Ghrelin levels increase after pictures showing food.
The neuropeptide ghrelin is a major signal for food intake in various species including humans. After exogenous ghrelin administration, food intake and body weight increase in rodents. In normal human subjects, ghrelin administration increases self-rated appetite and calorie intake and prompts the imagination of favorite meals. It is unclear so far whether ghrelin levels are affected by external cues such as sight of food. We investigated the influence of pictures showing food compared to neutral pictures on ghrelin levels in young normal male subjects (n = 8). The study consisted of two consecutive sessions with a one-week interval. During each session, blood for later analysis of plasma concentrations of ghrelin was collected between 08:15 and 13:00 every 15 min (between 10:30 and 11:30 every 10 min). Breakfast and lunch was provided at 08:30 and 12:00, respectively. Fifty pictures were presented from 10:30 to 10:45 showing neutral images during the first session and food contents during the second session. As expected, ghrelin levels increased before each meal independent of the picture contents. In addition, ghrelin levels during the 30-min interval following the presentation of pictures with food increased significantly compared to the 30-min interval before this presentation (area under the curve (AUC): 188 % vs. 158 %, P < 0.05). The difference in the increases between the two picture conditions was also significant (P < 0.05). Our findings suggest that sight of food elevates ghrelin levels in healthy volunteers.


Relationship between social determinants of health and clinical outcomes in adults with type 2 diabetes in Lebanon.
A growing number of ethnic minority populations in the United States are from the Middle East and North Africa (MENA) region, specifically Lebanon. This region is witnessing one of the highest expected increases in diabetes prevalence. However, limited data exists on how social determinants of health impact clinical care for diabetes in this population. The aim of this study was to assess the social determinants of health and their impact on clinical outcomes in Lebanese adults with type 2 diabetes (T2DM). A convenience sample of Lebanese patients with T2DM was recruited from primary health care centers in Lebanon. Data on demographics and social determinants of health, including socioeconomic status, neighborhood and built environment, as well as psychosocial variables were collected. Clinical outcomes including Hemoglobin A1c (A1C), systolic (SBP) and diastolic blood pressure (DBP) were measured. Unadjusted and adjusted linear regression models were used to test for associations between the independent variables and each of the outcomes. Out of the 300 adults with T2DM, 52% were men, 73% were married and 64% had an education level below high school. Results from multivariate analyses showed that food insecurity (β = 0.16, p = 0.01), owning an air conditioner (β = -0.64, p = 0.01), and commuting by walking (β = -0.93, p = 0.01) were independently associated with A1C. Predictors of DBP were male gender (β = 3.59, p = 0.03), age (β = -0.19, p = 0.005) and lack of confidence in filling medical forms (β = -4.89, p = 0.007), while male gender was the only predictor of SBP (β = 7.41, p = 0.008). This is the first study to examine the relationship between social determinants of health and clinical outcomes for diabetes in the MENA region. Our findings suggest that living in an underprivileged neighborhood and built environment was significantly and independently associated with poor clinical outcomes among adults with T2DM in Lebanon. Findings from this study will inform care for immigrant populations with diabetes from the MENA region.


The corpus callosum, interhemisphere interactions, and the function of the right hemisphere of the brain.
A complex clinical-neuropsychological study was performed by the Luriya method before and after surgery in 36 patients with arteriovenous malformations (AVM) of the corpus callosum. The symptoms of local lesions to the various parts of the corpus callosum are described. Symptoms of partial lesioning of the corpus callosum were found to be modality-specific, though only relatively. The symptoms of dyscopia or dysgraphia could appear in isolation fro each other. Combined lesions of the medial parts of the brain (cingulate cortex, frontal lobes) and the corpus callosum significantly increased the level of dysfunction of these medial parts. Patients with lesions to the anterior parts of the corpus callosum showed symptoms of frontal lobe dysfunction. Lesions to the corpus callosum led to dysfunction of the right hemisphere in the spheres of emotion, perception, and spatial activity. Previous studies have demonstrated that the right hemisphere integrates impulses from both sides of the space and is the first zone involved in activity, performing its initial stages. The author believes that this synthetic activity of the right hemisphere, with tight connections with the "conscious" left hemisphere, is required for the formation of the overall conceptualization of both individual objects and particular types of activity. From this point of view, it is the right hemisphere that can, in a sense, be regarded as dominant, rather than the left hemisphere.


Plasma concentrations of lidocaine and bupivacaine after subarachnoid administration.
Plasma concentrations were measured after subarachnoid administration of 75 mg lidocaine in a hyperbaric solution and 15 mg bupivacaine in either a hyperbaric or an isobaric solution. Peak concentration times (tmax), peak concentrations (Cmax), apparent elimination half-lives (t1/2el), and areas under the curves (AUC) were determined. The values of tmax, Cmax, t1/2el and AUC were 66 +/- 32 min, 444 +/- 203 ng/ml, 2.0 +/- 0.3 h, and 87.0 +/- 9.8 mg . 1(-1) . min, respectively, for lidocaine. Those obtained after administration of a hyperbaric bupivacaine solution were 54 +/- 11 min, 63 +/- 22 ng/ml, 3.6 +/- 1.4 h, and 19.1 +/- 5.4 mg . 1(-1) . min. Results, obtained with isobaric bupivacaine solutions, were: 86 +/- 24 min, 63 +/- 15 ng/ml, 3.2 +/- 0.4 h, and 18.1 +/- 5.4 mg . 1(-1) . min. The results indicate roughly similar absorption rates from the subarachnoid space into the general circulation after administration of hyperbaric solutions of lidocaine and bupivacaine. Bupivacaine tended to be absorbed slower when it is administered in an isobaric solution.


Social approach-avoidance behavior of inbred mouse strains towards DBA/2 mice.
Little is known about the genetics of social approach-avoidance behaviors. We measured social approach-avoidance of prepubescent female C57BL/6J, DBA/2J, FVB/NJ, AKR/J, A/J, and BALB/cJ mice towards prepubescent DBA/2J female mice. C57BL/6J mice showed the greatest predominance of approach, while BALB/cJ mice showed the greatest predominance of avoidance. Thus, this phenotype is affected by spontaneous genetic variation in mice and can be measured in an assay useful for future neurogenetic studies.


The Impact of Co-occurring ADHD on Social Competence Intervention Outcomes in Youth with Autism Spectrum Disorder.
The co-occurrence of autism spectrum disorder (ASD) and attention- deficit/hyperactivity disorder (ADHD) is significant and associated with a host of negative outcomes. Studies investigating social functioning in the presence of the ASD/ADHD co-occurrence have produced mixed findings. The present study further evaluated the impact of co-occurring ADHD on social functioning among youth with ASD and compared treatment response to a social competence intervention between youth with ASD and ASD + ADHD. Two-way repeated measures analyses of variance (ANOVAs) were computed with diagnostic group and time as the independent variables and measures of social functioning as dependent variables. Group and Time effects and Group by Time interactions were examined. Youth with co-occurring ADHD displayed more impairments related to social awareness, but not in other social areas. Participants in both the ASD and ASD + ADHD groups demonstrated significant improvement following a social competence intervention. Co-occurring ADHD did not negatively affect treatment response. Youth with ASD + ADHD may benefit highly structured interventions with a scaffolded teaching design.


Radiogrammetry of the metacarpal: a critical reappraisal.
The precise estimation of osteoporosis is hampered by the lack of a generally accepted method of evaluation. Measurement of the combined cortical thickness (CCT) of the centre point of the second metacarpal has been widely used for this purpose, but the wide normal variation found in population studies has reduced its value in the diagnosis of this condition in the individual. The factors leading this normal variability are discussed and the three centre metacarpals are compared with each other. It is concluded that simple CCT measurement is preferable to any of the indices so far devised, but that a single measurement of a given metacarpal is too imprecise to be of real value. If a single metacarpal is to be chosen, three measurements of the third metacarpal gives a coefficient of variation lower than those of the second or fourth, and an average of nine measurements of the three centre metacarpals produces a further useful reduction in variability.


On the potential role of trypsin and trypsin inhibitors in acute pancreatitis.
The protective role of alpha 2-macroglobulin, alpha 1-antitrypsin and Aprotinin against trypsin-induced effects on C3 and kininogen was studied in a human in vitro model. When human cationic trypsin was added to human serum or plasma, there was a gradual saturation of alpha 2-macroglobulin and later of alpha 1-antitrypsin. When alpha 2-macroglobulin was 70% saturated, there was a prompt cleavage of both C3 and kininogen, in spite of 80% free and active alpha 1-antitrypsin. These biochemical changes and antiprotease levels are identical to our findings in patients with acute pancreatitis, especially in their peritoneal exudate. Very high concentrations of Aprotinin, 5-15 times higher than ever used clinically, blocked the cleavage of both C3 and kininogen, while doses commonly used clinically were without significant effect. The clinical implications are: A trypsin-induced activation of both the complement and kinin system with clinical consequence is possible in patients with acute pancreatitis because of very low alpha 2-macroglobulin levels. Aprotinin in adequate doses, 5-15 times higher than ever used clinically, seems to protect against activation of two systems.


Outcome of lower extremity malignancy survivors treated with transfemoral amputation.
To determine outcomes of surviving patients who underwent transfemoral amputation as part of treatment for lower extremity malignancy at a mean 15 years postoperatively, with a minimum 2-year follow-up. Retrospective, case control. Tertiary care university medical center. Thirty-five of 38 consecutively admitted patients free of metastatic disease managed with transfemoral amputation as part of treatment of a lower extremity bone and/or soft tissue malignancy between 1966 and 1997 at 1 institution. The control group included 35 age- and gender-matched subjects recruited from the local driver's license office. Not applicable. Musculoskeletal Function Assessment (MFA), Short Form-12 General Health Status Survey (SF-12), physical performance battery, cost, and demographic data. Controls showed superior scores as measured by the MFA (P < .0001), the physical component summary of the SF-12 (P = .0002), and the physical performance battery (P < .0001), but had inferior scores on the mental component summary of the SF-12 (P < .0001). With the numbers available, no differences were found between study and control subjects in terms of employment rate (P = .51), education level (P = .66), income level (P =.44), marital status (P = .79), incidence of self-reported health problems (P = .14), and alcohol (P =.42) and tobacco (P = .82) use. Ten patients were included in the cost analysis; the mean cost to obtain and maintain a lower extremity prosthesis was $4225 per year (range, 623 dollars-8517 dollars). Although the decrease in physical performance was anticipated in the study group, the group differed very little from the control population in terms of employment, education level, income, marital and home status, incidence of self-reported health problems, incidence of self-reported depression, and alcohol and tobacco use. Also, the long-term cost of maintaining a lower extremity prosthesis is noted.


