Music interventions for improving psychological and physical outcomes in cancer patients.
Having cancer may result in extensive emotional, physical and social suffering. Music interventions have been used to alleviate symptoms and treatment side effects in cancer patients. To assess and compare the effects of music therapy and music medicine interventions for psychological and physical outcomes in people with cancer. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 1), MEDLINE, Embase, CINAHL, PsycINFO, LILACS, Science Citation Index, CancerLit, CAIRSS, Proquest Digital Dissertations, ClinicalTrials.gov, Current Controlled Trials, the RILM Abstracts of Music Literature, http://www.wfmt.info/Musictherapyworld/ and the National Research Register. We searched all databases, except for the last two, from their inception to January 2016; the other two are no longer functional, so we searched them until their termination date. We handsearched music therapy journals, reviewed reference lists and contacted experts. There was no language restriction. We included all randomized and quasi-randomized controlled trials of music interventions for improving psychological and physical outcomes in adult and pediatric patients with cancer. We excluded participants undergoing biopsy and aspiration for diagnostic purposes. Two review authors independently extracted the data and assessed the risk of bias. Where possible, we presented results in meta-analyses using mean differences and standardized mean differences. We used post-test scores. In cases of significant baseline difference, we used change scores. We identified 22 new trials for inclusion in this update. In total, the evidence of this review rests on 52 trials with a total of 3731 participants. We included music therapy interventions offered by trained music therapists, as well as music medicine interventions, which are defined as listening to pre-recorded music, offered by medical staff. We categorized 23 trials as music therapy trials and 29 as music medicine trials.The results suggest that music interventions may have a beneficial effect on anxiety in people with cancer, with a reported average anxiety reduction of 8.54 units (95% confidence interval (CI) -12.04 to -5.05, P < 0.0001) on the Spielberger State Anxiety Inventory - State Anxiety (STAI-S) scale (range 20 to 80) and -0.71 standardized units (13 studies, 1028 participants; 95% CI -0.98 to -0.43, P < 0.00001; low quality evidence) on other anxiety scales, a moderate to strong effect. Results also suggested a moderately strong, positive impact on depression (7 studies, 723 participants; standardized mean difference (SMD): -0.40, 95% CI -0.74 to -0.06, P = 0.02; very low quality evidence), but because of the very low quality of the evidence for this outcome, this result needs to be interpreted with caution. We found no support for an effect of music interventions on mood or distress.Music interventions may lead to small reductions in heart rate, respiratory rate and blood pressure but do not appear to impact oxygen saturation level. We found a large pain-reducing effect (7 studies, 528 participants; SMD: -0.91, 95% CI -1.46 to -0.36, P = 0.001, low quality evidence). In addition, music interventions had a small to moderate treatment effect on fatigue (6 studies, 253 participants; SMD: -0.38, 95% CI -0.72 to -0.04, P = 0.03; low quality evidence), but we did not find strong evidence for improvement in physical functioning.The results suggest a large effect of music interventions on patients' quality of life (QoL), but the results were highly inconsistent across studies, and the pooled effect size for the music medicine and music therapy studies was accompanied by a large confidence interval (SMD: 0.98, 95% CI -0.36 to 2.33, P = 0.15, low quality evidence). A comparison between music therapy and music medicine interventions suggests a moderate effect of music therapy interventions for patients' quality of life (QoL) (3 studies, 132 participants; SMD: 0.42, 95% CI 0.06 to 0.78, P = 0.02; very low quality evidence), but we found no evidence of an effect for music medicine interventions. A comparison between music therapy and music medicine studies was also possible for anxiety, depression and mood, but we found no difference between the two types of interventions for these outcomes.The results of single studies suggest that music listening may reduce the need for anesthetics and analgesics as well as decrease recovery time and duration of hospitalization, but more research is needed for these outcomes.We could not draw any conclusions regarding the effect of music interventions on immunologic functioning, coping, resilience or communication outcomes because either we could not pool the results of the studies that included these outcomes or we could only identify one trial. For spiritual well-being, we found no evidence of an effect in adolescents or young adults, and we could not draw any conclusions in adults.The majority of studies included in this review update presented a high risk of bias, and therefore the quality of evidence is low. This systematic review indicates that music interventions may have beneficial effects on anxiety, pain, fatigue and QoL in people with cancer. Furthermore, music may have a small effect on heart rate, respiratory rate and blood pressure. Most trials were at high risk of bias and, therefore, these results need to be interpreted with caution.


Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study.
While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis. We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = <0.001-0.013) in males in BLSA. In ADNI, we found a modest sex-specific effect indicating that lower serum concentrations of CA and CDCA were associated with faster brain atrophy (FDR p = 0.049) in males.Step 2: In the Clinical Practice Research Datalink (CPRD) dataset, covering >4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings. We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.


Characterization of atypical isolates of Yersinia intermedia and definition of two new biotypes.
The species Yersinia intermedia is a member of the genus Yersinia which belongs to the Enterobacteriaceae family. This species is divided into eight biotypes, according to Brenner's biotyping scheme. This scheme relies on five tests (utilization of Simmons citrate and acid production from d-melibiose, d-raffinose, alpha-methyl-d-glucoside [alphaMG], and l-rhamnose). The collection of the French Yersinia Reference Laboratory (Institut Pasteur, Paris, France) contained 44 strains that were originally identified as Y. intermedia but whose characteristics did not fit into the biotyping scheme. These 44 strains were separated into two biochemical groups: variant 1 (positive for acid production from l-rhamnose and alphaMG and positive for Simmons citrate utlization) and variant 2 (positive for acid production from l-rhamnose and alphaMG). These atypical strains could correspond to new biotypes of Y. intermedia, to Y. frederiksenii strains having the atypical property of fermenting alphaMG, or to new Yersinia species. These strains did not exhibit growth or phenotypic properties different from those of Y. intermedia and Y. frederiksenii and did not harbor any of the virulence traits usually found in pathogenic species. DNA-DNA hybridizations performed between one strain each of variants 1 and 2 and the Y. intermedia and Y. frederiksenii type strains demonstrated that these variants do belong to the Y. intermedia species. We thus propose that Brenner's biotyping scheme be updated by adding two new biotypes: 9 (for variant 1) and 10 (for variant 2) to the species Y. intermedia.


Anesthetic propofol causes glycogen synthase kinase-3β-regulated lysosomal/mitochondrial apoptosis in macrophages.
Overdose propofol treatment with a prolong time causes injury to multiple cell types; however, its molecular mechanisms remain unclear. Activation of glycogen synthase kinase (GSK)-3β is proapoptotic under death stimuli. The authors therefore hypothesize that propofol overdose induces macrophage apoptosis through GSK-3β. Phagocytic analysis by uptake of Staphylococcus aureus showed the effects of propofol overdose on murine macrophages RAW264.7 and BV2 and primary human neutrophils in vitro. The authors further investigated cell apoptosis in vitro and in vivo, lysosomal membrane permeabilization, and the loss of mitochondrial transmembrane potential (MTP) by propidium iodide, annexin V, acridine orange, and rhodamine 123 staining, respectively. Protein analysis identified activation of apoptotic signals, and pharmacologic inhibition and genetic knockdown using lentiviral-based short hairpin RNA were further used to clarify their roles. A high dose of propofol caused phagocytic inhibition and apoptosis in vitro for 24 h (25 μg/ml, in triplicate) and in vivo for 6 h (10 mg/kg/h, n = 5 for each group). Propofol induced lysosomal membrane permeabilization and MTP loss while stabilizing MTP and inhibiting caspase protected cells from mitochondrial apoptosis. Lysosomal cathepsin B was required for propofol-induced lysosomal membrane permeabilization, MTP loss, and apoptosis. Propofol decreased antiapoptotic Bcl-2 family proteins and then caused proapoptotic Bcl-2-associated X protein (Bax) activation. Propofol-activated GSK-3β and inhibiting GSK-3β prevented Mcl-1 destabilization, MTP loss, and lysosomal/mitochondrial apoptosis. Forced expression of Mcl-1 prevented the apoptotic effects of propofol. Decreased Akt was important for GSK-3β activation caused by propofol. These results suggest an essential role of GSK-3β in propofol-induced lysosomal/mitochondrial apoptosis.


IGF1 receptor signaling regulates adaptive radioprotection in glioma stem cells.
Cancer stem cells (CSCs) play an important role in disease recurrence after radiation treatment as a result of intrinsic properties such as high DNA repair capability and antioxidative capacity. It is unclear, however, how CSCs further adapt to escape the toxicity of the repeated irradiation regimens used in clinical practice. Here, we have exposed a population of murine glioma stem cells (GSCs) to fractionated radiation in order to investigate the associated adaptive changes, with the ultimate goal of identifying a targetable factor that regulates acquired radioresistance. We have shown that fractionated radiation induces an increase in IGF1 secretion and a gradual upregulation of the IGF type 1 receptor (IGF1R) in GSCs. Interestingly, IGF1R upregulation exerts a dual radioprotective effect. In the resting state, continuous IGF1 stimulation ultimately induces downregulation of Akt/extracellular-signal-regulated kinases (ERK) and FoxO3a activation, which results in slower proliferation and enhanced self-renewal. In contrast, after acute radiation, the abundance of IGF1R and increased secretion of IGF1 promote a rapid shift from a latent state toward activation of Akt survival signaling, protecting GSCs from radiation toxicity. Treatment of tumors formed by the radioresistant GSCs with an IGF1R inhibitor resulted in a marked increase in radiosensitivity, suggesting that blockade of IGF1R signaling is an effective strategy to reverse radioresistance. Together, our results show that GSCs evade the damage of repeated radiation not only through innate properties but also through gradual inducement of resistance pathways and identify the dynamic regulation of GSCs by IGF1R signaling as a novel mechanism of adaptive radioprotection.


