Depressive disorders: Processes leading to neurogeneration and potential novel treatments.
Mood disorders are wide spread with estimates that one in seven of the population are affected at some time in their life (Kessler et al., 2012). Many of those affected with severe depressive disorders have cognitive deficits which may progress to frank neurodegeneration. There are several peripheral markers shown by patients who have cognitive deficits that could represent causative factors and could potentially serve as guides to the prevention or even treatment of neurodegeneration. Circadian rhythm misalignment, immune dysfunction and oxidative stress are key pathologic processes implicated in neurodegeneration and cognitive dysfunction in depressive disorders. Novel treatments targeting these pathways may therefore potentially improve patient outcomes whereby the primary mechanism of action is outside of the monoaminergic system. Moreover, targeting immune dysfunction, oxidative stress and circadian rhythm misalignment (rather than primarily the monoaminergic system) may hold promise for truly disease modifying treatments that may prevent neurodegeneration rather than simply alleviating symptoms with no curative intent. Further research is required to more comprehensively understand the contributions of these pathways to the pathophysiology of depressive disorders to allow for disease modifying treatments to be discovered.


Exploring Adult Learners' Viewpoints and Motivation Regarding Distance Learning in Medical Education.
Literature in education and training supports the notion that distance learning (DL) is the most effective mode of learning for health care workers to improve the quality of patient care. However, implementing DL requires pre-assessing learners' perspectives and attitudes for providing better delivery, essential support, and facilities. This study aimed to identify the viewpoints and attitudes of dental graduates toward DL in medical education and their point views of the effectiveness and efficacy of DL tools. A structured, self-administered questionnaire was distributed to registered adult graduates working in government- or private hospitals in a permanent position or for a long term (3 months or more). Data were collected and analyzed. Two-thirds (67.9%) of the participants had previously attended a DL course. The highest ranked items on the participants' views on DL were ease of access, ability to take the course from any location, and be taught from anywhere in the world. Their perception of DL was analyzed in relation to gender and previous exposure to DL. This investigation revealed a positive attitude among graduates on the effectiveness of DL. Most respondents appreciated DL's convenience in terms of time flexibility and online attendance. Residents' attitudes toward DL and DL characteristics are major factors to consider when instituting or planning for DL. Continuous medical education through DL will continue to generate considerable interest as an international movement.


Complementation of human immunodeficiency virus glycoprotein mutations in trans.
The external glycoproteins of human immunodeficiency virus type 1 (HIV-1) (gp120) and HIV-2 (gp105) are responsible for binding the cellular receptor CD4. The proteins are functionally identical although their affinity for CD4 varies, with gp120 binding 10- to 20-fold more efficiently than gp105. To investigate the structural requirements for CD4 binding in each molecule we have constructed a number of hybrid glycoproteins in which sequences are exchanged between the two molecules via conserved residues and subsequently tested for their ability to bind to CD4. We found that two constructs in which the V1/V2 or V3 loops of gp105 are exchanged for those of gp120 continue to bind to CD4. Surprisingly, however, all other domain exchange mutants failed to bind to CD4 suggesting that long-range interactions within the molecule are sequence-specific. Mixing mutant molecules in vitro did not rescue CD4 binding. However, co-expression of a number of mutant glycoprotein pairs within the same cell produced complementation of CD4 binding ability; complementing molecules were shown to be heteromeric in structure. Alignment of the molecules within each complementation group allowed the interactive sequences necessary for receptor binding to be determined. These sequences constitute a novel target for the disruption of gp120 function.


An effective model for reorganization of perinatal services in a metropolitan area: a descriptive analysis and historical perspective.
The expansion and development of regionalized perinatal care has faltered during the past 10 years as clinical and financial polarization created by institutional and individual competition has supplanted original ethical and altruistic precepts. An integrated practice model is described for the reorganization of perinatal services on the basis of findings from nine community hospitals with level II nurseries developed and administered by a private practice group of neonatologists functioning in coordination with established university level III facilities and staff. Nine hospitals (seven private and two affiliated with a health maintenance organization) were located in urban and suburban communities in two counties within a 725-square-mile area encompassing a greater metropolitan area. Guidelines were created to define the level of care provided at each hospital. All neonates, including infants who had intended delivery at estimated gestational ages > or = 32 weeks, were at least initially provided care at their community hospital. Neonates who required assisted ventilation, surgical intervention, evaluation for suspected cardiac disease, or selective diagnostic procedures were transferred to one of the tertiary facilities. Gestational age and birth weight specific categories for the 36,014 neonates delivered in 1988 to 1989 at the community practice hospitals are delineated for need of transport from level II to level III unit, deaths, and percent survival. Retrospective comparison of the community hospitals before and after establishment of the practice demonstrated a significant decrease in infants transported to a higher level of care and increase in neonates returned from level III to II units. Associated with improved capability of these level II nurseries was a reduction in mortality of neonates with diagnoses consistent with potential viability. Strict adherence to practice guidelines for maternal transfer resulted in significant reductions in delivery of low birth weight and very low birth weight neonates at level II community practice hospitals. The safety, efficacy, and potential cost effectiveness of this community hospital practice is discussed as a viable alternative model to the current widespread competitive disorganization that now characterizes regionalization of most metropolitan perinatal services.


Properties of an almost localized Fermi liquid in an applied magnetic field revisited: a statistically consistent Gutzwiller approach.
We discuss the Hubbard model in an applied magnetic field and analyze the properties of neutral spin-[Formula: see text] fermions within the so-called statistically consistent Gutzwiller approximation. The magnetization curve reproduces in a semiquantitative manner the experimental data for liquid (3)He in the regime of moderate correlations and in the presence of a small number of vacant cells, modeled by a non-half-filled band situation, when a small number of vacancies (∼5%) is introduced in the virtual fcc lattice. We also present the results for the magnetic susceptibility and the specific heat, in which a metamagnetic-like behavior is also singled out in a non-half-filled band case.


Pycnogenol® Supplementation Attenuates Memory Deficits and Protects Hippocampal CA1 Pyramidal Neurons via Antioxidative Role in a Gerbil Model of Transient Forebrain Ischemia.
Pycnogenol® (an extract of the bark of French maritime pine tree) is used for dietary supplement and known to have excellent antioxidative efficacy. However, there are few reports on neuroprotective effect of Pycnogenol® supplementation and its mechanisms against ischemic injury following transient forebrain ischemia (TFI) in gerbils. Now, we examined neuroprotective effect and its mechanisms of Pycnogenol® in the gerbils with 5-min TFI, which evokes a significant death (loss) of pyramidal cells located in the cornu ammonis (CA1) region of gerbil hippocampus from 4-5 days post-TFI. Gerbils were pretreated with 30, 40, and 50 mg/kg of Pycnogenol® once a day for 7 days before TFI surgery. Treatment with 50 mg/kg, not 30 or 40 mg/kg, of Pycnogenol® potently protected learning and memory, as well as CA1 pyramidal cells, from ischemic injury. Treatment with 50 mg/kg Pycnogenol® significantly enhanced immunoreactivity of antioxidant enzymes (superoxide dismutases and catalase) in the pyramidal cells before and after TFI induction. Furthermore, the treatment significantly reduced the generation of superoxide anion, ribonucleic acid oxidation and lipid peroxidation in the pyramidal cells. Moreover, interestingly, its neuroprotective effect was abolished by administration of sodium azide (a potent inhibitor of SODs and catalase activities). Taken together, current results clearly indicate that Pycnogenol® supplementation can prevent neurons from ischemic stroke through its potent antioxidative role.