Thiacloprid impairs honeybee worker learning and memory with inducing neuronal apoptosis and downregulating memory-related genes.
Neonicotinoids are among the most widely used insecticides in the world and are recognized as a potential cause of pollinator decline. Previous studies have demonstrated that the neonicotinoid thiacloprid has adverse effects on foraging and memory behaviors. However, there is no direct evidence linking thiacloprid-induced neuronal cell damage in the brains of honeybees to learning and memory dysfunction. Adult honeybee (Apis mellifera L.) workers were chronically exposed to sub-lethal concentrations of thiacloprid. We discovered that thiacloprid negatively affected their survival, food consumption, and body weight. In addition, sucrose sensitivity and memory performance were impaired. We evaluated the apoptosis of honeybee brain cells using TUNEL (Terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP-biotin nick-end labeling) and Caspase-3 assays, which revealed that thiacloprid increases the dose-dependent apoptosis of neurons in the mushroom bodies (MB) and antennal lobes (AL). We also determined the abnormal transcripts of multiple genes, including vitellogenin (Vg), immune system genes (apidaecin and catalase), and memory-associated genes (pka, creb, Nmdar1, Dop2, Oa1, Oa-2R, and Oa-3R). These results indicate that exposure to sublethal concentrations of thiacloprid cause abnormal expression of memory-related genes and apoptosis of brain cells in the AL and MB, which may contribute to the memory disorder induced by thiacloprid exposure.


Plasma, apolipoprotein, A-I and A-II levels in hyperlipidemia.
Some of the component moieties of high density lipoproteins (HDL) were analyzed in normal subjects and in patients with hyperlipidemia. Apoproteins A-I and A-II were quantified by radioimmunoassay, HDL cholesterol and triglycerides were assessed on heparin-MnCl2 supernates of fasting plasmas. We found that HDL is enriched in triglycerides in all forms of hyperlipidemia, while the proportion of ApoA-II is unaltered and the proportion of ApoA-I is decreased. Thus, the composition of HDL is altered in hupertirglyceridemia. The molecular associations of ApoA-I and ApoA-II in plasma were also examined by assaying the apoprotein contents of plasma fractions prepared by ultracentrifugation and by gel filtration column chromatograpy. The ApoA-I contents of d smaller than 1.063 fraction increased in hyperlipidemia from smaller than 0.5% to approximately 2%, but the ApoA-I contents of the d greater than 1.21 fraction remained at less than 12% of total plasmas with triglyceride levels smaller than 1500 mg/dl. d greater than 1.21 ApoA-I rose to 23% in one plasma with a triglyceride level of greater than 1700 mg/dl. On column chromatography, ApoA-I eluted with the lipoproteins and also in a fraction whose molecular weight (MW) appeared to be approximately 50,000 daltons. The proportion of plasma ApoA-I which eluted in the 50,000 MW peak was positively correlated with plasma triglyceride levels, but at triglyceride levels of less than 1500 mg/dl, less than 20% of ApoA-I was in the 50,000 MW peak. Between levels of approximately 2000 and 12,000 mg/dl, the percentage "50,000 M.W. ApoA-1" was 20-25%. The ApoA-II contents of d smaller than 1.063 fractions were also increased in hyperlipidemia, but greater than 95% of ApoA-II was found in the HDL fractions in both normal and hyperlipidemic plasma both by column chromatography and ultracentrifugation. Thus, the molecular association of ApoA-I appears to be altered in hyperlipidemia.


Misuses of correlation and regression analyses in orthodontic research: the problem of mathematical coupling.
The aim of this article was to encourage good practice in the statistical analyses of orthodontic research data. Our objective was to highlight the statistical problems caused by mathematical coupling (MC) in correlation and regression analyses. These statistical problems are among the most common pitfalls in orthodontic research when exploring associations among clinical variables. This article will show why these problems arise and how they can be avoided and overcome. Four orthodontic journals were electronically and manually searched for articles that used correlation and regression analyses. Studies that seemed to suffer from MC in their statistical analyses were identified and carefully examined. Several examples from our search illustrate that MC in correlation and regression analyses can potentially cause misleading results. More appropriate statistical methods are available and should be used to eliminate confusing results and improve any subsequent interpretations. Because many clinical and radiographic variables used in orthodontic research are correlated due to direct or indirect MC, interpretation of studies in the literature needs to be cautious. Correlation and regression analyses are useful tools in orthodontic research when their assumptions and limitations are recognized. However, greater care is required in formulating research questions and experimental designs. It is prudent to seek statistical advice when orthodontic research involves complex data analyses.


Perceptions of environmental supports on the physical activity behaviors of university men and women: a preliminary investigation.
To examine perception differences between genders of university sidewalks and safety from crime on the physical activity (PA) behaviors of undergraduate students. Five hundred and sixty undergraduate students participated in this study. The authors derived questions from the South Carolina Environmental Supports for Physical Activity Questionnaire (SCESPAQ) and National College Health Risk Behavior Survey (NCHRS) PA module. The authors found a significant mean difference between genders for the Moderate Intensity Item (eg, walking and biking) and the Flexibility Item, t(558)=3.602, p=.001, and t(558)=1.946, p=.050, respectively. Of participants surveyed, 30% of women perceived this campus to be extremely safe compared with 49% of men, t(558)=4.240, p=.001. Gender and the perceptions of sidewalk presence were significantly related (p<.05) to respondents' walking or bicycling patterns. Perceptions of sidewalks and safety from crime on this university campus were related to students' PA behaviors.


Molecular versus exciton diffusion in fluorescence-based explosive vapour sensors.
The diffusion of p-nitrotoluene vapours into polymer or dendrimer sensing films follows Super Case II dynamics in which the quenching efficiency is strongly correlated to an accelerating analyte front propagating through the neat film rather than being reliant on exciton diffusion.


Pemetrexed combined with paclitaxel: a dose-finding study evaluating three schedules in solid tumors.
The objectives of this phase I study were to determine the maximum tolerated dose (MTD), recommended phase II dose (RD), antitumor activity, safety, and pharmacokinetics of pemetrexed-paclitaxel combination. Patients (N = 95) with advanced solid tumors were assigned to three schedules (21-day cycles [q21d]). Starting doses for each schedule of pemetrexed and paclitaxel, respectively, were: (S1) 400 and 135 mg/m(2) on d1; (S2) 400 mg/m(2) d1 and 40 mg/m(2) d1 and d8; S3) 400 mg/m(2) d8 and 30 mg/m(2) d1 and d8. MTD was 500/135 mg/m(2) (S1), 400/40 mg/m(2) (S2), and 500/120 mg/m(2) (S3). Most common dose limiting toxicities were febrile neutropenia, fatigue, and neuromotor toxicities. Most common toxicity was grade 3/4 lymphopenia. Four patients had partial response, 43 patients had stable disease. The RD determined was pemetrexed 500 mg/m(2) (d8) and paclitaxel 90 mg/m(2) (d1 and d8), q21d. The combination was well tolerated and showed efficacy in thyroid carcinoma and mesothelioma.


Oncolytic adenovirus expressing relaxin (YDC002) enhances therapeutic efficacy of gemcitabine against pancreatic cancer.
Pancreatic cancer is a highly lethal disease for which limited therapeutic options are available. Pancreatic cancer exhibits a pronounced collagen-rich stromal reaction, which induces chemoresistance by inhibiting drug diffusion into the tumor. Complementary treatment with oncolytic virus such as an oncolytic adenovirus expressing relaxin (YDC002) is an innovative treatment option for combating chemoresistant pancreatic cancer. Here, we examined the ability of combined treatment with gemcitabine and YDC002, which degrades extracellular matrix (ECM), to efficiently treat chemoresistant and desmoplastic pancreatic cancer. Gemcitabine alone exhibited similarly low cytotoxicity toward pancreatic cancer cells throughout the concentration range (1-50 μM) used, whereas the combination of YDC002 and a subtherapeutic dose of gemcitabine (0.01-0.05 μM) resulted in potent anticancer effects through effective induction of apoptosis. Importantly, YDC002 combined with gemcitabine significantly attenuated the expression of major ECM components including collagens, fibronectin, and elastin in tumor spheroids and xenograft tumors compared with gemcitabine alone, resulting in potent induction of apoptosis, gemcitabine-mediated cytotoxicity, and an oncolytic effect through degradation of tumor ECM. Our results demonstrate that YDC002 can selectively degrade aberrant ECM and attenuate the ECM-induced chemoresistance observed in desmoplastic pancreatic tumor, resulting in a potent antitumor effect through effective induction of apoptosis.


Comparison of pH and ionic strength dependence of interactions between monoclonal antibodies and bovine beta-lactoglobulin.
A panel of 13 monoclonal antibodies (mAbs) against distinct determinants on bovine beta-lactoglobulin, a model protein antigen, were examined and compared for their ability to bind and desorb from the antigen at differing pHs and ionic strengths by an enzyme-linked immunosorbent assay and elution assay. Among them, mAb 61C1 was found to be highly sensitive to the pH, and 3 in 4 mAbs directed to the region 42-56 also strongly depended on the change in ionic strength. Because of the large proportion of charged amino acid residues in the region 42-56, the electrostatic forces are considered to be more predominant than the hydrophobic interactions in the latter antigen-antibody reactions, thereby resulting in their high sensitivity to the ionic strength.


Turkey egg white lysozyme. Free energy, enthalpy, and steady state kinetics of reaction with N-acetylglucosamine oligosaccharides.
Equilibrium and calorimetric studies of substrate binding to turkey egg white (TEW) lysozyme were carried out at 30degrees as a function of pH (2 to 9) and ligand size (monosaccharide to hexasaccharide of N-acetylglucosamine). Steady state kinetic measurements using the N-acetylglucosamine hexasaccharide were carried out as a function of pH (2 to 9) and temperature (20-60degrees). These experiments allow comparison of the properties of TEW lysozyme with those of the hen egg white (HEW) enzyme reported previously (Banerjee, S. K., Holler, E., Hess, G. P., and Rupley, J. A. (1975) J. Biol. Chem. 250, 4355-4367, and references therein). The free energies and enthalpies of oligosaccharide binding are the same for TEW and HEW lysozymes at pH 2 but are less negative for TEW lysozyme at pH 5. The pH dependence of the binding of (GlcNAc)3 and higher oligomers to TEW lysozyme is like that for the binding of beta-methyl-N-acetylglucosaminide to TEW lysozyme. These data indicate that oligosaccharide ligands bind identically with HEW and TEW lysozymes, except for the interactions of residue 101, which is aspartic acid in the HEW protein and glycine in the TEW protein (Larue, J. N., and Speck, J. C., Jr. (1970) J. Biol. Chem. 245, 1985-1991). The pH dependence of kcat is described by apparent pK values of 3.9 and 6.8 and a maximum value of kcat of 0.135 s-1. A value of 21.0 kcal/mol was calculated for deltaH from the temperature dependence of kcat. These values and the dependence of the transglycosylation reaction on acceptor concentration are within experimental error the same as those for HEW lysozyme. The more acid pK seen in the pH rate profile reflects the ionization of Asp-52 in the lysozyme-(GlcNAc)6 complex. The pK of Asp-52 in the free protein is 0.3 pK unit lower. The essential identity of the active sites of the HEW and TEW enzymes, except for the Asp-101 interactions, allows estimation of the thermodynamic properties associated with formation of the two hydrogen bonds between Asp-101 and substrate as deltaG0 = -1.2 kcal/mol, DeltaH0 = -3.6 kcal/mol, and deltaS0 = -7.9 e.u.


