Adjunctive huperzine A for cognitive deficits in schizophrenia: a systematic review and meta-analysis.
The aim of this study was to examine the efficacy of huperzine A (HupA), an isolate of Huperzine serrata, in the treatment of cognitive deficits in schizophrenia spectrum disorders. PubMed, PsycINFO, Embase, Cochrane Library, Cochrane Controlled Trials Register, WanFang, Chinese Biomedical, and China Journal Net databases were searched from inception to 15 July 2015 for randomized controlled trials (RCTs) in English or Chinese of HupA augmentation of antipsychotic drug therapy versus placebo or ongoing antipsychotic treatment. Twelve RCTs (n = 1117) lasting 11.7 ± 6.0 weeks met inclusion criteria. All had been conducted in China. HupA outperformed comparators on the following outcome measures: the Wechsler Memory Scale-Revised including memory quotient (weighted mean difference (WMD: 10.59; 95% confidence interval (CI): 5.65, 15.53; p < 0.0001); Wechsler Adult Intelligence Scale-Revised including verbal intelligence quotient (IQ), performance IQ, and full IQ (WMD: 3.97 to 5.66; 95%CI: 0.20, 8.58; p = 0.01 to 0.00001); Wisconsin Card Sorting Test including response administer and non-perseverative errors (WMD: -12.79 to -12.29; 95%CI: -23.70, -0.88; p = 0.03 to 0.003). In studies using the Positive and Negative Syndrome Scale (n = 7)/Brief Psychiatric Rating Scale (n = 1), the differences in total score were significant (standard mean difference: -0.77; 95%CI: -1.27, -0.27; p = 0.002). All-cause discontinuation (risk ratio: 0.67; 95%CI: 0.36, 1.24; p = 0.20) and adverse events were similar between groups. This review suggests that adjunctive HupA is an effective choice for improving cognitive function for patients with schizophrenia spectrum disorders. More well-designed RCTs are needed to further confirm HupA's efficacy. Copyright © 2016 John Wiley & Sons, Ltd.


Does Kinesio Taping of the Knee Improve Pain and Functionality in Patients with Knee Osteoarthritis?: A Randomized Controlled Clinical Trial.
This study investigated the effect of Kinesio taping on the functionality, pain, range of motion (ROM), and muscle strength in patients with knee osteoarthritis compared with a placebo Kinesio tape (KT) application. Forty-two consecutive patients were randomized to a KT group and a placebo taping group. The assessments were performed at baseline, after the initial KT application, the third KT application, and 1 month later. The functional status of patients was evaluated using the Aggregated Locomotor Function score and the Western Ontario and McMaster Universities Osteoarthritis scale. Pain level, muscle strength, and active ROM were measured using the Visual Analog Scale (VAS), a handheld dynamometer, and digital goniometer, respectively. Patients receiving the KT application demonstrated large decrease in VAS activity and walking task scores compared with the placebo taping group from the initial taping application to after the third taping application (P = 0.009 and P < 0.001, respectively) to the 1-month follow-up (P = 0.007 and P < 0.001, respectively). The KT group exhibited short-term improvement in VAS night and knee-flexion ROM after the 1-month follow-up (P < 0.05). There was no statistically significant difference in outcome measures in ROM and muscle strength between 2 groups. This study demonstrates that Kinesio taping resulted in superior short-term effects on walking task, pain, and knee-flexion ROM compared with placebo taping in patients with knee osteoarthritis.


Introduction of Inactivated Poliovirus Vaccine and Switch from Trivalent to Bivalent Oral Poliovirus Vaccine - Worldwide, 2013-2016.
Since the 1988 World Health Assembly resolution to eradicate poliomyelitis (polio), transmission of wild poliovirus (WPV) has been interrupted in all countries except Afghanistan, Nigeria, and Pakistan. No polio cases caused by WPV type 2 (WPV2) have been identified since 1999, and WPV type 3 has not been detected since November 11, 2012. This progress has been achieved through widespread use of oral poliovirus vaccine (OPV), most commonly trivalent OPV (tOPV), which contains types 1, 2, and 3 live, attenuated polioviruses. OPV polioviruses can undergo genetic changes during intestinal replication, and rarely, in communities with low vaccination coverage, such changes can result in vaccine-derived polioviruses (VDPVs) capable of causing paralytic polio. Eliminating the risk for polio caused by VDPVs will require stopping all OPV use. Among 686 cases of paralytic polio caused by circulating VDPVs (cVDPVs) that have been detected since 2006, type 2 cVDPVs (cVDPV2s) accounted for >97%. To eliminate the risks posed by cVDPV2s, OPV serotype 2 will be withdrawn from all immunization activities and programs through a global, synchronized replacement of all tOPV with bivalent OPV (bOPV) containing only types 1 and 3 polioviruses. This switch from tOPV to bOPV is scheduled for April 2016. To reduce the risk for cVDPV2 outbreaks and to facilitate responses to outbreaks that do occur, injectable trivalent inactivated poliovirus vaccine (IPV) is being introduced into routine immunization schedules in all countries. As of June 24, 2015, 90 (46%) of 194 World Health Organization (WHO) member states were using IPV, 102 (53%) had established dates for the introduction of IPV, and two (1%) intended to introduce IPV in 2015 but had not set dates for doing so. In addition to IPV introduction in all countries, careful synchronization of the switch from tOPV to bOPV will be needed within and across all 156 countries currently using tOPV. This report summarizes progress in introducing IPV and preparations for the switch from tOPV to bOPV.


Protective Effect of Dietary Calcium Intake on Esophageal Cancer Risk: A Meta-Analysis of Observational Studies.
Although several epidemiological studies have investigated the association between dietary calcium intake and the risk of esophageal cancer, the results are inconsistent. This study aimed to make a comprehensive evaluation regarding the association between calcium intake and risk of esophageal cancer through a meta-analysis approach. We searched for all relevant articles from the inception to April 2017, using PUBMED, EMBASE, and Web of Knowledge. The pooled odds ratio (ORs) with the 95% confidence interval (95% CI) for the highest versus the lowest categories of calcium intake was calculated using a Mantel-Haenszel fixed-effect model. In total, 15 articles reporting 17 studies including 3396 esophageal cancer cases and 346,815 controls were selected for the meta-analysis. By comparing the highest vs. the lowest levels of dietary calcium intake, we found that dietary calcium intake was inversely associated with the risk of esophageal cancer (OR = 0.80, 95% CI: 0.71-0.91, I² = 33.6%). The subgroup analysis indicated that the protective function of dietary calcium intake were observed in esophageal squamous cell cancer, but not in esophageal adenocarcinoma in the studies conducted in Asia, but not those in Europe and America. In conclusion, our results suggest that higher dietary calcium intake is associated with a lower risk of esophageal cancer-especially esophageal squamous cell cancer-in Asian populations, though more data from prospective cohort studies are needed.


Augmented responses to vasoconstrictor stimuli in hypercholesterolemic and atherosclerotic monkeys.
We examined effects of hypercholesterolemia and atherosclerosis on vasoconstrictor responses to norepinephrine and serotonin. Responses were compared in normal, atherosclerotic, and hypercholesterolemic but non-atherosclerotic cynomolgus monkeys. The hindlimb was perfused at constant flow so that changes in perfusion pressure indicated changes in vascular resistance. We measured the pressure gradient from the iliac to the dorsal pedal artery so that responses of the large artery segment could be determined. Serotonin decreased total hindlimb resistance in normal and hypercholesterolemic monkeys, but increased total resistance in atherosclerotic monkeys. There was a greater than 10-fold increase in constrictor responses of large arteries to serotonin in atherosclerotic monkeys, compared with normal and hypercholesterolemic monkeys. In contrast, we found that vasoconstrictor responses to norepinephrine are normal in atherosclerotic monkeys and increased in hypercholesterolemic monkeys prior to development of atherosclerosis. Hypercholesterolemia augmented responses of small vessels to norepinephrine. We conclude that, during early stages of hypercholesterolemia in cynomolgus monkeys, vasoconstrictor responses to norepinephrine are increased in small vessels. At a later stage, as atherosclerosis develops, responses to norepinephrine return to normal, but vasoconstrictor effects of large arteries to serotonin are greatly potentiated.


Rufinamide in children and adults with Lennox-Gastaut syndrome: first Italian multicenter experience.
This is the first multicenter Italian experience with rufinamide as an adjunctive drug in children, adolescents and adults with Lennox-Gastaut syndrome. The patients were enrolled in a prospective, add-on, open-label treatment study from 11 Italian centers for children and adolescent epilepsy care. Forty-three patients (26 males, 17 females), aged between 4 and 34 years (mean 15.9 ± 7.3, median 15.0), were treated with rufinamide for a mean period of 12.3 months (range 3-21 months). Twenty patients were diagnosed as cryptogenic and 23 as symptomatic. Rufinamide was added to the baseline therapy at the starting dose of 10mg/kg body weight, evenly divided in two daily doses and then increased by 10mg/kg approximately every 3 days up to a maximum of 1000 mg/day in children aged ≥4 years with a body weight less than 30 kg. In patients more than 30 kg body weight, rufinamide could be titrated up to 3200 mg/day. After a mean follow-up period of 12.3 months (range 3-21 months), the final mean dose of rufinamide was 33.5mg/kg/24h (range 11.5-60) if combined to valproic acid, and of 54.5mg/kg/24h (range 21.8-85.6) without valproic acid. The response rate (≥50% decrease in countable seizures) was 60.5% (26 of 45 patients) in total; 51.1% experienced a 50-99% reduction in seizure frequency and complete seizure control was achieved in the last 4 weeks follow-up by 9.3% of patients. Two patients (4.7%) had a 25-50% seizure reduction, while seizure frequency remained unchanged in 13 (30.2%) and increased in 2 (4.7%). Reliable data for atypical absence seizures and myoclonic seizures were not available, as these are usually impossible to count. Ten patients (23.2%) reported adverse side effects, while taking rufinamide. They were generally mild and transient and most frequently included vomiting, drowsiness, irritability and loss of appetite. In conclusion, rufinamide as an adjunctive therapy reduced the number of drop attacks and major motor seizures in about 60% of patients with Lennox-Gastaut syndrome and produced only mild or moderate adverse side effects.