Increased expression of complement regulators CD55 and CD59 on peripheral blood cells in patients with EAHEC O104:H4 infection.
An outbreak of Shiga Toxin 2 (Stx-2) producing enterohemorrhagic and enteroaggregative E.coli (EAHEC) O104H4 infection in May 2011 caused enterocolitis and an unprecedented high 22% rate of hemolytic uremic syndrome (HUS). The monoclonal anti-C5 antibody Eculizumab (ECU) has been used experimentally in EAHEC patients with HUS but treatment efficacy is uncertain. ECU can effectively prevent hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) caused by a lack of complement-regulating CD55 and CD59 on blood cells. We hypothesized a low expression of CD55 and CD59, as seen in PNH, might correlate with HUS development in EAHEC patients. 76 EAHEC patients (34 only gastrointestinal symptoms [GI], 23: HUS, 19: HUS and neurological symptoms [HUS/N]) and 12 healthy controls (HC) were tested for the expression of CD55 and CD59 on erythrocytes and leukocytes retrospectively. Additionally, the effect of Stx-2 on CD55 and CD59 expression on erythrocytes and leukocytes was studied ex vivo. CD55 expression on erythrocytes was similar in all patient groups and HC while CD59 showed a significantly higher expression in HUS and HUS/N patients compared to HC and the GI group. CD55 and CD59 expression on leukocytes and their subsets was significantly higher in all patient groups compared to HC regardless of treatment type. However, CD59 expression on erythrocytes was significantly higher in HUS and HUS/N patients treated combined with plasma separation (PS) and ECU compared to HC. Adding Stx-2 ex vivo had no effect on CD55 and CD59 expression on leukocytes from HC or patients. HUS evolved independently from CD55 and CD59 expression on peripheral blood cells in EAHEC O104:H4 infected patients. Our data do not support a role for CD55 and CD59 in HUS development during EAHEC O104:H4 infection and point to a different mechanism within the complement system for HUS development in EAHEC patients.


Systems analysis of energy metabolism elucidates the affected respiratory chain complex in Leigh's syndrome.
Leigh's syndrome is a complex neurological disease with little known correlation between causes and symptoms. Mutations in pyruvate dehydrogenase and electron transport chain complexes have been associated with this syndrome, although the identification of affected enzymes is difficult, if not impossible, with non-invasive clinical tests. In this study, isotopomer analysis is used to characterize the metabolic phenotype of normal and Leigh's syndrome fibroblasts (GM01503), thereby identifying affected enzymes in the diseased cells. Fibroblasts are grown with DMEM media enriched with (13)C labeled glucose. Amino acids from media and proteins as well as lactate are analyzed with GC-MS to identify their label distributions. A computational model accounting for all major pathways in fibroblast metabolism (including 430 metabolites and 508 reactions) is built to determine the metabolic steady states of the normal and Leigh's cell lines based on measured substrate uptake and secretion rates and isotopomer data. Results show that (i) Leigh's syndrome affected cells have slower metabolism than control fibroblasts as evidenced by their overall slower substrate utilization and lower secretion of end products; (ii) intracellular fluxes predicted by the models, some of which are validated by biochemical studies published in the literature, show that the respiratory chain in Leigh's affected cells can produce ATP at a similar rate as the controls, but with a more restricted flux range; and (iii) mutations causing the defects observed in the Leigh's cells are likely to be in succinate cytochrome c reductase.


Prevalence and dissemination of oqxAB in Escherichia coli isolates from animals, farmworkers, and the environment.
OqxAB has recently been identified as one of the mechanisms of plasmid-mediated quinolone resistance (PMQR). Compared to what is observed for other PMQR determinants, there is a paucity of data with regard to the prevalence and epidemiology of OqxAB and its contribution to resistance to different antimicrobials. In this study, the prevalence and dissemination of oqxAB and other PMQR genes in Escherichia coli isolates from animals, farmworkers, and the environment in 2002 in China were investigated. Of the 172 E. coli isolates, 39.0% carried oqxA, while only 4.1%, 2.9%, and 0.6% carried qnr (1 qnrB6 isolate, 5 qnrS1 isolates, and 1 qnrD isolate), qepA, and aac(6')-Ib-cr, respectively. Among the 33 isolates from farmworkers, 10 (30.3%) were positive for oqxA. oqxAB was associated with IS26 and was carried on the 43- to 115-kb IncF transferable plasmid. Transconjugants carrying oqxAB showed 4- to 16-fold increases in the MICs of quinolones, 16- to 64-fold increases in the MICs of quinoxalines, 8- to 32-fold increases in the MICs of chloramphenicol and trimethoprim-sulfamethoxazole, and 4- to 8-fold increases in the MICs of florfenicol compared to the levels for the recipient. The pulsed-field gel electrophoresis (PFGE) analysis showed that the high levels of prevalence and dissemination of oqxAB in E. coli in animal farms were primarily due to the transmission of plasmids carrying oqxAB, although clonal transmission between human and swine E. coli isolates was observed. It is concluded that oqxAB was widespread in animal farms in China, which may be due to the overuse of quinoxalines in animals. This study warrants the prudent use of quinoxalines in food animals.


Proventriculotomy in ostriches: 18 cases (1990-1992).
Over a 3-year period, proventriculotomy was performed on 18 ostriches to relieve impaction of the proventriculus. Diagnosis was confirmed by abdominal palpation, abdominal radiography, and in some cases, exploratory proventriculotomy. In addition to proventriculotomy, an esophagotomy was performed in 5 birds that were debilitated to allow force-feeding during the postoperative period. The median age of ostriches treated surgically for proventricular impaction was 7.5 months (range, 3 months to 18 years). Impactions consisted of sand, rocks, or gravel in combination with grass, leaves, wood, or other fibrous materials. In 7 birds, small pieces of wire or nails were also removed from the proventriculus. In 1 bird, a large metal punch was removed via the proventriculotomy. Six ostriches died at the hospital in the immediate postoperative period. Four of these died within 24 hours of surgery. All 4 birds were emaciated and in a severely weakened condition at admission, and they continued to deteriorate after surgery. One bird died 8 days after surgery as a result of complications associated with a septic joint unrelated to the proventriculotomy procedure. Another bird was euthanatized 6 days after surgery because its condition failed to improve and the owners did not want to pursue further treatment because of expense. Follow-up information was obtained for 12 surviving ostriches 1 week to 29 months (median, 5.5 months) after they were discharged from the hospital. Four of the 12 birds died within 30 days of discharge from the hospital. The remaining 8 birds (44%) were alive at follow-up evaluation (median, 10.5 months after surgery; range, 5 to 29 months).(ABSTRACT TRUNCATED AT 250 WORDS)


The substance of love when encountering suffering: an interpretative research synthesis with an abductive approach.
This study presents the results of an interpretative research synthesis undertaken to explore the essence of love when encountering suffering. The idea of caring as an expression of love and compassion belongs with ideas that have shaped caring for hundreds of years. Love and suffering are the core concepts in caring science and thus demand a basic research approach. The synthesis was undertaken by the interpretation of 15 articles focusing on love in different aspects, but within a caring science perspective. The research process was guided by a hermeneutical perspective with an abductive approach. The substance of love, when encountering suffering, reveals itself in three themes: love as a holy power, love as fundamental for being and love as an ethical act, which are to be found, respectively, within three dimensions: love as holiness, love as a communion and love as an art. Love is a holy power and encompasses everything; it is the well of strength that heals. No human can exist without love: this points to the ethical responsibility one has as a neighbour. In the ethical act, love is evident in concrete caring actions. The core of the substance of love within the three dimensions can be understood as agape. Agape connects and mirrors the dimensions, while at the same time it is clear that agape stems from and moves towards holiness, enabling love to be the ethical foundation when encountering suffering. Through the dimensions of love as communion and love as an art agape intertwine with eros forming caritas enabling the human being to move towards the dimension of holiness, which signifies becoming through suffering.