Twice-daily therapeutical plasma exchange-based salvage therapy in severe autoimmune thrombotic thrombocytopenic purpura: the French TMA Reference Center experience.
Daily therapeutic plasma exchange (TPE) and rituximab improved thrombotic thrombocytopenic purpura (TTP) prognosis. In the more severe cases, salvage therapies including twice-daily TPE and/or cyclophosphamide may be proposed and require evaluation. TTP was defined as a thrombotic microangiopathy (TMA) with severe (<10%) acquired ADAMTS13 deficiency. Among patients included in the French Reference Center for TMA registry, we considered those with a severe disease (i.e., unresponsive to daily TPE and rituximab) who received twice-daily TPE. Nineteen of 289 (6.6%) patients with TTP were treated by twice-daily TPE between 2008 and 2014. Twice-daily TPE was associated with rituximab in 16 cases. The median duration of twice-daily TPE treatment was 3 d (2-22 d). In 6 patients (31.6%), additional treatments (mainly pulses of cyclophosphamide) were performed because of a persistently refractory disease (4 cases) or an exacerbation (2 cases), despite twice-daily TPE. Only one patient (5.3%) died. The other 18 achieved a durable complete remission 25.5 d (13-68 d) after the first TPE. The median follow-up was 14.4 months (7 d-45 months). Twice-daily TPE may be an efficient strategy in the more severe TTP patients with a short-term life-threatening disease that could overcome their poor prognosis.


Detection of polar metabolites through the use of gas chromatography-mass spectrometry.
Gas chromatography-mass spectrometry (GC-MS) is a highly reproducible and sensitive analytical technique that has had significant use in the area of metabolite profiling. GC-MS is able to detect a wide variety of metabolites, with highly differing chemistries. In general, extracted biological samples are volatilized prior to separation on a capillary column with a stationary phase suited to the analysis of the compounds of interest. Separated compounds are eluted into a mass spectrometer equipped with an electron impact ionization source, thereby generating a quantifiable mass spectral fingerprint. This chapter describes a method for the trimethylsilyl derivatization of polar metabolites, followed by detection and relative quantification using a gas chromatograph coupled to a single quadrupole mass spectrometer. Using this method will enable the profiling of the greatest range of polar metabolites.


Cerebrospinal fluid homovanillic acid and 5-hydroxy-indoleacetic acid in adults with attention deficit disorder, residual type.
Following the hypothesis that attention deficit disorder in adults (attention deficit disorder, residual type; ADD, RT), as well as in children, is associated with decreased central dopaminergic activity, the authors measured lumbar cerebrospinal fluid monoamine metabolites in a group of adults with ADD, RT and matched control subjects. Patients were then entered into a double-blind, placebo-controlled trial of methylphenidate. It was predicted that the patients would have lower levels of homovanillic acid (HVA), the major dopamine metabolite in humans. Patients who had a significant response to methylphenidate showed a trend in this direction. Nonresponding patients had significantly higher levels of HVA than controls.


Optimization of 2-DE and multiplexed detection of O-GlcNAcome, phosphoproteome and whole proteome protocol of synapse-associated proteins within the rat sensorimotor cortex.
Several studies have shown the importance of phosphorylation, O-GlcNAcylation and their interplay in neuronal processes. To get understanding about molecular mechanisms of synaptic plasticity, we performed a preparation of synaptic protein-enriched fraction on a small sample of rat sensorimotor cortex. We then optimized a multiplexed proteomic strategy to detect O-GlcNAcylated proteins, phosphoproteins, and the whole proteome within the same bidimensional gel. We compared different protocols (solubilisation buffer, reticulation and composition of the gel, migration buffer) to optimize separating conditions for 2D-gel electrophoresis of synaptic proteins. The O-GlcNAcome was revealed using Click chemistry and the azide-alkyne cycloaddition of a fluorophore on O-GlcNAc moieties. The phosphoproteome was detected by Phospho-Tag staining, while the whole proteome was visualized through SYPRORuby staining. This method permitted, after sequential image acquisition, the direct in-gel detection of O-GlcNAcome, phosphoproteome, and whole proteome of synapse-associated proteins. This original method of differential proteomic analysis will permit to identify key markers of synaptic plasticity that are O-GlcNAcylated and/or phosphorylated, and their molecular regulations in neuronal processes.


"Words are too small": exploring artmaking as a tool to facilitate dialogues with young South African women about their sexual and reproductive health experiences.
Adolescents and young women are at high risk for sexually transmitted infections (STIs) and unintended pregnancies. However, conversations about sexual and reproductive health (S&RH) are difficult and stigmatised. Visual art-based approaches have been a useful adjunct to language-dependent interviews, encouraging embodied memory recall. Here, we explored a novel visual art-based methodology-"Stories from the Edge"-with a cohort of young women to understand how artmaking might facilitate dialogue of how S&RH experiences influenced behaviour, to enrich dialogues captured in the individual in-depth interviews (IDIs). Seven isiXhosa-speaking young women (aged 21-25 years) were recruited into a six-session art-based engagement, painting the stories of their S&RH experiences. Large format artmaking and IDIs contributed to the data set. IDIs were audio recorded, transcribed, and translated and then analysed thematically. Young women felt that the visual art-based methodology eased barriers to communicating experiences of S&RH-seeking behaviours, with one woman commenting that "words are too small" to capture lived experiences. Artmaking provided the opportunity to express emotional complexities of the pleasures of intimate relationships and the heartbreak of betrayal for which they had no language. Significant social relationships (family, partners, peers) influenced sexual and reproduction attitudes and practices more than healthcare facilities and staff and more distal socio-cultural attitudes/practices. These influences shifted from adolescence to adulthood-from family to peer and partners. Young women valued using the art-based methodology, which facilitated recall and verbalising their S&RH experiences more fully than language-only research. The process outlined here could provide a creative method that builds communication skills to negotiate the needs and desires of young women with partners and staff at S&RH services.


Expression of a novel histone 2B during mouse spermiogenesis.
During mammalian spermiogenesis transitional proteins and protamines replace histones on the DNA as the chromatin condenses. While previous studies suggested that histone genes are inactive postmeiotically, we have shown both by steady-state RNA analysis and nuclear run-off transcription assays that histone 2b (H2b) transcription occurs in mouse round spermatids. In addition, a novel H2b cDNA clone has been isolated from an adult mouse testes cDNA library. The sequence of this cDNA clone predicts a protein that is extremely similar to other mouse H2b proteins, except at the carboxyl-terminus where the testes H2b contains an additional 12 amino acids, seven of which are hydrophobic. In contrast to the replication-dependent histone mRNAs, the 3' untranslated region of this cDNA contains the poly(A) addition sequence (AAUAAA) upstream of a poly(A) tract. Furthermore, the conserved hairpin structure immediately upstream of replication-dependent histone mRNA termini is not present. Northern blot analysis of RNA from embryonic, ovarian, spermatogenic, and a variety of somatic tissues reveals that this novel H2b transcript is spermatid specific. The H2b mRNA is in polyribosomes isolated from spermatogenic cells, strongly suggesting that it is translated during spermiogenesis.


Somatostatin-induced changes in the hemostasis of rats.
Somatostatin (SRIF) given intravenously, either as a single bolus or as a 2 hr infusion caused a significant prolongation of partial thromboplastin time (PTT) and depressed platelet counts and platelet aggregation in the rat. Following daily injections of protamin-zinc SRIF for 2 weeks the platelet count returned to normal, PTT remained prolonged and platelet aggregation was enhanced. The doses of SRIF used in this work were adequate to suppress the secretion of insulin and glucagon by the isolated pancreatic islets of treated animals.


Hand deformities in Filippino Lippi's Magrini Altarpiece (c. 1482).
Examination of the four saints in Filippino Lippi's Magrini Altarpiece (c. 1482) shows that they all have hand deformities of various kinds. The two saints on the viewer's left, St Rocco and St Sebastian, are portrayed as young, aristocratic men. Those on the viewer's right, St Jerome and St Helena, are depicted as a much older man and a young woman, respectively. It is of interest that the two young men have more significant deformities, while the older man and the young woman are less severely affected. The realism of the depiction of the young men's hands makes it probable that the artist deliberately chose models with arthritic deformities or else painted the hands from memory after having observed other arthritis sufferers. As a more speculative concluding note, it is also suggested, on the basis of comparisons with other paintings from the same period, that the artist may have chosen to depict the young male saints' hands in this way to emphasise both their aristocratic standing and the role of suffering and martyrdom in their traditional biographies.


Childhood tracheobronchial mucoepidermoid carcinoma: a case report and review of the literature.
Mucoepidermoid carcinoma of the lung presenting in childhood is an uncommon neoplasm. Symptoms of progressive bronchial obstruction proceed the recognition of this lesion. The well-confined local growth and minimal metastatic potential of childhood mucoepidermoid carcinoma make local resection with maximum conservation of pulmonary parenchyma the recommended operative treatment. Adequate surgical resection precludes the need for further radiation therapy or chemotherapy. This report details the presentation and treatment of a child with this rare tumor and reviews the present literature experience with childhood mucoepidermoid carcinoma.


Isolation and characterization of biosurfactant-producing and diesel oil degrading Pseudomonas sp. CQ2 from Changqing oil field, China.
In the present research investigation, 13 indigenous bacteria (from CQ1 to CQ13) were isolated from soil collected from Changqing oil field of Xi'an, China. Four promising biosurfactant producers (CQ1, CQ2, CQ4, and CQ13) were selected through primary screening among these 13 strains, including via drop collapse and oil-spreading methods. However, only the strain CQ2 showed the best biosurfactant production and was further screened by hemolytic assay, cetyl trimethyl ammonium bromide (CTAB), surface tension and emulsifying activity. The bacterium CQ2 has the ability to produce about 3.015 g L-1 of biosurfactant using glucose as the sole carbon source without any optimization. The produced biosurfactant could greatly reduce surface tension from 72.66 to 24.72 mN m-1 with a critical micelle concentration (CMC) of 30 mg L-1 and emulsify diesel oil up to 60.1%. The cell-free broth was found to be stable in wide temperature (4-100 °C), pH (6-12) and salinity (2-20%) ranges for surface and emulsifying activity. This biosurfactant was preliminarily found to be of a glycolipid nature as evident from thin-layer chromatographic (TLC) and Fourier transform infra-red spectroscopic (FTIR) analyses. Moreover, CQ2 was able to degrade 54.7% of diesel oil, which surprisingly could form a substantial amount of bioflocculants during the degradation process. Furthermore, the 16S rDNA sequence using the Genbank BLAST tool revealed that isolated CQ2 was closely related to species of Pseudomonas genus and, thus, was entitled Pseudomonas sp. CQ2. The results of residual diesel oil contents measured by GC-MS showed that C7-C28 hydrocarbons could be degraded by Pseudomonas sp. CQ2. Thus, these findings revealed that CQ2 could be applied for remediation of diesel oil/petroleum-contaminated waters and soils on a large scale.