The examination of commercial printing defects to assess common origin, batch variation, and error rate.
The examination of printing defects, or imperfections, found on printed or copied documents has been recognized as a generally accepted approach for linking questioned documents to a common source. This research paper will highlight the results from two mutually exclusive studies. The first involved the examination and characterization of printing defects found in a controlled production run of 500,000 envelopes bearing text and images. It was concluded that printing defects are random occurrences and that morphological differences can be used to identify variations within the same production batch. The second part incorporated a blind study to assess the error rate of associating randomly selected envelopes from different retail locations to a known source. The examination was based on the comparison of printing defects in the security patterns found in some envelopes. The results demonstrated that it is possible to associate envelopes to a common origin with a 0% error rate.


Physical activity, gender, weight status, and wellbeing in 9- to 11-year-old children: a cross sectional survey.
The aim of this study was to examine the relationship between physical activity and wellbeing in children, and to further explore the extent to which this may vary by gender and weight status. A representative sample of 1424 9- to 11-year-olds completed a self-report measure of physical activity, the Child Health and Illness Profile, KIDSCREEN, and a self-esteem scale. Body Mass Index (BMI) measurements were also obtained. 24% of children achieved the recommended level of 60 minutes of moderate-to-vigorous intensity physical activity (MVPA) per day, with more boys than girls achieving this level. Children achieving the recommended level of MVPA scored significantly higher on measures of the Child Health and Illness Profile (F(5, 1354) = 5.03; P < .001), KIDSCREEN (F(3, 1298) = 4.68; P = .003), and self-esteem (F(1, 1271) = 18.73; P = .003) than less active children although the effect sizes were small (ηp2 ≈ .01). Substantial gender differences in wellbeing were found reflecting gender specific behaviors and socialization. Weight status had negligible influence on wellbeing. Children who meet the recommended guidelines of MVPA were more likely to have better wellbeing. When attempting to raise children's physical activity levels consideration should be given to the specific relationships between wellbeing and physical activity.


Description and process evaluation of pharmacists' interventions in a pharmacist-led information technology-enabled multicentre cluster randomised controlled trial for reducing medication errors in general practice (PINCER trial).
To undertake a process evaluation of pharmacists' recommendations arising in the context of a complex IT-enabled pharmacist-delivered randomised controlled trial (PINCER trial) to reduce the risk of hazardous medicines management in general practices. PINCER pharmacists manually recorded patients' demographics, details of interventions recommended, actions undertaken by practice staff and time taken to manage individual cases of hazardous medicines management. Data were coded, double-entered into SPSS version 15 and then summarised using percentages for categorical data (with 95% confidence interval (CI)) and, as appropriate, means (± standard deviation) or medians (interquartile range) for continuous data. Pharmacists spent a median of 20 min (interquartile range 10, 30) reviewing medical records, recommending interventions and completing actions in each case of hazardous medicines management. Pharmacists judged 72% (95% CI 70, 74; 1463/2026) of cases of hazardous medicines management to be clinically relevant. Pharmacists recommended 2105 interventions in 74% (95% CI 73, 76; 1516/2038) of cases and 1685 actions were taken in 61% (95% CI 59, 63; 1246/2038) of cases; 66% (95% CI 64, 68; 1383/2105) of interventions recommended by pharmacists were completed and 5% (95% CI 4, 6; 104/2105) of recommendations were accepted by general practitioners (GPs), but not completed at the end of the pharmacists' placement; the remaining recommendations were rejected or considered not relevant by GPs. The outcome measures were used to target pharmacist activity in general practice towards patients at risk from hazardous medicines management. Recommendations from trained PINCER pharmacists were found to be broadly acceptable to GPs and led to ameliorative action in the majority of cases. It seems likely that the approach used by the PINCER pharmacists could be employed by other practice pharmacists following appropriate training.


Age-dependent hypertension in Mpv17-deficient mice, a transgenic model of glomerulosclerosis and inner ear disease.
The mutant mouse strain Mpv17-/-, carries a retroviral germline integration that inactivates the Mpv17 gene. Mpv17-deficient mice develop progressive glomerulosclerosis and sensineural deafness at early age. Characteristic basement membrane alterations are found in both sites of pathology. Mpv17 is a peroxisomal protein involved in the metabolism of reactive oxygen species, yet its molecular function is unknown. Dysregulation of antioxidant enzymes and basal membrane components has been established in this model and successful therapeutic intervention with antioxidants prove the causal role of reactive oxygen species in the development of the disease phenotype. We here investigated if the Mpv17-/- mice might be hypertensive. Indeed, our study revealed that Mpv17-/- mice developed significant systemic hypertension and tachycardia between 4 weeks and 5 months of age, accompanied by polyuria and elevated natriuresis. Judging from serum and urine parameters, the hypertensive condition develops concomitantly with the renal disease. Biochemical and pharmacological studies that used the endothelin receptor antagonist bosentan and the angiotensin converting enzyme inhibitor cilazapril indicated no involvement of the endothelin and renin-angiotensin systems in this hypertension, suggesting a potential novel mechanism of blood pressure regulation in this new murine hypertension model. Thus, Mpv17-/- mice unravel an intriguing new association between a defect in reactive oxygen metabolism and the age-dependent development of hypertension.


Trends in socioeconomic inequalities in adolescent alcohol use in Germany between 1994 and 2006.
To examine socioeconomic differences in adolescent alcohol use in Germany as well as their changes between 1994 and 2006. Data were obtained from the "Health Behaviour in School-aged Children" study conducted in North Rhine-Westphalia, Germany in 1994, 1998, 2002 and 2006. The analysis is based on 5.074 15-year-old students. Prevalence and trends were analysed for each category of family affluence and educational track separately using log-binominal regression models. An increase in weekly alcohol use between 1994 and 2002 was followed by a strong decrease from 2002 to 2006. Family affluence only had a weak effect on weekly drinking with a tendency for lower-affluent students reporting less alcohol use. Educational track showed almost no relationship with weekly alcohol use. Trend analyses within the subgroups revealed that the overall trend in alcohol use was similar in all socioeconomic and educational groups. Socioeconomic patterns in drinking behaviour are not yet developed in 15-year-old adolescents. Adolescence could therefore be an important time frame for tackling inequalities in alcohol use later in life.


Thoracoscopic placement of dual-rod instrumentation in thoracic spinal trauma.
Traditionally, thoracic fractures that require anterior stabilization are treated through an open thoracotomy approach. Thoracoscopic instrumentation avoids many of the complications associated with an open thoracotomy but is technically challenging. We report the first cases of dual-rod internal fixation systems placed thoracoscopically for thoracic spinal trauma. Two male patients sustained midthoracic spinal trauma falling from motorcycles in separate incidents. Both injuries led to unstable spinal columns, but the patients had no neurological deficits and had minimal spinal cord compression. One patient had a complex spiral fracture from T6 to T8; the other had T7 burst and T8 compression fractures. Based on the complex morphological features of the patients' fractures, anterior internal fixation was the treatment of choice for both. The two available options for an anterior stabilization were open thoracotomy and thoracoscopic instrumentation. Because extensive decompression was unnecessary, a thoracoscopic approach was used. A dual-rod internal fixation system (Medtronic Sofamor Danek, Inc., Memphis, TN) was placed with two screws each in the T6 and T9 vertebral bodies of each patient. Thoracoscopy was used for direct visualization of the operative site with fluoroscopic guidance for screw placement. Surgery was completed without complications, and both patients did well afterward. Upright and supine x-rays demonstrated that the constructs were stable at 10 weeks and 6 months, respectively. Thoracoscopic instrumentation offers the advantages of a minimally invasive approach but is technically challenging. The characteristics of dual-rod fixation systems (small-profile components and step-wise insertion) provide the best biomechanical profile and facilitate thoracoscopic instrumentation.


Validation study of microRNAs previously associated with antidepressant response in older adults treated for late-life depression with venlafaxine.
MicroRNAs (miRNAs) are small 22 nucleotides long, non-coding RNAs that are potential biomarkers for antidepressant treatment response. We aimed to replicate previous associations of miRNAs with antidepressant treatment response in a sample of older adults diagnosed with late-life depression. Our sample included 184 older adults diagnosed with moderately severe depression that received open-label venlafaxine (up to 300 mg/day) for approximately 12 weeks. We quantified miRNA expression levels at baseline and week 12 for miRNAs miR-1202, miR-135a-5p, miR-16-5p, miR-146a-5p, miR-146b-5p, miR-425-3p, and miR-24-3p to explore their association with remission status, response trajectories, and time-to-remission. At T0 and T12, there were no differences in miRNA expression levels between remitters and non-remitters. However, remitters showed a trend toward higher baseline miR-135a-5p (Median = 11.3 [9.9, 15.7], p = .083). Prior to correction, baseline miR-135a-5p expression levels showed an association with remission status (OR = 1.8 [1.0, 3.3], p = .037). Individuals with higher baseline miR-135a-5p showed better response trajectories (F = 4.5, FDR-corrected p = 4.4 × 10-4), particularly at weeks 10 and 12 (p < .05). In addition, individuals with higher miR-135a-5p expression reached remission faster than those with lower expression (HR = 0.6 [0.4, 0.9], FDR-corrected p = .055). Although the sample size was relatively modest, our findings are consistent with the literature suggesting that higher miR-135a-5p levels may be associated with better antidepressant treatment response. However, the miRNA signature of antidepressant response in older adults may be different as compared to younger adults.


Large complex globular domains of type VII procollagen contribute to the structure of anchoring fibrils.
Type VII collagen, in the form of an antiparallel dimer, is a major protein component of anchoring fibrils. The ultrastructural appearance of these fibrils suggests that they may serve to anchor the basement membrane zone to the underlying connective tissue matrix. We report here the identification and initial characterization of Type VII procollagen, recovered from the media of epidermoid carcinoma cell cultures. Immunoblotting using monospecific antibodies to Type VII procollagen identifies a single, homogeneous band of at least Mr 320,000 following disulfide bond reduction. This chain contains 170 kDa of collagen triple helix and 150 kDa of non-helical domain at the carboxyl terminus. Pepsin digestion of this material yields Type VII collagen identical to that isolated from whole tissue and a series of quasi-stable peptides derived from the carboxyl-terminal region. Cell extracts contain procollagen chains identical in size to those secreted into the media. There is no evidence for processing of this material in cell culture. Partial purification by velocity sedimentation and transmission electron microscopic observation following rotary shadowing reveals both monomers (426 nm) and dimers (785 nm). Dimers are antiparallel and interact through 60-nm overlap, with amino-terminal globular domains present at the ends of the overlap. The multi-domain carboxyl-terminal region appears as three similar arms originating from a centralized globular region adjacent to the collagen helix. The carboxyl globular domain is present in whole tissue and may participate in the unique fibril form of this collagen. The amino-terminal globule may function in the antiparallel assembly of dimers.