"Being Holistic Is a Lot to Ask": A Qualitative, Cross-National Exploration of Occupational Therapists' Perceptions and Experiences of Holistic Practice.
Being holistic is often used by occupational therapists to describe their practice and philosophy worldwide. This study explores the perspectives of 33 occupational therapists, working in 13 different countries, on their understanding of holistic epistemology and practice and how they seek to incorporate holism in their work. On the basis of a qualitative study design, individual interviews were conducted with the participants by 18 Norwegian undergraduate occupational therapy students, supported by their supervisors. The authors subsequently analyzed the transcribed data, using a thematic analysis approach. Three principal themes emerged: (1) holism as a broad and narrow concept, (2) being holistic spans from treating body parts to teaching marginalized children, and (3) being holistic is a lot to ask. When talking about holism and holistic practice, participants described their holistic practices in various ways, and their accounts reflected different understandings and cultural contexts. Participants characterized a holistic approach as one emphasizing the importance of occupations and activities and helping patients regain independence in their everyday lives. However, they also highlighted the specific challenges they faced, including cultural factors and inadequate resources. Significantly, participants from both Western and non-Western contexts emphasized the importance of holistic practice, suggesting that a dichotomous understanding of Eastern versus Western philosophical approaches does not necessarily make sense in occupational therapy interventions. Therapists' degree of commitment to client-centered practice appears of greater relevance. With its international perspective, our study sheds light on important areas of contemporary occupational therapy practice, including the difficulties occupational therapists face when seeking to cover "everything" in an effort to be more holistic.


Sheep have an unusual variant of the brain-specific metallothionein, metallothionein-III.
Sheep metallothionein-III (MT-III) cDNA was isolated from a brain cDNA library and characterized. In contrast with MT-III from other species, sheep MT-III cDNA is predicted to encode a protein with significantly different metal-binding properties, owing to the loss of three of its cysteine residues. RT-PCR from other sheep confirmed that this aberrant structure is ubiquitous in this species. MT-III was successfully isolated from sheep brain, demonstrating that the cDNA does give rise to a protein product of the predicted structure. Sheep MT-III is similar to other mammalian MT-IIIs in that it retains the Cys-Pro-Cys-Pro motif which is thought to encode growth-inhibitory activity, and we show that it is likewise able to inhibit neuron survival in vitro. This is the first naturally occurring variant of MT-III (or any other major mammalian MT gene) which gives rise to a protein product. These findings are discussed in light of proposed roles of MT in the mammalian brain.


VacA and CagA Status as Biomarker of Two Opposite End Outcomes of Helicobacter pylori Infection (Gastric Cancer and Duodenal Ulcer) in a Moroccan Population.
Helicobacter pylori (H. pylori) infection induces inflammation of the gastric mucosa, which may progress to precancerous lesions leading to gastric cancer. Pathological determinism is associated to some virulence genes of the bacterium, notably the vacA and cagA genes. The present study aimed to determine the H. pylori genotypes distribution and their association with sex, age and gastric diseases in a Moroccan population. Gastric biopsy was taken from 1079 consenting patients. The specimens were processed by PCR to identify H. pylori and to determine the genotypic profile by PCR characterizing vacA s, vacA m and vacA i regions directly from biopsies H. pylori positives. VacA genotyping revealed the predominance of vacA m2 (53.2%), vacA s2 (52.9%) and vacA i2 (52%). The most virulent vacA alleles (s1, i1 and m1) are more predominant in men (47.3%, 41.9% and 46.1% respectively) than in women (38.3%, 33.3% and 37% respectively). However, the association between vacA genotypes and age did not reach a statistical significant value. Logistic regression analysis results show that vacA i1m1 and vacA i1m2 genotypes were strongly associated with the risk of GC, the Odds Ratio (95% confidence interval) was 29.73 [5.08-173.73] and 9.17 [2.06-40.82] respectively, while vacAs1/cagA+ seems to be a risk factor for DU since it is inversely associated with GC (OR was 0.13 [0.02-0.75]. The results of this study suggest that vacA i1 genotype independently to vacAm status may be of a clinical usefulness and will help to identify patients at a high risk of GC development.


Conversion of seaweed waste to biochar for the removal of heavy metal ions from aqueous solution: A sustainable method to address eutrophication problem in water bodies.
The present study investigated the sustainable approach for wastewater treatment using waste algal blooms. The current study investigated the removal of toxic metals namely chromium (Cr), nickel (Ni), and zinc (Zn) from aqueous solutions in batch and column studies using biochar produced by the marine algae Ulva reticulata. SEM/EDX, FTIR, and XRD were used to examine the adsorbents' properties and stability. The removal efficiency of toxic metals in batch operations was investigated by varying the parameters, which included pH, biochar dose, initial metal ion concentration, and contact time. Similarly, in the column study, the removal efficiency of heavy metal ions was investigated by varying bed height, flow rate, and initial metal ion concentration. Response Surface Methodology (Central Composite Design (CCD)) was used to confirm the linearity between the observed and estimated values of the adsorption quantity. The packed bed column demonstrated successful removal rates of 90.38% for Cr, 91.23% for Ni, and 89.92% for Zn heavy metals from aqueous solutions, under a controlled environment. The breakthrough analysis also shows that the Thomas and Adams-Bohart models best fit the regression values, allowing prior breakthroughs in the packed bed column to be predicted. Desorption studies were conducted to understand sorption and elution during different regeneration cycles. Adding 0.3 N sulfuric acid over 40 min resulted in the highest desorption rate of the column and adsorbent used for all three metal ions.


[Valeology and biophysical medicine].
We analysed the official statistical data about the morbidity in different Ukrainian regions, its copulas over is brought with the ecological features in the environmental contamination of age-old features of development pathologies, which result in the loss of capacity and country's depopylation. Cited data about the medicinally conditioned diseases and by-reactions after drugs introduction. The own material contains the clinical supervisions results after additional application the instrumental oroterapy procedure--the drived gas environment with lowered oxygen partial pressure in co-operating with the traditional treatment for the patients suffering with the child's cerebral paralysis. The positive instrumental oroterapy effects was shown on the motive functions state, electroencephalography dates, about the main brain complex activity from 53 childrens with pulsy. Drawn conclusion about the appropriateness of including the natural or instrumental oroterapy in the children's rehabilitation programs or for physiology regeneration in youth and adults.


