Predictive clinical features and outcomes of vitrectomy for proliferative diabetic retinopathy.
To study the preoperative characteristics, complications and outcomes of vitrectomy for proliferative diabetic retinopathy and to identify any factors that may predict visual outcome. Prospective study of 174 consecutive vitrectomies in 148 patients, with a minimum follow-up of 4 months. 41 (27.7%) patients had a vision of <6/60 in their better eye at presentation. Posterior retinal breaks occurred in 47 (27.0%) eyes. Postoperative complications included vitreous cavity haemorrhage in 37 (22.0%) eyes, retinal detachment in five eyes (3.0%), and rubeotic glaucoma in five eyes (3.0%). 124 (74.7%) eyes improved by at least 0.3 LogMAR units, and 15 (9.0%) worsened by at least 0.3 LogMAR units. 119 (71.7%) eyes had a visual acuity of 6/60 or better, and 27 (16.3%) were counting fingers or worse. Only 16 (11.1%) patients had a vision of <6/60 in both eyes at latest follow-up. Preoperative vision in both the operated eye and the contralateral eye, macular detachment, and long-acting intraocular tamponade were independent predictors of poor postoperative vision, but this model accounted for only a small proportion of the observed variation in outcomes. Major complications are rare after vitrectomy for proliferative diabetic retinopathy, and >70% of eyes will regain vision of 6/60 or better. Visual outcomes remain unpredictable.


Phase III study of interstitial thermoradiotherapy compared with interstitial radiotherapy alone in the treatment of recurrent or persistent human tumors. A prospectively controlled randomized study by the Radiation Therapy Group.
The objectives of this randomized trial were to determine if interstitial thermoradiotherapy (ITRT) improves tumor regression/control in accessible lesions in comparison with interstitial radiotherapy (IRT) alone and to assess the skin and soft tissue complications with either modality. From January 1986 to June 1992, 184 patients with persistent or recurrent tumors after previous radiotherapy and/or surgery, which were amenable to interstitial radiotherapy, were accessioned to a protocol developed by the Radiation Therapy Oncology Group (RTOG). One hundred seventy-three cases were analyzed (87 patients in the IRT group and 86 in the ITRT arm). The two arms were well balanced regarding stratification criteria. Most tumors were in the head and neck (40% in the IRT group and 46% in the ITRT group), and pelvis (42% and 43%, respectively). Eighty-four percent of patients in both arms had prior radiation therapy (> or = 40 Gy); 50% and 40%, respectively, had prior surgery, and 34% in each arm had prior chemotherapy. The dose of radiation therapy administered was dependent on the previous radiation dose and did not exceed a total cumulative dose of 100 Gy. Hyperthermia was delivered in one or two sessions, either before or before and after interstitial implant. The intended goal of the hyperthermia was to maintain a minimal tumor temperature of 42.5 degrees C for 30 to 60 min. There was no difference in any of the study end points between the two arms. Complete response (CR) was 53% and 55% in both arms. Two-year survival was 34% and 35%, respectively. Complete response rate for persistent lesions was 69% and 63% in the two treatment arms as compared with 40% and 48% for recurrent lesions. A set of minimal adequacy criteria for the delivery of hyperthermia was developed. When these criteria were applied, only one patient had an adequate hyperthermia session. Acute Grade 3 and 4 toxicities were 12% for IRT and 22 % for ITRT. Late Grade 3 and 4 toxicities were 15% for IRT and 20% for ITRT. The difference was not significant. Interstitial hyperthermia, as applied in this randomized study, did not show any additional beneficial effects over interstitial radiotherapy alone. Delivery of hyperthermia remains a major obstacle (since only one patient met the basic minimum adequacy criteria as defined in this study). The benefit of hyperthermia in addition to radiation therapy still remains to be proven in properly randomized prospective clinical trials after substantial technical improvements in heat delivery and dosimetry are achieved.


A naturalistic comparison of the effectiveness of methadone and two sublingual formulations of buprenorphine on maintenance treatment outcomes: findings from a retrospective multisite study.
This study sought to compare the effectiveness of the 3 most commonly prescribed maintenance medications in the United States indicated for the treatment of opioid dependence in reducing illicit drug use and retaining patients in treatment. Data were abstracted from electronic medical records for 3,233 patients admitted to 34 maintenance treatment facilities located throughout the United States during the period of July 1, 2012, through July 1, 2013. Patients were grouped into 1 of 3 medication categories based on their selection at intake (methadone [n = 2,738; M dosage = 64.64 mg/d, SD = 25.58], Suboxone [n = 102; M dosage = 9.75 mg/d, SD = 4.04], or Subutex [n = 393; M dosage = 12.21 mg/d, SD = 5.31]) and were studied through retrospective chart review for 6 months or until treatment discharge. Two measures of patient retention in treatment and urinalysis drug screen (UDS) findings for both opioids and various nonopioid substances comprised the study outcomes. The average length of stay (LOS) in terms of days in treatment for the methadone group (M = 169.86, SE = 5.02) was significantly longer than both the Subutex (M = 69.34, SE = 23.43) and Suboxone (M = 119.35, SE = 20.82) groups. The Suboxone group evinced a significantly longer average LOS relative to the Subutex group. After adjustment for relevant covariates, patients maintained on methadone were 3.73 times (95% confidence interval [CI]= 2.82-4.92) and 2.48 times (95% CI = 1.57-3.92) more likely to be retained in treatment at 6 months than patients prescribed Subutex and Suboxone, respectively. The 6-month prevalence rates of positive UDS findings for both opioids and nonopioid substances were similar across medication groups. Comparable rates of illicit drug use at 6 months may be expected irrespective of maintenance medication, while increased retention may be expected for patients maintained on methadone relative to those maintained on Suboxone or Subutex.


The shf gene of a Shigella flexneri homologue on the virulent plasmid pAA2 of enteroaggregative Escherichia coli 042 is required for firm biofilm formation.
Enteroaggregative Escherichia coli (EAEC) is an increasingly important cause of diarrhea in both developing and industrialized countries, and is characterized by strong biofilm formation on the intestinal mucosa. Sequencing of the virulent plasmid pAA2 of the prototype EAEC 042 revealed a cluster of three open reading frames (ORFs; shf, capU, and virK) ca. 93% identical to a similar cluster located in Shigella flexneri. The function of the first ORF Shf protein is not known, but the closest well-characterized homologue is the IcaB protein of Staphylococcus epidermidis, which plays a crucial role in exopolysaccharide modification in bacterial biofilm formation. To investigate the role of this cluster in the virulence of EAEC, we mutated three genes at this locus. All the mutants maintained the aggregative phenotype in the liquid phase. However, the insertional mutant of shf formed a less abundant biofilm in a microtiter plate assay than did the wild type, while the capU mutant and the virK mutant did not. The complementation of the shf mutant with this cluster restored the thick biofilm similar to that of the wild type. The shf transcriptional level decreased in the transcriptional regulator aggR mutant and was restored when the mutant was complemented with aggR. These results suggest that the shf gene is required for the firm biofilm formation of EAEC 042, and transcription of the shf gene is dependent on AggR.


Efficiency Optimization of CRISPR/Cas9-Mediated Targeted Mutagenesis in Grape.
Clustered regularly interspersed short palindromic repeats (CRISPR)/Cas system is an efficient targeted genome editing method. Although CRISPR/Cas9-mediated mutagenesis has been applied successfully in grape, few studies have examined the technique's efficiency. To optimize CRISPR/Cas9 editing efficiency in Vitis vinifera, we surveyed three key parameters: GC content of single guide RNA (sgRNA), variety of transformant cells used, and SpCas9 expression levels in transgenic cell mass. Four sgRNAs with differing GC content were designed to target exon sites of the V. vinifera phytoene desaturase gene. Suspension cells of 'Chardonnay' and '41B' varieties were used as the transgenic cell mass. Both T7EI and PCR/RE assays showed that CRISPR/Cas9 editing efficiency increases proportionally with sgRNA GC content with 65% GC content yielding highest editing efficiency in both varieties. Additionally, gene editing was more efficient in '41B' than in 'Chardonnay.' CRISPR/Cas9 systems with different editing efficiency showed different SpCas9 expression level, but compared with GC content of sgRNA, SpCas9 expression level has less influence on editing efficiency. Taken together, these results help optimize of CRISPR/Cas9 performance in grape.


Plasma flow reactor for steady state monitoring of physical and chemical processes at high temperatures.
We present the development of a steady state plasma flow reactor to investigate gas phase physical and chemical processes that occur at high temperature (1000 < T < 5000 K) and atmospheric pressure. The reactor consists of a glass tube that is attached to an inductively coupled argon plasma generator via an adaptor (ring flow injector). We have modeled the system using computational fluid dynamics simulations that are bounded by measured temperatures. In situ line-of-sight optical emission and absorption spectroscopy have been used to determine the structures and concentrations of molecules formed during rapid cooling of reactants after they pass through the plasma. Emission spectroscopy also enables us to determine the temperatures at which these dynamic processes occur. A sample collection probe inserted from the open end of the reactor is used to collect condensed materials and analyze them ex situ using electron microscopy. The preliminary results of two separate investigations involving the condensation of metal oxides and chemical kinetics of high-temperature gas reactions are discussed.


Cross-cultural adaptation and validation with reliability, validity, and responsiveness of the Italian version of the Oxford Hip Score in patients with hip osteoarthritis.
The purpose of this study was to translate the Oxford Hip Score (OHS) into Italian and to evaluate the psychometric properties by testing the feasibility, internal consistency, reproducibility, construct validity, and responsiveness in patients with hip osteoarthritis (OA). The OHS Italian version was developed and evaluated in Italian-speaking patients with hip OA. The psychometric properties assessed were feasibility with floor and ceiling effect; internal consistency with Cronbach's Alpha; reproducibility with intraclass correlation coefficient (ICC); construct validity with evaluating correlation with the SF-36 and visual analogue scale (VAS) for pain; responsiveness to intra-articular hyaluronate injections. The standardized effect size (ES) and standardized response mean (SRM) were also evaluated. A total of 96 patients were recruited (mean age 62.7 ± 5.8 years, range 49-77). No floor or ceiling effect was observed prior to or after treatment with HA injections. Cronbach's alpha value was 0.85 at baseline and 0.89 after treatment. The reproducibility was good with an ICC of 0.89. A strong correlation was found between OHS, VAS, and some SF-36 subscales, indicating good cross-sectional and longitudinal construct validity. The mean OHS improved from 16.4 ± 5.8 to 28.0 ± 9.0 after hyaluronate injections (P < 0.01). The ES and SRM values were 1.98 and 1.12, respectively. The Italian OHS questionnaire is valid, reliable, and responsive for use in Italian patients with symptomatic hip OA receiving hyaluronate injections.