A general strategy for colloidal stable ultrasmall amorphous mineral clusters in organic solvents.
While nature exerts precise control over the size and chemical composition of minerals, this is still a challenging task for artificial syntheses. Despite its significance, until now, there are still no reports on colloidal mineral nanoparticles in the subnanometer range. Here we developed a general gas diffusion strategy using 10,12-pentacosadiynoic acid as a ligand and ethanol as a solvent to fabricate stable amorphous mineral clusters with a core size of less than 2 nm. First discovered for CaCO3, the method was successfully extended to produce monolayer protected clusters of MgCO3, SrCO3, Eu2(CO3)3, Tb2(CO3)3, Ce2(CO3)3, Ca x (PO4) y , CaC2O4 and their hybrid minerals, Ca x Mg y (CO3) z and Ca x (CO3) y (PO4) z . All the mineral clusters can be well dispersed in organic solvents like toluene, and are stable for a long period without further crystallization. Our work paves a way for the artificial synthesis of colloidal mineral clusters, which may have various uses in both fundamental research and industry.


Identification of defect sites on MgO(100) thin films by decoration with Pd atoms and studying CO adsorption properties.
CO adsorption on Pd atoms deposited on MgO(100) thin films has been studied by means of thermal desorption (TDS) and Fourier transform infrared (FTIR) spectroscopies. CO desorbs from the adsorbed Pd atoms at a temperature of about 250 K, which corresponds to a binding energy, E(b), of about 0.7 +/- 0.1 eV. FTIR spectra suggest that at saturation two different sites for CO adsorption exist on a single Pd atom. The vibrational frequency of the most stable, singly adsorbed CO molecule is 2055 cm(-)(1). Density functional cluster model calculations have been used to model possible defect sites at the MgO surface where the Pd atoms are likely to be adsorbed. CO/Pd complexes located at regular or low-coordinated O anions of the surface exhibit considerably stronger binding energies, E(b) = 2-2.5 eV, and larger vibrational shifts than were observed in the experiment. CO/Pd complexes located at oxygen vacancies (F or F(+) centers) are characterized by much smaller binding energies, E(b) = 0.5 +/- 0.2 or 0.7 +/- 0.2 eV, which are in agreement with the experimental value. CO/Pd complexes located at the paramagnetic F(+) centers show vibrational frequencies in closest agreement with the experimental data. These comparisons therefore suggest that the Pd atoms are mainly adsorbed at oxygen vacancies.


Myosin Heavy Chain 10 (MYH10) Gene Silencing Reduces Cell Migration and Invasion in the Glioma Cell Lines U251, T98G, and SHG44 by Inhibiting the Wnt/β-Catenin Pathway.
BACKGROUND The myosin heavy chain 10 or MYH10 gene encodes non-muscle myosin II B (NM IIB), and is involved in tumor cell migration, invasion, extracellular matrix (ECM) production, and epithelial-mesenchymal transition (EMT). This study aimed to investigate the effects of the MYH10 gene on normal human glial cells and glioma cell lines in vitro, by gene silencing, and to determine the signaling pathways involved. MATERIAL AND METHODS The normal human glial cell line HEB, and the glioma cell lines, U251, T98G, and SHG44 were studied. Plasmid transfection silenced the MYH10 gene. The cell counting kit-8 (CCK-8) assay evaluated cell viability. Cell migration and invasion were evaluated using scratch and transwell assays. Western blot measured the protein expression levels, and quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression levels, for MYH10, metastasis-associated protein 1 (MTA-1), matrix metalloproteinase (MMP)-1, MMP-9, tissue inhibitor of metalloproteinases 2 (TIMP2), collagen 1, E-cadherin, vimentin, Wnt3a, β-catenin, and cyclin D1. RESULTS The MYH10 gene was overexpressed in U251, T98G, and SHG44 cells. MYH10 expression was down-regulated following siMYH10 plasmid interference, which also inhibited glioma cell migration and invasion. MYH10 gene silencing resulted in reduced expression of MTA-1, MPP-2, MMP-9 and vimentin, and increased expression of TIMP-2, E-cadherin and collagen 1 at the protein and mRNA level, and inhibited the Wnt/β-catenin pathway. CONCLUSIONS In human glioma cell lines, silencing the MYH10 gene reduced cell migration and invasion, by inhibiting the Wnt/β-catenin pathway, which may regulate the ECM and inhibit EMT in human glioma.


Citrin deficiency: A treatable cause of acute psychosis in adults.
Citrin deficiency is an autosomal recessive genetic disorder caused by a defect in the mitochondrial aspartate/glutamate antiporter, citrin. The disorder manifests either as neonatal intra-hepatic cholestasis or occurs in adulthood with recurrent hyperammonemia and neuropsychiatric disturbances. It has a high prevalence in the East Asian population, but is actually pan-ethnic. We report the case of a 26-year-old male patient presenting with episodes of abnormal neuro-psychiatric behavior associated with hyperammonemia, who was diagnosed to be having citrin deficiency. Sequencing of the SLC25A13 gene revealed two novel mutations, a single base pair deletion, c. 650delT (p.Phe217SerfsFNx0133) in exon 7, and a missense mutation, c. 869T>C (p.Ile290Thr) in exon 9. Confirmation of the diagnosis allowed establishment of the appropriate management. The latter is an essential pre-requisite for obtaining a good prognosis as well as for family counseling.


Advances in genetic manipulation of obligate intracellular bacterial pathogens.
Infections by obligate intracellular bacterial pathogens result in significant morbidity and mortality worldwide. These bacteria include Chlamydia spp., which causes millions of cases of sexually transmitted disease and blinding trachoma annually, and members of the α-proteobacterial genera Anaplasma, Ehrlichia, Orientia, and Rickettsia, agents of serious human illnesses including epidemic typhus. Coxiella burnetii, the agent of human Q fever, has also been considered a prototypical obligate intracellular bacterium, but recent host cell-free (axenic) growth has rescued it from obligatism. The historic genetic intractability of obligate intracellular bacteria has severely limited molecular dissection of their unique lifestyles and virulence factors involved in pathogenesis. Host cell restricted growth is a significant barrier to genetic transformation that can make simple procedures for free-living bacteria, such as cloning, exceedingly difficult. Low transformation efficiency requiring long-term culture in host cells to expand small transformant populations is another obstacle. Despite numerous technical limitations, the last decade has witnessed significant gains in genetic manipulation of obligate intracellular bacteria including allelic exchange. Continued development of genetic tools should soon enable routine mutation and complementation strategies for virulence factor discovery and stimulate renewed interest in these refractory pathogens. In this review, we discuss the technical challenges associated with genetic transformation of obligate intracellular bacteria and highlight advances made with individual genera.


Glial reactivity, an early feature of diabetic retinopathy.
To characterize early structural gliotic reactions in retinal Müller cells, astrocytes, and microglia in experimentally induced diabetes. Rats were rendered diabetic by streptozotocin injection and killed after 2, 4, 12, or 20 weeks. Cell densities were determined in flatmounted retinas or transverse semithin sections. Expression of glial fibrillary acidic protein (GFAP) was localized on frozen sections or flatmounts by immunofluorescence and confocal microscopy, and GFAP content was evaluated by Western blot analysis. Microglial cells were visualized by binding of isolectin B4 or staining with antibodies to phosphotyrosine residues. The integrity of the blood-retinal barrier was assessed by intravenous injection of Evans blue. The density of Müller cells and microglia was significantly increased at 4 weeks of diabetes compared with nondiabetic controls. GFAP expression in Müller cells was not detected at 4 weeks but was prominent at 12 weeks. The number of astrocytes was significantly reduced at 4 weeks in the peripapillary and far peripheral retina. Shape changes of microglial cells indicated functional activation. Leakage of the blood-retinal barrier was observed at 2 weeks of hyperglycemia, the earliest time point investigated. The leakage of the blood-retinal barrier before glial reactivity suggests that glia are early targets of vascular hyperpermeability. The individual glial cell types react differentially to the diabetic state. Müller cells undergo hyperplasia preceding GFAP expression, and microglial cells are activated, whereas astrocytes regress. This glial behavior may contribute decisively to the onset and development of neuropathy in the diabetic retina.


Intrahepatic, perihilar and distal cholangiocarcinoma: Management and outcomes.
Introduction and aims. Cholangiocarcinomas are a heterogeneous group of tumors that can be classified into three clinically distinct types of cancers, intrahepatic, perihilar and distal cholangiocarcinoma. The inconsistent use of nomenclature for these cancers has obscured a true knowledge of the epidemiology, natural history and response to therapy of these cancers. Our aims were to define demographic characteristics, management and outcomes of these three distinct cancer types. A retrospective study of patients enrolled in an institutional cancer registry from 1992 to 2010. Median survival was compared between different treatment modalities over three time periods for the three types of cholangiocarcinoma at different stages of the disease using Kaplan Meyer analysis. 242 patients were identified. All cases were reviewed and classified into intrahepatic (90 patients), distal (48 patients) or perihilar (104 patients) cholangiocarcinomas. These cancers differed in median age of onset, gender distribution, median survival and stage. 13.8% of patients presented with stage I, 5.8% with stage II, 9.6% with stage III, 28% with stage IV, with 41.8% having unknown stage. The overall median survival was 15.8 months, and was 23, 25, 14, and 4.5 months for stages I, II, III, and IV respectively. Surgery improved survival in both early and advanced stages. Multimodality therapies further improved outcomes, particularly for perihilar cholangiocarcinoma. Perihilar, distal and intrahepatic cholangiocarcinoma vary in their presentation, natural history and therapeutic approach to management. A consistently applied classification is essential for meaningful interpretation of studies of these cancers.


Conformational flexibility of the peptide hormone ghrelin in solution and lipid membrane bound: a molecular dynamics study.
Human ghrelin is a peptide hormone of 28 aminoacid residues, in which the Ser3 is modified by an octanoyl group. Ghrelin has a major role in the energy metabolism of the human body stimulating growth hormone release as well as food intake. Here we perform molecular dynamics simulations in explicit water and in a DMPC-lipid bilayer/water system in order to structurally characterize this highly flexible peptide and its lipid binding properties. We find a loop structure with residues Glu17 to Lys 20 in the bending region and a short alpha-helix from residues Pro7 to Glu13. The presence of a lipid membrane does not influence these structural features, but reduces the overall flexibility of the molecule as revealed by reduced root mean square fluctuations of the atom coordinates. The octanoyl-side chain does not insert into the lipid membrane but points into the water phase. The peptide binds to the lipid membrane with its bending region involving residues Arg15, Lys16, Glu17, and Ser18. The implications of these results for the binding pocket of the ghrelin receptor are discussed.