OFM-recirculation and OFM-suction: advanced in-vivo open flow microperfusion (OFM) methods for direct and absolute quantification of albumin in interstitial fluid.
To implement OFM-recirculation and OFM-suction capable of direct and absolute in-vivo quantification of albumin in the ISF of pigs. OFM-recirculation and OFM-suction were used to collect ISF in-vivo in pigs and lymph was collected from the same pigs after OFM sampling. Blood was collected before and after OFM sampling, plasma was isolated and mean albumin plasma concentrations per pig were used to yield albumin ISF-to-plasma ratios. We characterized the quality of the collected undiluted ISF via (1) stable albumin ISF-to-plasma ratio in OFM-recirculation and in OFM-suction samples, (2) comparison of albumin ISF-to-plasma ratios from OFM-recirculation and OFM-suction and (3) comparison of normalized albumin concentrations in the ISF and lymph. Both advanced OFM methods were successfully implemented and albumin was quantified from the collected ISF samples. OFM-recirculation reached stable albumin ISF-to-plasma ratios after 20 recirculation cycles. Absolute ISF albumin concentrations were 11.2 mg ml-1 (OFM-recirculation) and 14.2 mg ml-1 (OFM-suction). Albumin ISF-to-plasma ratios were 0.39 ± 0.04 (OFM -recirculation) and 0.47 ± 0.1 (OFM-suction). Knowledge of the ISF protein content is of major importance when assessing PK/PD effects, especially of highly protein bound drugs. Up to now, only blood albumin values have been available to determine the degree of protein binding in several tissues. OFM-recirculation and OFM-suction allow direct, absolute quantification of albumin in ISF for the first time and enable investigation of the degree of protein binding of a drug directly in its target tissue.


Health promotion for the mind, body, and spirit: a college course for older adults with dementia.
This article describes a pilot study of an experimental college course for individuals with newly diagnosed dementia, with a focus on teaching methods for promoting and maintaining optimal health. Community involvement included recruitment by the local Alzheimer's Association chapter and an off-campus site at a local assisted living center with easy access for the students. Course topics covered over the 10-week period, included modules on: physical and cognitive fitness, nutrition, recreation, communication, understanding the disease process, depression, coping, relationships, and driving issues. Stress, depression, self-efficacy, and self-esteem were evaluated both prior to and after the 10-week course. Providing education early in the course of the disease, empowers the older adult student and provides an element of personal control and dignity. The course also attempts to prevent future problems by teaching new habits and lifestyles early in the disease process. Attempts to change habits and behavior later in the course of the disease often fail due to the difficulty of learning new behaviors.


The effectiveness of nursing education as an intervention to decrease fatigue in Turkish patients receiving chemotherapy.
To determine whether a nurse-led educational intervention decreased the perception of fatigue in patients diagnosed with gastrointestinal (GI) cancers (colon, stomach, liver, rectum, pancreas) who were receiving chemotherapy for the first time. Quasi-experimental, descriptive. Outpatient department in a large university hospital in Izmir, Turkey. 35 patients receiving chemotherapy for GI cancers. Baseline demographic data were collected using a personal information form developed by the researchers. Fatigue and quality of life (QOL) were then assessed using the Brief Fatigue Inventory, the Piper Fatigue Scale, and the European Organisation for Research and Treatment of Cancer Quality of Life (EORTC QLQ C-30) scale before their first cycle of chemotherapy, on the 10th day after (T1), and again 10 days after the second cycle of chemotherapy (T2). Patients received an individual educational intervention at baseline, T1, and T2 based on the results of their fatigue assessment in accordance with the National Comprehensive Cancer Network (NCCN) cancer-related fatigue guidelines. Patients were given an educational booklet on fatigue prior to treatment and symptom specific booklets as required at T1 and T2. Subjective reports of patients' fatigue and QOL. Patients' mean fatigue scores showed a statistically significant decrease and their EORTC QLQC-30 scores were better at T1 and T2 compared with baseline. Nurse-led educational interventions have the potential to reduce fatigue in patients with GI cancer receiving chemotherapy for the first time. The administration of chemotherapy should be preceded by a formal fatigue assessment and the provision of individually tailored educational interventions to reduce the severity of fatigue and improve QOL.


PI3K and Bcl-2 inhibition primes glioblastoma cells to apoptosis through downregulation of Mcl-1 and Phospho-BAD.
Glioblastoma multiforme (GBM) is a highly malignant human brain neoplasm with limited therapeutic options. GBMs display a deregulated apoptotic pathway with high levels of the antiapoptotic Bcl-2 family of proteins and overt activity of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Therefore, combined interference of the PI3K pathway and the Bcl-2 family of proteins is a reasonable therapeutic strategy. ABT-263 (Navitoclax), an orally available small-molecule Bcl-2 inhibitor, and GDC-0941, a PI3K inhibitor, were used to treat established glioblastoma and glioblastoma neurosphere cells, alone or in combination. Although GDC-0941 alone had a modest effect on cell viability, treatment with ABT-263 displayed a marked reduction of cell viability and induction of apoptotic cell death. Moreover, combinatorial therapy using ABT-263 and GDC-0941 showed an enhanced effect, with a further decrease in cellular viability. Furthermore, combination treatment abrogated the ability of stem cell-like glioma cells to form neurospheres. ABT-263 and GDC-0941, in combination, resulted in a consistent and significant increase of Annexin V positive cells and loss of mitochondrial membrane potential compared with either monotherapy. The combination treatment led to enhanced cleavage of both initiator and effector caspases. Mechanistically, GDC-0941 depleted pAKT (Serine 473) levels and suppressed Mcl-1 protein levels, lowering the threshold for the cytotoxic actions of ABT-263. GDC-0941 decreased Mcl-1 in a posttranslational manner and significantly decreased the half-life of Mcl-1 protein. Ectopic expression of human Mcl-1 mitigated apoptotic cell death induced by the drug combination. Furthermore, GDC-0941 modulated the phosphorylation status of BAD, thereby further enhancing ABT-263-mediated cell death. Combination therapy with ABT-263 and GDC-0941 has novel therapeutic potential by specifically targeting aberrantly active, deregulated pathways in GBM, overcoming endogenous resistance to apoptosis.


Urinary UBC Rapid and NMP22 Test for Bladder Cancer Surveillance in Comparison to Urinary Cytology: Results from a Prospective Single-Center Study.
Background: Non-muscle invasive bladder cancer (NMIBC) is associated with high rates of recurrence, resulting in frequent follow-up cystoscopies. We evaluated the use of two point-of-care tests - the nuclear matrix protein 22 (NMP22) and urinary bladder cancer antigen (UBC) Rapid - compared to routine follow-up in patients with a previous history of NMIBC. Methods: 31 patients with cystoscopy-verified active bladder cancer, and 44 follow-up patients without disease as confirmed by cystoscopy were prospectively enrolled. All urine samples were analyzed by voided urine and bladder washing cytology, NMP22 and UBC rapid test (qualitatively and quantitatively). The best cutoff (highest Youden index; ≥6.7 ng/ml) for the quantitative UBC was determined by receiver operating characteristic curves. Results: Voided urine and barbotage cytology resulted in a sensitivity of 25.8% and 32.3%, and a specificity of 100% and 100%, while the NMP22 showed a sensitivity and specificity of 12.9% and 100%, respectively. The qualitative and quantitative UBC Rapid revealed a sensitivity of 61.3% and 64.5%, with a specificity of 77.3% and 81.8%. Barbotage cytology and qualitative UBC test proved to be the best dual combination with the highest overall sensitivity (77.4%). In contrast to barbotage cytology alone, sensitivity increased from 21.4% to 50% for detecting low-grade tumors, and from 43.8% to 100% for high-grade cancers, but reducing specificity from 100% to 77.3%. Conclusion: Compared to urinary cytology, UBC tests alone as well as UBC tests in combination with bladder washing cytology revealed higher sensitivities in detecting low- and high-grade tumors, but at the expense of a lower specificity. Thus, currently cystoscopy cannot be replaced by any of the evaluated methods.


A computer graphics program system for protein structure representation.
We have developed a computer graphics program system for the schematic representation of several protein secondary structure analysis algorithms. The programs calculate the probability of occurrence of alpha-helix, beta-sheet and beta-turns by the method of Chou and Fasman and assign unique predicted structure to each residue using a novel conflict resolution algorithm based on maximum likelihood. A detailed structure map containing secondary structure, hydrophobicity, sequence identity, sequence numbering and the location of putative N-linked glycosylation sites is then produced. In addition, helical wheel diagrams and hydrophobic moment calculations can be performed to further analyze the properties of selected regions of the sequence. As they require only structure specification as input, the graphics programs can easily be adapted for use with other secondary structure prediction schemes. The use of these programs to analyze protein structure-function relationships is described and evaluated.


Chronic mild hypoxia protects heart-derived H9c2 cells against acute hypoxia/reoxygenation by regulating expression of the SUR2A subunit of the ATP-sensitive K+ channel.
Chronic exposure to lower oxygen tension may increase cellular resistance to different types of acute metabolic stress. Here, we show that 24-h-long exposure to slightly decreased oxygen tension (partial pressure of oxygen (PO2) of 100 mm Hg instead of normal 144 mm Hg) confers resistance against acute hypoxia/reoxygenation-induced Ca2+ loading in heart-derived H9c2 cells. The number of ATP-sensitive K+ (K(ATP)) channels were increased in cells exposed to PO2 = 100 mm Hg relative to cells exposed to PO2 = 144 mm Hg. This was due to an increase in transcription of SUR2A, a K(ATP) channel regulatory subunit, but not Kir6.2, a K(ATP) channel pore-forming subunit. PO2 = 100 mm Hg also increased the SUR2 gene promoter activity. Experiments with cells overexpressing wild type of hypoxia-inducible factor (HIF)-1alpha and dominant negative HIF-1beta suggested that the HIF-1-signaling pathway did not participate in observed PO2-mediated regulation of SUR2A expression. On the other hand, NADH inhibited the effect of PO2 = 100 mm Hg but not the effect of PO2 = 20 mm Hg. LY 294002 and PD 184 352 prevented PO2-mediated regulation of K(ATP) channels, whereas rapamycin was without any effect. HMR 1098 inhibited the cytoprotective effect of PO2 = 100 mm Hg, and a decrease of PO2 from 144 to 100 mm Hg did not change the expression of any other gene, including those involved in stress and hypoxic response, as revealed by Affymetrix high density oligonucleotide arrays. We conclude that slight hypoxia activates HIF-1alpha-independent signaling cascade leading to an increase in SUR2A protein, a higher density of K(ATP) channels, and a cellular phenotype more resistant to acute metabolic stress.