Depression and diabetes.
The comorbidity of mental and physical disorders is a major challenge for health care worldwide. Its prevalence is increasing and is likely to continue to grow due to the increase in life expectancy and a variety of other reasons. The comorbidity of depression and diabetes can be seen as a prototypical example of mental/physical comorbidity. The prevalence of both conditions is growing, and depression is twice as frequent in people with diabetes compared with those without diabetes. Health services are by and large inadequately prepared to deal with comorbid depression and diabetes, and the increasing specialization (and fragmentation) of medicine will probably make things worse. This paper reviews the epidemiology and risk factors of the comorbidity of depression and diabetes and describes areas that should be given attention in order to reduce problems arising as a result of the comorbidity of these two conditions.


Beta-thalassaemia/haemoglobin E tissue ferritins. II: A comparison of heart and pancreas ferritins with those of liver and spleen.
Tissue ferritins from beta-thalassaemia/haemoglobin E heart and pancreas were characterized by native PAGE, SDS/PAGE and isoelectric focussing, and compared with those isolated from corresponding liver and spleen tissue. On PAGE, all ferritins consisted of a single band assigned to the protein monomer. Small differences in electrophoretic mobility were found between the bands. The ferritins were resolved by SDS/PAGE into two major subunits, H and L, corresponding to molecular masses of 22.5 kDa and 19 kDa, respectively. The L subunit was predominant in all cases. The isoferritin profiles of all tissue ferritins were remarkably similar, consisting of a complex pattern of bands which were appreciably more basic than those obtained for horse spleen ferritin. The subunit composition and isoferritin profiles of the four tissue ferritins almost certainly reflect the defense mechanism of the body in synthesizing in all four tissue types a more stable long-term iron-storage isoferritin in order to detoxify and store the excess iron present due to the pathological condition of beta-thalassaemia/HbE.


The 'patient's physician one-step removed': the evolving roles of medical tourism facilitators.
Medical tourism involves patients travelling internationally to receive medical services. This practice raises a range of ethical issues, including potential harms to the patient's home and destination country and risks to the patient's own health. Medical tourists often engage the services of a facilitator who may book travel and accommodation and link the patient with a hospital abroad. Facilitators have the potential to exacerbate or mitigate the ethical concerns associated with medical tourism, but their roles are poorly understood. 12 facilitators were interviewed from 10 Canadian medical tourism companies. Three themes were identified: facilitators' roles towards the patient, health system and medical tourism industry. Facilitators' roles towards the patient were typically described in terms of advocacy and the provision of information, but limited by facilitators' legal liability. Facilitators felt they played a positive role in the lives of their patients and the Canadian health system and served as catalysts for reform, although they noted an adversarial relationship with some Canadian physicians. Many facilitators described personally visiting medical tourism sites and forming personal relationships with surgeons abroad, but noted the need for greater regulation of their industry. Facilitators play a substantial and evolving role in the practice of medical tourism and may be entering a period of professionalisation. Because of the key role of facilitators in determining the effects of medical tourism on patients and public health, this paper recommends a planned conversation between medical tourism stakeholders to define and shape facilitators' roles.


Protease activity in the larval stage of the parasitoid wasp, Eulophus pennicornis (Nees) (Hymenoptera: Eulophidae); effects of protease inhibitors.
Hymenopteran, parasitoid wasps have good potential for use in integrated pest management (IPM); for example, the gregarious ectoparasitoid, Eulophus pennicornis, has been suggested as a biological control agent for larvae of the tomato moth (Lacanobia oleracea L.). However, the processes by which such parasitic larvae are able to utilize the nutritional resource provided by the host have been little studied. Protease activity was present in E. pennicornis larvae, and characterization of the enzymes responsible for proteolysis was performed using a range of synthetic substrates and specific inhibitors. Serine protease enzymes was both trypsin- and chymotrypsin-like activities were present. A range of plant-derived serine protease inhibitors was tested for activity against these enzymes. Certain inhibitors, notably soybean Kunitz inhibitor (SKTI), inhibited enzyme activity by > 80% at < 10(-5) M. When SKTI was fed to L. oleracea larvae in an artificial diet, the inhibitor was subsequently detected within the larval haemolymph, showing that protease inhibitors in the host diet can be delivered to a parasitoid via the host haemolymph. If transgenic plants expressing foreign protease inhibitors for protection against insect pests are to form a component of IPM systems, possible adverse effects, whether direct or indirect, of transgene expression on parasitoids like E. pennicornis should be considered.


Comprehensive genomic analysis reveals virulence factors and antibiotic resistance genes in Pantoea agglomerans KM1, a potential opportunistic pathogen.
Pantoea agglomerans is a Gram-negative facultative anaerobic bacillus causing a wide range of opportunistic infections in humans including septicemia, pneumonia, septic arthritis, wound infections and meningitis. To date, the determinants of virulence, antibiotic resistance, metabolic features conferring survival and host-associated pathogenic potential of this bacterium remain largely underexplored. In this study, we sequenced and assembled the whole-genome of P. agglomerans KM1 isolated from kimchi in South Korea. The genome contained one circular chromosome of 4,039,945 bp, 3 mega plasmids, and 2 prophages. The phage-derived genes encoded integrase, lysozyme and terminase. Six CRISPR loci were identified within the bacterial chromosome. Further in-depth analysis showed that the genome contained 13 antibiotic resistance genes conferring resistance to clinically important antibiotics such as penicillin G, bacitracin, rifampicin, vancomycin, and fosfomycin. Genes involved in adaptations to environmental stress were also identified which included factors providing resistance to osmotic lysis, oxidative stress, as well as heat and cold shock. The genomic analysis of virulence factors led to identification of a type VI secretion system, hemolysin, filamentous hemagglutinin, and genes involved in iron uptake and sequestration. Finally, the data provided here show that, the KM1 isolate exerted strong immunostimulatory properties on RAW 264.7 macrophages in vitro. Stimulated cells produced Nitric Oxide (NO) and pro-inflammatory cytokines TNF-α, IL-6 and the anti-inflammatory cytokine IL-10. The upstream signaling for production of TNF-α, IL-6, IL-10, and NO depended on TLR4 and TLR1/2. While production of TNF-α, IL-6 and NO involved solely activation of the NF-κB, IL-10 secretion was largely dependent on NF-κB and to a lesser extent on MAPK Kinases. Taken together, the analysis of the whole-genome and immunostimulatory properties provided in-depth characterization of the P. agglomerans KM1 isolate shedding a new light on determinants of virulence that drive its interactions with the environment, other microorganisms and eukaryotic hosts.


Differentiation of human primary testicular cells in the presence of SCF using the organoid culture system.
Development of organoids using human primary testicular cells has remained a challenge due to the complexity of the mammalian testicular cytoarchitecture and culture methods. In this study, we generated testicular organoids derived from human primary testicular cells. Then, we evaluated the effect of stem cell factor (SCF) on cell differentiation and apoptosis in the testicular organoid model. The testicular cells were harvested from the three brain-dead donors. Human spermatogonial stem cells (SSCs) were characterized using immunocytochemistry (ICC), RT-PCR and flow cytometry. Testicular organoids were generated from primary testicular cells by hanging drop culture method and were cultured in three groups: control group, experimental group 1 (treated FSH and retinoic acid (RA)), and experimental group 2 (treated FSH, RA and SCF), for five weeks. We assessed the expression of SCP3 (Synaptonemal Complex Protein 3) as a meiotic gene, PRM2 (Protamine 2) as a post-meiotic marker and apoptotic genes of Bax (BCL2-Associated X Protein) and Bcl-2 (B-cell lymphoma 2), respectively by using RT-qPCR. In addition, we identified the expression of PRM2 by immunohistochemistry (IHC). Relative expression of SCP3, PRM2 and Bcl-2 were highest in group 2 after five weeks of culture. In contrast, BAX expression level was lower in experimental group 2 in comparison with other groups. IHC analyses indicated the highest expression of PRM2 as a postmeiotic marker in group 2 in comparison to 2D culture and control groups but not find significant differences between experimental group 1 and experimental group 2 groups. Morphological evaluations revealed that organoids are compact spherical structures and in the peripheral region composed of uncharacterized elongated fibroblast-like cells. Our findings revealed that the testicular organoid culture system promote the spermatogonial stem cell (SSC) differentiation, especially in presence of SCF. Developed organoids are capable of recapitulating many important properties of a stem cell niche.


Solvation and stabilization of palladium nanoparticles in phosphonium-based ionic liquids: a combined infrared spectroscopic and density functional theory study.
Analysis of infrared spectra of palladium nanoparticles (NPs) immersed in the tri-tert-butyl-R-phosphonium-based ionic liquids (ILs) demonstrates that both cations and anions of the ILs interact with the NPs. According to quantum-chemical simulations of these interactions, the binding energy of anions to the Pd6 cluster, taken as a minimal-size model of the NPs, increases from ∼6 to ∼27 kcal mol(-1) in the order [PF6](-)≈ [BF4](-) < [Tf2N](-) < [OTf](-) < [Br](-)≪ [TFA](-). In contrast, the binding energy for all types of the [Bu(t)3PR](+) cations slightly varies at about ∼22 kcal mol(-1) only moderately depending on the choice of the R moiety (n-pentyl, 2-hydroxyethyl, 2-methoxyethyl, 2-ethoxy-2-oxoethyl). As a result, the energies of interaction between a Pd6 cluster and various ion pairs, formed by the abovementioned counter-ions, follow the order found for the anions and vary from ∼24 to ∼47 kcal mol(-1). These values are smaller than the energy of addition of a Pd atom to a Pdn cluster (∼58 kcal mol(-1)), which suggests kinetic stabilization of the NPs in phosphonium-based ILs rather than thermodynamic stabilization. The results are qualitatively similar to the trends found earlier for interactions between palladium clusters and components of imidazolium-based ILs, in spite of much larger contributions of the London dispersion forces to the binding of the [Bu(t)3PR](+) cations to the cluster (up to 80%) relative to the case of 1-R-3-methylimidazolium cations (up to 40%).