Ultrafast transient liquid assisted growth of high current density superconducting films.
The achievement of high growth rates in YBa2Cu3O7 epitaxial high-temperature superconducting films has become strategic to enable high-throughput manufacturing of long length coated conductors for energy and large magnet applications. We report on a transient liquid assisted growth process capable of achieving ultrafast growth rates (100 nm s-1) and high critical current densities (5 MA cm-2 at 77 K). This is based on the kinetic preference of Ba-Cu-O to form transient liquids prior to crystalline thermodynamic equilibrium phases, and as such is a non-equilibrium approach. The transient liquid-assisted growth process is combined with chemical solution deposition, proposing a scalable method for superconducting tapes manufacturing. Additionally, using colloidal solutions, the growth process is extended towards fabrication of nanocomposite films for enhanced superconducting properties at high magnetic fields. Fast acquisition in situ synchrotron X-ray diffraction and high resolution scanning transmission electron microscopy (STEM) become crucial measurements in disentangling key aspects of the growth process.


Nanoplasmonic Ruler for Measuring Separation Distance between Supported Lipid Bilayers and Oxide Surfaces.
Unraveling the details of how supported lipid bilayers (SLBs) are coupled to oxide surfaces is experimentally challenging, and there is an outstanding need to develop highly surface-sensitive measurement strategies to determine SLB separation distances. Indeed, subtle variations in separation distance can be associated with significant differences in bilayer-substrate interaction energy. Herein, we report a nanoplasmonic ruler strategy to measure the absolute separation distance between SLBs and oxide surfaces. A localized surface plasmon resonance (LSPR) sensor was employed to track SLB formation onto titania- and silica-coated gold nanodisk arrays. To interpret measurement data, an analytical model relating the LSPR measurement response to bilayer-substrate separation distance was developed based on finite-difference time-domain (FDTD) simulations and theoretical calculations. The results indicate that there is a larger separation distance between SLBs and titania surfaces than silica surfaces, and the trend was consistent across three tested lipid compositions. We discuss these findings within the context of the interfacial forces underpinning bilayer-substrate interactions, and the nanoplasmonic ruler strategy provides the first direct experimental evidence comparing SLB separation distances on titania and silica surfaces.


Genomic maps and comparative analysis of histone modifications in human and mouse.
We mapped histone H3 lysine 4 di- and trimethylation and lysine 9/14 acetylation across the nonrepetitive portions of human chromosomes 21 and 22 and compared patterns of lysine 4 dimethylation for several orthologous human and mouse loci. Both chromosomes show punctate sites enriched for modified histones. Sites showing trimethylation correlate with transcription starts, while those showing mainly dimethylation occur elsewhere in the vicinity of active genes. Punctate methylation patterns are also evident at the cytokine and IL-4 receptor loci. The Hox clusters present a strikingly different picture, with broad lysine 4-methylated regions that overlay multiple active genes. We suggest these regions represent active chromatin domains required for the maintenance of Hox gene expression. Methylation patterns at orthologous loci are strongly conserved between human and mouse even though many methylated sites do not show sequence conservation notably higher than background. This suggests that the DNA elements that direct the methylation represent only a small fraction of the region or lie at some distance from the site.


PKCα and ERβ Are Associated with Triple-Negative Breast Cancers in African American and Caucasian Patients.
Although the incidence of breast cancer in the United States is higher in Caucasian women compared with African American women, African-American patients have more aggressive disease as characterized by a higher percentage of triple-negative breast cancers (TNBCs), high-grade tumors, and a higher mortality rate. PKCα is a biomarker associated with endocrine resistance and poor prognosis and ERβ is emerging as a protective biomarker. Immunohistochemical analysis of ERβ and PKCα expression was performed on 198 formalin-fixed paraffin-embedded primary infiltrating ductal carcinomas from 105 African-American and 93 Caucasian patients. PKCα is positively correlated with TNBC in patients of both races and with high tumor grade in African-American patients. Patients with TNBC express less nuclear ERβ compared with all other subtypes. We find no difference in frequency or intensity of PKCα or ERβ expression between African-American and Caucasian patients. PKCα and ERβ are discussed as potential therapeutic targets for the treatment of patients with TNBC.


The feasibility of coherent energy transfer in microtubules.
It was once purported that biological systems were far too 'warm and wet' to support quantum phenomena mainly owing to thermal effects disrupting quantum coherence. However, recent experimental results and theoretical analyses have shown that thermal energy may assist, rather than disrupt, quantum coherent transport, especially in the 'dry' hydrophobic interiors of biomolecules. Specifically, evidence has been accumulating for the necessary involvement of quantum coherent energy transfer between uniquely arranged chromophores in light harvesting photosynthetic complexes. The 'tubulin' subunit proteins, which comprise microtubules, also possess a distinct architecture of chromophores, namely aromatic amino acids, including tryptophan. The geometry and dipolar properties of these aromatics are similar to those found in photosynthetic units indicating that tubulin may support coherent energy transfer. Tubulin aggregated into microtubule geometric lattices may support such energy transfer, which could be important for biological signalling and communication essential to living processes. Here, we perform a computational investigation of energy transfer between chromophoric amino acids in tubulin via dipole excitations coupled to the surrounding thermal environment. We present the spatial structure and energetic properties of the tryptophan residues in the microtubule constituent protein tubulin. Plausibility arguments for the conditions favouring a quantum mechanism of signal propagation along a microtubule are provided. Overall, we find that coherent energy transfer in tubulin and microtubules is biologically feasible.


Effects of timing of initiation and planning on smoking cessation outcomes: study protocol for a randomised controlled trial.
Recent theoretical and empirical work has led to debate over the benefit of delaying the implementation of a decision to quit smoking in order to plan the attempt. These two need not be linked, planning can occur before a commitment to quit is made, or after it is implemented, as well as in between. This study will test whether there are independent benefits for encouraging smokers to act immediately on a definite decision to quit smoking, and to engage in structured planning. A complex randomised controlled trial with a factorial design, testing the presence of a recommendation to quit immediately (or not) and encouragement to structured planning (or not) as additions to standard care, a web-based automated tailored advice program (QuitCoach). Participants are recruited from users of the QuitCoach who reside in Australia, do not report a mental health condition for which they are taking medication, are adult daily smokers, and at least open to the possibility of quitting. For the Immediate arm they could not have committed to quit within 2 days, while the Planning arm included all these and those quit within the last 4 days. This creates 6 groups: 2 × 3, with 2 × 2 fully randomised, and 2 only randomised for the planning arm. Follow-up assessments are conducted around 1 month (targeting two weeks after the quit attempt started), and 6 months later. The primary outcome is 6-month sustained abstinence at 6 months. Secondary outcomes include point-prevalence abstinence at both follow-ups, and making quit attempts during the intervention period. We will also explore differences in actual behaviour (timing and planning) by intervention, and relate this to outcomes. This study will result in a better understanding of the roles of planning and delay in influencing the success of quit attempts. Australian New Zealand Clinical Trials Registry http://ACTRN12612000613808.


Multiple disordered loops function in corepressor-induced dimerization of the biotin repressor.
Cooperative association of the Escherichia coli biotin repressor with the biotin operator is allosterically activated by binding of the corepressor, bio-5'-AMP. The corepressor function of the adenylate is due, in part, to its ability to induce repressor dimerization. Since a high-resolution structure of only the apo or unliganded repressor is currently available, the location of the dimerization interface on the protein structure is not known. Here, five mutants in the corepressor-binding domain of the repressor have been analyzed with respect to their DNA-binding and self-assembly properties. Results of these studies reveal that four of the mutant proteins exhibit defects in DNA binding. These same proteins are compromised in self-assembly. Furthermore, in the three-dimensional structure of the apo protein the mutations all lie in partially disordered surface loops, one of which is known to participate directly in corepressor binding. These results suggest that multiple disordered surface loops function in the corepressor-induced dimerization required for sequence-specific DNA binding by the biotin repressor.


Comparisons of Clinical and Procedural Outcomes Between Transradial and Transfemoral Approaches in Percutaneous Coronary Intervention (from the Korean Transradial Intervention Prospective Registry).
As few studies have reported the impact of transradial interventions (TRIs) versus transfemoral interventions (TFIs) on percutaneous coronary interventions using real-world registry data, we compared the clinical and procedural outcomes between TRIs and TFIs in the Korean Transradial Intervention Prospective Registry. Patients undergoing percutaneous coronary interventions were consecutively registered from February 2014 to July 2014 in this multicenter registry. Composite events were evaluated for all-cause deaths, nonfatal myocardial infarctions, and repeat revascularizations within 30 days. Nonlesion complications included access site complications and bleeding events. A total of 1,225 patients (232 for TFIs and 993 for TRIs) were analyzed. All-cause deaths and composite events were more frequent in the TFI group than in the TRI group. Procedure failures and nonlesion complications were also more frequent in the TFI group, whereas lesion complication rates were similar in the 2 groups. Procedure times were not different between the 2 groups, whereas fluoroscopy times were longer and contrast volumes were larger in the TFI group. However, in a propensity score-matched cohort, all-cause deaths, composite events, procedure failures, and lesion and nonlesion complications were not different between the 2 groups. In contrast, in the matched cohort, the procedure and fluoroscopy times were longer and the contrast volumes were larger in the TFI group. In conclusion, TRI was as effective and safe as TFI in terms of short-term clinical outcomes, procedure success rates, and complication rates, whereas TRI was more effective for reducing procedure times and hazardous exposure to radiation and contrast media.


