablation technique in the treatment of Association of Asian Nations (ASEAN) patients with symptomatic uterine leiomyomas. This study included 33 women who underwent HIFU treatment. Tissue characteristics of leiomyomas were assessed based on T2- and T1-weighted MRI. The immediate nonperfused volume (NPV) ratio and the treatment effectiveness of MRI-guided HIFU on the basis of the degrees of volume reduction and improvement in transformed symptom severity score (SSS) were assessed. The median immediate NPV ratio was 89.8%. Additionally, the median acoustic sonication power and HIFU treatment durations were 150 W and 125 min, respectively. At six-month follow-up, the median leiomyoma volume had decreased from 139 mL at baseline to 84 mL and the median transformed SSS had decreased from 56.2 at baseline to 18.8. No major adverse events were observed. The preliminary results demonstrated that volumetric MRI-guided HIFU therapy for the treatment of symptomatic leiomyomas in ASEAN patients appears to be clinically acceptable with regard to treatment effectiveness and safety.


Cocaine-induced elevation of plasma adrenocorticotropin hormone and corticosterone is mediated by serotonergic neurons.
We investigated the hypothesis that cocaine-induced elevations of plasma adrenocorticotropin hormone (ACTH) and corticosterone are mediated by brain serotonin (5-HT) neurons. Adult male rats were pretreated with the 5-HT depleting agent p-chlorophenylalanine, the 5-HT neurotoxin 5,7-dihydroxytryptamine, the partial 5-HT1A agonist 8-(2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl)-8- azaspirol[4,5]-decane-7,9-dione (BMY 7378) or the 5-HT1C/2 antagonist ritanserin. The effects of cocaine (2-15 mg/kg, i.p.) on plasma ACTH and corticosterone were then examined. Cocaine dose-dependently increased ACTH and corticosterone concentration. This increase was prevented by 5-HT depletion with PCPA and by destruction of 5-HT neurons with i.c.v. injections of 5,7-dihydroxytryptamine. The cocaine-induced elevation of ACTH and corticosterone was not significantly modified by administration of the partial 5-HT1A agonist BMY 7378, suggesting that 5-HT1A receptors probably do not mediate ACTH and corticosterone secretion. However, pretreatment with the 5-HT2/5-HT1C antagonist ritanserin virtually eliminated the cocaine-induced elevation of corticosterone. To determine whether these effects of cocaine are centrally mediated, conscious rats received cocaine injections into the cerebral ventricle through chronically implanted cannulas. Plasma ACTH concentrations were dose-dependently increased, whereas low doses (50 micrograms/kg, i.c.v.) produced a maximal increase in corticosterone concentration. These data indicate that the cocaine-induced stimulation of ACTH and corticosterone secretion is mediated by 5-HT neurons in brain, and furthermore, that 5-HT2 or 5-HT1C receptors are responsible for this effect.


Children's experiences of living with juvenile idiopathic arthritis: a thematic synthesis of qualitative studies.
To describe the experiences and perspectives of children and adolescents living with juvenile idiopathic arthritis (JIA). We conducted a systematic review of qualitative studies that explored the experiences of children living with JIA. We searched electronic databases (to week 2 of July 2011) and reference lists of relevant articles. Twenty-seven studies that reported the experiences of more than 542 participants were included. Six major themes were identified: aversion to being different (unrelenting and unpredictable pain, disablement, internal disfigurement, differential treatment, and forced dependency on others); striving for normality (preserving social identity, resourcefulness, sense of community, focus on remission, and mastery over body and pain); stigma and misunderstanding (trivialization of disease, invisible pain, and discrimination); suspension in uncertainty (control versus powerlessness, hope versus disappointment); managing treatment (benefits of taking medicines, respect and involvement in health care, and motivation for physical therapy); and desire for knowledge (medical treatment and advances, lifestyle management). JIA disrupts a child's sense of normality and impairs his or her capacity for social participation. Children with JIA have a sense of being misunderstood and stigmatized, and they feel perpetually caught between having hope and control over their bodies and overwhelming pain and despair. To increase their confidence, the ability to manage pain, and their resourcefulness for self-management, children need ongoing information about treatments and lifestyle management, strong social support, community advocacy, and active involvement in their own health decision making.


Cluster analysis identifies aminoacid compositional features that indicate Toxoplasma gondii adhesin proteins.
Toxoplasma gondii invade host cells using a multi-step process that depends on the regulated secretion of adhesions. To identify key primary sequence features of adhesins in this parasite, we analyze the relative frequency of individual amino acids, their dipeptide frequencies, and the polarity, polarizability and Van der Waals volume of the individual amino acids by using cluster analysis. This method identified cysteine as a key amino acid in the Toxoplasma adhesin group. The best vector algorithm of non-concatenated features was for 2 attributes: the single amino acid relative frequency and the dipeptide frequency. Polarity, polarizability and Van der Waals volume were not good classificatory attributes. Single amino acid attributes clustered unambiguously 67 apicomplexan hypothetical adhesins. This algorithm was also useful for clustering hypothetical Toxoplasma target host receptors. All of the cluster performances had over 70% sensitivity and 80% specificity. Compositional aminoacid data can be useful for improving machine learning-based prediction software when homology and structural data are not sufficient.