Updated treatment strategies for intestinal Behçet's disease.
Behçet's disease (BD) is a chronic, idiopathic, relapsing immune-mediated disease involving multiple organs, and is characterized by recurrent oral and genital ulcers, ocular disease, gastrointestinal ulcers, vascular diseases, and skin lesions. In particular, gastrointestinal involvement in BD is followed by severe complications, including massive bleeding, bowel perforation, and fistula, which can lead to significant morbidity and mortality. However, the management of intestinal BD has not yet been properly established. Intestinal BD patients with a severe clinical course experience frequent disease aggravations and often require recurrent corticosteroid and/or immunomodulatory therapies, or even surgery. However, a considerable number of patients with intestinal BD are often refractory to conventional therapies such as corticosteroids and immunomodulators. Recently, there has been a line of evidence suggesting that biologics such as infliximab and adalimumab are effective in treating intestinal BD. Moreover, new biologics targeting proteins other than tumor necrosis factor α are emerging and are under active investigation. Therefore, in this paper, we review the current therapeutic strategies and new clinical data for the treatment of intestinal BD.


A randomized trial of therapies for type 2 diabetes and coronary artery disease.
Optimal treatment for patients with both type 2 diabetes mellitus and stable ischemic heart disease has not been established. We randomly assigned 2368 patients with both type 2 diabetes and heart disease to undergo either prompt revascularization with intensive medical therapy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy. Primary end points were the rate of death and a composite of death, myocardial infarction, or stroke (major cardiovascular events). Randomization was stratified according to the choice of percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) as the more appropriate intervention. At 5 years, rates of survival did not differ significantly between the revascularization group (88.3%) and the medical-therapy group (87.8%, P=0.97) or between the insulin-sensitization group (88.2%) and the insulin-provision group (87.9%, P=0.89). The rates of freedom from major cardiovascular events also did not differ significantly among the groups: 77.2% in the revascularization group and 75.9% in the medical-treatment group (P=0.70) and 77.7% in the insulin-sensitization group and 75.4% in the insulin-provision group (P=0.13). In the PCI stratum, there was no significant difference in primary end points between the revascularization group and the medical-therapy group. In the CABG stratum, the rate of major cardiovascular events was significantly lower in the revascularization group (22.4%) than in the medical-therapy group (30.5%, P=0.01; P=0.002 for interaction between stratum and study group). Adverse events and serious adverse events were generally similar among the groups, although severe hypoglycemia was more frequent in the insulin-provision group (9.2%) than in the insulin-sensitization group (5.9%, P=0.003). Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision. (ClinicalTrials.gov number, NCT00006305.)


Fine-scale genetic analyses reveal unexpected spatial-temporal heterogeneity in two natural populations of the commercial mushroom Agaricus bisporus.
This study examined the fine-scale genetic variation of the commercial mushroom, Agaricus bisporus, over 2 years at two sites in France. One site was a meadow fertilized with horse manure and disturbed regularly by humans; the other was a Monterey cypress forest free of human disturbance. Altogether, 50 mushrooms were collected and analysed for mitochondrial and nuclear genetic variation marked by RFLPs and multilocus enzyme electrophoretic polymorphisms. Population samples from these two sites were genetically different and both sites contained high levels of genetic diversity. No identical genotypes were found at either site between the 2 years and there was little evidence for extensive vegetative clonality for this species. Contrary to expectations, very limited evidence of pseudohomothallic reproduction was found. Results from tests of Hardy-Weinberg equilibrium and genotypic equilibrium showed that outcrossing and recombination have played significant roles in both populations. The results demonstrated spatial-temporal genetic heterogeneity of A. bisporus in natural populations.


Clinical models of telehealth in genetics: A regional telegenetics landscape.
The use of live video consultations in genetics has been shown to improve patient access with high satisfaction; however, little is known about the current landscape of clinical telehealth models in the field of genetics (i.e., telegenetics). This survey aimed to address that gap across seven states and the District of Columbia. Among 51 self-defined telegenetics programs responding to an online survey, 32 currently utilized live videoconferencing as at least one of their technologies (i.e., were "video-capable"). Analysis of this subgroup revealed that medical institutions were the most common program setting, and prenatal and cancer services were the most common sub-specialty. Forty-seven percent of these programs reported billing insurance for patient care. When exploring measures of patient access among these programs, 56% had a wait time of under 2 weeks, 25% saw more than 50 patients per month, 50% estimated their geographic reach at over 200 miles, and 59% were able to provide remote telegenetics consultations to patients' homes. Professional licensure was reported as the biggest barrier, and patient access and convenience were reported as the largest benefit and success. Among the 19 remaining programs, eight currently active programs exclusively used telephone technology; these were less likely to have a geneticist (p = 0.01), had a shorter wait time (p = 0.04), and had been established for a longer time (p = 0.02) when compared to video-capable programs. Further, two currently active programs indicated the use of store-and-forward telehealth. Finally, nine programs were currently planning their programs, with a focus on video-capable technologies and more varied patient specialties. We observed a diverse landscape of telehealth models being utilized to provide genetic services, and the data demonstrated that these programs are focused on enhancing patient access. Our query about telegenetics drew responses from programs that were not using live videoconferencing technology models, which prompts further exploration, and challenges us to develop consensus around the meaning of "telegenetics." Similarly, our data suggest a need for continued research to assess the equivalency, accessibility, and role of telephone consultations across genetic services. While a multitude of policy factors influence which service delivery models are utilized, further research on these varied approaches, and their associated patient outcomes, is also needed to inform program development.


Patterns of visual dyslexia.
This study reports two Hebrew-speaking individuals with acquired visual dyslexia. They made predominantly visual errors in reading, in all positions of the target words. Although both of them produced visual errors, their reading patterns crucially differed in three respects. KD had almost exclusively letter substitutions, and SF also made letter omissions, additions, letter position errors, and between-word migrations. KD had difficulties accessing abstract letter identity in single-letter tasks, and in letter naming, unlike SF, who named letters well. KD did not show lexical effects such as frequency and orthographic neighbourhood effects and produced nonword responses, whereas SF showed lexical effects, with a strong tendency to produce word responses. We suggest that these two patterns stem from two different deficits - KD has letter identity visual dyslexia, which results from a deficit in abstract letter identification in the orthographic-visual analysis system, yielding erroneous letter identities, whereas SF has visual-output dyslexia, which results from a deficit at a later stage, a stage that combines the outputs of the various functions of the orthographic-visual analyzer.


Significance of chronic toxoplasmosis in epidemiology of road traffic accidents in Russian Federation.
Studies carried out in Moscow residents have revealed that the prevalence of chronic toxoplasmosis is very close to those in countries of Eastern and Central Europe. Our findings also demonstrated a statistically significant relationship between the rate of traffic accidents and the seroprevalence of chronic toxoplasmosis in drivers who were held responsible for accidents. The latter was 2.37 times higher in drivers who were involved in road accidents compared with control groups. These results suggest that the consequences of chronic toxoplasmosis (particularly a slower reaction time and decreased concentration) might contribute to the peculiarities of the epidemiology of road traffic accidents in the Russian Federation and might interfere with the successful implementation of the Federal Programme named "Increase road traffic safety". Suggestions for how to address overcome this problem are discussed in this paper.


Comparing laboratory- and field-measured biota-sediment accumulation factors.
Standardized laboratory protocols for measuring the accumulation of chemicals from sediments are used in assessing new and existing chemicals, evaluating navigational dredging materials, and establishing site-specific biota-sediment accumulation factors (BSAFs) for contaminated sediment sites. The BSAFs resulting from the testing protocols provide insight into the behavior and risks associated with individual chemicals. In addition to laboratory measurement, BSAFs can also be calculated from field data, including samples from studies using in situ exposure chambers and caging studies. The objective of this report is to compare and evaluate paired laboratory and field measurement of BSAFs and to evaluate the extent of their agreement. The peer-reviewed literature was searched for studies that conducted laboratory and field measurements of chemical bioaccumulation using the same or taxonomically related organisms. In addition, numerous Superfund and contaminated sediment site study reports were examined for relevant data. A limited number of studies were identified with paired laboratory and field measurements of BSAFs. BSAF comparisons were made between field-collected oligochaetes and the laboratory test organism Lumbriculus variegatus and field-collected bivalves and the laboratory test organisms Macoma nasuta and Corbicula fluminea. Our analysis suggests that laboratory BSAFs for the oligochaete L. variegatus are typically within a factor of 2 of the BSAFs for field-collected oligochaetes. Bivalve study results also suggest that laboratory BSAFs can provide reasonable estimates of field BSAF values if certain precautions are taken, such as ensuring that steady-state values are compared and that extrapolation among bivalve species is conducted with caution.


Improvements to the percolator algorithm for Peptide identification from shotgun proteomics data sets.
Shotgun proteomics coupled with database search software allows the identification of a large number of peptides in a single experiment. However, some existing search algorithms, such as SEQUEST, use score functions that are designed primarily to identify the best peptide for a given spectrum. Consequently, when comparing identifications across spectra, the SEQUEST score function Xcorr fails to discriminate accurately between correct and incorrect peptide identifications. Several machine learning methods have been proposed to address the resulting classification task of distinguishing between correct and incorrect peptide-spectrum matches (PSMs). A recent example is Percolator, which uses semisupervised learning and a decoy database search strategy to learn to distinguish between correct and incorrect PSMs identified by a database search algorithm. The current work describes three improvements to Percolator. (1) Percolator's heuristic optimization is replaced with a clear objective function, with intuitive reasons behind its choice. (2) Tractable nonlinear models are used instead of linear models, leading to improved accuracy over the original Percolator. (3) A method, Q-ranker, for directly optimizing the number of identified spectra at a specified q value is proposed, which achieves further gains.