Food for patients at nutritional risk: a model of food sensory quality to promote intake.
The aim was to investigate food sensory quality as experienced and perceived by patients at nutritional risk within the context of establishing a framework to develop foods to develop foods to promote intake. Patients at nutritional risk (NRS-2002; food intake ≤ 75% of requirements) were observed at meals in hospital (food choice, hunger/fullness/appetite scores). This was followed by a semi-structured interview based on the observations and focusing on food sensory perception and eating ability as related to food quality. Two weeks post-discharge, a 3-day food record was taken and interviews were repeated by phone. Interviews were transcribed, coded, and analysed thematically. Patients (N = 22) from departments of gastrointestinal surgery, oncology, infectious medicine, cardiology, and hepatology were interviewed at meals (N = 65) in hospital (82%) and post-discharge (18%). Food sensory perception and eating ability dictated specific food sensory needs (i.e., appearance, aroma, taste, texture, temperature, and variety defining food sensory quality to promote intake) within the context of motivation to eat including: pleasure, comfort, and survival. Patients exhibited large inter- and intra-individual variability in their food sensory needs. The study generated a model for optimising food sensory quality and developing user-driven, innovative foods to promote intake in patients at nutritional risk.


Co-N heteroatomic interface engineering in peanut Shell-Derived porous carbon for enhanced oxygen reduction reaction.
The development of high-efficiency and low-cost oxygen reduction electrocatalysts have become an urgent need to push fuel cells into practical application. Herein, an effective electrocatalyst Co/NC was successfully constructed, which was derived from abundant peanut shells, obtained by doping with cobalt ions and pyrolyzing in NH3 atmosphere. Due to the abundant Co-N active sites triggered by Co-N heteroatomic interface, the prepared electrocatalysts present excellent oxygen reduction reaction (ORR) performance with more positive half-wave potential (E1/2 = 0.83 V), incremental limiting current density (JL = 5.45 mA cm-2), higher durability and stronger resistance to methanol, which is superior to that of Pt/C (E1/2 = 0.81 V and JL = 5.19 mA cm-2). This work proposes a potential strategy to synthesize efficient ORR electrocatalysts to instead of Pt-based catalysts.


Substitution treatment or active intravenous drug use should not be contraindications for antiviral treatment in drug users with chronic hepatitis C.
International guidelines and routine clinical practice express concerns about antiviral treatment in intravenous drug users (IDUs). We analysed the effect of IDU and/or substitution therapy on chronic hepatitis C (CHC) treatment adherence and response. Intravenous drug users with CHC were divided into three groups: (A) patients on a substitution programme; (B) active users; and (C) past IDUs. Patients were treated according to the standard of care and followed by a specialist team. A total of 175 patients (mean age 39.4±8.8) were included. One hundred and forty-four (65%) were adherent to therapy (completing treatment and 6 months of follow-up). Twenty-two patients (36%) discontinued because of side effects, 28 (46%) discontinued on their own and 11 (18%) completed treatment but did not present at follow-up. Of 142 patients with available treatment outcome, 99 (69.7%) achieved a sustained virological response (SVR), with no differences among the study groups. Patients with genotypes 2-3 and those who completed the treatment schedule had 2.78-fold (95% CI: 1.3-5.8) and 6.4-fold (95% CI: 2.6-15.6) higher probability of achieving SVR. Active use of illicit drugs and/or drug substitution do not affect the treatment outcome in patients with CHC as long as they are closely followed and remain adherent to the treatment.


Transcutaneous oxygen and carbon dioxide pressure monitoring to determine severity of limb ischemia and to predict surgical outcome.
Transcutaneous oxygen and carbon dioxide pressure (PO2 and PCO2) foot monitoring was compared with ankle Doppler-derived systolic pressure regarding their respective abilities to discriminate the severity of limb ischemia before vascular reconstruction and to predict surgical outcome early in the postoperative period. Transcutaneous PO2 (tcPCO2), foot-chest tcPO2 index, transcutaneous PCO2 (tcPCO2), foot tcPO2/tcPCO2 index (tcPO2/tcPCO2), ankle Doppler systolic pressure (AP), and ankle-brachial pressure index (ABI) were determined in 89 revascularized limbs. The measurement of tcPO2 and foot-chest tcPO2 was found to be more sensitive to degrees of severity of limb ischemia and more closely associated with the outcome of revascularization than AP and ABI. TcPCO2 and tcPO2/tcPCO2 were not useful in assessment of the vascular patient undergoing reconstructive surgery. Before operation, tcPO2 less than or equal to 22 torr and foot-chest tcPO2 less than or equal to 0.46 indicate severe limb ischemia requiring urgent revascularization. After operation, tcPO2 less than or equal to 22 torr and foot-chest tcPO2 index less than or equal to 0.53 indicate that revascularization is likely to fail. We conclude that tcPO2 monitoring, as a metabolic test of actual tissue perfusion, is a more reliable indicator of preoperative limb ischemia and postoperative outcome of revascularization than hemodynamic, Doppler-derived pressure tests.


Antimicrobial activity of the investigational pleuromutilin compound BC-3781 tested against Gram-positive organisms commonly associated with acute bacterial skin and skin structure infections.
BC-3781 is a novel semisynthetic pleuromutilin antimicrobial agent developed as an intravenous and oral therapy for acute bacterial skin and skin structure infections (ABSSSI) and respiratory tract infections (RTI). BC-3781 and comparator agents were tested by the broth microdilution method against 1,893 clinical Gram-positive organisms predominantly causing ABSSSI. BC-3781 exhibited potent activity against methicillin-resistant Staphylococcus aureus (MIC(50/90), 0.12/0.25 μg/ml), coagulase-negative staphylococci (MIC(50/90), 0.06/0.12 μg/ml), β-hemolytic streptococci (MIC(50/90), 0.03/0.06 μg/ml), viridans group streptococci (MIC(50/90), 0.12/0.5 μg/ml), and Enterococcus faecium (including vancomycin-nonsusceptible strains) (MIC(50/90), 0.12/2 μg/ml). Compared with other antibiotics in use for the treatment of ABSSSI, BC-3781 displayed the lowest MICs and only a minimal potential for cross-resistance with other antimicrobial classes.


Plasma enkephalin-like peptide response to chronic nicotine infusion in guinea pig.
Nicotine administration, using mini-osmotic pumps, to male guinea pigs (31 micrograms/h for 10 days) resulted in a significant elevation of plasma epinephrine and enkephalin-like peptides but not norepinephrine. The increase in plasma epinephrine and enkephalin-like peptides was not accompanied by corresponding alterations in either adrenal medullary synthesis or blood pressure and heart rate. These findings may provide a partial explanation for the observation that chronic smoking does not induce hypertension.


Correction: Saeed, S., et al. Enhancement of Photorefraction in Vanadium-Doped Lithium Niobate through Iron and Zirconium Co-Doping. Materials 2019, Vol. 12, 3143.
The authors wish to make the following corrections to this paper [...].


[A reliable orthopedic technic in the treatment of humeral diaphyseal fractures in the adult: the hanging plaster. Report of a series of 74 cases (author's transl)].
The authors treated 74 humeral shaft fractures with "hanging cast" technique. They study the benefits and difficulties of the method, compared to other orthopaedic and surgical possibilities. Stiffness of the shoulder represent the most important part of 12% bad results. There are only 3% pseudarthrosis. It is a simple and safe treatment, with appliance to most humeral shaft fractures in cooperant patients.


Hemorrhagic stroke associated with essential thrombocythemia: Case report and literature review.
Hemorrhagic stroke associated with essential thrombocythemia (ET) is very infrequent. Herein, we report a case of a 33-year-old woman with a 2-year history of ET who developed intracerebral and subarachnoid hemorrhage. Angiography demonstrated severe vessel irregularity in the bilateral cerebral arteries. Molecular genetic testing revealed a calreticulin mutation. To our knowledge, hemorrhagic stroke has been reported in only six other patients with ET, and this is the first report of hemorrhagic stroke in an ET patient with a calreticulin mutation. We review the current literature and discuss the possible underlying mechanisms.


Antiplatelet activity of nifedipine is mediated by inhibition of NF-κB activation caused by enhancement of PPAR-β/-γ activity.
The transcription factor NF-κB, stimulates platelet aggregation through a non-genomic mechanism. Nifedipine, a voltage-gated L-type calcium channel blocker, is widely used to treat hypertension. Nifedipine also displays antiplatelet activity, but the underlying mechanisms involved remain unclear. This study was designed to investigate whether the antiplatelet effects of nifedipine are mediated by regulating NF-κB-dependent responses. Platelet aggregation was measured turbidimetrically using an aggregometer. NF-κB and PPAR activation, intracellular Ca2+ mobilization, PKCα activity, surface glycoprotein IIb/IIIa (GPIIb/IIIa) expression and platelet activation-related signalling pathways were determined in control and nifedipine-treated platelets in the presence or absence of PPAR antagonists or betulinic acid, a NF-κB activator. Exposure of platelets to nifedipine significantly increased the PPAR-β/-γ activity in activated human platelets. Treatment with nifedipine reduced collagen-induced NF-κB events, including the phosphorylation of IκB kinase-β, IκBα and p65NF-κB, which were markedly attenuated by GSK0660, a PPAR-β antagonist, or GW9662, a PPAR-γ antagonist. Furthermore, the interaction of PPAR-β/-γ with NF-κB and the PPAR-β/-γ-up-regulated NO/cGMP/PKG1 cascade may contribute to inhibition of NF-κB activation by nifedipine. Suppressing PPAR-β/-γ activity or increasing NF-κB activation greatly reversed the inhibitory effect of nifedipine on collagen-induced platelet aggregation, intracellular Ca2+ mobilization, PKCα activity and surface GPIIb/IIIa expression.CONCLUSIONS AND IMPLICATIONSPPAR-β/-γ-dependent inhibition of NF-κB activation contributes to the antiplatelet activity of nifedipine. These findings provide a novel mechanism underlying the beneficial effects of nifedipine on platelet hyperactivity-related vascular and inflammatory diseases.