Regulation of markers of synaptic function in mouse models of depression: chronic mild stress and decreased expression of VGLUT1.
Depression has been linked to failure in synaptic plasticity originating from environmental and/or genetic risk factors. The chronic mild stress model regulates the expression of synaptic markers of neurotransmitter function and associated depressive-like behaviour. Moreover, mice heterozygous for the synaptic vesicle protein vesicular glutamate transporter 1 (VGLUT1), have been proposed as a genetic model of deficient glutamate function linked to depressive-like behaviour. Here, we aimed to identify, in these two experimental models, mechanisms of failure in synaptic plasticity, common to stress and impaired glutamate function. First, we show that chronic mild stress induced a transient decrease of different plasticity markers (VGLUT1, synapsin 1, sinaptophysin, rab3A and activity regulated cytoskeletal protein - Arc) but a long-lasting decrease of the brain derived neurotrophic factor as well as depressive-like behaviour. The immediate early gene Arc was also down-regulated in VGLUT1+/- heterozygous mice. In contrast, an opposite regulation of synapsin 1 was observed. Finally, both models showed a marked increase of cortical Arc response to novelty. Increased Arc response to novelty could be suggested as a molecular mechanism underlying failure to adapt to environmental changes, common to chronic stress and altered glutamate function. Further studies should investigate whether these changes are associated to depressive-like behaviour both in animal models and in depressed patients.


Heparin-modified dendrimer cross-linked collagen matrices for the delivery of basic fibroblast growth factor (FGF-2).
Tissue integration between a tissue-engineered corneal equivalent and the host eye is of critical importance in ensuring long-term implant success. A novel dendrimer cross-linked collagen scaffold has previously shown good corneal epithelial cell compatibility in vitro particularly when the highly functional dendrimer cross-linkers were functionalized to introduce additional biological groups. Herein we investigated heparinization of these materials and their potential to facilitate the delivery of basic fibroblast growth factor (FGF-2) in an active form, ultimately for use as a corneal tissue scaffold. Collagen gels cross-linked with 1-ethyl-3-(3-dimethyl aminopropyl) carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) chemistry, and varying amounts of polypropyleneimine octaamine generation 2 (G2) dendimer and heparin were synthesized. Swelling studies and differential scanning calorimetry characterization indicated higher gel stability with the introduction of dendrimer cross-linking, which was not compromised by heparin integration. Dendrimer cross-linked gels with or without heparin gave multiple denaturation peaks, as did the heparinized EDC gels. This is thought to be the result of the heterogeneous cross-linking possible between collagen, the dendrimer and heparin. Release of FGF-2 from collagen gels showed typical first-order kinetics, with an initial burst followed by a prolonged gradual release. Heparinized dendrimer cross-linked gels released approx. 40% of the growth factor over a 2-week period, with significance maintenance of growth factor activity. Incorporation of heparin resulted in somewhat prolonged release from these systems.


Directly observed therapy (DOT) for nonadherent HIV-infected youth: lessons learned, challenges ahead.
Adherence to medications is critical to optimizing HIV care and is a major challenge in youth. The utility of directly observed therapy (DOT) to improve adherence in youth with HIV remains undefined and prompted this pilot study. Four U.S. sites were selected for this 24-week cooperative group study to assess feasibility and to identify the logistics of providing DOT to HIV-infected youth with demonstrated adherence problems. Once-a-day DOT was provided by DOT facilitators at the participant's choice of a community-based location and DOT tapered over 12 weeks to self-administered therapy based on ongoing adherence assessments. Twenty participants, median age 21 years and median CD4 227 cells/microl, were enrolled. Participants chose their homes for 82% of DOT visits. Compliance with recommended DOT visits was (median) 91%, 91%, and 83% at weeks 4, 8, and 12, respectively. Six participants completed >90% of the study-specified DOT visits and successfully progressed to self-administered therapy (DOT success); only half sustained >90% medication adherence 12 weeks after discontinuing DOT. Participants considered DOT successes were more likely to have higher baseline depression scores (p = 0.046). Via exit surveys participants reported that meeting with the facilitator was easy, DOT increased their motivation to take medications, they felt sad when DOT ended, and 100% would recommend DOT to a friend. In conclusion, this study shows that while community-based DOT is safe, feasible, and as per participant feedback, acceptable to youth, DOT is not for all and the benefits appear short-lived. Depressed youth appear to be one subgroup that would benefit from this intervention. Study findings should help inform the design of larger community-based DOT intervention studies in youth.