First Report of Fusarium Yellows of Sugar Beet Caused by Fusarium oxysporum in Michigan.
Fusarium yellows of sugar beet (Beta vulgaris L.), caused by Fusarium oxysporum Schlechtend.Fr. f. sp. betae (Stewart) Snyd & Hans., has been a long-term problem in the western United States (3) and recently was reported in Minnesota and North Dakota (4). This disease is typified by interveinal yellowing and wilting of the foliage. Roots have no external symptoms but show internal vascular discoloration. In 2005, 12 sugar beet roots from Michigan with yellows-type symptoms were received by the author. Isolations were made from the cortical and vascular tissue of the crown and tap root. Fusarium spp. isolates were obtained from 10 of the beets, and 16 isolates were identified as Fusarium oxysporum on the basis of morphology and pigmentation on potato dextrose agar and spores and phialides on carnation leaf agar (2). F. oxysporum isolates were tested for pathogenicity by dipping roots of 5-week-old susceptible sugar beet plants (FC716) in a suspension of 104 spores per ml for 8 min, 10 plants per isolate. Two known pathogenic isolates of F. oxysporum f. sp. betae, Fob13 and Fob216c (4), were used for comparison. For a negative control, plants were dipped in sterile water. Beets were planted in Cone-tainers (3.8 cm diameter × 21 cm) containing pasteurized potting mix. Plants were placed in a greenhouse at 24 to 27°C and fertilized with 15-30-15 fertilizer every 2 weeks to avoid chlorosis from nutrient deficiency. Plants were rated weekly for foliar symptoms for 6 weeks using a Fusarium yellows rating scale of 0 to 4 in which 0 = no disease and 4 = complete plant death (1). After the final rating, plants were removed from soil and the tap root examined for root symptoms. Root segments were surface disinfested with 0.5% sodium hypochlorite and cultured on potato dextrose agar to confirm presence of the pathogen. The experiment was done twice. Seven F. oxysporum isolates tested caused typical Fusarium yellows symptoms including interveinal yellowing, stunting, and wilting of inoculated plants. Pathogenic isolates were obtained from 7 of the 10 beets that yielded F. oxysporum. Symptoms were indistinguishable from those caused by Fob13 (average ratings ranged from 1.8 to 2.4) and milder than those caused by Fob216c (average rating 3.1). No interveinal chlorosis or wilting was observed on the control plants. Isolations from inoculated plants provided F. oxysporum cultures morphologically similar to those used in inoculation by the methods of Nelson et al. (2). No F. oxysporum was isolated from control plants. To my knowledge, this is the first report of F. oxysporum causing Fusarium yellows on beet in Michigan. References: (1) L. E. Hanson and A. L. Hill. J. Sugar Beet Res. 41:163, 2004. (2) P. E. Nelson et al. Fusarium species: An Illustrated Manual for Identification. The Pennsylvania State University Press, University Park, 1983. (3). C. L. Schneider and E. D. Whitney. Fusarium Yellows. Page 18 in: Compendium of Beet Diseases and Insects. C. L. Schneider and E. D. Whitney, eds. The American Phytopathological Society, St. Paul, MN, 1986. (4) C. E. Windels et al. Plant Dis. 89:341, 2005.


Eosinophilic, Solid, and Cystic Renal Cell Carcinoma: Clinicopathologic Study of 16 Unique, Sporadic Neoplasms Occurring in Women.
A unique renal neoplasm characterized by eosinophilic cytoplasm and solid and cystic growth was recently reported in patients with tuberous sclerosis complex (TSC). We searched multiple institutional archives and consult files in an attempt to identify a sporadic counterpart. We identified 16 morphologically identical cases, all in women, without clinical features of TSC. The median age was 57 years (range, 31 to 75 y). Macroscopically, tumors were tan and had a solid and macrocystic (12) or only solid appearance (4). Average tumor size was 50 mm (median, 38.5 mm; range, 15 to 135 mm). Microscopically, the tumors showed solid areas admixed with variably sized macrocysts and microcysts that were lined by cells with a pronounced hobnail arrangement. The cells had voluminous eosinophilic cytoplasm with prominent granular cytoplasmic stippling and round to oval nuclei with prominent nucleoli. Scattered histiocytes and lymphocytes were invariably present. Thirteen of 16 patients were stage pT1; 2 were pT2, and 1 was pT3a. The cells demonstrated a distinct immunoprofile: nuclear PAX8 expression, predominant CK20-positive/CK7-negative phenotype, patchy AMACR staining, but no CD117 reactivity. Thirteen of 14 patients with follow-up were alive and without disease progression after 2 to 138 months (mean: 53 mo; median: 37.5 mo); 1 patient died of other causes. Although similar to a subset of renal cell carcinomas (RCCs) seen in TSC, we propose that sporadic "eosinophilic, solid, and cystic RCC," which occurs predominantly in female individuals and is characterized by distinct morphologic features, predominant CK20-positive/CK7-negative immunophenotype, and indolent behavior, represents a novel subtype of RCC.


Nonhistone protein antigen profiles of five leukemic cell lines reflect the extent of myeloid differentiation.
The human leukemic cell lines, K562, KG-1, and HL-60, and the blast subclones, KG-1a and HL-60 blast, were utilized to relate differences in nonhistone protein antigens to stages of myeloid cell differentiation. Chromatin proteins were separated on SDS-polyacrylamide gels, transferred electrophoretically to nitrocellulose sheets, and visualized by the peroxidase-antiperoxidase method of Sternberger. Screening with antisera raised against total and dehistonized chromatin and a nuclear extract from these cells revealed quantitative as well as qualitative differences between the cell lines. A decrease in antigen content seemed to parallel progressive stages of myeloid cell development. The results indicate that a number of chromosomal protein antigens are lost or modified during differentiation. An antigen(s) of approximately 55,000 molecular weight was found in HL-60 chromatin, but was not present in its less differentiated subclone or in the other lines representative of earlier stage cells. Upon the induction of HL-60 cells to mature to end stages with 4 microM retinoic acid, a significant increase in the mol wt 55,000 activity was seen. This antigen was detected only with antisera against HL-60 total chromatin and granulocyte nuclei, and it was found only in normal mature granulocytes and in the later stage cells of the HL-60 culture. Thus, the antigen appears to be associated with a differentiated myeloid function.


Relationship of the Ubiquilin 1 gene with Alzheimer's and Parkinson's disease and cognitive function.
Ubiquilin 1 (UBQLN1) is involved in the ubiquitination machinery, which has been implicated in Alzheimer's disease (AD) as well as Parkinson's disease (PD). A polymorphism in the gene encoding for UBQLN1 has been previously associated with a higher risk of AD. We studied the role of the SNP rs12344615 on the UBQLN 1 gene in AD, PD and cognitive function in a population-based study, the Rotterdam Study, and a family-based study embedded in the genetic research in isolated population (GRIP) program. The Rotterdam Study includes 549 patients with AD and 157 patients with PD. The GRIP program includes a series of 123 patients with AD and a study of 1049 persons who are characterized for cognitive function. Data were analysed using logistic and multiple regression analysis. We found no significant difference in risk of AD or PD by the UBQLN1 SNP rs12344615 in our overall and stratified analyses in the Rotterdam Study. In our family-based study, we did not find evidence for linkage of AD to the region including the UBQLN1 gene. In the family-based study we also failed to detect an effect of this polymorphism on cognitive function. Our results suggest that it is unlikely that the SNP rs12344615 of the UBQLN1 gene is related to the onset of AD, PD or cognitive function.


Defining the Independence of the Liver Circadian Clock.
Mammals rely on a network of circadian clocks to control daily systemic metabolism and physiology. The central pacemaker in the suprachiasmatic nucleus (SCN) is considered hierarchically dominant over peripheral clocks, whose degree of independence, or tissue-level autonomy, has never been ascertained in vivo. Using arrhythmic Bmal1-null mice, we generated animals with reconstituted circadian expression of BMAL1 exclusively in the liver (Liver-RE). High-throughput transcriptomics and metabolomics show that the liver has independent circadian functions specific for metabolic processes such as the NAD+ salvage pathway and glycogen turnover. However, although BMAL1 occupies chromatin at most genomic targets in Liver-RE mice, circadian expression is restricted to ∼10% of normally rhythmic transcripts. Finally, rhythmic clock gene expression is lost in Liver-RE mice under constant darkness. Hence, full circadian function in the liver depends on signals emanating from other clocks, and light contributes to tissue-autonomous clock function.


Changes in translational efficiency is a dominant regulatory mechanism in the environmental response of bacteria.
To understand how cell physiological state affects mRNA translation, we used Shewanella oneidensis MR-1 grown under steady state conditions at either 20% or 8.5% O2. Using a combination of quantitative proteomics and RNA-Seq, we generated high-confidence data on >1000 mRNA and protein pairs. By using a steady state model, we found that differences in protein-mRNA ratios were primarily due to differences in the translational efficiency of specific genes. When oxygen levels were lowered, 28% of the proteins showed at least a 2-fold change in expression. Transcription levels were sp. significantly altered for 26% of the protein changes; translational efficiency was significantly altered for 46% and a combination of both was responsible for the remaining 28%. Changes in translational efficiency were significantly correlated with the codon usage pattern of the genes and measurable tRNA pools changed in response to altered O2 levels. Our results suggest that changes in the translational efficiency of proteins, in part due to altered tRNA pools, is a major determinant of regulated alterations in protein expression levels in bacteria.


WHY PATIENTS SHOULD BE INVOLVED IN HEALTH TECHNOLOGY ASSESSMENT.
Some countries make considerable effort to involve patients and patient groups in their health technology assessment (HTA) processes; others are only just considering or are yet to consider patient involvement in HTA. This commentary offers four arguments why patient involvement should be prioritized by those HTA agencies that do not yet involve patients: (1) from a patients' rights perspective, (2) based on patient and community values, (3) centering on evidentiary contributions, and (4) from a methodological perspective. The first argument builds on the Alma-Ata Declaration, which holds that patients have a right and duty to have a say in the planning and delivery of their health care, individually and collectively. Where HTA is used to determine access to technologies and services, we argue that patients have a right to be heard. The second argues that decisions about treatments and services need to be aligned with the core values and morals of the patients whom the health system serves. The third argues that patients have unique knowledge and insights about living with a health condition and their needs for services and treatments regarding that condition, which can add to the knowledge base and value of the HTA process. The fourth argues that involvement of patients can facilitate methodological advancement of HTA, in areas such as early scientific advice and managed entry with evidence development. An HTA process that includes patient perspectives can, therefore, provide added value to patients, policy makers and healthcare professionals alike.