Reported Church Attendance at the Time of Entry into HIV Care is Associated with Viral Load Suppression at 12 Months.
The Southeast has high rates of church attendance and HIV infection rates. We evaluated the relationship between church attendance and HIV viremia in a Southeastern US, HIV-infected cohort. Viremia (viral load ≥200 copies/ml) was analyzed 12 months after initiation of care. Univariate and multivariable logistic regression models were fit for variables potentially related to viremia. Of 382 patients, 74 % were virally suppressed at 12 months. Protective variables included church attendance (AOR 0.5; 95 % CI 0.2, 0.9), being on antiretroviral therapy (AOR 0.01; 95 % CI 0.004, 0.04), CD4(+) T lymphocyte count 200-350 cells/mm(3) at care entry (AOR 0.3; 95 % 0.1, 0.9), and education (AOR 0.5; 95 % CI 0.2, 0.9). Variables predicting viremia included black race (AOR 3.2; 95 % CI 1.4, 7.4) and selective disclosure of HIV status (AOR 2.7; 95 % CI 1.2, 5.6). Church attendance may provide needed support for patients entering HIV care for the first time.


Study on tumor microvasculature damage induced by alternate cooling and heating.
Tumor vasculature damage induced by various thermal treatments has been studied in vivo via laser confocal microscopy. Murine mammary carcinoma 4T1 was implanted in the nude mice dorsal skin fold window chamber. The implanted tumor was treated by alternate cooling and heating. Results showed that the treatment was much more effective as compared with that of cooling or heating alone, especially in damaging the tumor vasculature. In general, tumor vascular response to thermal stimuli was heterogeneous. All the treatments of hyperthermia at 42 degrees C (for 1 h), alternate cooling at 1 degrees C and heating at 42 degrees C (for 1/2 h each) and that of -10 degrees C/42 degrees C (for 1/2 h each) enhanced liposome extravasation. Pre-cooling tumor at 1 degrees C preserved most of the vascular integrity but partially inhibited the effect of post-hyperthermia at 42 degrees C. On the other hand, cooling at -10 degrees C for 1/2 h before heating at 42 degrees C caused severe vessel damage. Histo-pathological analyses further confirmed the effect as rare tumor vessel recurrence and large necrotic tumor tissue areas shown on the 7th day after the treatment.


Intracellular gradients of ion activities in the epithelial cells of the Necturus gallbladder recorded with ion-selective microelectrodes.
In Necturus gallbladder epithelial cells the intracellular electrical potential, as recorded with microelectrodes, varied from -28 mV in the mucosal end to about -50 mV in the serosal end of the transporting cell. The Na+ activity varied concurrently from about 39 mM to between 8 and 19 mM. Thus, within the cell both the recorded electrical and chemical gradients caused Na+ to move towards the serosal end. Serosal addition of ouabain (5 X 10(-4) M) caused the intracellular Na+ activity to attain electrochemical equilibrium within 30 min. However, the intracellular electrical potential gradient was only slowly affected. In cells from animals stored at 5 degrees C, the Cl- activity varied from about 55 mM in the mucosal end to 28 mM in the serosal end, and the K+ activity from 50 mM to between 95 and 131 mM. Both ions were close to electrochemical equilibrium within the cytoplasm but were too concentrated to be in equilibrium with the mucosal solution. Bubbling CO2 through the mucosal solution caused the intracellular gradients to vanish. When Na+ in the bathing solutions was exchanged for K+, the intracellular electrical potential became roughly constant at about -5 mV. The Cl- activity became constant in 65 mM, and the K+ activity became constant at 109 mM, both close to equilibrium with the mucosal solution. The Na+ activity was reduced to about 1 mM. The ratio of cytoplasmic resistivities between cells bathed in K+-rich saline to cells bathed in Na+-rich saline was measured by means of triple-barreled electrodes and compared to the same ratio as assessed from the activity measurements. The two values were equal only if one assumes the mobility of Na+ inside the cell to be less than 1/10 of the mobility of K+ or Cl-. The same conclusion was reached by comparing the intracellular Na+ flux calculated from the gradient of electrochemical potential to that flux assess from the net solute absorption. Animals kept at 15 degrees C had lower intracellular Na+ activities, higher Cl- and K+ activities, and higher rates of absorption than animals stored at 5 degrees C. Finally, the degree to which the intracellularly recorded electrical and chemical potentials could reflect an electrode artefact is discussed.


Anticoagulation and the risk of complications in ventricular tachycardia and premature ventricular complex ablation.
Many patients undergoing ventricular tachycardia (VT) or premature ventricular complex (PVC) ablation receive antithrombotic medications. Their uninterrupted use has the potential to affect complication rates. We assessed the incidence of complications in a large cohort of patients undergoing these procedures, according to antithrombotic medication use. From June 2014 to June 2016, 201 VT and PVC ablations were performed at a single center. We allocated patients to three groups: (A) anticoagulation group (international normalized ratio ≥ 1.5 or non-vitamin K anticoagulant or full-dose low-molecular-weight (LMW) heparin on day of procedure); (B) antithrombotic group (antiplatelet therapy and/or prophylactic LMW heparin on day of procedure); and (C) no antithrombotics group. We assessed periprocedural complication rates in each group. Multivariable analysis was performed. Group A (47 patients) had 8.5% procedural complication rate: one stroke, one pseudoaneurysm, one femoral artery occlusion, and one access site hematoma. In this group, 37 patients had femoral arterial and 18 had epicardial access. In Group B (46 patients), the complication rate was 6.5%: two cardiac tamponades and one pericardial effusion without compromise. Group C (108 patients) had a 5.6% complication rate: three cardiac tamponades (with one periprocedural death and one concomitant gastric vessel injury), one pericardial effusion without compromise, one stomach perforation, and two access site hematomas. Multivariable analysis did not show any significant predictors of complications, though age approached significance. Complication rates were not significantly different between groups. These findings suggest that VT and PVC ablation can be performed safely in patients with uninterrupted antithrombotic medications.


Egr2 and 3 maintain anti-tumour responses of exhausted tumour infiltrating CD8 + T cells.
Although T cells can develop into an exhausted state in the tumour microenvironment, tumour infiltrating T cells (TILs) are important to control tumour growth. By analysing single cell RNA-sequencing data from human tumours, we found that the transcription factors Early Growth Response 2 (EGR2) and 3 were highly induced in TILs, but not peripheral CD8 + T cells, in multiple patient cohorts. We found that deficiency of Egr2 and 3 in T cells resulted in enhanced tumour growth and fewer TILs in mouse models. Egr2 is highly expressed together with checkpoint molecules in a proportion of CD8 + TILs and Egr2high cells exhibit better survival and proliferation than Egr2-/-Egr3-/- and Egr2low TILs. Anti-PD-1 treatment increases Egr2 expression in CD8 + TILs and reduces tumour growth, while anti-PD-1 efficacy is abrogated in the absence of Egr2 and 3. Thus, Egr2 and 3 are important for maintaining anti-tumour responses of exhausted CD8 + TILs.


Haemodynamics and oxygen consumption in the dog during high epidural block with special reference to the splanchnic region.
High epidural block (Th I-IV) with bupivacaine was carried out in 16 dogs. Mean arterial blood pressure decreased to 52% of control value owing to nearly equal decreases in systemic vascular resistance and cardiac output. Portal venous blood flow decreased from 25.8 +/- 8.6 to 16.7 +/- 7.2 ml/kg b.w. X min-1 following epidural block, while hepatic arterial blood flow remained unchanged at 9.1 +/- 3.1 ml/kg b.w. X min-1 owing to a reduction in hepatic arterial resistance of 51%. Hepatic oxygen uptake was maintained during the epidural block through increased oxygen extraction. However, total oxygen uptake decreased by 18% and, in spite of this, arteriovenous oxygen content difference increased by 25%, indicating circulatory depression.


Diagnostic Trajectories in Primary Care at 12 Months: An Observational Cohort Study.
Little is known about the epidemiology of diagnosis in primary care. A prospective observational cohort study was conducted of adults presenting between August and December 2018 to primary care clinics across two health systems with an undiagnosed medical problem. Primary outcomes were (1) likelihood of a definitive diagnosis by 12 months and (2) time to diagnosis. Multivariate logistic regression was used to assess for factors associated with the likelihood of reaching a diagnosis, and multivariable Cox regression was used to assess for factors associated with time to diagnosis. Bivariate models were used to explore unadjusted relationships between the cases' organ systems and likelihood of and time to diagnosis. Among 410 cases in a diverse patient population, 206 (50.2%) reached a final diagnosis within 12 months, with a median time to diagnosis of 5 days (interquartile range = 0-46). Among these cases, 32.4% reached a diagnosis within the first month. A majority of cases not diagnosed within a month of the first presentation remained undiagnosed at 12 months. The likelihood of diagnosis and time to diagnosis did not differ by clinician or patient characteristics, clinicians' level of diagnostic uncertainty, chronicity of the medical issue, or visit type. There were no significant associations between organ system and likelihood of time to diagnosis. Patients presenting with new or unresolved problems in ambulatory primary care often remain undiagnosed after a year. There were no provider or patient-level variables associated with such lack of diagnosis. The causes, contributors, and consequences of lack of timely diagnosis and potential solutions require further research.


Otolaryngologic management of dizziness in the older patient.
Studies report that dizziness is the most common presenting symptom in older patients who seek primary care. To understand the causes of dizziness, which is one of the major risk factors in causing falls in the older population, basic anatomy and physiology are reviewed in this article. Age-specific histopathologic changes occur in the labyrinth of the inner ear. To display evidence of the patient's symptoms, evaluation must include a comprehensive history, neurotologic examination, and diagnostic testing. There are common disorders associated with dizziness; thus, management depends on the cause. Once a diagnosis is secured, treatment is instituted based on sound medical principles.


Ferruccio Ritossa's scientific legacy 50 years after his discovery of the heat shock response: a new view of biology, a new society, and a new journal.
The pioneering discovery of the heat shock response by the Italian scientist Ferruccio Ritossa reached maturity this year, 2012. It was 50 years ago that Professor Ritossa, through an extraordinary combination of serendipity, curiosity, knowledge and inspiration, published the first observation that cells could mount very strong transcriptional activity when exposed to elevated temperatures, which was coined the heat shock response. This discovery led to the identification of heat shock proteins, which impact many areas of current biology and medicine, and has created a new avenue for more exciting discoveries. In recognition of the discovery of the heat shock response, Cell Stress Society International (CSSI) awarded Professor Ritossa with the CSSI medallion in October 2010 in Dozza, Italy. This article is based on a session of the Fifth CSSI Congress held in Québec commemorating Professor Ritossa and his discovery.