Mentoring junior URM scientists to engage in sleep health disparities research: experience of the NYU PRIDE Institute.
The aim of this study was to evaluate the National Institute of Health (NIH)-funded PRIDE Institute in Behavioral Medicine and Sleep Disorders Research at New York University (NYU) Langone Medical Center. The NYU PRIDE Institute provides intensive didactic and mentored research training to junior underrepresented minority (URM) faculty. The Kirkpatrick model, a mixed-methods program evaluation tool, was used to gather data on participant's satisfaction and program outcomes. Quantitative evaluation data were obtained from all 29 mentees using the PRIDE REDcap-based evaluation tool. In addition, in-depth interviews and focus groups were conducted with 17 mentees to learn about their experiences at the institute and their professional development activities. Quantitative data were examined, and emerging themes from in-depth interviews and focus groups were studied for patterns of connection and grouped into broader categories based on grounded theory. Overall, mentees rated all programmatic and mentoring aspects of the NYU PRIDE Institute very highly (80-100%). They identified the following areas as critical to their development: research and professional skills, mentorship, structured support and accountability, peer support, and continuous career development beyond the summer institute. Indicators of academic self-efficacy showed substantial improvement over time. Areas for improvement included tailoring programmatic activities to individual needs, greater assistance with publications, and identifying local mentors when K awards are sought. In order to promote career development, numerous factors that uniquely influence URM investigators' ability to succeed should be addressed. The NYU PRIDE Institute, which provides exposure to a well-resourced academic environment, leadership, didactic skills building, and intensive individualized mentorship proved successful in enabling URM mentees to excel in the academic environment. Overall, the institute accomplished its goals: to build an infrastructure enabling junior URM faculty to network with one another as well as with senior investigators, serving as a role model, in a supportive academic environment.


Effect of Pupil Dilation with Tropicamide on Retinal Vascular Caliber.
Purpose: The retinal blood vessels reflect changes in the brain's micro-circulation and these changes have been shown to correlate with the incidence of diseases such as stroke, heart disease and Alzheimer's disease. Studies investigating the retinal vasculature routinely use pupil dilation with tropicamide to optimize image acquisition and quality. The aim of this study was to investigate the effects of tropicamide on retinal vascular parameters using retinal photography.Methods: The study was performed on 41 healthy young subjects of both sexes, using tropicamide to dilate only the right pupil, leaving the left as a control.Results: Pupil dilation with tropicamide resulted in reduced retinal vessel width measures based on standardized approaches, particularly reduced arteriolar caliber (p < .0005). However, closer investigation of the images revealed reduced fundus image magnification in the post-tropicamide images, based on reduced optic nerve head diameter (p < .0005) and longitudinal analysis with image registration and affine transformation (p < .0001). No change in vessel width parameters was observed after adjustment for image magnification.Conclusion: These results suggest that tropicamide does not change the width of the retinal vessels, however width parameters as measured by standard approaches may be reduced due to image magnification changes resulting from cycloplegia. In this study, improved optic nerve head segmentation for image scale conversion removed the magnification error. With this correction, the tropicamide intervention had no effect on vessel width parameters in young healthy people and could be utilized in future without affecting the results of retinal vascular analysis.


A robust random number generator based on differential comparison of chaotic laser signals.
We experimentally realize a robust real-time random number generator by differentially comparing the signal from a chaotic semiconductor laser and its delayed signal through a 1-bit analog-to-digital converter. The probability density distribution of the output chaotic signal based on the differential comparison method possesses an extremely small coefficient of Pearson's median skewness (1.5 × 10⁻⁶), which can yield a balanced random sequence much easily than the previously reported method that compares the signal from the chaotic laser with a certain threshold value. Moveover, we experimently demonstrate that our method can stably generate good random numbers at rates of 1.44 Gbit/s with excellent immunity from external perturbations while the previously reported method fails.


Genetic characterization of Italian patients with Bardet-Biedl syndrome and correlation to ocular, renal and audio-vestibular phenotype: identification of eleven novel pathogenic sequence variants.
Bardet-Biedl syndrome (BBS) is a rare genetic disorder that features retinal degeneration, obesity, polydactyly, learning disabilities and renal abnormalities. The diagnosis is often missed at birth, the median age at diagnosis being 9 years. In the attempt to shed light on BBS and improve its diagnosis and treatment, we evaluated the genotype-phenotype relationship in patients with a molecular diagnosis of BBS. We analyzed three common BBS genes, BBS1, BBS10 and BBS2, in 25 Italian patients fulfilling the clinical criteria of BBS. In 12 patients, we identified gene-specific biallelic variants and thus correlated genotype to the ophthalmic, renal and audio-vestibular phenotypes. At least one sequence variant was found in 60% of patients. The most common mutated gene was BBS1 followed by BBS10. Of the 17 sequence variants we found, 11 have not previously been associated with BBS. In 12 patients, we identified biallelic pathogenic variants; they had retinitis pigmentosa with early onset of visual impairment. However, retinal dystrophy was less severe in patients with BBS1 than in those with BBS10 variants. Overall, we found a high prevalence of renal dysmorphism and dysfunction. Notably, patients with BBS10 variants had the most severe renal impairment, which resulted in a critical decline in renal function. All the patients who underwent audio-vestibular evaluation had dysfunction of the cochlear outer hair cells, thus confirming the presence of hearing defects. BBS1, BBS2 and BBS10 are major causative genes in Italian BBS patients. BBS10 was associated with the worse outcome in terms of the renal, ocular and audiovestibular phenotypes. Cochlear dysfunction should be included among the hallmarks of BBS.