Neurologic outcomes in Friedreich ataxia: Study of a single-site cohort.
To investigate the pattern of progression of neurologic impairment in Friedreich ataxia (FRDA) and identify patients with fast disease progression as detected by clinical rating scales. Clinical, demographic, and genetic data were analyzed from 54 patients with FRDA included at the Brussels site of the European Friedreich's Ataxia Consortium for Translational Studies, with an average prospective follow-up of 4 years. Afferent ataxia predated other features of FRDA, followed by cerebellar ataxia and pyramidal weakness. The Scale for the Assessment and Rating of Ataxia (SARA) best detected progression in ambulatory patients and in the first 20 years of disease duration but did not effectively capture progression in advanced disease. Dysarthria, sitting, and upper limb coordination items kept worsening after loss of ambulation. Eighty percent of patients needing support to walk lost ambulation within 2 years. Age at onset had a strong influence on progression of neurologic and functional deficits, which was maximal in patients with symptom onset before age 8 years. All these patients became unable to walk by 15 years after onset, significantly earlier than patients with later onset. Progression in the previous 1 or 2 years was not predictive of progression in the subsequent year. The SARA is a sensitive outcome measure in ambulatory patients with FRDA and has an excellent correlation with functional capabilities. Ambulatory patients with onset before age 8 years showed the fastest measurable worsening. Loss of ambulation in high-risk patients is a disease milestone that should be considered as an end point in clinical trials.


Recent developments in molecular epidemiology: A study of the effects of environmental polycyclic aromatic hydrocarbons on birth outcomes in Poland.
The authors briefly review the current potential and limitations of molecular epidemiology. This approach uses biomarkers to measure the internal and bioeffective dose of toxicants, early biologic effects likely to be predictive of cancer, and variations in individual susceptibility. The most frequent application of biomarkers has been in assessment of exposure/dose and susceptibility due to genetic and nongenetic factors. More research is needed to establish the predictive significance of biomarkers in terms of disease risk. To illustrate that molecular epidemiology has potential in identifying etiologic factors in disease, this article presents data from a recent study of the developmental effects of fetal exposure to polycyclic aromatic hydrocarbons (PAH) via ambient pollution. The study was carried out in an industrialized area of Poland with relatively high levels of PAH pollution from coal burning. PAH-DNA adducts in leukocytes and plasma cotinine were measured in umbilical cord blood as dosimeters of transplacental PAH and cigarette smoke, respectively. The study subjects were 70 newborns from the industrialized city of Krakow and 90 newborns from Limanowa, a rural town with far greater use of coal for home heating. Newborns whose levels of PAH-DNA adducts were above the median (3.85/10[8] nucleotides) had a significantly decreased birth length, weight, and head circumference. Cotinine was significantly inversely associated with birth weight and length. Although preliminary, these results provide a new molecular link between PAH exposure and developmental effects, generating initial data and hypotheses for further study.


Experimental analysis of the humidification of air in bubble columns for thermal water treatment systems☆.
The humidification-dehumidification process (HDH) for desalination is a promising technology to address water scarcity issues in rural regions. However, a low humidifier efficiency is a weakness of the process. Bubble column humidifiers (BCH) are promising for HDH, as they provide enhanced heat and mass transfer and have low maintenance requirements. Previous studies of HDH-systems with BCHs draw different conclusions regarding the impact of superficial air velocity and liquid height on the humidification. Furthermore, the impact of flow characteristics has never been investigated systematically at all. In this study, an optimized BCH test setup that allows for optical analysis of the humidifier is used and evaluated. Our test setup is validated, since the influence of water temperature on the humidification, which is exponential, is reproduced. Measurements with seawater show that the normalised system productivity is increased by about 56% with an increase in superficial air velocity from 0.5 cm/s to 5 cm/s. Furthermore, the system productivity is increased by around 29% with an increase in liquid height from 60 mm to 378 mm. While the impact of superficial air velocity can be traced back to temperature changes at the humidifier and dehumidifier outlets, the impact of liquid height is shown to be caused by a smaller heat loss surface in the humidifier with an increase in liquid height. For the impact of sieve plate orifice diameter, a clear influence on the humidification is not apparent, this parameter needs to be investigated further. Finally, our new test setup allows for analysing the humidification of air (1) in a systematic way, (2) in relevant measurement ranges and (3) in comparison with optical analyses of the flow characteristics.


Paclitaxel in cancer treatment: perspectives and prospects of its delivery challenges.
Paclitaxel (PTX) is a potent anticancer agent whose clinical usefulness is marred by a delivery problem that is caused by its unfavorable pharmacokinetic and physical properties. Paclitaxel is currently formulated in a mixture of Cremophor EL and ethanol, which is diluted 5-20 times with normal saline or 5% dextrose prior to administration via slow infusion to avoid precipitation in plasma. Many adverse reactions to the PTX formulation have been reported because of the presence of Cremophor EL, including hypersensitivity reactions, nephrotoxicity, and neurotoxicity. Cremophor EL also causes vasodilation, labored breathing, lethargy, hypotension, and leaching of plasticizers, such as diethylhexylpthalate, from the polyvinylchloride infusion bags/sets. Significant research efforts have been conducted to develop an alternative formulation approach to increase the aqueous solubility of PTX without using Cremophor, thereby decreasing its toxicity. This article reviews the various investigated formulation approaches including pastes; liposomes; conjugates with antibodies, peptides, and fatty acids; nanospheres and microspheres; cyclodextrin complexes; emulsions; mucoadhesive gel; prodrugs; and nanoparticulate systems. The pros and cons of each approach are also discussed. Finally, this review concludes with a discussion of nanoparticulate delivery, which is the most promising PTX delivery system of the future because it incorporates the benefits of other approaches such as conjugation, complexation, and prodrugs.


Protective effect of isoliquiritin against corticosterone-induced neurotoxicity in PC12 cells.
Isoliquiritin, a flavonoid glycoside compound from licorice, possesses a broad spectrum of pharmacological activities including antioxidant, anti-inflammatory and anti-depression activities. However, the neuroprotective mechanisms of antidepressant effects remain unclear. In this study, the aim was to investigate the cytoprotective efficiency and potential mechanisms of isoliquiritin in corticosterone-damaged PC12 cells. The results of this study showed that pretreatment of PC12 cells with isoliquiritin significantly prevented corticosterone-induced cell apoptosis. In addition, isoliquiritin increased the activity of dismutase (SOD) and catalase (CAT), decreased the contents of reactive oxygen species (ROS) and malondialdehyde (MDA). These findings suggest that isoliquiritin provides protective action against corticosterone-induced cell damage by reducing oxidative stress. Furthermore, pretreatment with isoliquiritin reduced corticosterone-induced mitochondrial dysfunction by preventing mitochondrial membrane potential dissipation. Our findings indicate that isoliquiritin might exert its therapeutic effects via regulating mitochondrial dysfunction. Moreover, isoliquiritin strongly attenuated intracellular calcium ([Ca2+]i) overload and down-regulation of Bax, caspase-3 and cytochrome C (Cyt-C) protein expression, and up-regulation of Bcl protein expression. In conclusion, isoliquiritin has a cytoprotective effect on corticosterone-induced neurotoxicity in PC12 cells, which may be related to its antioxidant action, inhibition of [Ca2+]i overload and inhibition of the mitochondrial apoptotic pathway.


Bulk-like dielectric and magnetic properties of sub 100 nm thick single crystal Cr2O3 films on an epitaxial oxide electrode.
The manipulation of antiferromagnetic order in magnetoelectric Cr2O3 using electric field has been of great interest due to its potential in low-power electronics. The substantial leakage and low dielectric breakdown observed in twinned Cr2O3 thin films, however, hinders its development in energy efficient spintronics. To compensate, large film thicknesses (250 nm or greater) have been employed at the expense of device scalability. Recently, epitaxial V2O3 thin film electrodes have been used to eliminate twin boundaries and significantly reduce the leakage of 300 nm thick single crystal films. Here we report the electrical endurance and magnetic properties of thin (less than 100 nm) single crystal Cr2O3 films on epitaxial V2O3 buffered Al2O3 (0001) single crystal substrates. The growth of Cr2O3 on isostructural V2O3 thin film electrodes helps eliminate the existence of twin domains in Cr2O3 films, therefore significantly reducing leakage current and increasing dielectric breakdown. 60 nm thick Cr2O3 films show bulk-like resistivity (~ 1012 Ω cm) with a breakdown voltage in the range of 150-300 MV/m. Exchange bias measurements of 30 nm thick Cr2O3 display a blocking temperature of ~ 285 K while room temperature optical second harmonic generation measurements possess the symmetry consistent with bulk magnetic order.


Qualitative feasibility of using three accelerometers with 2-3-year-old children and both parents.
This study assessed mothers' opinions about the feasibility and acceptability of using the ActiGraph GT3X+, Actiheart, and activPAL3 with their 2- to 3-year-old children, as well as with themselves and their husbands/partners, for an 8-day period. Six focus groups were run with Pakistani and White British mothers (n = 17), in English or Urdu, at Children's Centers in Bradford, United Kingdom. Each accelerometer was shown to the mothers while its characteristics and wearing procedures were explained. Mothers were then asked about their opinion on the feasibility of use with their toddlers, themselves, and husbands/partners, as well as their monitor preference. Data were transcribed verbatim and analyzed through thematic analysis. The ActiGraph was the most preferred accelerometer for use with children, while the Actiheart was the least favorable. The ActiGraph was also the most preferred accelerometer for use with both mothers and fathers. Main issues raised included unsuitability of the Actiheart for fathers due to chest hair, discomfort due to the large size of the activPAL3 in relation to children's thighs, and children pulling off the Actiheart or tampering with the device if its presence was noticed (ActiGraph/Actiheart). The most preferred/accepted accelerometer overall was the ActiGraph GT3X+ for both children and parents. Issues raised with the devices have potential to impact recruitment and compliance rates of studies targeting this population, which highlights the importance of assessing the feasibility/acceptability of different devices with the target population ahead of planning research involving physical activity measurement.


Development and use of standardised data collection tools to support and inform musculoskeletal practice.
Clinicians all over the world are increasingly being faced with the need to demonstrate and account for the way in which clinical services are delivered and the quality of the delivery. It is also imperative to develop a comprehensive profile of who is accessing these services, who benefits from these services; how much these services cost in terms of clinicians time, the use of other healthcare resources and the effectiveness of interventions utilised in relation to quality outcomes. Clinicians are themselves keen to have mechanisms to identify what approaches are being utilised in their own practice setting, how they work best and how they can be improved from a professional development perspective. They are also anxious to improve their skills based on informed reflective practice and identify gaps in their knowledge and skills. This masterclass identifies how standardised data collection (SDC) tools can be utilised in practice to gather the information required in a robust, agreed and accessible way. It summarises a method of SDC tool development and gives some examples of how SDC has been implemented in physiotherapy National Health Services and in physiotherapy private practice in the United Kingdom. The global relevance is that increasingly all physiotherapy services are being held and will be accountable for the quality and equity of care. In addition clinicians can find it useful to have benchmarks with which to compare their own and their departmental performance in terms of clinical activities and outcomes.