Identifying potential surgical candidates in patients with evidence of bitemporal epilepsy.
To determine which patients with evidence of medically refractory bitemporal epilepsy are potentially good candidates for surgical therapy. We reviewed 42 adults with intractable seizures who were found to have bitemporal ictal onsets, based on scalp video-EEG long-term monitoring (LTM). All underwent invasive LTM before surgery. Surgical outcomes were classified as seizure free, >75% reduction in seizures, or <75% reduction in seizures, >or=1 year after resection. We related the following factors to outcome: (a). >75% preponderance of interictal scalp EEG discharges to one temporal region; (b). magnetic resonance imaging (MRI) findings; (c). lateralizing deficits on verbal or visual reproduction memory testing; and (d). memory failure with injection contralateral to side of surgery on Wada testing. Twenty-six (62%) of 42 patients had unilateral ictal onsets based on intracranial studies. Seizure freedom (occurring in 64% of this group), or >75% seizure reduction (found in 12% of subjects) occurred only when at least one of the following three factors was concordant with the side of surgery: preponderance of interictal scalp EEG discharges, unilateral temporal lesion on MRI, or lateralizing verbal or visual reproduction memory deficits on neuropsychological tests (p = 0.004). Seven subjects with bilateral ictal onsets based on intracranial studies had resections based on preponderance of seizures to one side, or other lateralizing noninvasive abnormality. Five of these (all of whom had >or=80% of seizures originating from one side) had >75% reduction in seizures. Invasive monitoring to pursue possible surgical therapy for patients with surface EEG evidence of bitemporal epilepsy may be justified only when some lateralizing feature is found in other noninvasive assessments.


Laminin, fibronectin and type IV collagen in BM-like material from cultured arterial smooth muscle cells.
1. The intra- and extracellular distribution of fibronectin and laminin was studied by immunofluorescence in cultures of rabbit and human arterial smooth muscle cells. 2. Basement membrane (BM)-like material was isolated from the cell layer of arterial smooth muscle cells cultures and analysed by sodium dodecyl sulphate gel electrophoresis (SDS-PAGE) and immunoblotting. The major 220-240 kD component of arterial BM-like material was identified as fibronectin. Also a 200 kD fibronectin band was observed. 3. The 200 kD subunit of laminin was contained in isolated BM-like material, but no slower migrating laminin chains were detected. 4. Collagens were prepared from pepsinized BM-like material. The band pattern as resolved by SDS-PAGE and silver staining suggested that type IV collagen is the major collagen of arterial BM-like material.


Analgesic use, blood dyscrasias, and case-control pharmacoepidemiology. A critique of the International Agranulocytosis and Aplastic Anemia Study.
The International Agranulocytosis and Aplastic Anemia Study (IAAAS) of analgesic-induced risks of blood dyscrasias represents the current "state of the art" in case-control pharmacoepidemiology. We present a conceptual framework for examining the goal, methods, and analysis of an epidemiologic study of drug risks and review the IAAAS within this framework. In our view, the new risk estimates reported by the IAAAS are not inherently more accurate than existing ones, nor have they been measured in clinically and sociodemographically relevant groups of patients over the anticipated course of therapy. Thus, the reported risks cannot be used to guide clinical or regulatory decisions concerning available treatment options for such patients. Furthermore, we believe that the IAAAS methods for selection of cases and controls, ascertainment of exposure, and data analysis may well have led to invalid estimates even for those risks that are reported. We hope that closer attention to the conceptual framework we suggest and the methodologic issues we raise will enable future case-control pharmacoepidemiologic studies to provide more useful and accurate answers to questions concerning the adverse effects of drugs.


A cool runaway greenhouse without surface magma ocean.
Water vapour atmospheres with content equivalent to the Earth's oceans, resulting from impacts1 or a high insolation2,3, were found to yield a surface magma ocean4,5. This was, however, a consequence of assuming a fully convective structure2-11. Here, we report using a consistent climate model that pure steam atmospheres are commonly shaped by radiative layers, making their thermal structure strongly dependent on the stellar spectrum and internal heat flow. The surface is cooler when an adiabatic profile is not imposed; melting Earth's crust requires an insolation several times higher than today, which will not happen during the main sequence of the Sun. Venus's surface can solidify before the steam atmosphere escapes, which is the opposite of previous works4,5. Around the reddest stars (Teff < 3,000 K), surface magma oceans cannot form by stellar forcing alone, whatever the water content. These findings affect observable signatures of steam atmospheres and exoplanet mass-radius relationships, drastically changing current constraints on the water content of TRAPPIST-1 planets. Unlike adiabatic structures, radiative-convective profiles are sensitive to opacities. New measurements of poorly constrained high-pressure opacities, in particular far from the H2O absorption bands, are thus necessary to refine models of steam atmospheres, which are important stages in terrestrial planet evolution.


Dietary restraint, attributional styles for eating, and preloading effects.
A total of 319 undergraduates completed the Restraint Scale and an Eating Attributional Style Questionnaire (EASQ). Subsequently, 101 female students participated in the classic preloading experiment. The results indicated that restrained eating was associated with an external locus of control attribution style, particularly for indulgent food consumption (ELCifc). Partial preloading effects for Restraint were found: The amount consumed increased as a function of Restraint in the preload condition. A more complete pattern of preloading was found for the ELCifc attribution style. In addition, the relationship between Restraint and food consumed in the preload condition was no longer significant with the ELCifc attribution style partialled out. The findings supported the hypotheses that: (a) restrained eaters display an external attribution style of learned helplessness and (b) related cognitions serve as a cause of preloading effects.


Working memory retrieval: contributions of the left prefrontal cortex, the left posterior parietal cortex, and the hippocampus.
Functional magnetic resonance was used to identify regions involved in the working memory (WM) retrieval. Neural activation was examined in two WM tasks: an item recognition task, which can be mediated by a direct- access retrieval process, and a judgement of recency task that require a serial search. Dissociations were found in the activation patterns in the hippocampus and in the left inferior frontal gyrus (LIFG) when the probe contained the most recently studied serial position (where a test probe can be matched to the contents of focal attention)compared to when it contained all other positions (where retrieval is required). The data implicate the hippocampus and the LIFG in retrieval from WM, complementing their established role in long-term memory. Results further suggest that the left posterior parietal cortex (LPPC) support serial retrieval processes that are often required to recover temporal order information. Together this data suggest that the LPPC, the LIFG, and the hippocampus collectively support WM retrieval. Critically, the reported findings support accounts that posit a distinction between representations maintained in and outside of focal attention, but are at odds with traditional dual-store models that assume distinct mechanisms for short- and long-term memory representation.


Store-operated Ca(2+) channels and Stromal Interaction Molecule 1 (STIM1) are targets for the actions of bile acids on liver cells.
Cholestasis is a significant contributor to liver pathology and can lead to primary sclerosis and liver failure. Cholestatic bile acids induce apoptosis and necrosis in hepatocytes but these effects can be partially alleviated by the pharmacological application of choleretic bile acids. These actions of bile acids on hepatocytes require changes in the release of Ca(2+) from intracellular stores and in Ca(2+) entry. However, the nature of the Ca(2+) entry pathway affected is not known. We show here using whole cell patch clamp experiments with H4-IIE liver cells that taurodeoxycholic acid (TDCA) and other choleretic bile acids reversibly activate an inwardly-rectifying current with characteristics similar to those of store-operated Ca(2+) channels (SOCs), while lithocholic acid (LCA) and other cholestatic bile acids inhibit SOCs. The activation of Ca(2+) entry was observed upon direct addition of the bile acid to the incubation medium, whereas the inhibition of SOCs required a 12 h pre-incubation. In cells loaded with fura-2, choleretic bile acids activated a Gd(3+)-inhibitable Ca(2+) entry, while cholestatic bile acids inhibited the release of Ca(2+) from intracellular stores and Ca(2+) entry induced by 2,5-di-(tert-butyl)-1,4-benzohydro-quinone (DBHQ). TDCA and LCA each caused a reversible redistribution of stromal interaction molecule 1 (STIM1, the endoplasmic reticulum Ca(2+) sensor required for the activation of Ca(2+) release-activated Ca(2+) channels and some other SOCs) to puncta, similar to that induced by thapsigargin. Knockdown of Stim1 using siRNA caused substantial inhibition of Ca(2+)-entry activated by choleretic bile acids. It is concluded that choleretic and cholestatic bile acids activate and inhibit, respectively, the previously well-characterised Ca(2+)-selective hepatocyte SOCs through mechanisms which involve the bile acid-induced redistribution of STIM1.


Promotion of neuronal cell adhesion by members of the IgLON family occurs in the absence of either support or modification of neurite outgrowth.
The IgLONs are a family of glycosyl phosphatidyl inositol-linked cell adhesion molecules which are thought to modify neurite outgrowth and may play a role in cell-cell recognition. The family consists of LAMP, OBCAM, neurotrimin/CEPU-1 and neurotractin/kilon. In this paper we report the effect of recombinant LAMP, CEPU-1 and OBCAM, and transfected cell lines expressing these molecules, on the adhesion and outgrowth of dorsal root ganglion (DRG) and sympathetic neurones. CHO cells transfected with cDNA for CEPU-1 adhered to a recombinant CEPU-1-Fc substrate. However, DRG or sympathetic neurones only adhered to CEPU-1-Fc when presented on protein A. Although DRG and sympathetic neurones express IgLONs on their surface, both types of neurones exhibited differential adhesion to CEPU-1-Fc, LAMP-Fc and OBCAM-Fc. Neither DRG nor sympathetic neurones extended neurites on a protein A/IgLON-Fc substrate and overexpression of CEPU-1-GFP in DRG neurones also failed to stimulate neurite outgrowth on an IgLON-Fc substrate. DRG neurones adhered to and extended neurites equally on transfected and non-transfected cell lines and the recombinant proteins did not modulate the outgrowth of neurones on laminin. In contrast to previous reports we suggest that IgLONs may not have a primary role in axon guidance but may be more important for cell-cell adhesion and recognition.


[The systemic modification of regional public health system for enhancing availability and quality of population medical care].
The article deals with the main directions in modernization of public health system of Irkutskaya oblast in 2011-2012. The major indicators to evaluate the overall effectiveness and efficacy of the proposed modernization program are discussed. The measures proposed can promote the systemic settlement of regional public health problems, increase the availability and enhance quality of medical care to population.