Relationship of Polycystic Ovarian Syndrome with Cardiovascular Risk Factors.
Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. The two main documented pathogenic mechanisms are hyperinsulinemia and hyperandrogenemia but there is growing evidence for increased predisposition to cardiovascular disease, dyslipidemia, and type 2 diabetes mellitus. Our study aims to analyze the association of PCOS with cardiovascular risk factors. This is a prospective study which targeted 100 PCOS patients from Civil Hospital Karachi over a period of one year (July 2016 to July 2017). An equal number of age-matched healthy control participants were also included in the study. The student's t-test was used to assess the significance of differences using SPSS version (19). The statistical significance was set at a p-value of <.05. The most frequently presented feature associated with PCOS was primary infertility seen in 72% of the patients. Mean arterial pressure, fasting glucose and insulin levels and insulin resistance was found to be significantly different in PCOS patients as compared to their controls. A classic atherosclerotic lipid profile demonstrating elevated total cholesterol and low-density lipoprotein-C (LDL-C) levels and decreased serum high density lipoprotein-C(HDL-C) was observed in our study. This study established a significant yet independent association of PCOS with major cardiovascular risk factors. This association can effectively progress into CVD outcomes which necessitates early intervention programs and preventative strategies to reduce mortality from cardiovascular events. This study lays out the framework for conducting further researches on the PCOS women while exploring novel cardiovascular risk factors.


Characterisation of surface blebbing and membrane vesicles produced by Flavobacterium psychrophilum.
The surface of Flavobacterium psychrophilum was examined by electron microscopy to determine if previous findings of haemagglutination positive (HA+) and haemagglutination negative (HA-) abilities could be correlated with expression of pili or of a capsular layer. A thin capsular layer was observed in both HA+ and HA- strains but typical pili were absent. However, long, tubular blebs that released membrane vesicles (MVs) into the supernatant were observed on up to 94% of cells within 1 sample. The surface blebbing was increased for 1 strain following growth on media with restricted iron availability. The MVs had an intact membrane bilayer and were released from blebbing cells of both strains. The protein profiles of MVs, while containing some banding similarity with the profile of outer membrane preparations (OMPs) and of lysed whole cells (WCs), showed several bands that reacted strongly with rabbit anti-whole-cell antisera. Two distinct bands of approximately 62 and 58 kDA were highly expressed in the MVs and not seen in the OMP. MVs contained proteolytic activity towards gelatine but not towards casein and elastin, which were only degraded by live cells. Low molecular weight lipopolysaccharides (LPS) or lipooligosaccharides (LOS) were associated with the MVs. Only the MVs of the HA+ strain possessed haemagglutinin activity. These findings suggest that the F. psychrophilum may, through surface blebbing, release antigenic MVs that contain some proteolytic activity and may aid the bacterium in releasing nutrients from its surrounding environment as well as playing a role in impeding the immune response of its host.


The early 20th century warming: Anomalies, causes, and consequences.
The most pronounced warming in the historical global climate record prior to the recent warming occurred over the first half of the 20th century and is known as the Early Twentieth Century Warming (ETCW). Understanding this period and the subsequent slowdown of warming is key to disentangling the relationship between decadal variability and the response to human influences in the present and future climate. This review discusses the observed changes during the ETCW and hypotheses for the underlying causes and mechanisms. Attribution studies estimate that about a half (40-54%; p > .8) of the global warming from 1901 to 1950 was forced by a combination of increasing greenhouse gases and natural forcing, offset to some extent by aerosols. Natural variability also made a large contribution, particularly to regional anomalies like the Arctic warming in the 1920s and 1930s. The ETCW period also encompassed exceptional events, several of which are touched upon: Indian monsoon failures during the turn of the century, the "Dust Bowl" droughts and extreme heat waves in North America in the 1930s, the World War II period drought in Australia between 1937 and 1945; and the European droughts and heat waves of the late 1940s and early 1950s. Understanding the mechanisms involved in these events, and their links to large scale forcing is an important test for our understanding of modern climate change and for predicting impacts of future change. This article is categorized under:Paleoclimates and Current Trends > Modern Climate Change.


GluN2B in corticostriatal circuits governs choice learning and choice shifting.
A choice that reliably produces a preferred outcome can be automated to liberate cognitive resources for other tasks. Should an outcome become less desirable, behavior must adapt in parallel or it becomes perseverative. Corticostriatal systems are known to mediate choice learning and flexibility, but the molecular mechanisms of these processes are not well understood. We integrated mouse behavioral, immunocytochemical, in vivo electrophysiological, genetic and pharmacological approaches to study choice. We found that the dorsal striatum (DS) was increasingly activated with choice learning, whereas reversal of learned choice engaged prefrontal regions. In vivo, DS neurons showed activity associated with reward anticipation and receipt that emerged with learning and relearning. Corticostriatal or striatal deletion of Grin2b (encoding the NMDA-type glutamate receptor subunit GluN2B) or DS-restricted GluN2B antagonism impaired choice learning, whereas cortical Grin2b deletion or OFC GluN2B antagonism impaired shifting. Our convergent data demonstrate how corticostriatal GluN2B circuits govern the ability to learn and shift choice behavior.