Effect of cellulose on serum lipids in adolescent girls.
The effect on serum lipid concentration of adding 21 g cellulose to a controlled low-fibre diet of natural foods was studied in nine healthy adolescent girls. The experimental period consisted of two periods of three weeks with each subject serving as her own control. The addition of cellulose did not affect serum total lipids, cholesterol, phospholipids, triglycerides and free fatty acids.


[The application of aquaerobic as a form of therapeutic exercises for the prenatal preparation of the pregnant women].
The present review considers aquaerobic as a form of therapeutic exercises for the prenatal preparation of the pregnant women. It is shown that aquaerobic improves the parameters characterizing the degree of physical preparedness and physical development of the pregnant women, normalizes their general well-being, mood, sleep, physical activity, and working capacity. Moreover, regular aquaerobic exercises prevent the development of pregnancy complications.


49, XXXYY chromosome anomaly in a mentally retarded man.
A case of 49, XXXYY chromosome anomaly in an adult male is reported. Features of Klinefelter's syndrome are predominant among the clinical findings. Characteristics suggestive of acromegaly have been associated with this chromosomal anomaly. Despite prognathism and an overhanging brow, acromegaly was not present in this case. Psychological traits sometimes reported in males with the XXY and XYY karyotypes were seen in this patient, but the variability of expression of these characteristics calls into question the validity of their correlation with the presence of supernumerary sex chromosomes.


[Risk factors for cardiovascular diseases in Turks in Amsterdam and in Ankara].
To determine the prevalence of the main risk factors for cardiovascular disease in Turks in Amsterdam and in Ankara, and to compare the results obtained in these two groups with each other and also with those obtained in a group of indigenous Dutch residents living in the same districts. Cross-sectional observational study. Districts 'Oost' and 'De Pijp' in Amsterdam, the Netherlands, 'Camlik' and 'Beşikkaya' in Ankara, Turkey. Plasma glucose and lipids were determined in 149 Turkish residents living in Amsterdam and 145 Turkish subjects in Ankara with comparable socio-economic status (66 and 74% of those who were asked to participate). Blood pressure was also measured by mercury sphygmomanometry. Questionnaires were completed on smoking habits, alcohol consumption, physical activity, consumption of food containing saturated fat, and the existence of heart and vascular disease or hypertension. Results were compared between groups and also with the findings obtained in a group of indigenous Dutch subjects living in the same districts in Amsterdam by the Peilstationsproject of the Rijksinstituut voor Volksgezondheid en Milieu (Sounding station project, National Institute for Public Health and the Environment). Turkish men in Amsterdam had higher systolic blood pressures, lower HDL cholesterol values and higher total cholesterol/HDL cholesterol ratios, and were more obese than men in Ankara and Dutch men in Amsterdam. Glucose concentration and total cholesterol and LDL cholesterol concentrations of Turkish men in Amsterdam were higher than the values of men in Ankara. The risk profile of Turkish women was also more unfavourable compared with that of women in Ankara, but the differences were less than in the men. They had lower HDL cholesterol values, higher LDL cholesterol and glucose and smoked more often than women in Ankara. Turkish women in Amsterdam also had higher systolic and diastolic blood pressures and were more obese than Dutch women in Amsterdam. Turkish residents in Amsterdam have more risk factors for cardiovascular disease than their countrymen living in Ankara, and also compared with indigenous Dutch citizens living in the same districts. Their risk factor profile, therefore, is not intermediary between that of Turkish subjects in Ankara and the indigenous Dutch citizens, as might be expected in view of the mortality figures.


Is left-handedness associated with a more pronounced age-related cognitive decline?
The effect of handedness on cognitive functioning has been the subject of much controversy. The influential "pathological left-handedness theory" posited by Coren and Halpern (1991) claims that left-handedness is probabilistically related to deviations from the neurological and cognitive norm. Many studies have failed to find negative effects of left-handedness on cognitive functioning, but most of these studies related handedness to cognition at one moment in time. Such studies do not exclude the possibility that sinistrality may be related to a more pronounced age-related longitudinal decline in cognitive functions. This hypothesis was tested in the present study. In a longitudinal study involving a large population sample of cognitively intact people aged at least 50 years at baseline, we evaluated the effect of handedness on age-related decline in four major cognitive domains: speed of information processing, verbal learning, long-term verbal memory, and executive functioning. The results failed to provide support for the hypothesis that sinistrality is associated with a more pronounced age-related cognitive decline. Recommendations for future studies are provided.


Anaplastic oligodendroglioma.
Although uncommon, anaplastic oligodendrogliomas (AODs) are important to recognize, as they have unique molecular, histologic, and clinical features. Patients with new seizures or new focal neurologic deficits should be referred for brain MRI with contrast. If the MRI suggests a malignant glioma, maximal feasible tumor resection is advised for accurate diagnosis and for relief of tumor-related neurologic symptoms. Radiation therapy (XRT) is the most commonly prescribed postsurgical therapy for patients with AODs. The role and timing of adjuvant chemotherapy are less clear. Tumor responses to PCV (the combination of procarbazine, lomustine, and vincristine) and to temozolomide have been documented in patients with AODs. However, two prospective phase 3 trials in patients with newly diagnosed AOD have shown no difference in overall survival when PCV is added to XRT. Ongoing trials investigating the benefit of temozolomide plus XRT in patients with newly diagnosed AOD will inform about the value of this common practice. The recognition that 1p19q codeletion is a marker of oligodendroglial differentiation and the subsequent prospective confirmation of this marker's importance in predicting better prognosis have been critical discoveries. Tumors with intermediate oligodendroglial features or mixed astrocytic features should be referred for 1p19q assessment. Identification of 1p19q status is also required in clinical trials for patients with AOD, given the association of 1p19q codeletion with improved response to therapies and overall prognosis. There are not yet sufficient data to guide individual treatment planning based on 1p19q status, but several planned and ongoing trials will address this issue. Unfortunately, AOD remains a terminal brain cancer even with maximal therapies. As more therapeutic options become available and the full significance of molecular markers is understood, 1p19q and other markers are expected to help guide optimal antitumor therapies, and it is hoped that survival and function will improve for all patients with AOD.


Comparison of proteins expressed by Pseudomonas aeruginosa strains representing initial and chronic isolates from a cystic fibrosis patient: an analysis by 2-D gel electrophoresis and capillary column liquid chromatography-tandem mass spectrometry.
Isolates of Pseudomonas aeruginosa from chronic lung infections in cystic fibrosis (CF) patients have phenotypes distinct from those initially infecting CF patients, as well as from other clinical or environmental isolates. To gain a better understanding of the differences in these isolates, protein expression was followed using two-dimensional (2-D) gel electrophoresis and protein identification by peptide sequencing using micro-capillary column liquid chromatography-tandem mass spectrometry (microLC/MS/MS). The isolates selected for this analysis were from the sputum of a CF patient: strain 383 had a nonmucoid phenotype typical of isolates from the environment, and strain 2192, obtained from the same patient, had a mucoid phenotype typical of isolates from chronic CF lung infections. Strains 383 and 2192 were confirmed to be genetically identical by restriction endonuclease analysis, random amplified polymorphic DNA-PCR, and pulsed-field gel electrophoresis. Conditions of protein extraction were optimized for consistent high-resolution separation of several hundred proteins from these clinical isolates as detected by Coomassie staining of 2-D gels. Fourteen proteins were selected for analysis; this group included those whose expression was common between both strains as well as unique for each strain. The proteins were identified by microLC/MS/MS of the peptides produced by an in-gel tryptic digestion and compared to translated data from the Pseudomonas Genome Project; optimization of this technique has allowed for the comparison of proteins expressed by strains 383 and 2192.


Serial measurements of neutrophil gelatinase-associated lipocalin: prognostic value in patients with ST-segment elevation myocardial infarction treated with a primary percutaneous coronary intervention.
There are no previous data on serial changes in neutrophil gelatinase-associated lipocalin (NGAL) levels in ST-segment elevation myocardial infarction (STEMI) patients before and after a primary percutaneous coronary intervention (pPCI). The aim of the present study was to evaluate the prognostic value of serial NGAL measurements in patients with STEMI treated by pPCI. We identified 169 STEMI patients who underwent pPCI within 12 h of symptom onset and had plasma NGAL measurements before (pre-NGAL) and 6 h after (post-NGAL) pPCI. The primary endpoint was 30-day all-cause mortality, including cardiac death, whereas the secondary endpoint was the change in NGAL levels from before to after pPCI. The mean pre-NGAL and post-NGAL levels were 109.2±76.1 and 93.3±83.8 ng/ml, respectively. Thirty-day mortality occurred in 12 (7.1%) patients. In terms of changes in serial NGAL levels, post-NGAL levels were decreased in 132 (79%) patients. Patients with elevated post-NGAL levels showed increased mortality compared with patients with decreased post-NGAL levels (P=0.005). Multivariate analyses indicated that old age and high post-NGAL levels were independent risk factors for 30-day mortality. In a large percentage of STEMI patients, plasma post-pPCI NGAL levels were decreased compared with pre-pPCI NGAL levels, even with the administration of potentially nephrotoxic contrast medium. Post-NGAL levels seemed to be superior to pre-NGAL levels for the prediction of 30-day mortality outcome.


Therapeutic neuroscience education via e-mail: a case report.
Therapeutic neuroscience education (TNE) aims to alter a patient's thoughts and beliefs about pain and has shown efficacy in treating chronic pain. To date, TNE sessions mainly consist of one-on-one verbal communication. This approach limits availability of TNE to pain patients in remote areas. A 32-year-old patient with chronic low back pain (CLBP) who underwent surgery for thoracic outlet syndrome (TOS) attended a single clinic one-on-one TNE session followed by TNE via electronic mail (e-mail), pacing and graded exposure over a 4-month period. A physical examination, Numeric Rating Scale (NRS), Oswestry Disability Index (ODI), the Disabilities of Arm, Shoulder and Hand (DASH), and Fear-Avoidance Beliefs Questionnaire (FABQ) were assessed during her initial physical therapy visit as well as 1 and 4 months later. Pre-TNE, the patient reported: NPRS (arm) = 7/10; NPRS (leg) = 4/10; ODI = 10.0%; DASH = 36.7%; FABQ-W = 24; and FABQ-PA = 17. After 5 e-mail sessions all outcome measures improved, most noticeably NRS (arm) = 2/10; NRS (leg) = 0/10; DASH = 16.7%; FABQ-W = 8; and FABQ-PA = 7. TNE can potentially be delivered to suffering pain patients in remote areas or to individuals who have time and financial constraints, and likely at a significant reduced cost via e-mail.