The persistence of child and adolescence mental healthcare: results from registry data.
Previous studies on the persistence of child and adolescent mental healthcare do not consider the role of time-invariant individual characteristics. Estimating persistence of healthcare using standard linear models yields biased estimates due to unobserved heterogeneity and the autoregressive structure of the model. This study provides estimates of the persistence of child and adolescent mental healthcare taking these statistical issues into account. We use registry data of more than 80,000 Dutch children and adolescents between 2000 and 2012 from the Psychiatric Case Registry Northern Netherlands (PCR-NN). In order to account for autocorrelation due to the presence of a lagged dependent variable and to distinguish between persistence caused by time-invariant individual characteristics and a direct care effect we use difference GMM-IV estimation. In further analyses we assess the robustness of our results to policy reforms, different definitions of care and diagnosis decomposition. All estimation results for the direct care effect (true state-dependence) show a positive coefficient smaller than unity with a main effect of 0.215 (p<0.01), which indicates that the process is stable. Persistence of care is found to be 0.065 (p<0.05) higher for females. Additionally, the majority of persistence of care appears to be associated with time-invariant characteristics. Further analyses indicate that (1) results are robust to different definitions of care and (2) persistence of care does not differ significantly across subgroups. The results indicate that the majority of mental healthcare persistence for children and adolescents is due to time-invariant individuals characteristics. Additionally, we find that in the absence of further shocks a sudden increase of 10 care contacts in the present year is associated with an average of less than 3 additional care contacts at some point in the future. This result provides essential information about the necessity of budget increases for future years in the case of exogenous increases in healthcare use.


Elucidating the formation of 6-deoxyheptose: biochemical characterization of the GDP-D-glycero-d-manno-heptose C6 dehydratase, DmhA, and its associated C4 reductase, DmhB.
6-Deoxyheptose is found within the surface polysaccharides of several bacterial pathogens. In Yersinia pseudotuberculosis, it is important for the barrier function of the O-antigen in vitro and for bacterial dissemination in vivo. The putative C6 dehydratase DmhA and C4 reductase DmhB, that were identified as responsible for 6-deoxyheptose synthesis based on genetics data, represent potential therapeutical targets. Their detailed biochemical characterization is presented herein. The substrate, GDP-D-glycero-D-manno-heptose, was synthesized enzymatically from sedoheptulose 7-phosphate using overexpressed and purified GmhA/B/C/D enzymes from Aneurinibacillus thermoaerophilus. Overexpressed and purified DmhA used this substrate with high efficiency, as indicated by its K(m) of 0.23 mM and k(cat) of 1.1 s(-1). The mass spectrometry (MS) analysis of the reaction product was consistent with a C6 dehydration reaction. DmhB could readily reduce this compound in the presence of NAD(P)H to produce GDP-6-deoxy-D-manno-heptose, as indicated by MS and NMR analyses. DmhA also used GDP-mannose as a substrate with a K(m) of 0.32 mM and a k(cat) of 0.25 min(-1). This kinetic analysis indicates that although the K(m) values for GDP-mannose and GDP-manno-heptose were similar, the genuine substrate for DmhA is GDP-manno-heptose. DmhB was also able to reduce the GDP-4-keto-6-deoxymannose produced by DmhA, although with poor efficiency and exclusively in the presence of NADPH. This study is the first complete biochemical characterization of the 6-deoxyheptose biosynthesis pathway. Also, it allows the screening for inhibitors, the elucidation of substrate specificity determinants, and the synthesis of carbohydrate antigens of therapeutic relevance.


Infectious diseases in the elderly.
As the percent of our population over age 65 increases, infectious disease in this group is becoming a serious public health concern. Much of our knowledge of infections in the elderly is based on clinical experience and lacks a firm scientific foundation. The increased risk of infections observed with aging may be due to physiologic changes that accompany "normal" aging or the age-associated chronic diseases and the medical, surgical, and diagnostic interventions that accompany them. Epidemiologic studies on populations of well and hospitalized older persons in defined age ranges are needed to examine the relation between specific infectious diseases and risk factors. Although the increased susceptibility of older persons to infectious diseases frequently has been attributed to the decline in immune function that occurs with aging, there are very few data confirming this hypothesis. Additional research is clearly needed on other contributory factors such as nutrition, ciliary transport, bacterial adherence, neutrophil and macrophage function, and complement.


Next of kin's motives for psychosocial consultation-Oncology social workers' perceptions of 54 next of kin cases.
Although oncology social workers (OSWs) have emerged as a core profession in the provision of psychosocial services, there is a lack of empirical studies that describe their daily clinical work with next of kin (NOK). The overall aim of this study was to explore NOK's motives for consulting an OSW. This can provide us with insights into what types of skills OSWs need to have in order to fulfil their duties. From a nationwide survey, we used data from 54 NOK cases that Swedish OSWs met face to face. About half of the motives concerned help in dealing with personal grief connected to the patients' cancer and distressing symptoms, while the other half concerned needs for help in dealing with the position of being the NOK, relationship conflicts, and assistance with socio-economic issues. The motives show that NOK does not just ask for help to come to terms with distress related to the patient's situation. Based on the diversity of motives, we suggest that OSWs (at least in Sweden) need a broad education in counselling psychology. Furthermore, health care personnel need to be attentive to the NOK's own voice and not reduce it to the voice of the patient and the patient's needs in referrals.


Advances in protein turnover analysis at the global level and biological insights.
The concept of a dynamic state of body constituents, a precursor of the modern term of proteome dynamics, was conceived over a century ago. But, not until recently can we examine the dynamics of individual "constituents" for example, proteins at a truly global level. The path of advancement in our understanding of protein turnover at the global level is marked by the introduction of some key technological innovations. These methods include the isotopic tracer technique in the 1930s, the two-dimensional gel electrophoresis technique in the 1970s, the sector mass spectrometer that could analyze isotopomers of peptides in the early 1990s, the 2D gel/MALDI-TOF proteomics technology in the late 1990s, the booming liquid chromatography/mass spectrometry proteomics technology in this decade, and the recently emerging protein-tagging approaches that offer single-cell resolution for protein turnover measurements. The long-standing inquiry raised in the 1950s about the existence of a dynamic state in different organisms at different physiological conditions can now be answered with an individual "constituent" resolution on a truly global scale. Now it appears that protein degradation is not necessarily an end to the protein function. Rather, it can be the start of a new function because protein degradation clears the way for the action of other proteins. Protein turnover participates in a multi-layer complex regulatory network and shares equal importance with gene transcription and protein translation. The advances in technologies for protein turnover analysis and the improved understanding of the biological role of protein turnover will likely help to solve some long-standing biomedical problems such as the tuberculosis disease that at the present day still affects one-third of the world population.


Correlation between histone lysine methylation and developmental changes at the chicken beta-globin locus.
Methylation of histones at specific residues plays an important role in transcriptional regulation. Chromatin immunoprecipitation of dimethylated lysine 9 on histone H3 across 53 kilobases of the chicken beta-globin locus during erythropoiesis shows an almost complete anticorrelation between regions of elevated lysine 9 methylation and acetylation. Lysine 9 is methylated most over constitutive condensed chromatin and developmentally inactive globin genes. In contrast, lysine 4 methylation of histone H3 correlates with H3 acetylation. These results lead us to propose a mechanism by which the insulator in the beta-globin locus can protect the globin genes from being silenced by adjacent condensed chromatin.


Rho regulates membrane transport in the endocytic pathway to control plasma membrane specialization in oligodendroglial cells.
Differentiation of oligodendrocytes is associated with dramatic changes in plasma membrane structure, culminating in the formation of myelin membrane sheaths. Previous results have provided evidence that regulation of endocytosis may represent a mechanism to control myelin membrane growth. Immature oligodendrocytes have a high rate of clathrin-independent endocytosis for the transport of membrane to late endosomes/lysosomes (LE/Ls). After maturation and receiving signals from neurons, endocytosis is reduced and transport of membrane from LE/Ls to the plasma membrane is triggered. Here, we show that changes in Rho GTPase activity are responsible for switching between these two modes of membrane transport. Strikingly, Rho inactivation did not only reduce the transport of cargo to LE/L but also increased the dynamics of LE/L vesicles. Furthermore, we provide evidence that Rho inactivation results in the condensation of the plasma membrane in a polarized manner. In summary, our data reveal a novel role of Rho: to regulate the flow of membrane and to promote changes in cell surface structure and polarity in oligodendroglial cells. We suggest that Rho inactivation is required to trigger plasma membrane specialization in oligodendrocytes.


A portable image-based cytometer for rapid malaria detection and quantification.
Increasing resistance by malaria parasites to currently used antimalarials across the developing world warrants timely detection and classification so that appropriate drug combinations can be administered before clinical complications arise. However, this is often challenged by low levels of infection (referred to as parasitemia) and presence of predominantly young parasitic forms in the patients' peripheral blood. Herein, we developed a simple, inexpensive and portable image-based cytometer that detects and numerically counts Plasmodium falciparum infected red blood cells (iRBCs) from Giemsa-stained smears derived from infected blood. Our cytometer is able to classify all parasitic subpopulations by quantifying the area occupied by the parasites within iRBCs, with high specificity, sensitivity and negligible false positives (~ 0.0025%). Moreover, we demonstrate the application of our image-based cytometer in testing anti-malarial efficacy against a commercial flow cytometer and demonstrate comparable results between the two methods. Collectively, these results highlight the possibility to use our image-based cytometer as a cheap, rapid and accurate alternative for antimalarial testing without compromising on efficiency and minimal processing time. With appropriate filters applied into the algorithm, to rule out leukocytes and reticulocytes, our cytometer may also be used for field diagnosis of malaria.