Protein Phosphatase 2A in Lipopolysaccharide-Induced Cyclooxygenase-2 Expression in Murine Lymphatic Endothelial Cells.
The lymphatic endothelium plays an important role in the maintenance of tissue fluid homeostasis. It also participates in the pathogenesis of several inflammatory diseases. However, little is known about the underlying mechanisms by which lymphatic endothelial cell responds to inflammatory stimuli. In this study, we explored the mechanisms by which lipopolysaccharide (LPS) induces cyclooxygenase (COX)-2 expression in murine lymphatic endothelial cells (SV-LECs). LPS caused increases in cox-2 mRNA and protein levels, as well as in COX-2 promoter luciferase activity in SV-LECs. These actions were associated with protein phosphatase 2A (PP2A), apoptosis signal-regulating kinase 1 (ASK1), JNK1/2 and p38MAPK activation, and NF-κB subunit p65 and C/EBPβ phosphorylation. PP2A-ASK1 signaling blockade reduced LPS-induced JNK1/2, p38MAPK, p65 and C/EBPβ phosphorylation. Transfection with PP2A siRNA reduced LPS's effects on p65 and C/EBPβ binding to the COX-2 promoter region. Transfected with the NF-κB or C/EBPβ site deletion of COX-2 reporter construct also abrogated LPS's enhancing effect on COX-2 promoter luciferase activity in SV-LECs. Taken together, the induction of COX-2 in SV-LECs exposed to LPS may involve PP2A-ASK1-JNK and/or p38MAPK-NF-κB and/or C/EBPβ cascade.


Electrogenerated chemiluminescence logic gate operations based on molecule-responsive organic microwires.
Complex logic gate operations using organic microwires as signal transducers based on electrogenerated chemiluminescence (ECL) intensity as the optical readout signal have been developed by taking advantage of the unique ECL reaction between organic semiconductor 9,10-bis(phenylethynyl)anthracene (BPEA) microwires and small molecules. The BPEA microwires, prepared on cleaned-ITO substrate using a simple physical vapor transport (PVT) method, were subsequently used for construction of the ECL sensors. The developed sensor exhibits high ECL efficiency and excellent stability in the presence of co-reactant tripropylamine. Based on the remarkable detection performance of BPEA MWs/TPrA system, the sensors manifested high sensitive ECL response in a wide linear range with low detection limit for the detection of dopamine, proline or methylene blue, which behaves on the basis of molecule-responsive ECL properties based on different ECL reaction mechanisms. Inspired by this, these sensing systems can be utilized to design OR, XOR and INHIBIT logic gates, which would be used for the determination of dopamine, proline and ethylene blue via logic outputs. Importantly, the individual logic gates can be easily brought together through three-input operations to function as integrated logic gates.


Rectus femoris transfer improves stiff knee gait in hemiplegic adults following stroke or traumatic brain injury.
The aim of this study was to provide quantitative evidence of the effect of rectus femoris (RF) transfer surgery on improving gait in adults suffering from stiff knee gait (SKG) following stroke or traumatic brain injury (TBI). Retrospective cohort study University hospital, department of orthopaedic surgery Hemiplegic patients with decreased peak knee flexion in swing, reduced total knee range of motion and spasticity of the RF demonstrated by a positive Duncan Ely test and a pathologic dynamic electromyography of the RF. Ten right hemiplegic patients had a distal RF transfer. Pre- and postoperative kinematic, kinetic, and spatiotemporal parameters derived from 3D gait analysis and parameters from clinical examinations were retrospectively compared. All patients (average age 40 ± 29 years) had an improvement of their gait. Statistically significant improvements were observed in walking velocity and peak knee flexion in swing (19.93° ±11.80°), knee flexion velocity at toe-off (110.26° ± 65.74°) and total knee range of motion (20.78° ± 0.66°). RF transfer improves knee flexion in swing in adult patients suffering from SKG following stroke or TBI and is thus a reliable treatment option.


Plant responses to climatic extremes: within-species variation equals among-species variation.
Within-species and among-species differences in growth responses to a changing climate have been well documented, yet the relative magnitude of within-species vs. among-species variation has remained largely unexplored. This missing comparison impedes our ability to make general predictions of biodiversity change and to project future species distributions using models. We present a direct comparison of among- versus within-species variation in response to three of the main stresses anticipated with climate change: drought, warming, and frost. Two earlier experiments had experimentally induced (i) summer drought and (ii) spring frost for four common European grass species and their ecotypes from across Europe. To supplement existing data, a third experiment was carried out, to compare variation among species from different functional groups to within-species variation. Here, we simulated (iii) winter warming plus frost for four grasses, two nonleguminous, and two leguminous forbs, in addition to eleven European ecotypes of the widespread grass Arrhenatherum elatius. For each experiment, we measured: (i) C/N ratio and biomass, (ii) chlorophyll content and biomass, and (iii) plant greenness, root (15) N uptake, and live and dead tissue mass. Using coefficients of variation (CVs) for each experiment and response parameter, a total of 156 within- vs. among-species comparisons were conducted, comparing within-species variation in each of four species with among-species variation for each seed origin (five countries). Of the six significant differences, within-species CVs were higher than among-species CVs in four cases. Partitioning of variance within each treatment in two of the three experiments showed that within-species variability (ecotypes) could explain an additional 9% of response variation after accounting for the among-species variation. Our observation that within-species variation was generally as high as among-species variation emphasizes the importance of including both within- and among-species variability in ecological theory (e.g., the insurance hypothesis) and for practical applications (e.g., biodiversity conservation).