Design and tests of prospective property predictions for novel antimalarial 2-aminopropylaminoquinolones.
There is a pressing need to improve the efficiency of drug development, and nowhere is that need more clear than in the case of neglected diseases like malaria. The peculiarities of pyrimidine metabolism in Plasmodium species make inhibition of dihydroorotate dehydrogenase (DHODH) an attractive target for antimalarial drug design. By applying a pair of complementary quantitative structure-activity relationships derived for inhibition of a truncated, soluble form of the enzyme from Plasmodium falciparum (s-PfDHODH) to data from a large-scale phenotypic screen against cultured parasites, we were able to identify a class of antimalarial leads that inhibit the enzyme and abolish parasite growth in blood culture. Novel analogs extending that class were designed and synthesized with a goal of improving potency as well as the general pharmacokinetic and toxicological profiles. Their synthesis also represented an opportunity to prospectively validate our in silico property predictions. The seven analogs synthesized exhibited physicochemical properties in good agreement with prediction, and five of them were more active against P. falciparum growing in blood culture than any of the compounds in the published lead series. The particular analogs prepared did not inhibit s-PfDHODH in vitro, but advanced biological assays indicated that other examples from the class did inhibit intact PfDHODH bound to the mitochondrial membrane. The new analogs, however, killed the parasites by acting through some other, unidentified mechanism 24-48 h before PfDHODH inhibition would be expected to do so.


Apolipoprotein epsilon 4 genotype is associated with less improvement in cognitive function five years after cardiac surgery: a retrospective cohort study.
Cognitive performance after cardiac surgery can be impaired, and genetic risk factors have previously been suggested. When compared with other isoforms of the gene, the apolipoprotein epsilon 4 (APOE4) allele is associated with worse outcomes in many neurologic disorders. We hypothesized that the APOE4 allele is associated with less favourable cognitive function five years after surgery. Caucasian patients enrolled in previously reported prospective cognitive trials in both cardiac and non-cardiac surgery participated in this retrospective cohort study. Neuropsychological function was assessed at baseline and five years postoperatively. The relationship between change in cognitive index score and APOE was evaluated using multivariable linear regression. An additive genetic model toward the epsilon 4 allele was applied with adjustment for baseline cognition, years of education, age, presence of diabetes in both cohorts, and presence of coronary artery disease in the non-cardiac surgery cohort. A total of 357 patients were included in this study. In the cardiac surgery group (n = 233), baseline cognitive index (P < 0.001), years of education (P = 0.04), age at time of surgery (P < 0.001), and the APOE4 allele (P = 0.009), were associated with a five-year change in cognitive index. Patients carrying the APOE4 allele showed less improvement in cognitive index scores five years after cardiac surgery compared with patients without the APOE4 allele. In the non-cardiac surgery (n = 124) group, no association was found between APOE4 allele status and change in cognitive index. We report an association between APOE4 and neurocognitive function five years following cardiac surgery. Preoperative identification of patients with the APOE4 genotype may improve stratification of cardiac surgery patients at risk for a less favourable cognitive trajectory.


Molecular regulation of tumor cell vasculogenic mimicry by tyrosine phosphorylation: role of epithelial cell kinase (Eck/EphA2).
During embryogenesis, blood vessels are formed initially by the process of vasculogenesis, the in situ differentiation of mesenchymal cells into endothelial cells, which form a primitive, patterned vasculogenic network. This is followed by angiogenesis, the sprouting of new vessels from preexisting vasculature, to yield a more refined microcirculation. However, we and our collaborators have recently described a process termed "vasculogenic mimicry," which consists of the formation of patterned, tubular networks by aggressive melanoma tumor cells (in three-dimensional cultures in vitro), that mimics endothelial-formed vasculogenic networks and correlates with poor clinical prognosis in patients. Previous microarray analysis from our laboratory comparing the highly aggressive versus the poorly aggressive melanoma cells revealed a significant increased expression of tyrosine kinases associated with the aggressive melanoma phenotype. Because of the important role of protein tyrosine kinases in phosphorylating various signal transduction proteins that are critical for many cellular processes (e.g., cell adhesion, migration, and invasion), we examined whether protein tyrosine kinases are involved in melanoma vasculogenic mimicry. Immunofluorescence analysis of aggressive melanoma cells forming tubular networks in vitro showed that tyrosine phosphorylation activity colocalized specifically within areas of tubular network formation. A phosphotyrosine profile of the aggressive melanoma cells capable of forming tubular networks indicated differences in tyrosine phosphorylated proteins compared with the poorly aggressive melanoma cells (incapable of forming tubular networks). Most notably, we identified epithelial cell kinase (EphA2) as being one receptor tyrosine kinase expressed and phosphorylated exclusively in the aggressive metastatic melanoma cells. Furthermore, general inhibitors of protein tyrosine kinases hindered tube formation, and transient knockout of EphA2 abrogated the ability of tumor cells to form tubular structures. These results suggest that protein tyrosine kinases, particularly EphA2, are involved in the formation of tubular networks by aggressive melanoma tumor cells in vitro, which may represent a novel therapeutic target for further clinical investigation.


Improved renal recovery in patients with atypical hemolytic uremic syndrome following rapid initiation of eculizumab treatment.
Eculizumab is approved for atypical hemolytic uremic syndrome (aHUS). Guidelines discuss the importance of prompt treatment. We report a post hoc analysis investigating the effect of baseline factors, including patient characteristics and time from the latest aHUS manifestation to eculizumab initiation, on change from baseline in estimated glomerular filtration rate (eGFR) and other outcomes. Data were pooled from four phase 2, open-label, single-arm, prospective clinical studies of eculizumab for patients with aHUS. Multivariate regressions identified predictors of eGFR change from baseline. The proportion of patients achieving sustained eGFR increase (defined: ≥15 ml/min/1.73 m2 for ≥28 days) and platelet count normalization were evaluated 1 year post-treatment. Baseline characteristics and eGFR outcomes were summarized by time to treatment from last aHUS manifestation [≤7 days (n = 21) versus >7 days (n = 76)]. Baseline eGFR were similar between groups. Multivariate regression analysis demonstrated time from aHUS manifestation to eculizumab treatment, age, baseline lactate dehydrogenase (LDH) and baseline hemoglobin were independently predictive of eGFR change from baseline. Mean eGFR change from baseline at 1 year was significantly higher in patients treated in ≤7 days than >7 days (57 vs. 23 ml/min/1.73 m2, p = 0.0098). After 1 year, 17/21 and 36/76 patients in the ≤7 and >7 day groups, respectively, achieved a sustained increase in eGFR. Mean time to platelet count normalization was similar between groups. Younger age, higher baseline LDH and lower baseline hemoglobin were associated with greater eGFR improvements. Early eculizumab initiation led to improved renal recovery, demonstrating the importance of rapid diagnosis and treatment of patients with aHUS.


Ideal Cardiovascular Health Metrics and Incident Hyperuricemia.
Hyperuricemia has been shown to be associated with increased risks of gout and cardiovascular diseases. We prospectively investigated the association between the American Heart Association (AHA) ideal cardiovascular health metrics, including smoking, body mass index, dietary intake, physical activity, blood pressure, total cholesterol, and fasting blood glucose, and the risk of developing hyperuricemia. We included 77,787 Chinese adults, ages ≥18 years (60,951 men and 16,836 women), without hyperuricemia at the baseline (2006) in this study. Information on the cardiovascular health metrics at baseline was collected. Incident hyperuricemia cases were identified by elevated serum uric acid concentrations, which were repeatedly assessed in 2006, 2008, 2010, and 2012, respectively. Cox regression was used to calculate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident hyperuricemia according to the baseline ideal cardiovascular health metrics. We observed an inverse relation between the greater numbers of ideal cardiovascular health metrics at baseline and lower risks of developing hyperuricemia during 6 years of followup. After adjusting for age, sex, alcohol consumption, and other potential confounders, the HRs for incident hyperuricemia were 0.95, 0.84, 0.72, and 0.64 (95% CIs 0.58-0.70, P for trend < 0.0001) for participants who met 2, 3, 4, and 5-7 metrics, respectively, compared with those who met 0-1 cardiovascular health metrics. Greater cardiovascular health metrics were associated with lower risk of hyperuricemia in this Chinese population, suggesting that the modifiable construct defined by the AHA could be of significance in reducing the risk of developing hyperuricemia-related diseases, such as gout.