MALDI-TOF MS for the identification of veterinary non-C. neoformans-C. gattii Cryptococcus spp. isolates from Italy.
Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) offers an effective alternative to phenotypic and molecular methods for the rapid identification of microorganisms. Our aim in this study was to create an in-house library for a set of strains of nine uncommonly reported human and animal cryptococcal species, including Cryptococcus adeliensis, C. albidosimilis, C. albidus, C. aureus, C. carnescens, C. laurentii, C. magnus, C. victoriae and C. uniguttulatus, and to use this library to make timely and correct identifications using MALDI-TOF MS for use in routine laboratory diagnostics. Protein extracts obtained via the formic acid extraction method of 62 veterinary non-C. neoformans-C. gattii cryptococcal isolates were studied. The obtained mass spectra correctly grouped all 62 studied isolates according to species identification previously obtained by internal transcribe spacer sequence analysis. The in-house database was than exported and successfully uploaded to the Microflex LT (Maldi Biotyper; Bruker Daltonics) instrument at a different diagnostic laboratory in Italy. Scores >2.7 obtained from isolates reanalyzed in the latter laboratory supported the high reproducibility of the method. The possibility of creating and transferring an in-house library adds to the usefulness MALDI-TOF MS an important tool for the rapid and inexpensive identification of pathogenic and saprophytic fungi as required for differential diagnosis of human and animal mycoses.


Alternative splicing of a beta4 subunit proline-rich motif regulates voltage-dependent gating and toxin block of Cav2.1 Ca2+ channels.
Ca2+ channel beta subunits modify alpha1 subunit gating properties through direct interactions with intracellular linker domains. In a previous report (Helton and Horne, 2002), we showed that alternative splicing of the beta4 subunit had alpha1 subunit subtype-specific effects on Ca2+ channel activation and fast inactivation. We extend these findings in the present report to include effects on slow inactivation and block by the peptide toxin omega-conotoxin (CTx)-MVIIC. N-terminal deletion and site-directed mutagenesis experiments revealed that the effects of alternative splicing on toxin block and all aspects of gating could be attributed to a proline-rich motif found within N-terminal beta4b amino acids 10-20. Interestingly, this motif is conserved within the third postsynaptic density-95 (PSD-95)/Discs large/zona occludens-1 domain of the distantly related membrane-associated guanylate kinase homolog, PSD-95. Sequence identity of approximately 30% made possible the building of beta4a and beta4b three-dimensional structural models using PSD-95 as the target sequence. The models (1) reveal that alternative splicing of the beta4 N terminus results in dramatic differences in surface charge distribution and (2) localize the proline-rich motif of beta4b to an extended arm structure that flanks what would be the equivalent of a highly modified PSD-95 carboxylate binding loop. Northern blot analysis revealed a markedly different pattern of distribution for beta4a versus beta4b in the human CNS. Whereas beta4a is distributed throughout evolutionarily older regions of the CNS, beta4b is concentrated heavily in the forebrain. These results raise interesting questions about the functional role that alternative splicing of the beta4 subunit has played in the evolution of complex neural networks.


NIOM for spinal deformity surgery: there's more than one way to skin a cat.
This was a 23-year retrospective study of 3436 consecutive pediatric orthopedic spinal surgery patients between 1995 and 2008. To demonstrate the effectiveness of multimodality electrophysiologic monitoring in reducing the incidence of iatrogenic neurologic deficit in a pediatric spinal surgery population. The elective nature of many pediatric spinal surgery procedures continues to drive the need for minimizing risk to each individual patient. Electrophysiologic monitoring has been proposed as an effective means of decreasing permanent neurologic injury in this population. A total of 3436 consecutive monitored pediatric spinal procedures at a single institution between January 1985 and September 2008 were reviewed. Monitoring included somatosensory evoked potentials, descending neurogenic evoked potentials, transcranial electric motor evoked potentials, and various nerve root monitoring techniques. Patients were divided into 10 diagnostic categories. True-positive and false-negative monitoring outcomes were analyzed for each category. Neurologic deficits were classified as transient or permanent. Seven of 10 diagnostic groups demonstrated true-positive findings resulting in surgical intervention. Seventy-four (2.2%) potential neurologic deficits were identified in 3436 pediatric surgical cases. Seven patients (0.2%) had false-negative monitoring outcomes. These patients awoke with neurologic deficits undetected by neuromonitoring. Intervention reduced permanent neurologic deficits to 6 (0.17%) patients. Monitoring data were able to detect permanent neurologic status in 99.6% of this population. The ratio of intraoperative events to total monitored cases was 1 event every 42 surgical cases and 1 permanent neurologic deficit every 573 cases. The combined use of somatosensory evoked potentials, transcranial electric motor evoked potentials, descending neurogenic evoked potentials, and electromyography monitoring allowed accurate detection of permanent neurologic status in 99.6% of 3436 patients and reduced the total number of permanent neurologic injuries to 6.


Serum ceruloplasmin and the risk of cancer in Finland.
The relationship between serum ceruloplasmin level and cancer incidence was investigated in a case-control study nested within a longitudinal study of 39,268 Finns participating in the Social Insurance Institution's Mobile Clinic Health Examination Survey carried out in 1968-1972. During a median follow-up of 8 years, 766 cancer cases were identified. Ceruloplasmin levels were determined from stored serum samples collected at the baseline from these cancer cases and from two matched controls per case. The overall incidence of cancer was positively associated with serum ceruloplasmin level. The association was strongest for lung cancer and other cancers related to smoking and, consequently, in males. The smoking-adjusted relative risk of lung cancer among men was 4.3 (95% confidence interval (CI) = 1.8-10.6) in the highest quintile of serum ceruloplasmin as compared with that in the lowest quintile. The corresponding relative risks for cancers related to smoking combined, and for cancers not related to smoking were 3.9 (CI = 1.9-8.4) and 0.9 (CI = 0.6-1.5), respectively. The elevated risk of lung cancer at high concentrations of serum ceruloplasmin persisted after further adjustment for several potential confounding factors such as serum levels of vitamins A and E and selenium. The risk was stronger during the first 6 years of follow-up than later, and strongest during the first 2 years. The most likely explanation of the present results thus is that high serum ceruloplasmin levels in lung cancer are mainly due to occult cancer.


Diet quality, stress and common mental health problems: A cohort study of 121,008 adults.
Overall diet quality may partially mediate the detrimental effects of stress and neuroticism on common mental health problems: stressed and/or neurotic individuals may be more prone to unhealthy dietary habits, which in turn may contribute to depression and anxiety. Lifestyle interventions for depressed, anxious or at-risk individuals hinge on this idea, but evidence to support such pathway is missing. Here, we aim to prospectively evaluate the role of overall diet quality in common pathways to developing depression and anxiety. At baseline, N = 121,008 individuals from the general population (age 18-93) completed an extensive food frequency questionnaire, based on which overall diet quality was estimated. Participants also reported on two established risk factors for mental health problems, i.e. past-year stress exposure (long-term difficulties, stressful life-events) and four neuroticism traits (anger-hostility, self-consciousness, impulsivity, vulnerability). Depression and anxiety were assessed at baseline and follow-up (n = 65,342, +3.6 years). Overall diet quality was modeled as a mediator in logistic regression models predicting the development of depression and anxiety from common risk factors. High stress and high neuroticism scores were - albeit weakly - associated with poorer diet quality. Poor diet quality, in turn, did not predict mental health problems. Overall diet quality did not mediate the relationship between stress/neuroticism and common mental health problems: effects of stress, neuroticism and stress-by-neuroticism interactions on mental health problems at follow-up consisted entirely of direct effects (98.6%-100%). Diet quality plays no mediating role in two established pathways to common mental health problems. As overall diet quality was reduced in stressed and neurotic individuals, these groups may benefit from dietary interventions. However, such interventions are unlikely to prevent the onset or recurrence of depression and anxiety.


Rapid assessment and response studies of injection drug use: knowledge gain, capacity building, and intervention development in a multisite study.
We evaluated the World Health Organization's rapid assessment and response (RAR) method of assessing injection drug use and its associated health problems, focusing on knowledge gain, capacity building, and whether RAR leads to the development of interventions reducing the health effects of injection drug use. Data were derived from RAR studies conducted in Beijing, China; Bogotá, Colombia; Greater Rosario, Argentina; Hanoi, Vietnam; Kharkiv, Ukraine; Minsk, Belarus; Nairobi, Kenya; Penang, Malaysia; St. Petersburg, Russia; and Tehran, Iran. Substantial gains in knowledge and response capacity were reported at all of the study sites. Before RAR initiation, prevention and intervention programs had been absent or inadequate at most of the sites. The RARs resulted in many new or modified interventions; 7 sites reported 24 health-related interventions that were subsequently developed and influenced by the RARs. RARs, which require relatively little external funding, appear to be effective in linking assessment to development of appropriate interventions. The present results add to the evidence that rapid assessment is an important public health tool.


Regions of the T cell receptor alpha and beta chains that are responsible for interactions with CD3.
The T cell antigen receptor consists of the Ti alpha/beta heterodimer which recognizes antigen, and the associated CD3 chains, thought to be involved in signal transduction. To understand the nature of the interaction between Ti and CD3, chimeric molecules which included the COOH-terminal segments of Ti alpha or beta linked to the extracellular segment of CD8, were transfected into a mutant T cell deficient in Ti beta chain expression and cell surface CD3. Both chimeric chains were required to express the chimeric Ti and to restore CD3 surface expression. CD8/Ti and CD3 cointernalized and coimmunoprecipitated. Stimulation of the chimeric receptor induced transmembrane signaling events and cell activation. These results demonstrate that the Ti alpha and beta COOH termini containing the transmembrane domains are sufficient for structural and functional coupling of Ti to CD3.