Validation of the chronic heart failure questionnaire (Chinese version).
A striking rise in the incidence and prevalence of congestive heart failure (CHF) in the Chinese population has been reported. While promoting the quality of life (QOL) of these patients is widely recognized as an important clinical priority, there is not a validated Chinese disease-specific QOL measure for CHF patients. The aim of this study was to validate the Chinese version of Chronic Heart Failure Questionnaire (CHQ-C) which measures the disease-specific QOL of patients with CHF. A sample of 110 CHF elderly patients and a comparison group of 64 healthy elderly people was recruited. Structured questionnaires were administered by a research nurse. Criterion and construct validity of CHQ-C was demonstrated by its significant correlation with the New York Heart Association classification (Spearman r = -0.52, p < 0.001) and the Chinese version of Hospital Anxiety and Depression scale (Pearson r = -0.74, p < 0.001), respectively. Known-groups comparison also demonstrated the ability of CHQ-C to differentiate the QOL of people with or without CHF. Confirmatory factor analysis supported the original four-factor structure of CHQ. In terms of internal consistency and test-retest reliability, CHQ-C demonstrated a Cronbach's alpha of 0.95 and an intraclass correlation coefficient (ICC) of 0.75, respectively. The responsiveness coefficient of CHQ-C was 0.63. In conclusion, CHQ-C is recommended as a valid and reliable tool for evaluating the QOL of Chinese patients with CHF.


The relationship between sodium concentrations in spot urine and blood pressure increases: a prospective study of Japanese general population: the Circulatory Risk in Communities Study (CIRCS).
Although several cross-sectional and intervention studies showed that sodium intake or excretion was associated with blood pressure levels, no prospective study has examined the long-term association between sodium excretion in spot urine and blood pressure changes. We conducted a prospective study of 889 normotensive subjects (295 men and 594 women, mean age 57.3 years) who underwent the baseline survey including spot urine test in 2005 and the follow-up survey in 2009 to 2011 (mean follow-up period: 5.8 years). We examined the association between sodium concentration in spot urine, a validated index of sodium excretion occurring over 24-h, and blood pressure changes between baseline and follow-up survey in all, non-overweight (body mass index(BMI) ≤ 25 kg/m(2)) and overweight normotensives. For all subjects, sodium concentrations in spot urine were not associated with either systolic or diastolic blood pressure changes. When stratified by BMI at baseline survey, sodium concentrations were positively associated with systolic blood pressure changes in non-overweight subjects, but not in overweight subjects. After adjustment for age, sex, BMI, alcohol intake status, current smoking and estimated glomerular filtration rate, the multivariable-adjusted mean values of the systolic blood pressure change among non-overweight subjects was +7.3 mmHg in the highest quartiles of sodium concentrations, while it was +3.9 mmHg in the lowest quartile (P for difference = 0.021, P for trend = 0.040). After further adjustment of baseline blood pressure levels, the association was slightly weakened; the multivariable-adjusted mean values of the systolic blood pressure changes were +7.0 mmHg and +4.2 mmHg (P for difference = 0.047, P for trend = 0.071). High sodium concentrations in spot urine were associated with subsequent systolic blood pressure increases among non-overweight normotensive individuals. (272 words).


Perioperative oxygen fraction - effect on surgical site infection and pulmonary complications after abdominal surgery: a randomized clinical trial. Rationale and design of the PROXI-Trial.
A high perioperative inspiratory oxygen fraction may reduce the risk of surgical site infections, as bacterial eradication by neutrophils depends on wound oxygen tension. Two trials have shown that a high perioperative inspiratory oxygen fraction (FiO(2) = 0.80) significantly reduced risk of surgical site infections after elective colorectal surgery, but a third trial was stopped early because the frequency of surgical site infections was more than doubled in the group receiving FiO(2) = 0.80. It has not been settled if a high inspiratory oxygen fraction increases the risk of pulmonary complications, such as atelectasis, pneumonia and respiratory failure. The aim of our trial is to assess the potential benefits and harms of a high perioperative oxygen fraction in patients undergoing abdominal surgery. The PROXI-Trial is a randomized, patient- and assessor blinded trial of perioperative supplemental oxygen in 1400 patients undergoing acute or elective laparotomy in 14 Danish hospitals. Patients are randomized to receive either 80% oxygen (FiO(2) = 0.80) or 30% oxygen (FiO(2) = 0.30) during surgery and for the first 2 postoperative hours. The primary outcome is surgical site infection within 14 days. The secondary outcomes are: atelectasis, pneumonia, respiratory failure, re-operation, mortality, duration of postoperative hospitalization, and admission to intensive care unit. The sample size allows detection of a 33% relative risk reduction in the primary outcome with 80% power. This trial assesses benefits and harms of a high inspiratory oxygen fraction, and the trial may be generalizable to a general surgical population undergoing laparotomy. ClinicalTrials.gov identifier: NCT00364741.


Influence of endogenous GM1 ganglioside on TrkB activity, in cultured neurons.
We verified the hypothesis that changes in the endogenous GM1 ganglioside density in the environment of TrkB, receptor of brain-derived neurotrophic factor, can affect receptor activity, and focused on rat cerebellar granule cells expressing both GM1 and TrkB. Changes of the amount of GM1 associated to immunoprecipitated TrkB and of receptor tyrosine phosphorylation were evaluated after treatment with phorbol-12-myristate-13-acetate (1 microM, 7 min), reported to affect the plasma membrane distribution of endogenous gangliosides in the same cells. After treatment, the amount of GM1 associated to receptor and TrkB phosphorylation decreased by about 40%. The amount of associated GM1 decreased by about 33% also after concomitant treatment with phorbol ester and brain-derived neurotrophic factor, but in this case the neurotrophin was unable to enhance receptor tyrosine phosphorylation. These results for the first time suggest that changes in the amount of endogenous GM1 in the environment of TrkB can modulate receptor activity, and offer new clues for a better understanding of physiological and pathological events of the nervous system.


Paeoniflorin protects NOD mice from T1D through regulating gut microbiota and TLR4 mediated myD88/TRIF pathway.
This study aimed to explore the effect of PF in regulating the progression of T1D through regulating gut microbiota and inhibiting TLR4-myD88/TRIF pathway. T1D mouse models were established and received PF treatment through intraperitoneal injection. The glucose, sugar tolerance, the incidence of T1D and H&E staining were detected to verify the effect of PF on T1D. Meanwhile, the changes of gut microbiota and the permeability of intestines in mice were also measured. On parallel, the number and function of immune cells were detected by Flow Cytometry. The expressions of ZO-1, ZO-2 and TLR4-myD88/TRIF pathway related proteins were detected by western blotting. Mice received PF treatment had decreased incidence of T1D and inflammatory infiltration in islet tissues compared with those received PBS treatment. In addition to that, PF treated mice had increased Sutterella species and decreased intestinal permeability, in which the decreased ratio of Th1/Th17 and increased Treg cells were also identified. The expression of TLR4-myD88/TRIF pathway was also suppressed in response to PF treatment. Moreover, further treatment with TLR4 agonist, LPS, could reverse the effect of PF on T1D mice. PF can suppress the TLR4 mediated myD88/TRIF pathway to change the distribution of gut microbiota, so as to protect NOD mice from T1D.


Application of a multi-channel in-situ infrared spectroscopy: The case of LLM-105.
The thermal decomposition process of 2,6-diamino-3,5-dinitropyrazine-1-oxide(LLM-105)under several constant temperatures (100 °C, 115 °C, 130 °C, and 145 °C) have been studied by a multi-channel in-situ reaction system. Almost 1000 spectra were obtained within 24 days by Fourier-transform infrared spectroscopy (FT-IR). The thermal decomposition activation energies (Eα) of C-NH2 and C-NO2 in LLM-105 were calculated by the Arrhenius equation to be 89.65 and 145.09 kJ mol-1, respectively. The thermal decomposition process of LLM-105 under long-term constant temperature is divided into two paths: intramolecular H-transfer and C-NO2 partition. It is feasible to study the aging process of materials using a combination of a multi-channel in-situ reaction system and FT-IR, which can effectively monitor the evolution of structure.


Happy and healthy only if occupied? Perceptions of health sciences students on occupation in later life.
In this study, we bring attention to the university education of health science students with respect to occupation in later life. Our goal was to provide descriptive data from narratives of a group of undergraduate students and initiate discussion about the place of occupation in the context of ageing to answer the following questions: (i) How young people perceive successful ageing in relation to occupation? and (ii) can spirituality-related activities be considered occupations in later life? Based on a thematic selection, the quality of photographs and reflective narratives, 60 Photovoice assignments created by health sciences students were analysed using content analysis. The findings of this study indicate that students seem to neglect the benefits of 'being' through spiritual engagement, and instead emphasise the importance of 'doing', and perpetuate pervasive successful ageing discourses in Western societies. Occupational therapists have potential to take an active role in undergraduate health science education and to inform the development of holistic models that would include spirituality as an avenue to live late life to its fullest potential. Photovoice emerged as a powerful teaching method to increase awareness, empathy and compassion of young adults towards ageing.


Discriminating the direction of second-order motion at short stimulus durations.
We measured the ability of human observers to discriminate the direction of motion of different spatial patterns presented for durations ranging from 0.021 to 0.67 sec. The patterns were: (1) a vertical grating (spatial frequency 0.93 c/deg at 5% contrast); (2) a "beat" pattern made by adding vertical gratings of 6.3 and 5.4 c/deg both at 5% contrast moving in opposite directions (this pattern appears as a horizontally moving, 0.93 c/deg "beat"; i.e. spatial variation in the contrast of a stationary vertical grating of 5.8 c/deg); and (3) a "plaid" pattern made by adding gratings of 5.9 c/deg orientated +/- 81 deg from vertical (this pattern can also be expressed as a horizontally moving 1.9 c/deg beat in a horizontal grating of 5.8 c/deg). The direction of motion of the grating and the plaid pattern were discriminable at all durations tested. The direction of motion of the beat could only be discriminated at durations above approx. 200 msec. We suggest that this is a consequence of the fact that the moving beat is only visible to second-order mechanisms, and that second-order mechanisms for the analysis of motion operate more slowly than first-order mechanisms.