Optimization of the synthetic parameters of lipid polymer hybrid nanoparticles dual loaded with darunavir and ritonavir for the treatment of HIV.
Human Immunodeficiency Virus (HIV) is a global health concern to which nanomedicine approaches provide opportunities to improve the bioavailability of existing drugs used to treat HIV.In this article, lipid polymer hybrid nanoparticles (LPHNs) were developed as a system to provide a combination drug delivery of two leading antiretroviral drugs; darunavir (DRV) and its pharmacokinetic enhancer ritonavir (RTV).The LPHNs were designed with a poly(D, l-lactide-co-glycolide) (PLGA) core, and soybean lecithin (SBL) and Brij 78 as the stabilizers. The LPHNs were prepared by modified nanoprecipitation and the effect of synthetic conditions on the particle properties was studied, which included the Z-average diameter and polydispersity index of LPHNs in water and phosphate buffered saline, and the morphology of the particles. This investigation aimed to prepare a formulation that could be stored in its dry and redispersible form, therefore avoiding the challenges associated with storage of dispersions. The optimum ratio of stabilizer to polymer core was established at 20% w/w, and Brij 78 was found to be crucial in providing colloidal stability in physiological solutions; the minimum amount of Brij 78 required to provide stability in phosphate buffered saline was 70% w/w of the total stabilizer mass. Viable formulations of LPHNs containing DRV and RTV in the clinically used 8:1 ratio were prepared containing 20% w/w DRV with respect to the PLGA mass. The use of cryoprotectant, polyethylene glycol, combined with freeze-drying yielded LPHNs with a Z-average diameter of 150 nm when the particles were re-dispersed in water. The oral absorption behavior was assessed using an in vitro triple culture model. Whilst the use of cryoprotectant and freeze-drying led to no improvement of the transcellular permeability compared to the unformulated drugs, the non-freeze-dried samples with the highest soybean lecithin led to increased transcellular permeability, revealing the potential of LPHNs for enhancing HIV treatment.


GLP-1R agonism enhances adjustable gastric banding in diet-induced obese rats.
Bariatric procedures vary in efficacy, but overall are more effective than behavioral and pharmaceutical treatment. Roux-en-Y gastric bypass causes increased secretion of glucagon-like peptide 1 (GLP-1) and reduces body weight (BW) more than adjustable gastric banding (AGB), which does not trigger increased GLP-1 secretion. Since GLP-1-based drugs consistently reduce BW, we hypothesized that GLP-1 receptor (GLP-1R) agonists would augment the effects of AGB. Male Long-Evans rats with diet-induced obesity received AGB implantation or sham surgery. GLP-1R agonism, cannabinoid receptor-1 (CB1-R) antagonism, or vehicle was combined with inflation to evaluate interaction between AGB and pharmacological treatments. GLP1-R agonism reduced BW in both sham and AGB rats (left uninflated) compared with vehicle-treated animals. Subsequent band inflation was ineffective in vehicle-treated rats but enhanced weight loss stimulated by GLP1-R agonism. In contrast, there was no additional BW loss when CB1-R antagonism was given with AGB. We found band inflation to trigger neural activation in areas of the nucleus of the solitary tract known to be targeted by GLP-1R agonism, offering a potential mechanism for the interaction. These data show that GLP-1R agonism, but not CB1-R antagonism, improves weight loss achieved by AGB and suggest an opportunity to optimize bariatric surgery with adjunctive pharmacotherapy.


Decolonizing Decriminalization Analyses: Did the Ottomans Decriminalize Homosexuality in 1858?
Assessments of the decriminalization of homosexuality are rarely questioned. It is widely accepted that the Ottomans decriminalized homosexuality in 1858 owing to the absence of penalties assigned to private same-sex intimacy. The reason for this misanalysis rests upon the universalization of the Western formula for the decriminalization of homosexuality. This assumption about the Ottomans has been made without examining how they had criminalized homosexuality in the first place. Two penal cultures that criminalized homosexuality differently cannot decriminalize it by way of the same legal framework. The current method excludes, moreover, the subject country's history. This elicits neo-orientalist conclusions such as the Ottomans' decriminalization of homosexuality in 1858 via the introduction of the 1810 French Penal Code, without an accompanying examination of how the Ottomans had criminalized homosexuality before 1858. This assessment method not only facilitates neo-orientalism, but also casts a significant doubt on this method's validity.


Effects of prior vegetative growth, inoculum density, light, and mating on conidiation of Erysiphe necator.
Initiation of asexual sporulation in powdery mildews is preceded by a period of superficial vegetative growth of mildew colonies. We found evidence of a quorum-sensing signal in Erysiphe necator that was promulgated at the colony center and stimulated conidiation throughout the colony. Removal of the colony center after putative signal promulgation had no impact upon timing of sporulation by 48-h-old hyphae at the colony margin. However, removal of the colony center before signaling nearly doubled the latent period. A relationship between inoculum density and latent period was also observed, with latent period decreasing as the number of conidia deposited per square millimeter was increased. The effect was most pronounced at the lowest inoculum densities, with little decrease of the latent period as the density of inoculation increased above 10 spores/mm. Furthermore, light was shown to be necessary to initiate conidiation of sporulation-competent colonies. When plants were inoculated and maintained in a day-and-night cycle for 36 h but subjected to darkness after 36 h, colonies kept in darkness failed to sporulate for several days after plants kept in light had sporulated. Once returned to light, the dark-suppression was immediately reversed, and sporulation commenced within 12 h. Merging of colonies of compatible mating types resulted in near-cessation of sporulation, both in the region of merging and in more distant parts of the colonies. Colonies continued to expand but stopped producing new conidiophores once pairing of compatible mating types had occurred, and extant conidiophores stopped producing new conidia. Therefore, in addition to a quorum-sensing signal to initiate conidiation, there appears to be either signal repression or another signal that causes conidiation to cease once pairing has occurred and the pathogen has initiated the ascigerous stage for overwintering.


Influence of caecectomy and dietary protein concentration on apparent excreta amino acid digestibility in adult cockerels.
1. The influence of caecectomy and dietary crude protein content (50, 100, 150, 200 and 250 g/kg diet) on the apparent excreta amino acid digestibilities in adult cockerels fed on semi-purified diets containing soyabean meal (SBM) or cottonseed meal (CSM) as the sole source of protein was investigated. 2. Caecectomy had no influence on the apparent digestibilities of most amino acids in SBM, the exceptions being histidine, arginine and lysine, but lowered the apparent digestibility of amino acids in CSM. 3. The protein content in assay diets has a strong influence on the apparent amino acid digestibility values for poultry. Apparent values are lower when the dietary protein content is low. 4. The use of a single endogenous amino acid output value, generated by regression analysis or protein-free diets, for true digestibility adjustments across a wide range of protein intakes is questioned. In particular, such an application will penalise estimates of apparent digestibility when the dietary protein content is high.


Twelve tools for teaching medical students.
The aim of this paper is to outline strategies for teaching psychiatry to medical students. The background is that today's medical students are tomorrow's doctors. Undergraduate psychiatry teaching provides us a unique opportunity to instil positive attitudes, knowledge and skills in the medical workforce of the future. Moreover, teaching has many positives for the individual clinician, their service and the community. We outline 12 strategies that we find makes teaching not only enjoyable for us, but engaging, memorable and relevant for students.