Biophysical Characterization of Fluorotyrosine Probes Site-Specifically Incorporated into Enzymes: E. coli Ribonucleotide Reductase As an Example.
Fluorinated tyrosines (FnY's, n = 2 and 3) have been site-specifically incorporated into E. coli class Ia ribonucleotide reductase (RNR) using the recently evolved M. jannaschii Y-tRNA synthetase/tRNA pair. Class Ia RNRs require four redox active Y's, a stable Y radical (Y·) in the β subunit (position 122 in E. coli), and three transiently oxidized Y's (356 in β and 731 and 730 in α) to initiate the radical-dependent nucleotide reduction process. FnY (3,5; 2,3; 2,3,5; and 2,3,6) incorporation in place of Y122-β and the X-ray structures of each resulting β with a diferric cluster are reported and compared with wt-β2 crystallized under the same conditions. The essential diferric-FnY· cofactor is self-assembled from apo FnY-β2, Fe(2+), and O2 to produce ∼1 Y·/β2 and ∼3 Fe(3+)/β2. The FnY· are stable and active in nucleotide reduction with activities that vary from 5% to 85% that of wt-β2. Each FnY·-β2 has been characterized by 9 and 130 GHz electron paramagnetic resonance and high-field electron nuclear double resonance spectroscopies. The hyperfine interactions associated with the (19)F nucleus provide unique signatures of each FnY· that are readily distinguishable from unlabeled Y·'s. The variability of the abiotic FnY pKa's (6.4 to 7.8) and reduction potentials (-30 to +130 mV relative to Y at pH 7.5) provide probes of enzymatic reactions proposed to involve Y·'s in catalysis and to investigate the importance and identity of hopping Y·'s within redox active proteins proposed to protect them from uncoupled radical chemistry.


On the origin of mitochondria: a genomics perspective.
The availability of complete genome sequence data from both bacteria and eukaryotes provides information about the contribution of bacterial genes to the origin and evolution of mitochondria. Phylogenetic analyses based on genes located in the mitochondrial genome indicate that these genes originated from within the alpha-proteobacteria. A number of ancestral bacterial genes have also been transferred from the mitochondrial to the nuclear genome, as evidenced by the presence of orthologous genes in the mitochondrial genome in some species and in the nuclear genome of other species. However, a multitude of mitochondrial proteins encoded in the nucleus display no homology to bacterial proteins, indicating that these originated within the eukaryotic cell subsequent to the acquisition of the endosymbiont. An analysis of the expression patterns of yeast nuclear genes coding for mitochondrial proteins has shown that genes predicted to be of eukaryotic origin are mainly translated on polysomes that are free in the cytosol whereas those of putative bacterial origin are translated on polysomes attached to the mitochondrion. The strong relationship with alpha-proteobacterial genes observed for some mitochondrial genes, combined with the lack of such a relationship for others, indicates that the modern mitochondrial proteome is the product of both reductive and expansive processes.


Divergent roles of the Wnt/PCP Formin Daam1 in renal ciliogenesis.
Kidneys are composed of numerous ciliated epithelial tubules called nephrons. Each nephron functions to reabsorb nutrients and concentrate waste products into urine. Defects in primary cilia are associated with abnormal formation of nephrons and cyst formation in a wide range of kidney disorders. Previous work in Xenopus laevis and zebrafish embryos established that loss of components that make up the Wnt/PCP pathway, Daam1 and ArhGEF19 (wGEF) perturb kidney tubulogenesis. Dishevelled, which activates both the canonical and non-canonical Wnt/PCP pathway, affect cilia formation in multiciliated cells. In this study, we investigated the role of the noncanoncial Wnt/PCP components Daam1 and ArhGEF19 (wGEF) in renal ciliogenesis utilizing polarized mammalian kidney epithelia cells (MDCKII and IMCD3) and Xenopus laevis embryonic kidney. We demonstrate that knockdown of Daam1 and ArhGEF19 in MDCKII and IMCD3 cells leads to loss of cilia, and Daam1's effect on ciliogenesis is mediated by the formin-activity of Daam1. Moreover, Daam1 co-localizes with the ciliary transport protein Ift88 and is present in cilia. Interestingly, knocking down Daam1 in Xenopus kidney does not lead to loss of cilia. These data suggests a new role for Daam1 in the formation of primary cilia.


Cloning, mapping, and molecular characterization of the rRNA operons of Clostridium perfringens.
All 10 rRNA operons have been situated on the genome map of the anaerobic pathogen Clostridium perfringens. Four of these have been cloned and partially sequenced, and their transcriptional patterns in vivo and in vitro have been examined. Expression of rrnA, rrnB, and rrnE is directed by tandem promoters, P1 and P2, whereas rrnH is the only one to be expressed from a single promoter, which resembles P1. On inspection of the nucleotide sequences of the control regions, several sites which might be involved in the regulation of rrn expression were identified. These include a possible upstream activating region which could be recognized by the C. perfringens equivalent of the Escherichia coli Fis protein and a stringent response target site. Studies of maturation of 16S RNA identified two 5' cleavage sites and sequence analysis showed the dG+dC content of its gene, rrs, to be 52%, which is twice that of the genome.


An evaluation of a combined education and multi-project practice development programme in mental health.
This paper describes a unique mental health practice development programme, which aims to integrate education, research, clinical practice and culture change, and promote collaboration between academics, researchers and healthcare practitioners to meet current government policy needs. The programme combines academic qualifications within the context of practice development and aims to produce practitioners who are dynamic leaders, capable of critical thinking, influencing culture change and challenging the nature of conventional practice. The aim of the evaluation was to give insight into participants' experience of the programme using a qualitative approach. Open-ended questionnaires obtained participant's views on facilitation and module content. Focus groups discovered the views and experiences of participants of the programme. The findings showed that the programme was well-received and impacted positively on both patient care and the personal and professional development of participants. The findings were used to modify the programme for the next intake of participants. The research complements the existing body of knowledge on practice development and highlights the benefits for staff, nurses and service users, and the challenges of implementation. The framework and design has the potential to be applied to other areas of practice beyond mental health.


Limited Dorsal Myeloschisis and Congenital Dermal Sinus: Comparison of Clinical and MR Imaging Features.
While limited dorsal myeloschisis is a distinctive form of spinal dysraphism, it may be confused with congenital dermal sinus. The aim of this study was to describe clinical and MR imaging findings of limited dorsal myeloschisis that can distinguish it from congenital dermal sinus. We retrospectively reviewed the clinical and MR imaging findings of 12 patients with limited dorsal myeloschisis and 10 patients with congenital dermal sinus. Skin abnormalities, neurologic deficits, and infectious complication were evaluated on the basis of clinical information. We evaluated the following MR imaging features: visibility of the tract along the intrathecal course, attachment site of the tract, level of the conus medullaris, shape of the spinal cord, and presence of intradural lesions such as dermoid/epidermoid tumors. A crater covered with pale epithelium was the most common skin lesion in limited dorsal myeloschisis (10/12, 83%). Infectious complications were common in congenital dermal sinus (6/10, 60%), whereas none were found in limited dorsal myeloschisis (P = .003). The following MR imaging findings were significantly different between the 2 groups (P < .05): 1) higher visibility of the intrathecal tract in limited dorsal myeloschisis (10/12, 83%) versus in congenital dermal sinus (1/10, 10%), 2) the tract attached to the cord in limited dorsal myeloschisis (12/12, 100%) versus various tract attachments in congenital dermal sinus, 3) dorsal tenting of the cord in limited dorsal myeloschisis (10/12, 83%) versus in congenital dermal sinus (1/10, 10%), and 4) the presence of dermoid/epidermoid tumors in congenital dermal sinus (6/10, 60%) versus none in limited dorsal myeloschisis. Limited dorsal myeloschisis has distinct MR imaging features: a visible intrathecal tract with dorsal tenting of the cord at the tract-cord union. Limited dorsal myeloschisis was not associated with infection and dermoid/epidermoid tumors.


Strong coupling of in-plane propagating plasmon modes and its control.
We show anti-crossings due to strong in-plane coupling of grating excited propagating plasmon modes in dielectric-metal-dielectric structure with 2D dielectric pattern on top. Grating coupled propagating plasmon modes along with their complete dispersion in the measurement range and all different sample orientations are calculated first. Further a coupled mode theory is presented for the specific geometry presented here. Experimentally measured anti-crossing widths are compared with those calculated by coupled mode theory. It is shown that the coupling strength of the plasmon modes and thus the anti-crossing width can be controlled by the orientation of the sample.


Interferon alfa-n1 (Wellferon) in juvenile onset recurrent respiratory papillomatosis: results of a randomized study in twelve collaborative institutions.
Sixty-six patients with clinically severe juvenile-onset recurrent respiratory papillomatosis (RRP) were entered into a 12-month randomized crossover study to evaluate interferon alpha-n1 Wellferon (WFN) as an adjuvant to CO2 laser surgical excision. Eligibility required disease onset to be before age 16, and an endoscopic excision requirement of at least three operations in the 6 months immediately prior to entry. Patients were randomized to Observation versus WFN at a dose of 5 MU/m2 daily for 28 days and three times weekly for 5 months. The patient groups were comparable in extent of disease at entry. Total extent of disease was determined by a composite score derived from the number of diseased anatomic sites and extent of surface area and lumen encroachment present at each site. Standard endoscopic excisions were performed every 2 months and clinical courses compared on a basis of composite scores determined at each endoscopy. Statistically significant improvement occurred in the patient group which received WFN. We conclude that interferon alpha n-1 is an effective adjuvant to surgery in RRP management.