Qualitatively Incorrect Features in the TDDFT Spectrum of Thiophene-Based Compounds.
Ab initio molecular electronic structure computations of thiophene-based compounds constitute an active field of research prompted by the growing interest in low-cost materials for organic electronic devices. In particular, the modeling of electronically excited states and other time-dependent phenomena has moved toward the description of more realistic albeit challenging systems. We demonstrate that due to its underlying approximations, time-dependent density functional theory predicts results that are qualitatively incorrect for thiophene and thienoacenes, although not for oligothiophene chains. The failure includes spurious state inversion and excitation characters, wrong distribution of oscillator strengths and erroneous potential energy surfaces. We briefly analyze possible origins of this behavior and identify alternative methods that alleviate these problems.


In Vitro Metabolic Fate of the Synthetic Cannabinoid Receptor Agonists QMPSB and QMPCB (SGT-11) Including Isozyme Mapping and Esterase Activity.
Quinolin-8-yl 4-methyl-3-(piperidine-1-sulfonyl)benzoate (QMPSB) and quinolin-8-yl 4-methyl-3-(piperidine-1-carbonyl)benzoate (QMPCB, SGT-11) are synthetic cannabinoid receptor agonists (SCRAs). Knowing their metabolic fate is crucial for the identification of toxicological screening targets and to predict possible drug interactions. The presented study aimed to identify the in vitro phase I/II metabolites of QMPSB and QMPCB and to study the contribution of different monooxygenases and human carboxylesterases by using pooled human liver S9 fraction (pHLS9), recombinant human monooxygenases, three recombinant human carboxylesterases, and pooled human liver microsomes. Analyses were carried out by liquid chromatography high-resolution tandem mass spectrometry. QMPSB and QMPCB showed ester hydrolysis, and hydroxy and carboxylic acid products were detected in both cases. Mono/dihydroxy metabolites were formed, as were corresponding glucuronides and sulfates. Most of the metabolites could be detected in positive ionization mode with the exception of some QMPSB metabolites, which could only be found in negative mode. Monooxygenase activity screening revealed that CYP2B6/CYP2C8/CYP2C9/CYP2C19/CYP3A4/CYP3A5 were involved in hydroxylations. Esterase screening showed the involvement of all investigated isoforms. Additionally, extensive non-enzymatic ester hydrolysis was observed. Considering the results of the in vitro experiments, inclusion of the ester hydrolysis products and their glucuronides and monohydroxy metabolites into toxicological screening procedures is recommended.


Synthesis, biological evaluation and molecular modeling of novel azaspiro dihydrotriazines as influenza virus inhibitors targeting the host factor dihydrofolate reductase (DHFR).
Recently we identified cycloguanil-like dihydrotriazine derivatives, which provided host-factor directed antiviral activity against influenza viruses and respiratory syncytial virus (RSV), by targeting the human dihydrofolate reductase (hDHFR) enzyme. In this context we deemed interesting to further investigate the structure activity relationship (SAR) of our first series of cycloguanil-like dihydrotriazines, designing two novel azaspiro dihydrotriazine scaffolds. The present study allowed the exploration of the potential chemical space, around these new scaffolds, that are well tolerated for maintaining the antiviral effect by means of interaction with the hDHFR enzyme. The new derivatives confirmed their inhibitory profile against influenza viruses, especially type B. In particular, the two best compounds shared potent antiviral activity (4: EC50 = 0.29 μM; 6: EC50 = 0.19 μM), which was comparable to that of zanamivir (EC50 = 0.14 μM), and better than that of ribavirin (EC50 = 3.2 μM). In addition, these two compounds proved to be also effective against RSV (4: EC50 = 0.40 μM, SI ≥ 250; 6: EC50 = 1.8 μM, SI ≥ 56), surpassing the potency and selectivity index (SI) of ribavirin (EC50 = 5.8 μM, SI > 43). By a perspective of these results, the above adequately substituted azaspiro dihydrotriazines may represent valuable hit compounds worthy of further structural optimization to develop improved host DHFR-directed antiviral agents.


Effect of Curing Light Barriers and Light Types on Radiant Exposure and Composite Conversion.
Previous research investigated the effects of curing tip barriers on light output and composite properties, but no study has measured the effect of a wide variety of barriers and curing light types on delivered radiant exposure and the resulting composite cure 2 mm below the radiated surface. Six barrier materials and six curing light types were tested. Spectroradiometry was used to measure irradiance with and without barriers for each light type, and radiant exposure values were determined for a commercial camphorquinone-based dental composite material. Composite monomer conversion was measured at 10 minutes following exposure for each light type/barrier condition (N = 5) using infrared spectroscopy. Results were subjected to one-way analyses of variance for radiant exposure and conversion among barrier types within a given curing light: preset alpha 0.05. All barriers significantly reduced radiant exposure compared with the uncovered tip, but the use of the two polywave LEDs covered with a latex-based barrier demonstrated significantly lower conversion values. Although light-curing barriers reduce radiant exposure to a restorative material over a recommended exposure, this reduction is not sufficient to cause significant reduction in composite cure, except when using a latex-based barrier and a polywave LED curing light. Clinicians need to be aware of the possible interaction between curing light barriers and curing light type in order to optimally photocure restorative materials.