Synthetic peptides bind to high-affinity thrombin receptors and modulate thrombin mitogenesis.
Initiation of cell proliferation by thrombin requires signals generated by thrombin interaction with specific high-affinity receptors and thrombin enzymic activity. Using synthetic peptides representing various domains of thrombin, we have identified a region adjacent to the proteolytic pocket of thrombin which confers high-affinity binding and generation of mitogenic signals. One peptide, representing residues 508 to 530 of human prothrombin (p508-530), inhibits up to 70% of the specific binding of 125I-alpha-thrombin at concentrations of less than 100 nM, enhances the ability of thrombin to stimulate DNA synthesis and stimulates DNA synthesis in cells treated with 25 ng/ml phorbol myristate acetate (PMA). Thus, this peptide or a portion of this peptide appears to represent the high-affinity receptor binding domain of thrombin. In contrast to the 23 amino acid peptide (p508-530), the tetrapeptide RGDA (p517-520) contained in this region competes for 125I-thrombin binding at concentrations from 100 to 2000 nM, but inhibits rather than stimulates the mitogenic effects of alpha-thrombin. Non-homologous peptides, or fibronectin-specific peptides (such as RGDS or GRGDSP) do not compete for 125I-alpha-thrombin binding and have no effect on thrombin mitogenesis. These studies demonstrate that peptides representing portions of the binding domain of thrombin: i) can generate receptor-occupancy related signals that enhance thrombin mitogenesis and are themselves mitogenic in cells treated with PMA; or ii) in the case of RGDA (which may be too small to generate signals), can act as antagonists, inhibiting the mitogenic effects of thrombin by preventing thrombin-receptor interaction.


Perimortem fracture manifestations and mortality after hip fracture in a documented skeletal series.
Unhealed hip fractures are underrepresented in the archaeological record, suggesting that better identification criteria are required. This paper evaluates whether a sample of documented perimortem hip fractures displayed classic perimortem features and which features may facilitate better identification of such fractures in the archaeological record. Ten individuals from the Robert J. Terry Anatomical Skeletal Collection with documented hip fractures and intervals of survival. We observed the skeletal remains macroscopically and with a Keyence VHX-2000 digital microscope at a range of 5x to 100x magnification. 90% of the individuals and 64% of the fragments had identifiable perimortem features; hinging was the most consistent feature. Eburnation was found in two individuals who died 13 days after sustaining a hip fracture. This study underscores the importance of examining fracture margins for evidence of hinging. Eburnation may be added to the list of potential perimortem fracture identification criteria. Identifying perimortem trauma unequivocally remains challenging. Using collections with documented perimortem fractures aids in determining which criteria are most likely to appear in archaeological human bone. The fracture location patterning (70% intertrochanteric) may be the result of sample selection. Further intensive comparative investigation with the Hamann-Todd Collection would elucidate patterns further.


Perioperative factors associated with delayed graft function in renal transplant patients.
Successful renal transplant and consequent good graft function depend on a good surgical technique, an anesthetic that ensures the hemodynamic stability of the receiver, and appropriate conditions of graft and recipient. Several factors can interfere with the perfusion of the graft and compromise its viability. The objective of this study was to evaluate perioperative factors associated with delayed graft function (DGF) in renal transplantation patients. This is a historical cohort study of patients who underwent renal transplantation between 2011 and 2013. Three hundred and ten transplants were analyzed. DGF was defined as the need for dialysis during the first week post-transplant. Logistic regression with a stepwise technique was used to build statistical models. Multivariate analysis revealed the following risk factor for DGF: combined anesthesia technique (OR = 3.81, 95%CI, 1.71 to 9.19), a fluid regimen < 50 mL·kg-1 (OR = 3.71, 95%CI, 1.68 to 8.61), dialysis for more than 60 months (OR = 4.77, 95%CI, 1.93 to 12.80), basiliximab (OR = 3.34, 95%CI, 1.14 to 10.48), cold ischemia time > 12 hour (OR = 5.26, 95%CI, 2.62 to 11.31), living donor (OR = 0.19, 95%CI, 0.02 to 0.65), and early diuresis (OR = 0.02, 95%CI, 0.008 to 0.059). The accuracy of this model was 92.6%, calculated using the area under the ROC curve. The incidence of DGF in the study population was 76.1%. Combined anesthesia technique, dialysis for more than 60 months, basiliximab, and cold ischemia time > 12 hours are risk factor for DGF, while liberal fluid regimens and kidneys from living donors are protective factors.


What's new in haemolytic uraemic syndrome?
Recent advances in understanding the aetiology of the disorders that make up the haemolytic uraemic syndrome (HUS) permit a revised classification of the syndrome. With appropriate laboratory support, an aetiologically-based subgroup diagnosis can be made in all but a few cases. HUS caused by enterohaemorrhagic Escherichia coli remains by far the most prevalent subgroup, and new insights into this zoonosis are discussed. The most rapidly expanding area of interest is the subgroup of inherited and acquired abnormalities of complement regulation. Details of the pathogenesis are incomplete but it is reasonable to conclude that local activation of the alternative pathway of complement in the glomerulus is a central event. There is no evidence-based treatment for this diagnostic subgroup. However, in circumstances where there is a mutated plasma factor such as complement factor H, strategies to replace the abnormal protein by plasmapheresis or more radically by liver transplantation are logical, and anecdotal successes are reported. In summary, the clinical presentation of HUS gives a strong indication as to the underlying cause. Patients without evidence of EHEC infection should be fully investigated to determine the aetiology. Where complement abnormalities are suspected there is a strong argument for empirical and early plasma exchange, although rapid advances in this field may provide more specific treatments in the near future.


LGI1 mutations in temporal lobe epilepsies.
A number of familial temporal lobe epilepsies (TLE) have been recently recognized. Mutations in LGI1 (leucine-rich, glioma-inactivated 1 gene) have been found in a few families with the syndrome of autosomal dominant partial epilepsy with auditory features (ADPEAF). The authors aimed to determine the spectrum of TLE phenotypes with LGI1 mutations, to study the frequency of mutations in ADPEAF, and to examine the role of LGI1 paralogs in ADPEAF without LGI1 mutations. The authors performed a clinical and molecular analysis on 75 pedigrees comprising 54 with a variety of familial epilepsies associated with TLE and 21 sporadic TLE cases. All were studied for mutations in LGI1. ADPEAF families negative for LGI1 mutations were screened for mutations in LGI2, LGI3, and LGI4. Four families had ADPEAF, 22 had mesial TLE, 11 had TLE with febrile seizures, two had TLE with developmental abnormalities, and 15 had various other TLE syndromes. LGI1 mutations were found in two of four ADPEAF families, but in none of the other 50 families nor in the 21 individuals with sporadic TLE. The mutations were novel missense mutations in exons 1 (c.124T-->G; C42G) and 8 (c.1418C-->T; S473L). No mutations in LGI2, LGI3, or LGI4 were found in the other two ADPEAF families. In TLE, mutations in LGI1 are specific for ADPEAF but do not occur in all families. ADPEAF is genetically heterogeneous, but mutations in LGI2, LGI3, or LGI4 did not account for families without LGI1 mutations.