The expanding role of primary care in cancer control.
The nature of cancer control is changing, with an increasing emphasis, fuelled by public and political demand, on prevention, early diagnosis, and patient experience during and after treatment. At the same time, primary care is increasingly promoted, by governments and health funders worldwide, as the preferred setting for most health care for reasons of increasing need, to stabilise health-care costs, and to accommodate patient preference for care close to home. It is timely, then, to consider how this expanding role for primary care can work for cancer control, which has long been dominated by highly technical interventions centred on treatment, and in which the contribution of primary care has been largely perceived as marginal. In this Commission, expert opinion from primary care and public health professionals with academic and clinical cancer expertise—from epidemiologists, psychologists, policy makers, and cancer specialists—has contributed to a detailed consideration of the evidence for cancer control provided in primary care and community care settings. Ranging from primary prevention to end-of-life care, the scope for new models of care is explored, and the actions needed to effect change are outlined. The strengths of primary care—its continuous, coordinated, and comprehensive care for individuals and families—are particularly evident in prevention and diagnosis, in shared follow-up and survivorship care, and in end-of-life care. A strong theme of integration of care runs throughout, and its elements (clinical, vertical, and functional) and the tools needed for integrated working are described in detail. All of this change, as it evolves, will need to be underpinned by new research and by continuing and shared multiprofessional development.


Phase separation in symmetric mixtures of oppositely charged rodlike polyelectrolytes.
Phase separation in salt-free symmetric mixtures of oppositely charged rodlike polyelectrolytes is studied using quasi-analytical calculations. Stability analyses for the isotropic-isotropic and the isotropic-nematic phase transitions in the mixtures are carried out and demonstrate that electrostatic interactions favor nematic ordering. Coexistence curves for the symmetric mixtures are also constructed and are used to examine the effects of linear charge density and electrostatic interaction strength on rodlike polyelectrolyte complexation. It is found that the counterions are uniformly distributed in the coexisting phases for low electrostatic interaction strengths dictated by the linear charge density of the polyelectrolytes and Bjerrum's length. However, the counterions also partition along with the rodlike polyelectrolytes with an increase in the electrostatic interaction strength. It is shown that the number density of the counterions is higher in the concentrated (or "coacervate") phase than in the dilute (or supernatant) phase. In contrast to such rodlike mixtures, flexible polyelectrolyte mixtures can undergo only isotropic-isotropic phase separation. A comparison of the coexistence curves for weakly charged rodlike mixtures with those of analogous flexible polyelectrolyte mixtures reveals that the electrostatic driving force for the isotropic-isotropic phase separation is stronger in the flexible mixtures.


Synchronization and desynchronization in epilepsy: controversies and hypotheses.
Epilepsy has been historically seen as a functional brain disorder associated with excessive synchronization of large neuronal populations leading to a hypersynchronous state. Recent evidence showed that epileptiform phenomena, particularly seizures, result from complex interactions between neuronal networks characterized by heterogeneity of neuronal firing and dynamical evolution of synchronization. Desynchronization is often observed preceding seizures or during their early stages; in contrast, high levels of synchronization observed towards the end of seizures may facilitate termination. In this review we discuss cellular and network mechanisms responsible for such complex changes in synchronization. Recent work has identified cell-type-specific inhibitory and excitatory interactions, the dichotomy between neuronal firing and the non-local measurement of local field potentials distant to that firing, and the reflection of the neuronal dark matter problem in non-firing neurons active in seizures. These recent advances have challenged long-established views and are leading to a more rigorous and realistic understanding of the pathophysiology of epilepsy.


Plasmid-amplified comS enhances genetic competence and suppresses sinR in Bacillus subtilis.
The establishment of genetic competence in Bacillus subtilis is controlled by a vast signal transduction network involving the products of genes that function in several postexponential-phase processes. Two of these proteins, SinR and DegU, serve as molecular switches that influence a cell's decision to undergo either sporulation or genetic competence development. In order to determine the roles of SinR and DegU in competence control, multicopy suppression experiments with plasmid-amplified comS, SinR, and degU genes were undertaken. Multicopy comS was found to elevate competence gene transcription and transformation efficiency in both wild-type and sinR mutant cells but not in degU mutant cells. Multicopy degU failed to suppress comS or sinR mutations. No suppression of comS or degU by multicopy sinR was observed. The expression of a comS'::'lacZ translational fusion and srf-lacZ operon fusion was examined in sinR cells and cells bearing plasmid-amplified sinR. The expression of comS'::'lacZ gene fusion was reduced by the sinR mutation, but both comS'::'lacZ and srf-lacZ were repressed by multicopy sinR. Cells bearing plasmid-amplified sinR were poorly competent. These results suggest that sinR is required for optimal comS expression but not transcription from the srf promoter and that SinR at high concentrations represses srf transcription initiation.


Re-assessing the contribution of serum total cholesterol, blood pressure and cigarette smoking to the aetiology of coronary heart disease: impact of regression dilution bias.
To estimate the combined contribution of serum total cholesterol, blood pressure and cigarette smoking to coronary heart disease (CHD) risk after adjustment for regression dilution bias. Six thousand, five hundred and thirteen middle-aged British men without CHD were followed for major CHD events over 10 years. The population attributable risk fraction (PARF) was predicted for a range of risk factor thresholds before and after adjustment for regression dilution of serum total cholesterol and blood pressure. Defining 'low-risk' individuals as being in the bottom tenth of the population distributions of serum total cholesterol (<5.2 mmol/l) and diastolic blood pressure (<70 mmHg) and a non-cigarette smoker, the PARF was 75%, increasing to 86% after adjustment for regression dilution. Regardless of the threshold criteria chosen, the PARF was substantially greater than 65% before adjustment for regression dilution and greater than 75% after adjustment. Exclusion of ex-smokers and passive smokers from the low-risk group increased estimates further. Adjustment for other coronary risk factors had little effect on the results. At least 80% of major CHD events in middle-aged men can be attributed to the three strongest risk factors. Population-wide control of these factors is crucial for effective CHD prevention.


Mapping and expression of genes associated with raspberry fruit ripening and softening.
QTL mapping identifies a range of underlying and unrelated genes with apparent roles in raspberry fruit ripening and softening that show characteristic developing fruit expression profiles. Fruit softening is an important agronomical trait that involves a complex interaction of plant cell processes. We have used both qualitative and quantitative scoring of fruit firmness, length, mass, and resistance to applied force to identify QTL in a raspberry mapping population. QTLs were located primarily on linkage group (LG) 3 with other significant loci on LG 1 and LG 5 and showed mostly additive effects between the two parents. The expression of key genes that underlie these QTLs with roles in cell-wall solubility, water uptake, polyamine synthesis, transcription, and cell respiration was tested across five stages of fruit development, from immature green to red ripe fruit, using real-time RT-qPCR. Gene expression patterns showed variable expression patterns across fruit development with a highly significant positive and negative correlation between genes, supporting precise regulation of expression of different cell processes throughout raspberry fruit development. Variable timing in expression was also found in some genes at different fruit development stages between soft and firm cultivars. Multiple processes have a role to play in fruit softening and this will require development of multiple marker combinations to genes that characterise raspberry fruit softening.


Cost-effectiveness of exercise referral schemes: a systematic review of health economic studies.
This systematic review aimed to provide an overview of the existing literature on cost-effectiveness of exercise referral schemes (ERSs). A systematic search was performed in MEDLINE, EMBASE, EconLit, Web of Science and PsycINFO. Main inclusion criteria were: (1) insufficiently active people; (2) ERSs and (3) full health economic evaluations. No publication year limits were applied. The methodological quality was assessed independently by two reviewers using the Consensus Health Economic Criteria (CHEC) checklist. Fifteen eligible publications were retrieved, presenting results of 12 different studies. Compared with usual care, ERSs were found to be cost-effective in a majority of the analyses, but with modest health gains and costs per individual. These cost-effectiveness results were also sensitive to small changes in input parameters. Two studies found that ERSs combined with a pedometer/accelerometer are cost-effective, compared with usual ERS practice. Two other studies found that an ERS with phone support and an ERS with face-to-face support might be equally effective, with similar costs. Although the literature demonstrated that ERSs could be cost-effective compared with usual care, these results were not robust. Based on a small number of studies, ERSs could be optimized by using tracking devices, or by providing a choice to the participants about the delivery mode. There is need for clarity on the effectiveness of and attendance to ERS, as more certainty about these key input parameters will strengthen health-economic evidence, and thus will allow to provide a clearer message to health policy-makers.


Use of corticosteriods in the prevention of post-ERCP pancreatitis: results of a controlled prospective study.
The aim of this prospective controlled study was to determine whether prophylactic corticosteroids decrease the incidence of post-ERCP pancreatitis. A double-blind comparison of hydrocortisone (100 mg by i.v. infusion immediately before endoscopy) with placebo (sodium chloride administered in the same fashion). A total of 535 patients (286 women and 249 men, with an average age of 58.6 yr) who were scheduled to undergo diagnostic or operative ERCP underwent randomization. Six patients were excluded from the final evaluation for various reasons. The remaining 529 patients, 263 in the hydrocortisone group and 266 in the placebo group, were analyzed. Patients were divided into subgroups with regard to high risk factors for acute pancreatitis after ERCP. The overall incidence of acute pancreatitis was 5.3% (28 of 529 patients). Procedure-induced pancreatitis occurred in 15 of 263 (5.7%) patients treated with hydrocortisone and in 13 of 266 (4.9%) patients treated with placebo (p = NS). The results of analysis of risk factors for pancreatitis did not evidence any significant difference between the hydrocortisone group and the placebo group. Hydrocortisone does not prevent acute pancreatitis after diagnostic or therapeutic ERCP.


A View From the UK: The UK and Ireland Confidential Enquiry into Maternal Deaths and Morbidity.
The UK Confidential Enquiry into Maternal Deaths has been in operation for more than 60 years, during which time maternal mortality rates have fallen 10-fold. The program includes two aspects, surveillance and confidential case review, providing different information to aid quality improvement in maternity care. The enquiry now also reviews the care of women with specific severe morbidities. Recommendations have very clearly led to improved outcomes for women, most notably shown in the very low mortality rate due to hypertensive and related disorders of pregnancy. Maternal cardiac disease and mental health problems remain the major areas still to be addressed.


Photonic analog of Zitterbewegung in binary waveguide arrays.
An optical analog of Zitterbewegung (ZB), i.e., of the trembling motion of Dirac electrons caused by the interference between positive and negative energy states, is proposed for spatial beam propagation in binary waveguide arrays. In this optical system the ZB is simply observable as a quiver spatial oscillatory motion of the beam center of mass around its mean trajectory.