Immunogenicity, boostability, and sustainability of the immune response after vaccination against Influenza A virus (H1N1) 2009 in a healthy population.
The emergence of a new influenza A virus (H1N1) variant in 2009 led to a worldwide vaccination program, which was prepared in a relatively short period of time. This study investigated the humoral immunity against this virus before and after vaccination with a 2009 influenza A virus (H1N1) monovalent MF59-adjuvanted vaccine, as well as the persistence of vaccine-induced antibodies. Our prospective longitudinal study included 498 health care workers (mean age, 43 years; median age, 44 years). Most (89%) had never or only occasionally received a seasonal influenza virus vaccine, and 11% were vaccinated annually (on average, for >10 years). Antibody titers were determined by a hemagglutination inhibition (HI) assay at baseline, 3 weeks after the first vaccination, and 5 weeks and 7 months after the second vaccination. Four hundred thirty-five persons received two doses of the 2009 vaccine. After the first dose, 79.5% developed a HI titer of ≥40. This percentage increased to 83.3% after the second dose. Persistent antibodies were found in 71.9% of the group that had not received annual vaccinations and in 43.8% of the group that had received annual vaccinations. The latter group tended to have lower HI titers (P=0.09). With increasing age, HI titers decreased significantly, by 2.4% per year. A single dose of the 2009 vaccine was immunogenic in almost 80% of the study population, whereas an additional dose resulted in significantly increased titers only in persons over 50. Finally, a reduced HI antibody response against the 2009 vaccine was found in adults who had previously received seasonal influenza virus vaccination. More studies on the effect of yearly seasonal influenza virus vaccination on the immune response are warranted.


Acute injuries in recreational and competitive surfers: incidence, severity, location, type, and mechanism.
There are an estimated 37 million surfers worldwide, with 2.5 million recreational surfers in Australia. The recreational activity and sport of surfing has grown dramatically since the 1960s, but scientific research has been poorly mirrored in comparison with most other mainstream sports. To identify the incidence, severity, location, type, and mechanism of acute injuries in recreational and competitive surfers over a 12-month period. Descriptive epidemiology study. An online survey using an open-source survey application was utilized. The survey consisted of 2 primary sections: Section 1 included demographic information and participation levels (age, height, weight, hours surfed, competitive level); section 2 incorporated injury type, mechanism, severity, and injury management. A total of 1348 participants (91.3% males; 43.1% competitive surfers) were included in data analysis. A total of 512 acute injuries were classified as major, providing an incidence proportion of 0.38 (CI, 0.35-0.41) acute injuries per year. The incidence rate was calculated to be 1.79 (CI, 1.67-1.92) major injuries per 1000 hours of surfing. The shoulder, ankle, and head/face regions had the highest frequencies of acute injury, representing 16.4%, 14.6%, and 13.3%, respectively. Injuries were predominantly of muscular, joint, and skin origin, representing 30.3%, 27.7%, and 18.9%, respectively. Skin injuries were primarily a result of direct trauma, while joint and muscular injuries were mainly a result of maneuvers performed and repetitive actions. Key risk factors that increased the incidence of sustaining an acute injury included competitive status, hours surfed (>6.5 hours/week), and the ability to perform aerial maneuvers. The incidence proportion for surfers completing aerial maneuvers was calculated to be 0.48 (CI, 0.39-0.58) major injuries per year, this being the highest incidence proportion irrespective of competitive status. This is the largest surfing-specific survey that included both recreational and competitive surfers conducted in Australia to date. The shoulder, ankle, head, and face were identified as the key regions where acute injuries occur in surfers. This research may aid in reducing the occurrence of injury through musculoskeletal screening in these key injury-prone regions and through the use of sport-specific strength training and conditioning.


Shoulder musculature activation during upper extremity weight-bearing exercise.
Repeated-measures design comparing 7 static weight-bearing shoulder exercises. The purpose of this study was to determine the demand on shoulder musculature during weight-bearing exercises and the relationship between increasing weight-bearing posture and shoulder muscle activation. Weight-bearing shoulder exercises are commonly prescribed in the rehabilitation of shoulder injuries. Limited information is available as to the demands placed on shoulder musculature while these exercises are performed. Eighteen healthy college students volunteered for this study. Surface bipolar electrodes were applied over the infraspinatus, posterior deltoid, anterior deltoid, and pectoralis major muscles. Fine-wire bipolar intramuscular electrodes were inserted into the supraspinatus muscle. Electromyographic (EMG) root mean square signal intensity was normalized to 1 second of EMG obtained with a maximal voluntary isometric contraction (MVIC). Subjects were tested under 7 isometric exercise positions that progressively increased upper extremity weight-bearing posture. There was a high correlation between increasing weight-bearing posture and muscular activity (r = 0.97, P < 0.01). There was relatively little demand on the shoulder musculature for the prayer and quadruped positions (2%-10% MVIC). Muscular activation was greater for the infraspinatus than for other shoulder muscles throughout most of the exercise positions tested. These results indicate that alterations of weight-bearing exercises, by varying the amount of arm support and force, resulted in very different demands on the shoulder musculature. Specifically, the infraspinatus was particularly active during the weight-bearing exercises used in this study.


Open trial of supplements of omega 3 and 6 fatty acids, vitamins and minerals in atopic dermatitis.
To investigate whether dietary supplementation with polyunsaturated fatty acids (PUFA) of the omega 3 series (n-3 PUFA: 18:3, n-3; 20:5, n-3; and 22:6, n-3), the omega 6 series (n-6 PUFA: 18:3, n-6), vitamins and minerals have a clinical effect on atopic dermatitis. A total of 19 patients aged 17-43 years with moderate to severe atopic dermatitis participated in an open trial of high oral doses of n-3 and n-6 PUFA in dry form (powder) or omega 3,6,9 fatty acid capsules, vitamin E tablets (d-alpha-tocopherol), zinc solution or tablets, and multivitamin capsules daily for 16 weeks. The mean SCORAD improved in 14 of 17 patients by more than 50% after 8 weeks and 16 weeks of treatment (p<0.01 and p<0.001, respectively). The open nature of this trial and the small number of subjects are major limitations of this study. The possible role of dietary omega 3 and 6 fatty acids in the treatment of atopic dermatitis should be tested more extensively in a double-blind trial using high doses of antioxidants combined with PUFA.


Personality Predictors of Emergency Department Post-Discharge Outcomes.
Personality traits are important predictors of health behaviors, healthcare utilization, and health outcomes. However, we know little about the role of personality traits for emergency department outcomes. The present study used data from 200 patients (effective Ns range from 84 to 191), who were being discharged from the emergency department at an urban hospital, to investigate whether the Big Five personality traits were associated with post-discharge outcomes (i.e., filling prescriptions, following up with primary care physician, making an unscheduled return to the emergency department). Using logistic regression, we found few associations among the broad Big Five domains and post-discharge outcomes. However, results showed statistically significant associations between specific Big Five items (e.g., "responsible") and the three post-discharge outcomes. This study demonstrates the feasibility of assessing personality traits in an emergency medicine setting and highlights the utility of having information about patients' personality tendencies for predicting post-discharge compliance.


Population pharmacokinetic analysis of dutogliptin, a selective dipeptidyl peptidase-4 inhibitor.
Dutogliptin is a selective dipeptidyl peptidase-4 inhibitor shown to be efficacious and safe in patients with type 2 diabetes mellitus (T2DM). Population pharmacokinetic (PK) analysis of dutogliptin was performed based on data collected in 561 healthy subjects and patients with T2DM enrolled in Phase I and II studies to assess sources of variability and support dosing rationale. The effect of extrinsic (formulations, fed/fasting conditions, potential drug-drug interaction with metformin) and intrinsic (baseline characteristics, markers of renal function, renal impairment category, and disease status) covariates was evaluated using non-linear mixed effect modeling. Plasma concentrations of dutogliptin were best fitted with a two-compartment model with a first-order rate constant of absorption (Ka) and a lag time. No differences were observed between healthy subjects and patients with T2DM. Apparent clearance (CL/F) and terminal elimination half-life of dutogliptin were 176 L/h and 12.2 hours, respectively. Typical CL/F values in patients with mild and moderate renal impairment were 121 and 79 L/h, respectively. No drug-drug interaction was observed with metformin. These results suggest that a reduction in dosing from 400 to 200 mg daily is warranted in T2DM patients with moderate renal impairment. No dose adjustments were deemed necessary for other evaluated patient characteristics and coadministration with metformin.


Insulin effects on protein synthesis are independent of glucose and energy metabolism.
Protein synthesis was accelerated in rat hearts that were provided insulin compared with provision of glucose or pyruvate alone or a mixture of glucose and pyruvate. The faster synthetic rates were accompanied by a reduction in numbers of ribosomal subunits, indicating that peptide chain initiation was accelerated relative to elongation/termination. In hearts supplied glucose, 65% of the maximal effect on protein synthesis was achieved by addition of 1.7 X 10(-10) M insulin, but significant effects on glucose uptake as well as on tissue contents of glucose 6-phosphate and creatine phosphate were obtained only with 7 X 10(-10) M insulin. Addition of glucose to perfusates containing pyruvate did not accelerate protein synthesis, although the glucose 6-phosphate content was raised. Similarly, the stimulatory effects of insulin on protein synthesis in hearts supplied pyruvate did not depend on changes in glucose 6-phosphate content, creatine phosphate/creatine, ATP/ADP, or adenylate energy charge. These studies indicate that insulin accelerated peptide-chain initiation and protein synthesis in rat heart by mechanisms independent of the hormone's effect on glucose or energy metabolism.