Incidence, associated factors, and outcomes of delirium in critically ill children in china: a prospective cohort study.
Delirium occurs frequently in critically ill children and has been reported in many countries, but delirium is not well-characterized in China. The aim of this study was to represent the incidence of delirium in critically ill children in China, its associated factors, and the influence of delirium on in-hospital outcomes. This observational prospective cohort study was set up in a large academic medical center with a 57-bed PICU in southwestern China. Critically ill children who required PICU stays over 24 h and were admitted between November 2019 and February 2022 were included in this study. The Cornell Assessment of Pediatric Delirium was used twice daily for delirium evaluation by bedside nurses, and twenty-four clinical features were collected from medical and nursing records during hospitalization. The incidence of delirium was 26.0% (n = 410/1576). Multivariate analysis revealed that seven independent risk factors including days of mechanical ventilation and physical restraints, admission diagnosis (neurologic disorder), sleep deprivation, use of benzodiazepines and dexmedetomidine, liver failure/liver dysfunction associated with delirium in critically ill children. One potentially protective factor was the watching television /listening to music/playing with toys. Children with delirium had longer lengths of stay in the PICU (median 11 vs. 10 days, p < 0.001) and hospital (median 18 vs. 15 days, p < 0.001) compared to those without delirium. Additionally, the in-hospital mortality rates were 4.63% and 0.77% in patients with and without delirium (p < 0.05). Delirium is common in critically ill children in China and related to poor outcomes. Interventional studies are warranted to determine the best practices to reduce delirium exposure in at-risk children.


Melittin induces NSCLC apoptosis via inhibition of miR-183.
Non-small-cell lung cancer (NSCLC) has one of the highest mortality rates among cancers worldwide, with a poor prognosis. Previous studies have reported that melittin, an active component of apitoxin, exerts anti-inflammatory and antitumor effects via vascular endothelial growth factor or FoxO1. CCK8, flow cytometry assay and Western blotting were performed to evaluate the effect of melittin on NSCLC. The present study demonstrates that melittin activated caspase-2 by inhibiting miR-183 expression and, thus, induced NSCLC apoptosis in both NCI-H441 cancer cell line assays and an in vivo xenograft model. The results of the cell-based assays showed that melittin (2 μg/mL) robustly suppressed miR-183 expression level and resulted in decreased invasion and migration abilities of NCI-H441 cells. Additionally, a flow cytometry assay and Western blotting showed that melittin induced NSCLC NCI-H441 cell apoptosis along with significant elevation of caspase-2 and Bax, which are regulators of cell apoptosis, and reduced Bcl-2 protein expression compared with dimethyl sulfoxide control. Furthermore, subcutaneous injection of melittin (5 mg/kg) significantly suppressed NSCLC tumor growth compared with vehicle group tumors, determined through tumor size and weight. Taken together, the aforementioned findings contribute to identification of a novel therapeutic target in the treatment of NSCLC, in patients diagnosed with a high expression of miR-183. Moreover, this article provides solid evidence for the inhibitory effect of melittin on NSCLC cancer cell growth.


Incidence and outcome of perforations during medium vessel occlusion compared with large vessel occlusion thrombectomy.
Vessel perforation during thrombectomy is a severe complication and is hypothesized to be more frequent during medium vessel occlusion (MeVO) thrombectomy. The aim of this study was to compare the incidence and outcome of patients with perforation during MeVO and large vessel occlusion (LVO) thrombectomy and to report on the procedural steps that led to perforation. In this multicenter retrospective cohort study, data of consecutive patients with vessel perforation during thrombectomy between January 1, 2015 and September 30, 2022 were collected. The primary outcomes were independent functional outcome (ie, modified Rankin Scale 0-2) and all-cause mortality at 90 days. Binomial test, chi-squared test and t-test for unpaired samples were used for statistical analysis. During 25 769 thrombectomies (5124 MeVO, 20 645 LVO) in 25 stroke centers, perforation occurred in 335 patients (1.3%; mean age 72 years, 62% female). Perforation occurred more often in MeVO thrombectomy (2.4%) than in LVO thrombectomy (1.0%, p<0.001). More MeVO than LVO patients with perforation achieved functional independence at 3 months (25.7% vs 10.9%, p=0.001). All-cause mortality did not differ between groups (overall 51.6%). Navigation beyond the occlusion and retraction of stent retriever/aspiration catheter were the two most common procedural steps that led to perforation. In our cohort, perforation was approximately twice as frequent in MeVO than in LVO thrombectomy. Efforts to optimize the procedure may focus on navigation beyond the occlusion site and retraction of stent retriever/aspiration catheter. Further research is necessary in order to identify thrombectomy candidates at high risk of intraprocedural perforation and to provide data on the effectiveness of endovascular countermeasures.


Reticulocyte analysis using light microscopy and two different flow cytometric procedures.
The reticulocyte count is a clinically important indirect indicator of erythropoietic activity of the bone marrow. Reticulocyte enumeration by light microscopy is rather inaccurate and has poor reproducibility. Automation of the reticulocyte count by means of flow cytometry has considerably improved the quality of this investigation. In our study, we compared three methods of establishing the blood reticulocyte number: the microscopic brilliant cresyl blue method and two flow cytometric procedures using thiazole orange (TO), namely FACSort (Becton-Dickinson) and EPICS Profile (Coulter). The aims of the study were (1) to select the most suitable TO concentration to be used with the EPICS Profile cytometer, (2) to determine the correlation between the microscopic method and the two flow cytometric procedures, and (3) to appraise the suitability of flow cytometry for reticulocyte analysis in routine clinical work. According to our results, the most appropriate TO concentration for the EPICS Profile counter is 0.1 mg/L. We observed a good correlation between the three methods tested; the correlation coefficients ranged from 0.82 to 0.87. The mean intra-assay coefficients of variation for the microscopic method and the EPICS Profile and FACSort procedures were 27.5%, 8.4% and 6.3%, respectively.


Downstream Toll-like receptor signaling mediates adaptor-specific cytokine expression following focal cerebral ischemia.
Deletion of some Toll-like receptors (TLRs) affords protection against cerebral ischemia, but disruption of their known major downstream adaptors does not. To determine whether compensation in the production of downstream effectors by one pathway when the other is disrupted can explain these findings, we examined cytokine/chemokine expression and inflammatory infiltrates in wild-type (WT), MyD88(-/-) and TRIF-mutant mice following permanent middle cerebral artery occlusion (pMCAO). Cytokine/chemokine expression was measured with a 25-plex bead array in the serum and brains of all three groups of mice at baseline (no surgery/naïve) and at 3 hours and 24 hours following pMCAO. Brain inflammatory and neutrophil infiltrates were examined 24 hours following pMCAO. IL-6, keratinocyte chemoattractant (KC), granulocyte colony-stimulating factor (G-CSF) and IL-10 were significantly decreased in MyD88(-/-) mice compared to WT mice following pMCAO. Significantly, decreased levels of the neutrophil chemoattractants KC and G-CSF corresponded with a trend toward fewer neutrophils in the brains of MyD88(-/-) mice. IP-10 was significantly decreased when either pathway was disrupted. MIP-1 α was significantly decreased in TRIF-mutant mice, consistent with TRIF-dependent production. MyD88(-/-) mice showed elevations of a number of Th2 cytokines, such as IL-13, at baseline, which became significantly decreased following pMCAO. Both MyD88 and TRIF mediate pathway-specific cytokine production following focal cerebral ischemia. Our results also suggest a compensatory Th2-type skew at baseline in MyD88(-/-) mice and a paradoxical switch to a Th1 phenotype following focal cerebral ischemia. The MyD88 pathway directs the expression of neutrophil chemoattractants following cerebral ischemia.