Genetic diversity and population structure of Tasmanian devils, the largest marsupial carnivore.
Genetic diversity and population structure were investigated across the core range of Tasmanian devils (Sarcophilus laniarius; Dasyuridae), a wide-ranging marsupial carnivore restricted to the island of Tasmania. Heterozygosity (0.386-0.467) and allelic diversity (2.7-3.3) were low in all subpopulations and allelic size ranges were small and almost continuous, consistent with a founder effect. Island effects and repeated periods of low population density may also have contributed to the low variation. Within continuous habitat, gene flow appears extensive up to 50 km (high assignment rates to source or close neighbour populations; nonsignificant values of pairwise FST), in agreement with movement data. At larger scales (150-250 km), gene flow is reduced (significant pairwise FST) but there is no evidence for isolation by distance. The most substantial genetic structuring was observed for comparisons spanning unsuitable habitat, implying limited dispersal of devils between the well-connected, eastern populations and a smaller northwestern population. The genetic distinctiveness of the northwestern population was reflected in all analyses: unique alleles; multivariate analyses of gene frequency (multidimensional scaling, minimum spanning tree, nearest neighbour); high self-assignment (95%); two distinct populations for Tasmania were detected in isolation by distance and in Bayesian model-based clustering analyses. Marsupial carnivores appear to have stronger population subdivisions than their placental counterparts.


Patients' perception of their depressive illness.
Perception of illness has been described as an important predictor in the medical health psychology literature, but has been given little attention in the domain of mental disorders. The patient's Perception of Depression Questionnaire (PDIQ) is a newly developed measure whose factor structure and psychometric properties were evaluated on a sample of 174 outpatients meeting criteria for major depressive disorder. The clinical utility of the questionnaire was assessed on a sub-sample of 121 participants in a study of acupuncture treatment for depression. The questionnaire has four subscales, each with high internal consistency and high test-retest reliability. These four subscales are: Self-Efficacy, which reflects perceived controllability of the illness, Externalizing, which reflects attributing the illness to external causes, Hopeless/Flawed, which reflect a belief that depression is a personal trait and therefore there is little hope for cure, and Holistic, which reflects a belief in alternative therapies. Although the PDIQ did not predict outcome, its subscales were related to adherence to treatment, treatment preference, expectations, and therapeutic alliance. The subscales have adequate convergent/discriminant validity and are clinically relevant to aspects of treatment provision.


The consequences for human health of stratospheric ozone depletion in association with other environmental factors.
Due to the implementation of the Montreal Protocol, which has limited, and is now probably reversing, the depletion of the stratospheric ozone layer, only modest increases in solar UV-B radiation at the surface of the Earth have occurred. For many fair-skinned populations, changing behaviour with regard to exposure to the sun over the past half century - more time in the sun, less clothing cover (more skin exposed), and preference for a tan - has probably contributed more to greater levels of exposure to UV-B radiation than ozone depletion. Exposure to UV-B radiation has both adverse and beneficial effects on human health. This report focuses on an assessment of the evidence regarding these outcomes that has been published since our previous report in 2010. The skin and eyes are the organs exposed to solar UV radiation. Excessive solar irradiation causes skin cancer, including cutaneous malignant melanoma and the non-melanoma skin cancers, basal cell carcinoma and squamous cell carcinoma, and contributes to the development of other rare skin cancers such as Merkel cell carcinoma. Although the incidence of melanoma continues to increase in many countries, in some locations, primarily those with strong sun protection programmes, incidence has stabilised or decreased over the past 5 years, particularly in younger age-groups. However, the incidence of non-melanoma skin cancers is still increasing in most locations. Exposure of the skin to the sun also induces systemic immune suppression that may have adverse effects on health, such as through the reactivation of latent viral infections, but also beneficial effects through suppression of autoimmune reactivity. Solar UV-B radiation damages the eyes, causing cataracts and pterygium. UV-B irradiation of the skin is the main source of vitamin D in many geographic locations. Vitamin D plays a critical role in the maintenance of calcium homeostasis in the body; severe deficiency causes the bone diseases, rickets in children and osteomalacia in adults. Although many studies have implicated vitamin D deficiency in a wide range of diseases, such as cancer and cardiovascular disease, more recent evidence is less compelling, with meta-analyses of supplementation trials failing to show a beneficial effect on the health outcomes that have been tested. It continues to be difficult to provide public health messages to guide safe exposure to the sun that are accurate, simple, and can be used by people with different skin types, in different locations, and for different times of the year or day. There is increasing interest in relating sun protection messages to the UV Index. Current sun protection strategies are outlined and assessed. Climatic factors affect the amount of UV radiation received by the skin and eyes, separately from the effect of ozone depletion. For example, cloud cover can decrease or increase the intensity of UV radiation at Earth's surface and warmer temperatures and changes in precipitation patterns may alter the amount of time people spend outdoors and their choice of clothing. The combination of changes in climate and UV radiation may affect the number of pathogenic microorganisms in surface waters, and could have an impact on food security through effects on plant and aquatic systems. It remains difficult to quantify these effects and their possible importance for human health.