Pressure as a denaturing agent in studies of single-point mutants of an amyloidogenic protein human cystatin c.
Recently, we presented a convenient method combining a deuterium-hydrogen exchange and electrospray mass spectrometry for studying high-pressure denaturation of proteins (Stefanowicz et al., Biosci Rep 2009; 30:91-99). Here, we present results of pressure-induced denaturation studies of an amyloidogenic protein-the wild-type human cystatin C (hCC) and its single-point mutants, in which Val57 residue from the hinge region was substituted by Asn, Asp or Pro, respectively. The place of mutation and the substituting residues were chosen mainly on a basis of theoretical calculations. Observation of H/D isotopic exchange proceeding during pressure induced unfolding and subsequent refolding allowed us to detect differences in the proteins stability and folding dynamics. On the basis of the obtained results we can conclude that proline residue at the hinge region makes cystatin C structure more flexible and dynamic, what probably facilitates the dimerization process of this hCC variant. Polar asparagine does not influence stability of hCC conformation significantly, whereas charged aspartic acid in 57 position makes the protein structure slightly more prone to unfolding. Our experiments also point out pressure denaturation as a valuable supplementary method in denaturation studies of mutated proteins.


The relationship between self-reported received and perceived social support: a meta-analytic review.
Social support is broad term encompassing a variety of constructs, including support perceptions (perceived support) and receipt of supportive behaviors (received support). Of these constructs, only perceived support has been regarded as consistently linked to health, and researchers have offered differing assessments of the strength of the received-perceived support relationship. An overall estimate of the received-perceived support relationship would clearly further the dialogue on the relationship between received and perceived support and thus assist in the theoretical development of the field. This study evaluated all available studies using the Inventory of Socially Supportive Behaviors (ISSB; Barrera, Sandler, & Ramsey, 1981, American Journal of Community Psychology, 9, 435-447) and any measure of perceived social support. Using effect sizes from 23 studies, we found an average correlation of r = .35, p < .001. Implications of this estimate for further development of models of social support as well as interventions to enhance social support are discussed.


Hypertension and exercise training differentially affect oxytocin and oxytocin receptor expression in the brain.
We have previously shown that exercise training activates nucleus tractus solitarii (NTS) oxytocinergic projections, resulting in blunted exercise tachycardia. The objective of this study was to determine the effects of hypertension and training on oxytocin (OT) and OT receptor expression in the hypothalamic paraventricular nucleus (PVN) and projection areas (dorsal brain stem [DBS]). Male, normotensive, Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were trained (55% maximal exercise capacity, 3 months) or kept sedentary, and pressure was measured weekly. DBS sections were processed for immunohistochemistry (polyclonal guinea pig anti-OT) or in situ hybridization for OT and OT receptor (35S-oligonucleotide probes). Other groups of rats had brains removed and frozen to isolate the DBS and PVN; samples were processed for OT and OT receptor cDNA reverse transcription-polymerase chain reaction amplification with beta-actin as the housekeeping gene. Training was equally effective in improving running distance in both groups, with pressure reduction only in SHR (-10%, P<0.05). In trained WKY, baseline bradycardia (P<0.05) occurred simultaneously with increased NTS OT immunostaining and mRNA expression (+3.5-fold), without any change in OT receptor mRNA expression. PVN OT mRNA and DBS OT receptor mRNA expressions were significantly lower in SHR versus WKY (-39% and -56%, respectively). Training did not alter DBS OT receptor density in the SHR group but increased OT mRNA in both PVN and DBS areas (+78% and +45%, respectively). Our results show a marked hypertension-induced reduction in OT receptor mRNA expression, not altered by training. In contrast, training increased OT mRNA expression in sedentary and hypertensive rats, which may facilitate training-induced cardiac performance.


Structural and biophysical comparisons of the pomalidomide- and CC-220-induced interactions of SALL4 with cereblon.
The design of cereblon-binding molecular glues (MGs) that selectively recruit a desired protein while excluding teratogenic SALL4 is an area of significant interest when designing therapeutic agents. Previous studies show that SALL4 is degraded in the presence of IKZF1 degraders pomalidomide, and to a lesser extent by CC-220. To expand our understanding of the molecular basis for the interaction of SALL4 with cereblon, we performed biophysical and structural studies demonstrating that SALL4 zinc finger domains one and two (ZF1-2) interact with cereblon (CRBN) in a unique manner. ZF1 interacts with the N-terminal domain of cereblon and ZF2 binds as expected in the C-terminal IMiD-binding domain. Both ZF1 and ZF2 contribute to the potency of the interaction of ZF1-2 with CRBN:MG complexes and the affinities of SALL4 ZF1-2 for the cereblon:CC-220 complex are less potent than for the corresponding pomalidomide complex. Structural analysis provides a rationale for understanding the reduced affinity of SALL4 for cereblon in the presence of CC-220, which engages both ZF1 and ZF2. These studies further our understanding of the molecular glue-mediated interactions of zinc finger-based proteins with cereblon and may provide structural tools for the prospective design of compounds with reduced binding and degradation of SALL4.


Pulmonary rehabilitation for chronic obstructive pulmonary disease.
The widespread application of pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD) should be preceded by demonstrable improvements in function attributable to the programs. This review updates that reported in 2001. To determine the impact of rehabilitation on health-related quality of life (QoL) and exercise capacity in patients with COPD. We identified additional RCTs from the Cochrane Airways Group Specialised Register. Searches were current as of July 2004. We selected RCTs of rehabilitation in patients with COPD in which quality of life (QoL) and/or functional (FEC) or maximal (MEC) exercise capacity were measured. Rehabilitation was defined as exercise training for at least four weeks with or without education and/or psychological support. Control groups received conventional community care without rehabilitation. We calculated weighted mean differences (WMD) using a random-effects model. We requested missing data from the authors of the primary study. We included the 23 randomized controlled trials (RCTs) in the 2001 Cochrane review. Eight additional RCTs (for a total of 31) met the inclusion criteria. We found statistically significant improvements for all the outcomes. In four important domains of QoL (Chronic Respiratory Questionnaire scores for Dyspnea, Fatigue, Emotional function and Mastery), the effect was larger than the minimal clinically important difference of 0.5 units (for example: Dyspnoea score: WMD 1.0 units; 95% confidence interval: 0.8 to 1.3 units; n = 12 trials). Statistically significant improvements were noted in two of the three domains of the St. Georges Respiratory Questionnaire. For FEC and MEC, the effect was small and slightly below the threshold of clinical significance for the six-minute walking distance (WMD: 48 meters; 95% CI: 32 to 65; n = 16 trials). Rehabilitation relieves dyspnea and fatigue, improves emotional function and enhances patients' sense of control over their condition. These improvements are moderately large and clinically significant. Rehabilitation forms an important component of the management of COPD.


Adenoviral-mediated gene transfer into bone marrow: an effective surgical technique in rat.
The role of transforming growth factor-beta 1 (TGF-β₁) in the onset of bone marrow fibrosis has been confirmed in some animal models. To further understand the genetic expression of some myeloproliferative disorders affecting marrow stem cells, however, it is necessary to develop a specific and reliable procedure to deliver modified adenoviral vectors into the bone marrow cavity. The aim of this paper is to report a surgical technique designed to deliver an adenoviral vector-mediated gene expressing TGF-β₁ into the bone marrow of rat femurs. Forty-two Sprague-Dawley rats were used in the study. Rat femurs were exposed and the compact and trabecular bones at the proximal head removed. An intrabone marrow injection of a mutated TGF-β₁ adenoviral vector, a null adenoviral vector, or PBS was delivered into the bone. Three groups were accounted (n = 14 per group): fibrogenic and positive and negative controls. The quality of the surgical entrance was assessed by means of computerized tomography and histological changes were assessed by histochemistry. The concentration of TGF-β₁ in the bone marrow was determined by ELISA. The surgical technique was conducted under ideal timing (approx. 10 min) and no surgical or postsurgical complications were observed. Computerized tomography revealed no changes in the bone tissue and a clean entrance was delimited through the bone to the bone marrow. HE and Masson's trichrome staining indicated highly fibrotic areas in the profibrotic group and bone marrow lavage reported a significantly higher concentration of TGF-β₁ (p < 0.05) in that same group. The present study confirmed that the proposed surgical technique is an effective method to deliver adenoviral vectors into the femoral bone marrow to investigate the physiopathology of bone marrow fibrosis in rats.


Energy-resolved collision-induced dissociation pathways of model N-linked glycopeptides: implications for capturing glycan connectivity and peptide sequence in a single experiment.
Tandem mass spectrometry (MS/MS) of glycopeptides stands among the principal analytical approaches for assessing protein glycosylation in a site-specific manner. The aims of such experiments are often to determine the monosaccharide connectivity of the glycan, the amino acid sequence of the peptide, and the site of glycan attachment. This level of detail is often difficult to achieve using any single ion dissociation method; however, precedent does exist for use of collision-induced dissociation (CID) to establish either the connectivity of the oligosaccharide or the sequence of the polypeptide depending upon the applied collision energy. Unfortunately, the relative energy requirements for glycan and peptide cleavage have not been thoroughly characterized with respect to specific physicochemical characteristics of the precursor ions. This report describes case studies on the energy-resolved CID pathways of model tryptic glycopeptides derived from Erythrina cristagalli lectin and bovine ribonuclease B. While glycopeptide ions having disparate physical and chemical characteristics shared strikingly similar qualitative responses to increasing vibrational energy deposition, the absolute collision energies at which either glycan or peptide fragmentations were accessed varied substantially among the precursor ions examined. Nevertheless, these data suggest that the energy requirements for peptide and glycan cleavage may be somewhat predictable based on characteristics of the precursor ion. The practical usefulness of these observations was demonstrated through implementation of online collision energy modulation such that both glycan and peptide fragmentation were captured in the same spectrum, providing near-exhaustive glycopeptide characterization in a single experiment. Overall, these results highlight the potential to further extend the capabilities of CID in the context of glycoproteomics.