Bipolar depression: best practices for the hospitalized patient.
Bipolar depression remains one of the most challenging conditions for clinicians to accurately diagnose and effectively treat. For hospitalized patients with bipolar disorder, mood stabilizers--a term often used by clinicians to denote medications that treat acute manic, hypomanic, and depressive symptoms--are often used as first-line treatment. Despite the short- and long-term benefit of a mood stabilizer, comorbid factors, such as substance abuse, can affect patient treatment response. Thus, once the patient's mood is stable and diagnosis is confirmed, clinicians should work with patients on hospital discharge planning, including outpatient follow-up and psychosocial education. In addition to preventing bipolar depression relapse, outpatient initiatives may focus on substance abuse or other comorbid factors. In order to make an accurate diagnosis of bipolar depression, clinicians should perform a complete assessment of the patient and the patient's family at presentation as well as determine whether symptoms are due to bipolar type I disorder or bipolar type II disorder. Presence of substance abuse may complicate initial assessment as patients may be experiencing symptoms related to abuse, including withdrawal. Beyond mood stabilizers and atypical antipsychotics, which should be optimized and chosen based on the treatment history of the patient, antidepressants offer another treatment option for bipolar depression, although they should not be used first line or as monotherapy. As substance abuse often occurs comorbid with bipolar depression, both problems should be addressed with a treatment plan. This expert roundtable supplement addresses the course of diagnosis and treatment for hospitalized patients with bipolar depression and presents a case study to demonstrate clinical challenges related to bipolar patients. The onset and severity of bipolar depression, prevalence of substance abuse, psychosocial treatment options, and clinical issues for the long-term treatment of bipolar depression are also discussed.


Subcutaneous closure versus no subcutaneous closure after non-caesarean surgical procedures.
Most surgical procedures involve a cut in the skin that allows the surgeon to gain access to the surgical site. Most surgical wounds are closed fully at the end of the procedure, and this review focuses on these. The human body has multiple layers of tissues, and the skin is the outermost of these layers. The loose connective tissue just beneath the skin is called subcutaneous tissue, and this generally contains fat. There is uncertainty about closure of subcutaneous tissue after surgery: some surgeons advocate closure of subcutaneous tissue, as they consider this closes dead space and leads to a decrease in wound complications; others consider closure of subcutaneous tissue to be an unnecessary step that increases operating time and involves the use of additional suture material without offering any benefit. To compare the benefits (such as decreased wound-related complications) and consequences (such as increased operating time) of subcutaneous closure compared with no subcutaneous closure in participants undergoing non-caesarean surgical procedures. In August 2013 we searched the following databases: Cochrane Wounds Group Specialised Register (searched 29 August, 2013); The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 7); Ovid MEDLINE (1946 to August Week 3 2013); Ovid MEDLINE (In-Process & Other Non-Indexed Citations August 28, 2013); Ovid EMBASE (1974 to 2013 Week 34); and EBSCO CINAHL (1982 to 23 August 2013). We did not restrict studies with respect to language, date of publication or study setting. We included only randomised controlled trials (RCTs) comparing subcutaneous closure with no subcutaneous closure irrespective of the nature of the suture material(s) or whether continuous or interrupted sutures were used. We included all RCTs in the analysis, regardless of language, publication status, publication year, or sample size. Two review authors independently identified the trials and extracted data. We calculated the risk ratio (RR) with 95% confidence intervals (CI) for comparing binary (dichotomous) outcomes between the groups and calculated the mean difference (MD) with 95% CI for continuous outcomes. We performed meta-analysis using the fixed-effect model and random-effects model. We performed intention-to-treat analysis whenever possible. Eight RCTs met the inclusion criteria. Six of the trials provided data for this review and all of these were at high risk of bias. Six trials randomised a total of 815 participants to subcutaneous closure (410 participants) or no subcutaneous closure (405 participants). Overall, 7.7% of participants (63/815 of participants) developed superficial surgical site infections and there was no clear evidence of a difference between the two intervention groups (RR 0.84; 95% CI 0.53 to 1.33; very low quality evidence). Only two trials reported superficial wound dehiscence, with 7.9% (17/215) of participants developing the problem. It is not clear whether the lack of reporting of this outcome in other trials was because it did not occur, or was not measured. There was no clear evidence of a between-group difference in the proportion of participants who developed superficial wound dehiscence in the trials that reported this outcome (RR 0.56; 95% CI 0.22 to 1.41; very low quality evidence). Only one trial reported deep wound dehiscence, which occurred in 8.3% (5/60) of participants. There was no clear evidence of a difference in the proportion of participants who developed deep wound dehiscence between the two groups (RR 0.25; 95% CI 0.03 to 2.11; very low quality evidence). Three trials reported the length of hospital stay and found no significant difference between groups (MD 0.10 days; 95% CI -0.45 to 0.64; very low quality evidence). We do not know whether this review reveals a lack of effect or lack of evidence of effect. The confidence intervals for these outcomes were wide, and significant benefits or harms from subcutaneous closure cannot be ruled out. In addition, none of the trials assessed the impact of subcutaneous closure on quality of life, long-term patient outcomes (the follow-up period in the trials varied between one week and two months after surgery) or financial implications to the healthcare provider. There is currently evidence of very low quality which is insufficient to support or refute subcutaneous closure after non-caesarean operations. The use of subcutaneous closure has the potential to affect patient outcomes and utilisation of healthcare resources. Further well-designed trials at low risk of bias are necessary.


Assessment of Approximate Methods for Anharmonic Free Energies.
Quantitative evaluation of the thermodynamic properties of materials-most notably their stability, as measured by the free energy-must take into account the role of thermal and zero-point energy fluctuations. While these effects can easily be estimated within a harmonic approximation, corrections arising from the anharmonic nature of the interatomic potential are often crucial and require computationally costly path integral simulations to obtain results that are essentially exact for a given potential. Consequently, different approximate frameworks for computing affordable estimates of the anharmonic free energies have been developed over the years. Understanding which of the approximations involved are justified for a given system, and therefore choosing the most suitable method, is complicated by the lack of comparative benchmarks. To facilitate this choice we assess the accuracy and efficiency of some of the most commonly used approximate methods: the independent mode framework, the vibrational self-consistent field, and self-consistent phonons. We compare the anharmonic correction to the Helmholtz free energy against reference path integral calculations. These benchmarks are performed for a diverse set of systems, ranging from simple weakly anharmonic solids to flexible molecular crystals with freely rotating units. The results suggest that, for simple solids such as allotropes of carbon, these methods yield results that are in excellent agreement with the reference calculations, at a considerably lower computational cost. For more complex molecular systems such as polymorphs of ice and paracetamol the methods do not consistently provide a reliable approximation of the anharmonic correction. Despite substantial cancellation of errors when comparing the stability of different phases, we do not observe a systematic improvement over the harmonic approximation even for relative free energies. We conclude that, at least for the classes of materials considered here, efforts toward obtaining computationally feasible anharmonic free energies should therefore be directed toward reducing the expense of path integral methods.


Influenza vaccines: from surveillance through production to protection.
Influenza is an important contributor to population and individual morbidity and mortality. The current influenza pandemic with novel H1N1 has highlighted the need for health care professionals to better understand the processes involved in creating influenza vaccines, both for pandemic as well as for seasonal influenza. This review presents an overview of influenza-related topics to help meet this need and includes a discussion of the burden of disease, virology, epidemiology, viral surveillance, and vaccine strain selection. We then present an overview of influenza vaccine-related topics, including vaccine production, vaccine efficacy and effectiveness, influenza vaccine misperceptions, and populations that are recommended to receive vaccination. English-language articles in PubMed published between January 1, 1970, and October 7, 2009, were searched using key words human influenza, influenza vaccines, influenza A, and influenza B.


Class-specific regulation of anti-DNA antibody synthesis and the age-associated changes in (NZB x NZW)F1 hybrid mice.
Investigations of regulatory helper and suppressor T cells in the in vitro anti-DNA antibody synthesis in NZB x NZW (B/W) F1 hybrid mice were initiated by the development of an in vitro system in which G10-passed B cells from B/W F1 mice were cocultured with mitomycin C-treated T cells in the presence of Con A and either in the presence or in the absence of LPS. It was revealed that each IgG and IgM anti-DNA antibody synthesis was under the regulation of separate L3T4+ helper and Ly-2+ suppressor T cells. The function of these class-specific regulatory T cells was age-dependent. Although the helper effect of L3T4+ T cells on IgG antibody synthesis increased, the effect of L3T4+ T cells on IgM antibody production decreased in B/W F1 mice with aging. The IgG anti-DNA antibody production in the cocultures of L3T4+ T cells and B cells was suppressed by addition of Ly-2+ T cells from young but not aged B/W F1 mice, whereas the production of IgM anti-DNA antibodies was suppressed by Ly-2+ T cells from aged but not young B/W F1 mice. We also found that although IgM anti-DNA antibody-producing B cells were already present in 2-mo-old mice, B cells producing IgG antibodies under the influence of L3T4+ T cells appeared in mice at 7 mo of age. These data clearly indicate that separate class-specific regulatory T cells are involved in the production of IgM and IgG anti-DNA antibodies and that the total serum level of the antibodies is reflected by both their age-associated changes and the generation of antibody-forming B cells in B/W F1 mice.


Evidence that a single EF-Ts suffices for the recycling of multiple and divergent EF-Tu species in Streptomyces coelicolor A3(2) and Streptomyces ramocissimus.
The tsf genes from Streptomyces coelicolor A3(2) and Streptomyces ramocissimus, encoding the guanine-nucleotide exchange factor EF-Ts, were cloned and sequenced. Streptomycetes have multiple and highly divergent EF-Tu species, with EF-Tu1 and EF-Tu3 showing only about 65% amino acid sequence identity, and yet these can apparently interact with a single EF-Ts species. tsf lies in an operon with rpsB, which encodes ribosomal protein S2. The amino acid sequence of S2 from S. coelicolor differs from most other bacterial S2 homologues in having a C-terminal extension of 70 aa residues with a highly repetitive organization, the function of which is unknown. Transcription analysis of the rpsB-tsf operon of S. coelicolor by promoter probing, nuclease S1 mapping and Northern blotting revealed that the genes give rise to a bicistronic transcript from a single promoter upstream of rpsB. An attenuator was identified in the rpsB-tsf intergenic region; it results in an approximately 2:1 ratio of rpsB vs tsf transcripts. Although tuf1, encoding the major EF-Tu, is located in the rpsL ribosomal protein operon, an additional promoter in the fus-tuf1 intergenic region leads to a significant excess of EF-Tu over ribosomes. Most amino acid residues known from the Escherichia coli crystal structure of the EF-Tu-EF-Ts complex to be directly involved in interaction between the two elongation factors are conserved between E. coli and Streptomyces. However, whenever interaction residues in the EF-Tu moiety show divergence among Streptomyces EF-Tu1, EF-Tu2 and EF-Tu3, the single Streptomyces EF-Ts exhibits compensatory substitutions of the corresponding residues. These apparently enable productive interaction to occur with all three EF-Tus.