Repellent activity of catmint, Nepeta cataria, and iridoid nepetalactone isomers against Afro-tropical mosquitoes, ixodid ticks and red poultry mites.
The repellent activity of the essential oil of the catmint plant, Nepeta cataria (Lamiaceae), and the main iridoid compounds (4aS,7S,7aR) and (4aS,7S,7aS)-nepetalactone, was assessed against (i) major Afro-tropical pathogen vector mosquitoes, i.e. the malaria mosquito, Anopheles gambiae s.s. and the Southern house mosquito, Culex quinquefasciatus, using a World Health Organisation (WHO)-approved topical application bioassay (ii) the brown ear tick, Rhipicephalus appendiculatus, using a climbing repellency assay, and (iii) the red poultry mite, Dermanyssus gallinae, using field trapping experiments. Gas chromatography (GC) and coupled GC-mass spectrometry (GC-MS) analysis of two N. cataria chemotypes (A and B) used in the repellency assays showed that (4aS,7S,7aR) and (4aS,7S,7aS)-nepetalactone were present in different proportions, with one of the oils (from chemotype A) being dominated by the (4aS,7S,7aR) isomer (91.95% by GC), and the other oil (from chemotype B) containing the two (4aS,7S,7aR) and (4aS,7S,7aS) isomers in 16.98% and 69.83% (by GC), respectively. The sesquiterpene hydrocarbon (E)-(1R,9S)-caryophyllene was identified as the only other major component in the oils (8.05% and 13.19% by GC, respectively). Using the topical application bioassay, the oils showed high repellent activity (chemotype A RD(50)=0.081 mg cm(-2) and chemotype B RD(50)=0.091 mg cm(-2)) for An. gambiae comparable with the synthetic repellent DEET (RD(50)=0.12 mg cm(-2)), whilst for Cx. quinquefasciatus, lower repellent activity was recorded (chemotype A RD(50)=0.34 mg cm(-2) and chemotype B RD(50)=0.074 mg cm(-2)). Further repellency testing against An. gambiae using the purified (4aS,7S,7aR) and (4aS,7S,7aS)-nepetalactone isomers revealed overall lower repellent activity, compared to the chemotype A and B oils. Testing of binary mixtures of the (4aS,7S,7aR) and (4aS,7S,7aS) isomers across a range of ratios, but all at the same overall dose (0.1 mg), revealed not only a synergistic effect between the two, but also a surprising ratio-dependent effect, with lower activity for the pure isomers and equivalent or near-equivalent mixtures, but higher activity for non-equivalent ratios. Furthermore, a binary mixture of (4aS,7S,7aR) and (4aS,7S,7aS) isomers, in a ratio equivalent to that found in chemotype B oil, was less repellent than the oil itself, when tested at two doses equivalent to 0.1 and 0.01 mg chemotype B oil. The three-component blend including (E)-(1R,9S)-caryophyllene at the level found in chemotype B oil had the same activity as chemotype B oil. In a tick climbing repellency assay using R. appendiculatus, the oils showed high repellent activity comparable with data for other repellent essential oils (chemotype A RD(50)=0.005 mg and chemotype B RD(50)=0.0012 mg). In field trapping assays with D. gallinae, addition of the chemotype A and B oils, and a combination of the two, to traps pre-conditioned with D. gallinae, all resulted in a significant reduction of D. gallinae trap capture. In summary, these data suggest that although the nepetalactone isomers have the potential to be used in human and livestock protection against major pathogen vectors, intact, i.e. unfractionated, Nepeta spp. oils offer potentially greater protection, due to the presence of both nepetalactone isomers and other components such as (E)-(1R,9S)-caryophyllene.


PCL-TCP wet spun scaffolds carrying antibiotic-loaded microspheres for bone tissue engineering.
Scaffolds produced for tissue engineering applications are proven to be promising alternatives to be used in healing and regeneration of injured tissues and organs. In this study, porous and fibrous poly(ε-caprolactone) (PCL) scaffolds were prepared by wet spinning technique and modified by addition of tricalcium phosphate (TCP) and by immobilizing gelatin onto fibers. Meanwhile, gelatin microspheres carrying Ceftriaxone sodium (CS), a model antibiotic, were added onto the scaffolds and antimicrobial activity of CS was investigated against Escherichia coli (E. coli), a model gram-negative bacterium. TCP and gelatin were added to enhance mechanical properties while directing the scaffold towards osteogenic infrastructure and to increase hydrophilicity by activating cell attachment via protein molecules, respectively. Modifications with TCP and gelatin enhanced the compression modulus by about 70%, and attachment of Saos-2 cells by 60%, respectively. Release of the antibiotic demonstrated effective antimicrobial activity against E. coli. The bioactive scaffolds were shown to be good candidates for bone tissue engineering applications.