Assessment of the relationship between the level of patient knowledge on warfarin therapy and the quality of oral anticoagulation: A systematic review and meta-analysis.
The present study aimed to investigate the relationship between the level of patient knowledge on warfarin therapy and the quality of oral anticoagulation. This is a systematic review and meta-analysis written on the basis of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Searches at MEDLINE, EMBASE, Scopus and LILACS electronic databases were carried out on February 13, 2023, using the descriptors "Patient Medication Knowledge", "Patient Education as Topic", "Health Education", "Patient Education" and Warfarin. The steps of selection, data extraction and quality analysis of articles were performed independently by two reviewers. The analysis was performed considering patient knowledge as a possible modifier of time in therapeutic range (TTR). The meta-analysis included studies that reported the correlation coefficient (Pearson or Spearman) between patient knowledge and TTR. A subgroup analysis was performed according to questionnaires employed to measure patient knowledge. Twelve studies were selected with an overall sample size of 7634 participants and mean age 58.2 (standard deviation (SD)±12,8) years. Eleven (92.0%) cross-sectional studies. The mean TTR was 57.8% (SD±11,3%) and the average level of knowledge was 60.4%. The meta-analysis indicated that patient level of knowledge on warfarin therapy was moderately associated with TTR (rs = 0.435; 95% confidence interval (CI) = 0.163-0.645; I2 = 96%). Subgroup analysis indicated association between knowledge level and TTR in studies employing the OAK test (rs = 0.617; 95% CI = 0.192-0.847; I2 = 97%) and the AKA (rs = 0.269; 95% CI = 0.002 to 0.501; I2 = 94%). However, the subgroup analysis presented no significant difference between them (p = 0.14). The meta-regression showed a non-significant negative effect of age on the correlation (estimate = -0.028, 95% CI = -0.073 to 0.016, p = 0.207). No publication bias was noted (p = 0.881). To our knowledge, this is the first systematic review and meta-analysis gathering evidence about the relationship between the level of patient knowledge on oral anticoagulation with warfarin and TTR. The implementation of structured and patient-centered educational interventions is essential to effectively increase the level of patient knowledge and, thus, to improve the quality and safety of warfarin therapy. Systematic review registration number: PROSPERO CRD42023398030.


Controlling the Chimera Form in the Leaky Integrate-and-Fire Model.
We study the influence of broken connectivity and frequency disorder in systems of coupled neuronal oscillators. Under nonlocal coupling, systems of nonlinear oscillators, such as Kuramoto, FitzHugh-Nagumo, or integrate-and-fire oscillators, demonstrate nontrivial synchronization patterns. One of these patterns is the "chimera state," which consists of coexisting coherent and incoherent domains. In networks of biological neurons, the connectivity is not always perfect, but might be locally broken or interrupted due to pathologies, neuron degenerative disorders, or accidents. Our simulations show that destructed connectivity drastically affects synchronization, driving the coherent parts of the chimera state to cover symmetrically the region where the anomaly is located. The network synchronization decreases with the size of the destructed region as evidenced by the Kuramoto synchronization index. To the contrary, when keeping the connectivity of all nodes intact, altering the frequency in a block of oscillators drives the incoherent part of the chimera state toward the anomaly. This work is in line with recent dynamical approaches aiming to locate anomalies in the structure of brain networks, in particular when the anomalies have small, difficult-to-detect sizes.


Differential analysis of peripheral blood- and bone marrow-derived endothelial progenitor cells for enhanced vascularization in bone tissue engineering.
For tissue engineering applications, effective bone regeneration requires rapid neo-vascularization of implanted grafts to ensure the survival of cells in the early post-implantation phase. Incorporation of autologous endothelial progenitor cells (EPCs) for the promotion of primitive vascular network formation ex vivo has offered great promise for improved graft survival, enhanced rate of vascularization and bone regeneration in vivo. For clinical usage, identification of an optimal EPC isolation source from the patient is critical. We have, for the first time, characterized and directly compared EPCs from rabbit peripheral blood and bone marrow (PB-EPCs and BM-EPCs, respectively). PB-EPCs outperformed BM-EPCs on all measures. PB-EPCs displayed typical endothelial cell markers, such as CD31, as well as high angiogenic potential in three-dimensional extracellular matrix in vitro. Furthermore, PB-EPCs cultured simultaneously with mesenchymal stem cells, displayed significantly enhanced expression levels of key osteogenic and vascular markers, including alkaline phosphatase, bone morphogenetic protein 2, and vascular endothelial growth factor. On the contrary, putative BM-EPCs did not express CD31, and instead, expressed key smooth muscle markers. BM-EPCs further failed to display vasculogenic activity. Hence, the highly angiogenic PB-derived EPCs may serve as an ideal cell population for enhanced vascularization and success of engineered bone tissue.


Mammalian reproductive strategies: A generalized relation of litter size to body size.
A generalized relationship of litter size to mammalian body size was predicted by a graph model. The model was used to generate hypotheses explaining specific features of variation in gestation time, relative litter weight, birth weight, and reproductive capacity. The predictions were tested by means of data from the literature.Mammals were assumed to maximize neonatal survival of offspring to the limits allowed by litter weight per female body weight. Gestation time correlated negatively with the foetal growth rate of relative litter weight. Gestation time did not correlate with the foetal growth rate of individual offspring.Relative litter weight correlated negatively with adult body weight. This relationship was explained by the higher assimilation rate per unit weight relative to metabolic rate in small mammals.Birth weight correlated positively with body weight. However, small mammals produce larger offspring than predicted by the linear relationship of birth weight to body weight in large mammals. There is obviously a minimum birth weight which cannot be decreased without special arrangements for parental care.The prediction of the relationship of litter size to body size was derived from the relations of relative litter weight and birth weight to body weight. In small mammals (less than 1 kg) litter the correlation was negative. When litter size was compared with body length, the correlation was positive in small mammals (less than 30 cm) and negative in large mammals. In both sets of data there was a negative overall correlation between litter size and body size.Reproductive capacity, defined as the number of offspring per season, correlated negatively with life-span.


Laparoscopic gastric bypass in patients on thyroid replacement therapy for subnormal thyroid function - prevalence and short-term outcome.
Hypothyroidism is associated with increased body weight. Weight gain may occur despite normal levels of serum thyroid stimulating hormone (TSH) and thyroxine (T4) achieved by replacement therapy. We evaluated the prevalence of patients on thyroid replacement for subnormal thyroid function who were operated on for morbid obesity and monitored their postoperative weight loss pattern. Data was identified from a prospectively accrued database of patients undergoing laparoscopic Roux-en-Y gastric bypass (LRYGBP) or laparoscopic adjustable gastric banding (LAGB) for morbid obesity from February 2000 to November 2001. All patients with subnormal thyroid function, diagnosed by past thyroid function tests and treated by an endocrinologist, who were on thyroid replacement therapy, were identified; 5 of these were matched for age, gender, preoperative body mass index (BMI) and surgical procedure (LRYGBP) to 5 non-hypothyroid patients. Weight loss at 3 and 9 months after surgery was compared between the 2 groups. 192 patients underwent LRYGBP (n=155) or LAGB (n=37). Of the 21 patients (10.9%) on thyroid replacement identified, 14 were primary, 4 were postablative, and 3 were post-surgical; 17 underwent LRYGBP. All patients had normal preoperative serum levels of TSH and T4. Comparison of the 2 matched groups of patients revealed no difference in weight loss at 3 and 9 months after surgery (P=1.0). The prevalence of euthyroid patients on thyroid replacement for subnormal thyroid function who undergo surgical intervention for morbid obesity is high. Short-term weight loss in these patients is comparable to normal thyroid patients. Longer follow-up may be necessary to demonstrate the weight loss pattern in this group.


Effects of exposure to single and multiple parabens on asthma development in an experimental mouse model and a prospective cohort study.
Parabens are widely used preservatives present in consumer products like cosmetics and food. Although several epidemiological studies suggest that early-life exposure to parabens might alter the immune response and allergy risk in childhood, the evidence with respect to asthma is not clear. Therefore, we investigated the effect of paraben exposure on asthma development in mice and humans. Using a murine asthma model the experimental data show both, an asthma-reducing effect after direct exposure of adult mice to n-butyl paraben (nBuP) as well as an asthma-promoting effect after maternal exposure to ethyl paraben (EtP) in the female offspring. Interestingly, exposure of mice to a mixture of EtP and nBuP starting prenatally until the end of asthma induction in the adult offspring was without effect on allergic airway inflammation. In addition, parabens were determined within the German prospective mother-child cohort LINA and their single and mixture effect on asthma development in children within the first 10 years of life was estimated by logistic and Bayesian kernel machine regression (BKMR). Both approaches revealed no adverse effects of parabens on children's asthma development, neither when stratified for being at risk due to a positive family history of atopy nor when analysed separately for sex specificity. Therefore, we conclude that although single parabens might differentially impact asthma development, an adverse effect could not be seen in a multiple paraben exposure setting. Consequently, not only the time point of exposure but also multiple exposure scenarios to parabens should be considered in the evaluation of individuals' specific disease risk.


5-Azacytidine-induced undercondensations in human chromosomes.
The cytosine analogue 5-azacytidine induces very distinct undercondensations in human chromosomes if applied to lymphocyte cultures. The number of induced undercondensations and their chromosomal localization can be varied by the 5-azacytidine dose and the treatment time. "Pulverized" chromosomes or undercondensations in the G-band-positive chromosome regions are produced with high doses and long treatment times. If applied in low doses during the last hours of culture, 5-azacytidine induces specific undercondensations in the heterochromatin of chromosomes 1, 9, 15, 16, and Y. Optimum conditions required for inducing the various types of undercondensation in the chromosomes were determined. Various examples of the use of 5-azacytidine in the analysis of chromosome rearrangements involving heterochromatic regions are presented.


The OptiMARK clinical development program: summary of safety data.
To describe and summarize the safety data from the OptiMARK clinical development program. In the 18 clinical studies comprising the clinical program, doses ranging from 0.1 to 0.7 mmol/kg were administered to healthy adult volunteers, patients with hepatic or renal impairment, and patients with confirmed or highly suspected central nervous system (CNS), liver, breast, vascular, bone, or soft tissue pathologies. A total of 2038 injections of OptiMARK, Magnevist, or placebo were administered to 1684 subjects. Safety assessments were performed at appropriate intervals during all Phase 1, 2, and 3 studies. Of the 1684 subjects exposed to a study drug or placebo in the clinical development program, 646 subjects experienced 1293 adverse events. Thirty-one percent of the OptiMARK injections were associated with an adverse event. In comparison, 35% of Magnevist injections and 48% of placebo injections were associated with at least one adverse event. OptiMARK was safe and well-tolerated with a safety profile similar to that of Magnevist.


Studies on the F-actin.tropomyosin.troponin complex. II. Partial reconstitution of thin filament by F-actin, tropomyosin and the tropomyosin binding component of troponin (TN-T).
It was found that thin filaments are reconstituted from F-actin, tropomyosin and the tropomyosin binding component of troponin (TN-T) in vitro according to a self-assembly mechanism. Although a gel structure is formed when the three proteins are mixed in the order F-actin, TN-T and tropomyosin, it is in a metastable state and spontaneously transforms to dispersed filaments in an equilibrium state. The rate of the transformation is largely dependent on temperature. When the mixing order of TN-T and tropomyosin is reversed, large amounts of the complex appear immediately in the dispersed filament form. Dependence on the order of mixing is observed only when the molar ratio of TN-T to tropomyosin is about one, i.e. at the physiological ratio. When the molar ratio of TN-T to tropomyosin is either above or below one, a stable gel form or a stable dispersed filament form, was respectively, obtained independently of the mixing order of the three proteins.