Evaluation of nonlinear optimization for scheduling of follow-up cystoscopies to detect recurrent bladder cancer. The Bladder Cancer follow-up Group.
Standard recommendations for patients who have had superficial bladder cancer are inspection by cystoscopy quarterly for a year or two after tumor removal, then half-yearly and yearly. The authors assessed the potential for improvement in scheduling cystoscopies according to probabilistic optimization techniques. Eight hypothetical practices were created, based on retrospective analysis of 918 bladder-cancer-patient charts. Standard and alternative recommendations for the interval to next cystoscopy were compared. The alternatives were derived from patient-specific predictions of future tumor risks (based on the patient's prior recurrence rate and tumor stage and grade) and a nonlinear optimization approach to allocation of the same number of cystoscopies as were available for standard follow-up. The optimization proposed longer intervals between visits for low-risk patients and shorter intervals for high-risk patients. Overall, optimization reduced expected tumor detection delays by 30%, from 12.6 to 8.7 weeks. When optimization intervals were shorter than standard, cancer was found more often at subsequent cystoscopies (34% vs 27%, p less than 0.05), suggesting that the optimization was a better predictor of cancer recurrence. If reduction in tumor-detection delay is the goal of follow-up for recurrent cancers, then urologists can improve monitoring by using probabilistic optimization methods for scheduling cystoscopies. Further understanding of the accuracy of predictive models for bladder-cancer recurrence rates is desirable. Subsequently, the optimization method developed here may be tested prospectively.


Pro-MMP-9 is a specific macrophage product and is activated by osteoarthritic chondrocytes via MMP-3 or a MT1-MMP/MMP-13 cascade.
In joint diseases of both the inflammatory (rheumatoid arthritis, or RA) or the degenerative variety (osteoarthritis, or OA), matrix metalloproteinases (MMPs) are essential mediators of irreversible tissue destruction. MMP-9 is secreted as a stable, inactive zymogen and is proteolytically converted to the active enzyme. To understand the activation mechanism of MMP-9 in joint diseases, the process was investigated in serum-free cocultures of human articular chondrocytes and macrophages. Macrophages extensively expressed and secreted pro-MMP-9 whereas chondrocytes failed to produce the enzyme. However, efficient activation of pro-MMP-9 required soluble and membrane-associated chondrocyte proteinases. Two alternative activation pathways mainly involved MMPs and, marginally, serine or cysteine proteinases. MT1-MMP (MMP-14), the only MT-MMP expressed in chondrocytes, converted pro-MMP-13 which, in turn, cleaved pro-MMP-9. Alternatively, pro-MMP-9 was activated less efficiently by MMP-3, which was converted by autocatalysis or by serine or cysteine proteinases. Both pathways were triggered by chondrocytes from OA, but not normal joints. Therefore, articular chondrocytes are not innocent bystanders in joint diseases. They not only produce destructive enzymes guided by environmental cues but also they can instruct inflammatory cells or cells from surrounding tissues to do so by converting in several ways zymogens produced but not activated by these cells themselves.


Saccades during object viewing modulate oscillatory phase in the superior temporal sulcus.
Saccadic eye movements (SEMs) are the primary means of gating visual information in primates and strongly influence visual perception. The active exploration of the visual environment ("active vision") via SEMs produces suppression during saccades and enhancement afterward (i.e., during fixation) in occipital visual areas. In lateral temporal lobe visual areas, the influence, if any, of eye movements is less well understood, despite the necessity of these areas for forming coherent percepts of objects. The upper bank of the superior temporal sulcus (uSTS) is one such area whose sensitivity to SEMs is unknown. We therefore examined how saccades modulate local field potentials (LFPs) in the uSTS of macaque monkeys while they viewed face and nonface object stimuli. LFP phase concentration increased following fixation onset in the alpha (8-14 Hz), beta (14-30 Hz), and gamma (30-60 Hz) bands and was distinct from the image-evoked response. Furthermore, near-coincident onsets of fixation and image presentation--like those occurring in active vision--led to enhanced responses through greater phase concentration in the same frequency bands. Finally, single-unit activity was modulated by the phase of alpha, beta, and gamma oscillations, suggesting that the observed phase-locking influences spike timing in uSTS. Previous research implicates phase concentration in these frequency bands as a correlate of perceptual performance (Womelsdorf et al., 2006; Bosman et al., 2009). Together, these results demonstrate sensitivity to eye movements in an object-processing region of the brain and represent a plausible neural basis for the enhancement of object processing during active vision.


Clinical correlates of tourette's disorder across cultures: a comparative study between the United Arab Emirates and the United Kingdom.
Tourette's disorder is a neuropsychiatric disorder characterized by motor and vocal (phonic) tics. While the disorder has been researched extensively in the Western populations, the clinical correlates and associated features are less well known in other populations and cultures. This study examines the presentation and clinical correlates of Tourette's disorder in 2 distinct populations, namely the United Kingdom and the United Arab Emirates. A consecutive series of 35 Tourette's disorder patients of Arab descent recruited from 2001 to 2005 from the Child Psychiatry clinics in Al Ain, United Arab Emirates (U.A.E.), were compared with 35 age- and gender-matched white Tourette's disorder patients attending the Tourette Clinic at the National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom, from December 2004 to December 2005. Rates of occurrence of obsessive-compulsive disorder and attention-deficit/hyperactivity disorder were similar in the 2 cohorts. Coprolalia was higher in the U.K. cohort and was noted to correlate with the severity of Tourette's disorder. Comorbid oppositional defiant disorder and conduct disorder were also higher in the U.K. cohort (54.3% [N = 19] and 20.0% [N = 7], respectively) as compared to the U.A.E. cohort (11.4% [N = 4] and 5.7% [N = 2], respectively) but were not linked to any other clinical feature or severity of Tourette's disorder. The findings illustrate the similarity in the core clinical symptoms between the 2 populations, thus emphasizing the underlying biological and genetic basis of these symptoms. However, our finding of higher occurrence of behavioral symptoms in the Western sample has implications for our understanding of the phenotypic presentation of Tourette's disorder as well as the management.


Twitch potentiation after voluntary contraction and neuromuscular electrical stimulation at various frequencies in human quadriceps femoris.
In this study we aimed to compare the extent of twitch potentiation (TP) after voluntary contraction and percutaneous electrical stimulation of muscles (neuromuscular electrical stimulation: NMES) with various stimulation frequencies at equivalent target levels. Isometric knee extensions of 10 s were performed at a 40% maximal voluntary contraction level by voluntary or NMES conditioning contractions at 20, 40, and 80 HZ of the quadriceps femoris muscle. Twitch responses were elicited by stimulating the femoral nerve transcutaneously at supramaximal intensity. NMES at 80 HZ induced significantly less TP (128.7 ± 17.1%) than voluntary contraction (156.2 ± 23.1%), whereas no statistical difference was found in TP among voluntary and 20- and 40-HZ NMES conditioning contractions (170.8 ± 21.1% and 162.7 ± 16.9% for 20- and 40-HZ NMES, respectively). Stimulation frequency of NMES determines whether NMES can induce TP comparable to that after voluntary contraction.


[Weight gain from atypical neuroleptics--an underreported adverse effect?].
After the introduction of the so-called "atypical neuroleptics" in the clinical experience a marked weight gain was frequently observed in patients treated with some of these agents. In this review the frequency, amount and conditions of weight gain during the medication with 'atypical' neuroleptics were evaluated. A comparison is limited by the different designs and recruitment procedures of the reviewed studies. The available data show that the frequency as well as the amount of weight gain is particularly high in patients treated with clozapine, olanzapine, and likely also quetiapine and zotepine. Moderate changes of weight have been observed in the treatment with risperidone and probably also with amisulpride, while ziprasidone seems to induce only clinically irrelevant weight changes. Weight gain most frequently occurs in the first weeks of treatment. Underweighted patients are at highest risk to gain weight. The underlying pathomechanism still remains widely unclear. The relative receptor affinities of the atypical antipsychotics for histamine H1 as well as their quotient of 5-HT2/D2 receptor affinity appear to be a correlate of weight gain. Furthermore, the induction of leptin secretion may have an important impact on weight gain in subjects treated with atypical neuroleptics. Although many questions concerning the conditions of weight gain remain unsolved, this side-effect has to be considered in the medication with many atypical neuroleptics, particularly in view of compliance in long-term treatment and possible medical complications.


Slowing Down Ageing: The Role of Nutrients and Microbiota in Modulation of the Epigenome.
The human population is getting ageing. Both ageing and age-related diseases are correlated with an increased number of senescent cells in the organism. Senescent cells do not divide but are metabolically active and influence their environment by secreting many proteins due to a phenomenon known as senescence associated secretory phenotype (SASP). Senescent cells differ from young cells by several features. They possess more damaged DNA, more impaired mitochondria and an increased level of free radicals that cause the oxidation of macromolecules. However, not only biochemical and structural changes are related to senescence. Senescent cells have an altered chromatin structure, and in consequence, altered gene expression. With age, the level of heterochromatin decreases, and less condensed chromatin is more prone to DNA damage. On the one hand, some gene promoters are easily available for the transcriptional machinery; on the other hand, some genes are more protected (locally increased level of heterochromatin). The structure of chromatin is precisely regulated by the epigenetic modification of DNA and posttranslational modification of histones. The methylation of DNA inhibits transcription, histone methylation mostly leads to a more condensed chromatin structure (with some exceptions) and acetylation plays an opposing role. The modification of both DNA and histones is regulated by factors present in the diet. This means that compounds contained in daily food can alter gene expression and protect cells from senescence, and therefore protect the organism from ageing. An opinion prevailed for some time that compounds from the diet do not act through direct regulation of the processes in the organism but through modification of the physiology of the microbiome. In this review we try to explain the role of some food compounds, which by acting on the epigenetic level might protect the organism from age-related diseases and slow down ageing. We also try to shed some light on the role of microbiome in this process.