Time-resolved infrared spectroscopy reveals a stable ferric heme-NO intermediate in the reaction of Paracoccus pantotrophus cytochrome cd1 nitrite reductase with nitrite.
Cytochrome cd(1) is a respiratory enzyme that catalyzes the physiological one-electron reduction of nitrite to nitric oxide. The enzyme is a dimer, each monomer containing one c-type cytochrome center and one active site d(1) heme. We present stopped-flow Fourier transform infrared data showing the formation of a stable ferric heme d(1)-NO complex (formally d(1)Fe(II)-NO(+)) as a product of the reaction between fully reduced Paracoccus pantotrophus cytochrome cd(1) and nitrite, in the absence of excess reductant. The Fe-(14)NO nu(NO) stretching mode is observed at 1913 cm(-1) with the corresponding Fe-(15)NO band at 1876 cm(-1). This d(1) heme-NO complex is still readily observed after 15 min. EPR and visible absorption spectroscopic data show that within 4 ms of the initiation of the reaction, nitrite is reduced at the d(1) heme, and a cFe(III) d(1)Fe(II)-NO complex is formed. Over the next 100 ms there is an electron redistribution within the enzyme to give a mixed species, 55% cFe(III) d(1)Fe(II)-NO and 45% cFe(II) d(1)Fe(II)-NO(+). No kinetically competent release of NO could be detected, indicating that at least one additional factor is required for product release by the enzyme. Implications for the mechanism of P. pantotrophus cytochrome cd(1) are discussed.


Look before you seek: Preview adds a fixed benefit to all searches.
Knowing in advance what to look for speeds up search, but how this knowledge guides search is poorly understood. The little available evidence suggests that previewing the target produces larger reductions in search times for harder searches. To investigate this issue further, we performed seven experiments in which subjects searched for an oddball target after previewing the target, distracter, or an unrelated square. Consistent with previous studies, harder searches showed bigger reductions in search time for an informative preview. However, the same data replotted using the reciprocal of search time showed a remarkably different result: The informative preview showed a fixed additive increase in reciprocal search time across all searches regardless of difficulty. This is a nontrivial outcome because it cannot be explained using a simple relationship between search times in the informative and uninformative preview conditions. We interpret our findings by proposing that the reciprocal of search time reflects the strength of an underlying accumulating signal related to the distinctiveness or salience of the target over the distracters and that preview additively increases this signal for all searches. This in turn implies that the top-down signals related to target preview and bottom-up signals related to target-distracter salience sum linearly.


Small-scale fisheries, population dynamics, and resource use in Africa: the case of Moree, Ghana.
We consider population dynamics and sustainable use and development of fishery resources in Moree, a small-scale fishing and coastal community of 20,000 people in the Central Region of Ghana near Cape Coast. Moree suggests that relationships between population dynamics and fishery resources are more complex than the concept of Malthusian overfishing implies. Reasons include changing biophysical characteristics of the upwelling system along the coast of West Africa; qualitative as well as quantitative changes in fishing activity throughout the year; the market nature of fishing activity and nonlocal demands for fish; regular fishery migration; and institutions regulating fishery resource access at home and at migration destinations. Population and resource relationships in Moree may be the effects of fishery resource and economic changes on migration rather than population pressure on fishery resources. Fisheries management policies must take into account processes that lie beyond the influence of local fishermen.


Cord Blood Banking: Antenatal Care Provider's Roles and Responsibilities.
Umbilical Cord Blood (UCB) banking done either for private storage or for donation to public cord blood banks involves active participation of obstetricians. Counseling the expectant parents, providing them with unbiased and balanced information, and collecting the UCB with diligence confer a lot of social as well as moral responsibility upon obstetricians. This makes it even more important that the obstetricians in current practice stay well-informed and updated with UCB collection and its storage guidelines. The present study was conducted to assess the current status of obstetricians about UCB banking in terms of their awareness, attitude, and expectations from it. A cross-sectional study was conducted across three hospitals. A self-administered 22-item questionnaire was given to obstetricians to assess their awareness, attitude, and expectations about UCB banking. Finally, 154 completed questionnaires were analyzed using SPSS software (version 15.0). The awareness, attitude, and expectations were assessed and reported as primary endpoints and the self-rated knowledge levels, and sources of information were reported as secondary endpoints. Overall, the awareness was poor, but the attitude was favorable for UCB banking amongst obstetricians. Around 74% felt that obstetricians must be well-informed about UCB banking-related counseling and collection protocols. However, 55% felt it to be an additional burden for the obstetrician, and 57% believed that financial compensation must be given to obstetricians involved with cord blood collection procedures. The majority remained unclear about their expectations from UCB banking. The self-rated knowledge was poor and very poor for 75% obstetricians. 89.6% derived their information from representatives of private cord blood companies. Although poor in awareness levels, obstetricians possessed a favorable attitude towards UCB banking. Continuing medical education needs to focus more on such current issues of public importance to keep professionals updated. This is one way to minimise percolation of wrong facts and figures by the industries with conflicting interest to the healthcare providers.


Hyaluronic acid hydrogels for vocal fold wound healing.
The unique vibrational properties inherent to the human vocal fold have a significant detrimental impact on wound healing and scar formation. Hydrogels have taken prominence as a tissue engineered strategy to restore normal vocal structure and function as cellularity is low. The frequent vibrational and shear forces applied to, and present in this connective tissue make mechanical properties of such hydrogels a priority in this active area of research. Hyaluronic acid has been chemically modified in a variety of ways to address cell function while maintaining desirable tissue mechanical properties. These various modifications have had mixed results when injected in vivo typically resulting in better biomechanical function but not necessarily with a concomitant decrease in tissue fibrosis. Recent work has focused on seeding mesenchymal progenitor cells within 3D architecture of crosslinked hydrogels. The data from these studies demonstrate that this approach has a positive effect on cells in both early and late wound healing, but little work has been done regarding the biomechanical effects of these treatments. This paper provides an overview of the various hyaluronic acid derivatives, their crosslinking agents, and their effect when implanted into the vocal folds of various animal models.


Cell cycle-independent death of prostate adenocarcinoma is induced by the trk tyrosine kinase inhibitor CEP-751 (KT6587).
Advanced prostate cancer remains largely incurable, primarily because the very low growth fraction present in these tumors makes them generally resistant to treatment with standard chemotherapeutic agents that target cell division. Effective therapies should therefore induce death of prostate cancer cells, independent of their growth rate. trkA, the high-affinity tyrosine kinase-linked receptor for nerve growth factor, has been implicated in prostatic cancer growth and may represent a molecular target for therapeutic agents. At low mg/kg doses, the trk tyrosine kinase inhibitor CEP-751 (KT6587) inhibits prostatic cancer growth in nine different animal models independent of the tumor growth rate, androgen sensitivity, metastatic ability, or state of tumor differentiation. CEP-751 is selective for cancerous versus normal prostate cells and affects the growth of only a limited number of nonprostate tumors. Importantly, CEP-751 induces cell death of prostate cancer cells in a cell cycle-independent fashion and, therefore, represents a novel therapeutic approach to the management of both hormone-dependent and hormone-independent prostate cancer.


A cADP-ribose antagonist does not inhibit secretagogue-, caffeine- and nitric oxide-induced Ca2+ responses in rat pancreatic beta-cells.
It is controversial whether the Ca2+ mobilizing agent, cADP-ribose (cADPR), is implicated in secretagogue-mediated intracellular Ca2+ responses of pancreatic beta-cells. In this study we utilised a potent antagonist of cADPR, 8-amino-cADPR, to determine whether cADPR is involved in glucose-, acetylcholine-, caffeine- and nitric oxide-induced intracellular Ca2+ responses of isolated rat beta-cells. The antagonist was found to be effective in the complete inhibition of cADPR-induced Ca2+ release from sea urchin egg microsome preparations, when used at equivalent concentrations to cADPR (between 0.1-10 microM) in the assay. Isolated beta-cells were co-loaded with up to 50 microM 8-amino-cADPR, and Fura-2 or Fluo-3, by the whole-cell patch technique. At this concentration, the antagonist failed to affect standard glucose- and acetylcholine-induced increases in the intracellular free Ca2+ ([Ca2+]i) of isolated rat pancreatic beta-cells, as assessed by video ratio imaging and single wavelength microfluorimetry. Applying the same methodology, the antagonist also failed to affect NO- and caffeine-induced intracellular Ca2+ responses of rat beta-cells. These results suggest that cADPR does not appear to play a fundamental role in beta-cell Ca2+ signalling. As a control, patch-loading with heparin (2 mg/ml) however, abolished the acetylcholine response but neither affected the NO- or caffeine-induced mobilization of intracellular Ca2+. These results support the involvement of the IP3-receptor in acetylcholine-induced mobilization of intracellular Ca2+, but not that invoked by caffeine.


Prevalence of Antibiotic-Resistant Escherichia coli in Drinking Water Sources in Hangzhou City.
This study investigated the distribution of antibiotic resistant Escherichia coli (E. coli) and examined the possible relationship between water quality parameters and antibiotic resistance from two different drinking water sources (the Qiantang River and the Dongtiao Stream) in Hangzhou city of China. E. coli isolates were tested for their susceptibility to 18 antibiotics. Most of the isolates were resistant to tetracycline (TE), followed by ampicillin (AM), piperacillin (PIP), trimethoprim/sulfamethoxazole (SXT), and chloramphenicol (C). The antibiotic resistance rate of E. coli isolates from two water sources was similar; For E. coli isolates from the Qiantang River, their antibiotic resistance rates decreased from up- to downstream. Seasonally, the dry and wet season had little impact on antibiotic resistance. Spearman's rank correlation revealed significant correlation between resistance to TE and phenicols or ciprofloxacin (CIP), as well as quinolones (ciprofloxacin and levofloxacin) and cephalosporins or gentamicin (GM). Pearson's chi-square tests found certain water parameters such as nutrient concentration were strongly associated with resistance to some of the antibiotics. In addition, tet genes were detected from all 82 TE-resistant E. coli isolates, and most of the isolates (81.87%) contained multiple tet genes, which displayed 14 different combinations. Collectively, this study provided baseline data on antibiotic resistance of drinking water sources in Hangzhou city, which indicates drinking water sources could be the reservoir of antibiotic resistance, potentially presenting a public health risk.