Privatizing the English National Health Service: an irregular verb?
This article explores different stakeholder perspectives of "privatization" in the English National Health Service (NHS). Much of the academic literature makes empirical claims about privatization on the basis of absent or shaky definitions of the term, resulting in much of the debate on this issue largely being a "non-debate," where opponents talk past rather than to each other. We aim to throw light on privatization by applying the lens of the "three-dimensional" approach (ownership, finance, and regulation) of the mixed economy of welfare to the views of key voices within these debates. These stakeholder perspectives are political (parliamentary debates), public (opinion polls), clinical provider (British Medical Association and Royal College of Nursing), and campaigning groups. We argue that in terms of grammar, "privatize" seems to be an irregular verb: I want more private-sector involvement; you wish to privatize the NHS. The term privatization is multidimensional, and definitions and operationalizations of the term are often implicit, unclear, and conflicting, resulting in differing accounts of the occurrence, chronology, and degree of privatization in the NHS. Stakeholders have divergent interests, and they use "privatization" as a way to express them, resulting in a Tower of Babel.


Identification of a C3b/iC3 binding protein of rabbit platelets and leukocytes. A CR1-like candidate for the immune adherence receptor.
Immune adherence is the attachment of C-bearing immune complexes via the major activation fragment of the third component of C(C3b) to C3b binding membrane proteins. On primate E, the C3b-R, termed CR1, mediates immune adherence. In nonprimates, immune adherence involves platelets instead of E. However, these functional data have not been corroborated by the identification of the binding protein. In this work, we have identified a C3b/iC3 binding protein of rabbit platelets and characterized it as a single chain structure with a Mr of 150 kDa (nonreducing) or 175 kDa (reducing). This protein binds to rabbit iC3 or C3b but not C3d. This specificity of binding and the ability to rebind to a second column of iC3- or C3b-thiol-Sepharose are comparable to human CR1. Also, a molecule with the identical Mr as well as other structural and binding characteristics is present on rabbit PBMC. No such protein was isolated from rabbit E. Our data strongly suggest that the C3b/iC3 binding protein of rabbit platelets is the homologue of human CR1. If so, this represents an interesting evolutionary switch in the tissue specific expression of the immune adherence R from platelets in the nonprimate to E in the primate.


Aggressive forms of non-Hodgkin's lymphoma in two patients bearing coinfection of Epstein-Barr and hepatitis C viruses.
Although epidemiologic and experimental data suggest an etiopathogenetic role for both hepatitis C virus (HCV) and Epstein-Barr virus (EBV) infection in development of B-cell non-Hodgkin's lymphoma (NHL), potential interactions between EBV and HCV during progression of B-cell NHL have not yet been fully investigated. In the present study, tumor biopsy specimens from patients with both B-cell NHL and chronic HCV infection (HCV(+)) were analyzed for the presence of EBV-encoded RNA (EBER) by in situ hybridization (ISH). VH and VL gene segments were amplified from tumor biopsy specimen DNA by PCR. EBV infection (EBV(+)) was detected in tumors from 2 of 31 (6%) HCV(+) B-cell NHL patients. Clinical histories of these two EBV(+)/HCV(+) B-cell NHL patients indicated a particularly aggressive course of disease. Chemotherapy failed to induce long lasting remission for either of these EBV(+)/HCV(+) B-cell NHL patients. Amplification of CDR3 of the Ig heavy chain gene from DNA isolated from each EBV(+)/HCV(+) B-cell NHL indicated the presence of monoclonal B-cell expansion. Rearrangement of Ig genes in neoplastic B-cell clones from both EBV(+)/HCV(+) patients was similar to that previously reported for EBV(-)/HCV(+) B-cell NHL patients. Additionally, neoplastic B-cell clones from these two EBV(+)/HCV(+) B-cell NHL patients did not exhibit intraclonal variation. Previous studies have demonstrated that intraclonal variation is common among neoplastic B-cell clones from EBV(-)/HCV(+) patients. EBV infection may have prevented evolution of variant neoplastic B-cell clones by suppressing antibody affinity maturation. Together, these data suggest that EBV infection may cooperate with HCV infection during progression of B-cell NHL in immunocompetent individuals. Such an interaction may accelerate the course of disease in B-cell NHL patients.


The Sarcoglycan complex is expressed in the cerebrovascular system and is specifically regulated by astroglial Cx30 channels.
Astrocytes, the most prominent glial cell type in the brain, send specialized processes called endfeet, around blood vessels and express a large molecular repertoire regulating the cerebrovascular system physiology. One of the most striking properties of astrocyte endfeet is their enrichment in gap junction proteins Connexin 43 and 30 (Cx43 and Cx30) allowing in particular for direct intercellular trafficking of ions and small signaling molecules through perivascular astroglial networks. In this study, we addressed the specific role of Cx30 at the gliovascular interface. Using an inactivation mouse model for Cx30 (Cx30(Δ/Δ); Δ means deleted allele) we showed that absence of Cx30 does not affect blood-brain barrier (BBB) organization and permeability. However, it results in the cerebrovascular fraction, in a strong upregulation of Sgcg encoding γ-Sarcoglycan (γ-SG), a member of the Dystrophin-associated protein complex (DAPC) connecting cytoskeleton and the extracellular matrix. The same molecular event occurs in Cx30(T5M/T5M) mutated mice, where Cx30 channels are closed, demonstrating that Sgcg regulation relied on Cx30 channel functions. We further characterized the expression of other Sarcoglycan complex (SGC) molecules in the cerebrovascular system and showed the presence of α-, β-, δ-, γ-, ε- and ζ- SG, as well as Sarcospan. Their expression was however not modified in Cx30(Δ/Δ). These results suggest that a full SGC might be present in the cerebrovascular system, and that expression of one of its member, γ-SG, depends on Cx30 channels. As described in skeletal muscles, the SGC may contribute to membrane stabilization and signal transduction in the cerebrovascular system, which may therefore be regulated by Cx30 channel-mediated functions.


Paranasal Schwannomas: A Comprehensive Study of 2 Cases.
Paranasal sinus tumors are a heterogeneous group of neoplasms (with paranasal schwannomas being a rare subtype) that are often present with non-specific symptoms, such as nasal obstruction and epistaxis. Thus, early diagnosis is crucial for optimal management. This study presents 2 cases of paranasal schwannomas, detailing their clinical presentation, diagnostic methods, and treatment approaches. Both patients underwent endoscopic sinus surgery with successful tumor excision and had no significant complications or recurrences during follow-up. Diagnosis was based on a combination of clinical examination, radiological imaging (computed tomography and magnetic resonance imaging), and histopathological confirmation with immunohistochemical staining. Treatment consisted primarily of endonasal resection, with consideration of frontal craniotomy if necessary. This study aims to contribute to the understanding of paranasal schwannomas and emphasizes the importance of early detection and treatment to improve patient outcomes.


The effects of protein-coated surfaces on passaged porcine TMJ disc cells.
Implantation of synthetic temporomandibular joint (TMJ) disc replacements aimed to alleviate pain and restore functional losses caused by TMJ disorders. Unfortunately, these synthetic replacements have been largely unsuccessful and in some instances have incited severe immune responses. Tissue engineering, however, may provide viable TMJ disc replacements. Towards this end, we have studied TMJ disc gene expression as a measure of protein production potential. With passage, collagen type I and aggrecan gene expression decrease in TMJ disc cell cultures. We hypothesize that surfaces coated with TMJ disc proteins may rapidly recover the lost gene expression in passaged TMJ disc cells. To study these effects, passages 0, 1, and 2 TMJ disc cells were plated in wells coated with aggrecan, collagen type I, collagen type II, or decorin. Safranin O staining was conducted to visualize cell aggregation. At passage 0, cultures appeared similar on each surface; however, by passages 1 and 2, aggrecan-coated and decorin-coated surfaces appeared to have more cell aggregates. Gene expression data did not correspond to these visual changes. No treated surface offered a significant change in aggrecan, collagen type I, or decorin expression relative to untreated controls. Furthermore, aggrecan and collagen type I gene expression dropped relative to samples taken prior to plating. These results indicate that, despite visual changes described by cell aggregates, protein coatings have limited effects for recovering TMJ disc gene expression in monolayer cultures.


Changes in fetal position during labor and their association with epidural analgesia.
To evaluate whether epidural analgesia is associated with a higher rate of abnormal fetal head position at delivery. We conducted a prospective cohort study of 1,562 women to evaluate changes in fetal position during labor by using serial ultrasound examinations. Ultrasound examinations were performed at enrollment, epidural administration, 4 hours after the initial ultrasonography if epidural had not been administered, and late in labor (> 8 cm). Information about fetal head position at delivery was obtained from the provider. Regardless of fetal head position at enrollment (occiput transverse, occiput posterior, or occiput anterior), most fetuses were occiput anterior at delivery (enrollment position: occiput transverse 78%, occiput posterior 80%, occiput anterior 83%, P = .1). Final fetal position was established close to delivery. Of fetuses that were occiput posterior late in labor, only 20.7% were occiput posterior at delivery. Changes in fetal head position were common, and 36% of women had an occiput posterior fetus on at least one ultrasound examination. Women receiving epidural did not have more occiput posterior fetuses at the enrollment (23.4% epidural versus 26.0 no epidural, P = .9) or the epidural/4-hour ultrasound examination (24.9% epidural, 28.3% no epidural), but did have more occiput posterior fetuses at delivery (12.9% epidural versus 3.3% no epidural, P = .002); the association remained in a multivariate model (adjusted odds ratio 4.0, 95% confidence interval 1.4-11.1). Fetal position changes are common during labor, with the final fetal position established close to delivery. Our demonstration of a strong association of epidural with fetal occiput posterior position at delivery represents a mechanism that may contribute to the lower rate of spontaneous vaginal delivery consistently observed with epidural.


Identification of protein components from the mature ovary of the sea urchin Evechinus chloroticus (Echinodermata: Echinoidea).
The gonads of sea urchins are a high value seafood product, with considerable research being undertaken worldwide on the development of sea urchin aquaculture. As the best prices are obtained for specific gonad attributes, research has also focused on the development of artificial diets that enhance gonad quality and quantity. Total protein has been used as a measure of gonad quality; yet no studies to date have applied proteomics technology to diet development. Here we use a MudPIT and 2-DE approach to describe the major proteins in mature ovaries of a New Zealand sea urchin Evechinus chloroticus. This tissue, which is a target seafood product, contained 138 proteins that were identified from the recently completed sea urchin genome (Strongylocentrotus purpuratus) with high confidence. The majority of these proteins had general functions, with only 12 related to ovarian reproductive function. Eighteen proteins were located on the 2-DE; four of these were directly identified from S. purpuratus protein sequences. In combination this paper shows that the genome resources of S. purpuratus can be used to identify proteins in sea urchins from different families; describes the proteome of E. chloroticus mature ovary; and, provides proteomic tools for analysis of gonads from other edible sea urchins.


Characterization of zinc-solubilizing Bacillus isolates and their potential to influence zinc assimilation in soybean seeds.
One hundred thirty-four putative Bacillus isolates were recovered from soybean rhizosphere soils of Nimar region to select effective zinc solubilizers for increased assimilation of zinc (Zn) in soybean seeds. These isolates were screened in vitro for zinc-solubilization ability on Tris-minimal agar medium supplemented separately with 0.1% zinc in the form of zinc oxide, zinc phosphate, and zinc carbonate. Of all, 9 isolates and a reference Bacillus cereus ATCC 13061 were characterized and identified as Bacillus species based on Gram-positive reaction, endospore-forming cells, and the presence of iso-C₁₅:₀ and anteiso-C₁₅:₀ as predominant fatty acids. On plate assay, two isolates KHBD-6 and KHBAR-1 showed a greater diameter of solubilization halo and colony diameter on all the three zinc compounds. The isolates KHBD-6, KHBAR-1, BDSD-2-2C, and KHTH-4-1 and the reference strain ATCC 13061 had higher soluble zinc concentration in liquid medium supplemented with zinc phosphate and zinc carbonate compounds as compared with the other isolates and uninoculated control. Evaluation under microcosm conditions showed that inoculation of isolates KHBD-6 (57.34 μg/g), KHBAR-1 (55.67 μg/g), and strain ATCC 13061 (53.10 μg/g) significantly increased the Zn concentration in soybean seeds as compared with the other isolates and uninoculated control (47.14 μg/g). This study suggests the occurrence of zinc-solubilizing Bacillus in soils of Nimar region and isolates KHBD-6 and KHBAR-1 were found to be promising zinc solubilizers for increased assimilation of Zn in soybean seeds.


A memory clinic v. traditional community mental health team service: comparison of costs and quality.
Aims and method To compare the cost and quality of a memory-clinic-based service (MCS) with a traditional community mental health team (CMHT) service. Using a retrospective case-note review, we studied two groups, each with 33 participants. Consecutive referrals for diagnostic 'memory' assessments over 4 months were evaluated. Participants were evaluated for up to 6 months. Results The MCS was less costly than the CMHT service but the difference was not statistically significant (mean cost for MCS was £742, mean cost for CMHT service was £807). The MCS offered more multidisciplinary and comprehensive care, including: pre- and post-diagnostic counselling, more systematic screening of blood for reversible causes of dementia, more use of structured assessment instruments in patients/carers, signposting to the third sector as well as more consistent copying of letters to patients/carers. Clinical implications An MCS service offered more comprehensive and multidisciplinary service at no extra cost to secondary care.


Brief communication: prenatal and early postnatal stress exposure influences long bone length in adult rat offspring.
Stress during the prenatal and early postnatal periods (perinatal stress, PS) is known to impact offspring cognitive, behavioral, and physical development, but effects on skeletal growth are not clear. Our objective was to analyze effects of variable, mild, daily PS exposure on adult offspring long bone length. Twelve pregnant rat dams were randomly assigned to receive variable stress from gestational days 14-21 (Prenatal group), postpartum days 2-9 (Postnatal), both periods (Pre-Post), or no stress (Control). Differences in adult offspring tibia and femur length were analyzed among treatment groups. Mean tibia length differed among groups for males (P = 0.016) and females (P = 0.009), and differences for femur length approached significance for males (P = 0.051). Long bone length was shorter among PS-exposed offspring, especially those exposed to postnatal stress (Postnatal and Pre-Post groups). Results persisted when controlling for nose-tail length. These differences might reflect early stunting that is maintained in adulthood, or delayed growth among PS-exposed offspring. This study suggests that PS results in shorter long bones in adulthood, independently of effects on overall body size. Stunting and growth retardation are major global health burdens. Our study adds to a growing body of evidence suggesting that PS is a risk factor for poor linear growth.


The hydrolysis activity of adenosine triphosphate in myosin: a theoretical analysis of anomeric effects and the nature of the transition state.
Combined quantum mechanical/molecular mechanical (QM/MM) calculations with density functional theory are employed to analyze two issues related to the hydrolysis activity of adenosine triphosphate (ATP) in myosin. First, we compare the geometrical properties and electronic structure of ATP in the open (post-rigor) and closed (pre-powerstroke) active sites of the myosin motor domain. Compared to both solution and the open active site cases, the scissile P(gamma)-O(3beta) bond of ATP in the closed active site is shown to be substantially elongated. Natural bond orbital (NBO) analysis clearly shows that this structural feature is correlated with the stronger anomeric effects in the closed active site, which involve charge transfers from the lone pairs in the nonbridging oxygen in the gamma-phosphate to the antibonding orbital of the scissile bond. However, an energetic analysis finds that the ATP molecule is not significantly destabilized by the P(gamma)-O(3beta) bond elongation. Therefore, despite the notable perturbations in the geometry and electronic structure of ATP as its environment changes from solution to the hydrolysis-competent active site, ground-state destabilization is unlikely to play a major role in enhancing the hydrolysis activity in myosin. Second, two-dimensional potential energy maps are used to better characterize the energetic landscape near the hydrolysis transition state. The results indicate that the transition-state region is energetically flat and a range of structures representative of different mechanisms according to the classical nomenclature (e.g., "associative", "dissociative", and "concerted") are very close in energy. Therefore, at least in the case of ATP hydrolysis in myosin, the energetic distinction between different reaction mechanisms following the conventional nomenclature is likely small. This study highlights the importance of (i) explicitly evaluating the relevant energetic properties for determining whether a factor is essential to catalysis and (ii) broader explorations of the energy landscape beyond saddle points (even on free-energy surface) for characterizing the molecular mechanism of catalysis.


Social isolation and cognitive function in Appalachian older adults.
Investigating the relation between social isolation and cognitive function will allow us to identify components to incorporate into cognitive interventions. Data were collected from 267 Appalachian older adults (M = 78.5, range 70-94 years). Overall cognitive functioning and specific cognitive domains were assessed from data of a self-assembled neuropsychological battery of frequently used tasks. Social isolation, social disconnectedness, and perceived isolation were measured from the Lubben Social Network scale-6. Results indicated a significant positive association between all predictor variables (e.g., social isolation, social disconnectedness, and perceived isolation) and outcome variables (e.g., overall cognitive function, memory, executive functioning, attention, and language abilities). Perceived isolation accounted for nearly double the amount of variance in overall cognitive functioning than social disconnectedness (10.2% vs. 5.7%). Findings suggest that social isolation is associated with poorer overall cognitive functioning and this remains true across varied cognitive domains.


Activation of human raf transforming genes by deletion of normal amino-terminal coding sequences.
Three activated cellular raf genes have been detected by transfection of NIH 3T3 cells with human tumor DNAs. Blot hybridization analysis indicated that all three transforming raf genes had recombined with non-raf sequences in the vicinity of raf exon 7-intron 7, resulting in the deletion of about 40% of the normal coding sequence from the raf amino terminus. By cloning sequences upstream of the truncated raf loci we have shown that the rearrangements involve the fusion of three different 5' non-raf human sequences to the human raf gene. No rearrangements could be detected in the raf loci of the three original human tumor DNAs, suggesting that the raf genes were activated by DNA rearrangements occurring during transfection. Significant overexpression of raf mRNA was not evident in two of the three transformant lines, indicating that raf overexpression is not necessary and 5' truncation alone may be sufficient to activate the transforming potential of cellular raf genes.


Effect of Estrogen Receptor Expression Level and Hormonal Therapy on Prognosis of Early Breast Cancer.
Estrogen receptor (ER) expression in breast cancer plays an essential role in carcinogenesis and disease progression. Recently, tumors with low level (1%-10%) of ER expression have been separately defined as ER low positive (ERlow). It is suggested that ERlow tumors might be morphologically and behaviorally different from tumors with high ER expression (ERhigh). Retrospective analysis of a prospective cohort database was performed. Patients who underwent curative surgery for early breast cancer and had available medical records were included for analysis. Difference in clinicopathological characteristics, endocrine responsiveness and five-year recurrence-free survival was evaluated between different ER subgroups (ERhigh, ERlow, and ER-negative [ER-]). A total of 2,162 breast cancer patients were included in the analysis, Tis and T1 stage. Among them, 1,654 (76.5%) were ERhigh, 54 (2.5%) were ERlow, and 454 (21.0%) were ER- patients. ERlow cases were associated with smaller size, higher histologic grade, positive human epidermal growth factor receptor 2, negative progesterone receptor, and higher Ki-67 expression. Recurrence rate was highest in ER- tumors and was inversely proportional to ER expression. Recurrence-free survival was not affected by hormonal therapy in the ERlow group (p=0.418). ERlow breast cancer showed distinct clinicopathological features. ERlow tumors seemed to have higher recurrence rates compared to ERhigh tumors, and they showed no significant benefit from hormonal therapy. Future large scale prospective studies are necessary to validate the treatment options for ERlow breast cancer.


Depression among centenarians and the oldest old: contributions of cognition and personality.
An estimated 20% of adults over the age of 55 experience clinical mental disorders such as depression and anxiety. For older adults, mental health concerns are often undetected, concomitant with physical challenges, and ultimately go untreated. These realities have significant implications for older adults' day-to-day functioning, particularly among the oldest old. The present study examined the ability of cognition and personality in explaining depression within a sample of octogenarians and centenarians. Participants were assessed during the most recent cross-sectional data collection of the Georgia Centenarian Study. The final eligible sample included 76 octogenarians (mean: 84.25 years, SD: 2.82; range: 81-90) and 158 centenarians and near centenarians (mean: 99.82 years, SD: 1.72; range: 98-109). Hierarchical regression analyses were conducted to examine the relation between key variables and depressive symptoms in the two age groups. Blocks entered into the analyses included: demographics (i.e. age group, residential status, sex, and ethnicity) and functioning, memory and problem-solving ability, and personality (i.e. extraversion and neuroticism). Models differed for octogenarians and centenarians. Decreased problem-solving ability was related to greater depressive symptoms among octogenarians. For centenarians, institutional residence and increased neurotic tendencies were related to greater depressive symptoms. Study findings demonstrate the need to examine a variety of factors which influence mental health in later life and to consider the unique contexts and differential experiences of octogenarians and centenarians.


Activation of protein tyrosine phosphorylation after retinal branch vein occlusion in cats.
The authors examine the effect of retinal branch vein occlusion (BVO), a common retinal vascular disorder, on protein tyrosine phosphorylation, production of angiogenic growth factors, and activation of signal proteins in the tyrosine kinase pathways in the retina. Retinal branch vein occlusion was induced in cat retina by coagulation of retinal veins with diathermy. At 2 days, 1, 3, and 6 weeks after induction of BVO, the retina was divided into three parts: a part within the distribution of the occluded vein (BVO[IN]) or a part outside the distribution of the occluded vein (BVO[OUT]). Each part of the retina was prepared for Western blot analysis of tyrosine-phosphorylated proteins, vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and four signal proteins in the tyrosine kinase pathways, which were phospholipase C gamma (PLC gamma), C-Src, SH2-containing protein (SHC), and mitogen-activated protein kinase (MAPK). Overall, tyrosine-phosphorylated proteins were increased after BVO, especially in BVO(IN) at 2 days and 1 week. The VEGF and bFGF also were increased in BVO(IN) at 1 week and 2 days, respectively. The PLC gamma and MAPK were activated at these time points. The C-Src and SHC were not activated in the retina after BVO. The BVO increased overall protein tyrosine phosphorylation in the cat retina in association with increase of angiogenic growth factors (VEGF and bFGF) and activation of two signal proteins (PLC gamma and MAPK) in the tyrosine kinase pathways. These results suggest that the protein tyrosine phosphorylation may in part play an important role in mitogenesis of vascular endothelial cells and other retinal responses after BVO.


Exposures during pregnancy and at birth are associated with the risk of offspring eating disorders.
Eating disorders (ED) are severe psychiatric disorders, commonly debuting early. Aberrances in the intrauterine environment and at birth have been associated with risk of ED. Here, we explore if, and at what effect size, a variety of such exposures associate with offspring ED, that is, anorexia nervosa (AN), bulimia nervosa (BN), and eating disorder not otherwise specified (EDNOS). This population-based cohort study, conducted from September 2021 to August 2023, used Finnish national registries of all live births in 1996-2014 (N = 1,097,753). Cox proportional hazards modeling was used to compare ED risk in exposed versus unexposed offspring, adjusting for potential confounders and performing sex-stratified analyses. A total of 6614 offspring were diagnosed with an ED; 3668 AN, 666 BN, and 4248 EDNOS. Lower risk of offspring AN was seen with young mothers, continued smoking, and instrumental delivery, while higher risk was seen with older mothers, inflammatory disorders, prematurity, small for gestational age, and low Apgar. Offspring risk of BN was higher with continued smoking and prematurity, while lower with postmature birth. Offspring risk of EDNOS was lower with instrumental delivery, higher for older mothers, polycystic ovary syndrome, insulin-treated pregestational diabetes, antibacterial treatment, prematurity, and small for gestational age. Sex-specific associations were found. Several prenatal and at birth exposures are associated with offspring ED; however, we cannot exclude confounding by maternal BMI. Nevertheless, several exposures selectively associate with risk of either AN, BN, or EDNOS, and some are sex-specific, emphasizing the importance of subtype- and sex-stratified analyses of ED. We define environmental factors involved in the development of different ED, of importance as preventive measure, but also in order to aid in defining the molecular pathways involved and thus in the longer perspective contribute to the development of pharmacological treatment of ED.


Observations on C-peptide and free insulin in the blood during continuous subcutaneous insulin infusion and conventional insulin therapy.
As part of a multicenter trial, 70 individuals with insulin-dependent diabetes were randomized to either conventional insulin therapy (CIT) or continuous subcutaneous insulin infusion (CSII). In order to standardize patient selection in the six participating centers, one of the eligibility criteria was the demonstration that each patient had no residual endogenous insulin secretion as assessed by plasma C-peptide determinations. The patients were of average (+/- SEM) age of 33.0 +/- 1.6 yr, had had diabetes for a mean (+/- SEM) duration of 17.4 +/- 1.1 yr, and had both fasting and postglucagon stimulation C-peptide values of less than 0.1 pmol/ml, consistent with clinically insignificant endogenous insulin secretion. There was no change in C-peptide response at 4 or 8 mo compared with baseline values, whether or not the patient's glucose control remained unchanged (CIT group) or significantly improved to near-normoglycemia (CSII group). In a subgroup of 34 patients at three centers, the 24-h mean glucose concentration was significantly lower in the CSII group compared with the CIT group at 4 mo (126 +/- 10 versus 176 +/- 14 mg/dl) and at 8 mo (121 +/- 5 versus 183 +/- 15 mg/dl) (P less than 0.005). Although the 24-h mean serum free immunoreactive insulin levels were shown to be no different at baseline (27.4 +/- 3.8 versus 26.2 +/- 3.1 microU/ml) or after 4 mo (22.5 +/- 3.2 versus 25.6 +/- 3.2) or 8 mo (26.5 +/- 3.4 versus 28.8 +/- 3.4) of CIT or CSII therapy, respectively, the mean increase of free insulin concentrations in relation to the main meals was greater in the CSII group (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)


PECAM-1 (CD31) functions as a reservoir for and a modulator of tyrosine-phosphorylated beta-catenin.
Catenins function as regulators of cellular signaling events in addition to their previously documented roles in adherens junction formation and function. Evidence to date suggests that beta and gamma catenins can act as signaling molecules, bind transcriptional factors and translocate to the nucleus. Beta- and gamma-catenin are also major substrates for protein tyrosine kinases, and tyrosine phosphorylation of junctional proteins is correlated with decreased adhesiveness. One way in which catenin functions are modulated is by dynamic incorporation into junctional complexes which controls, in part, the cytoplasmic levels of catenins. Here we show that: (1) vascular endothelial growth factor (VEGF) induces beta-catenin tyrosine phosphorylation in a time-, and dose-dependent manner and that VEGF receptors co-localize to areas of endothelial cell-cell contact in vitro and in vivo. (2) Platelet-endothelial cell adhesion molecule (PECAM)-1 can function as a reservoir for, and modulator of, tyrosine phosphorylated beta-catenin. (3) PECAM-1 can prevent beta-catenin nuclear translocation in transfected SW480 colon carcinoma cells. We suggest that PECAM-1 may play a role in modulating beta-catenin tyrosine phosphorylation levels, localization and signaling and by doing so, functions as an important modulator of the endothelium.


Temperature changes in exhaled breath condensate collection devices affect observed acetone concentrations.
Chemical analysis of exhaled breath condensate (EBC) is an emerging method to non-invasively identify and measure potential biomarkers of disease. Various EBC collection methods have been proposed, each with strengths and weaknesses. Recent evidence in the literature suggests that sample collection methodologies could introduce potential artifacts in biomarker measurements. In this study, we tested the effect of thermal changes during condensate collection on measured EBC chemical concentrations. Using both actively-cooled and passively-cooled devices, we measured distinct differences in the amount of condensate that can be collected over discrete time periods. We also found that concentrations of acetone varied with the thermal profile changes in the collection devices, in apparently identical EBC samples. Together, this evidence suggests that great care should be taken to standardize EBC collection methods, and that small deviations in the thermal properties of the collection devices could contribute to confounding EBC measurement artifacts. This has implications for the design and development of future portable breath analysis systems, especially miniature hand-held devices.


[Analysis of rulings by the Brazilian Ministry of Health and reflections on national health policy management].
Ministry of Health rulings and provisions are important policy regulation tools that aim to orient the enforcement of health-related laws passed by the Legislative Branch, under the terms of the 1988 Federal Constitution. Such provisions have played a major role in the health sector, due not only to the number of documents submitted since the late 1990s, but mainly because of this tool's persuasive power in defining health sector policy. The current article aims to foster reflection on both national health policy management in Brazil and the main obstacles to the implementation of health reform operational aspects. The article classified and analyzed Ministry of Health rulings issued from 1990 to 2002. The study highlights the Ministry's centralizing approach and the use of financial and political persuasion tools that subject State and Municipal governments to the system's rules without creating a negotiated and sustained health policy that the country's institutional realities ratify and support.


The albumin in acute stroke (ALIAS) multicenter clinical trial: safety analysis of part 1 and rationale and design of part 2.
enrollment in the Albumin in Acute Stroke (ALIAS) Trial was suspended in late 2007 due to a safety concern. We present the safety data of that Trial ("Part 1") and the rationale for the design of Part 2. ALIAS Part 1 was designed to assess whether 25% albumin (ALB) started within 5 hours of stroke onset would confer neuroprotection in subjects with acute ischemic stroke and baseline National Institutes of Health Stroke Scale of ≥ 6. Exclusion criteria included recent or current congestive heart failure, myocardial infarction, or cardiac surgery. The study comprised 2 cohorts: subjects who received thrombolysis and those who did not, each with 1:1 randomization to ALB or placebo. The primary outcome was the National Institutes of Health Stroke Scale and modified Rankin Scales at 90 days. The intended sample size was 1800. four hundred thirty-four subjects were enrolled, and 424 were used in the safety analysis (ALB 207, saline 217). There were 36 deaths within the first 30 days in the ALB group and 21 in the saline group. In contrast, death rates after 30 days were similar by treatment. Large strokes were the predominant cause of early death in both groups. In subjects >83 years of age, 90-day death rates were 2.3-fold higher with ALB than with saline (95% CI, 1.04 to 5.12). Similarly, 90-day deaths in subjects receiving excessive fluids were 2.10-fold greater with ALB than with saline (CI, 1.10 to 3.98). The ALIAS Part 2 Trial, which started in early 2009, was modified as follows to enhance safety: upper age limit of 83 years; requirement for normal baseline serum troponin level; restriction of total intravenous fluids in the first 48 hours to ≤ 4200 mL; mandatory diuretic at 12 to 24 hours; and detailed site retraining. Because of insufficient nonthrombolysed subjects (22%) in Part 1, the 2-cohort design was eliminated. The Data Safety Monitoring Board has reviewed the safety data of Part 2 3 times and has approved continuation of the trial.