[Supply of emergency physicians for patients with stroke in the Münster area. A cross-sectional study of the quality of regional health care].
Advances in understanding the pathophysiology and treatment of stroke have led to changed requirements, including the prehospital phase, for the care of patients with acute stroke. Rapid transport to a regional stroke centre is nowadays considered to be the standard for optimal quality of care. A retrospective cross-sectional analysis was undertaken in 1996 in the region of the town of Münster to test the quality of medical care provided by physicians on emergency call. 250 of 3001 protocols (8.3%) filled in by emergency call physicians were selected in which the initial diagnosis of transitory ischaemic attack, stroke or cerebral haemorrhage had been made. Quality of patient care was assessed according to the following criteria; (1) complete medical treatment (blood sugar, blood pressure, cardiac rhythm and arterial oxygen saturation, including relevant treatment of any abnormality) (2) action time (arrival of emergency doctor within 12 min and arrival at hospital within 50 min); (3) type of the admission hospital (stroke centre defined as a hospital experienced in the treatment of stroke, with neurological and medical departments, as well as 24-hour cover for computed cranial tomography). A summated indicator of "optimal care" was used to determine whether the three stated criteria were met. Mean age of the stroke patients was 72.3 years. While the above mentioned quality criteria for the action time were met in 93.5% of patients, only 56.0% were admitted to a stroke centre, and this was significantly more often the final destination for patients under the age of 65 years than for older ones (p = 0.049). The quality indicator "complete medical treatment" was met for 27.2% of the transported patients. Measured according to present-day criteria, only 18.6% of patients received such optimal treatment. This analysis indicates that modern prehospital treatment of stroke patients does not reach adequate standards. In particular, it is not comprehensive. While the "action time" is usually adequate, there are deficiencies regarding the quality of medical care and the choice of the admission hospital. Further education for emergency physicians with respect to the management of stroke syndrome should be an integral part of any regional quality programme. The number of hospitals with adequate competence in the acute management of stroke cases is still insufficient.


A comparison of foot kinematics in people with normal- and flat-arched feet using the Oxford Foot Model.
Foot posture is thought to influence predisposition to overuse injuries of the lower limb. Although the mechanisms underlying this proposed relationship are unclear, it is thought that altered foot kinematics may play a role. Therefore, this study was designed to investigate differences in foot motion between people with normal- and flat-arched feet using the Oxford Foot Model (OFM). Foot posture in 19 participants was documented as normal-arched (n=10) or flat-arched (n=9) using a foot screening protocol incorporating measurements from weightbearing antero-posterior and lateral foot radiographs. Differences between the groups in triplanar motion of the tibia, rearfoot and forefoot during walking were evaluated using a three-dimensional motion analysis system incorporating a multi-segment foot model (OFM). Participants with flat-arched feet demonstrated greater peak forefoot plantar-flexion (-13.7° ± 5.6° vs -6.5° ± 3.7°; p=0.004), forefoot abduction (-12.9° ± 6.9° vs -1.8° ± 6.3°; p=0.002), and rearfoot internal rotation (10.6° ± 7.5° vs -0.2°± 9.9°; p=0.018) compared to those with normal-arched feet. Additionally, participants with flat-arched feet demonstrated decreased peak forefoot adduction (-7.0° ± 9.2° vs 5.6° ± 7.3°; p=0.004) and a trend towards increased rearfoot eversion (-5.8° ± 4.4° vs -2.5° ± 2.6°; p=0.06). These findings support the notion that flat-arched feet have altered motion associated with greater pronation during gait; factors that may increase the risk of overuse injury.


America's "undiscovered" laboratory for health services research.
Debate over reforming the nation's healthcare system has stimulated a need for health services research (HSR) models that are nationally applicable. Toward this end, the authors identify the Military Health System (MHS) as America's "undiscovered" laboratory for HSR. Although many may confuse the MHS with the Department of Veterans Affairs (VA), the 2 systems vary dramatically with respect to their beneficiary populations, access to care, and other important attributes. In this article, the authors describe key characteristics of the MHS including its large beneficiary base, its direct care operating environment, its dedicated medical school and graduate education programs, and its fully operational integrated health information system. Although a few health systems (eg, Kaiser Permanente, Partners Healthcare, and Department of Veterans Affairs) possess some characteristics, no other has all of these components in place. This article sets the stage for contemporary HSR studies with broad applicability to current issues in American healthcare that could be performed within the MHS. Inclusion of the MHS environment in HSR studies of health services delivery modalities, adoption of health information technology, access to care, relationship of medical education to effective safe care delivery, health disparities, child health, and behavioral health would provide strong underpinnings for proposed changes in American healthcare delivery. Finally, the article highlights current regulatory barriers to research within the MHS whereas suggesting steps to minimize their impact in conducting HSR.


Measuring elusive benefits: on the value of health.
Can analysts provide better guidance to policymakers about the valuation of health effects? This paper argues that valuation questions usually cannot be easily sidestepped by the use of cost-effectiveness analysis. Valuations are implicit in the measures of program outcome that we use, as illustrated by an examination of a policy of maximizing discounted quality-adjusted life-years (QALYs). The paper concludes that surveys focused directly on the questions that health and safety policymakers face could be a most fruitful source of guidance.


[Thurstone model application to difference sensory tests].
Part of understanding why judges perform better on some difference tests than others requires an understanding of how information coming from the mouth to the brain is processed. For some tests it is processed more efficiently than others. This is described by what has been called Thurstonian modeling. This brief review introduces the concepts and ideas involved in Thurstonian modeling as applied to sensory difference measurement. It summarizes the literature concerned with the theorizing and confirmation of Thurstonian models. It introduces the important concept of stimulus variability and the fundamental measure of sensory difference: d'. It indicates how the paradox of discriminatory non-discriminators, which had puzzled researchers for years, can be simply explained using the model. It considers how memory effects and the complex interactions in the mouth can reduce d' by increasing the variance of sensory distributions.


Ethanol (EtOH)-Related Behaviors in α-Synuclein Mutant Mice and Association of SNCA SNPs with Anxiety in EtOH-Dependent Patients.
Data have shown a role of α-synuclein in anxiety and also in addiction, particularly in alcohol use disorders (AUD). Since the comorbidity between AUD and anxiety is very high and because anxiety is an important factor in ethanol (EtOH) relapse, the aim of the present study was to investigate the role of α-synuclein in moderating EtOH intake, the anxiolytic effects of EtOH, and EtOH withdrawal-induced anxiety and convulsions in mice. The study aimed to determine whether SNCA variants moderated anxiety in EtOH-dependent patients. We analyzed the moderator effect of 3 SNCA Tag-single nucleotide polymorphisms (Tag-SNPs) rs356200, rs356219, and rs2119787 on the anxiety symptoms in 128 EtOH-dependent patients. We used the C57BL/6JOlaHsd Snca mutant mice to assess EtOH intake; sensitivity to the anxiolytic effects of EtOH in a test battery comprising the open field, the light-dark box, and the elevated plus maze; and both anxiety and convulsions induced by EtOH withdrawal. Our results demonstrated a reduction in both EtOH intake and preference and also a lack of sensitivity to the anxiolytic effects of EtOH in α-synuclein mutant mice. Results on anxiety-like behavior were mixed, but mutant mice displayed increased anxiety when exposed to a low anxiogenic environment. Mutant mice also displayed an increase in handling-induced convulsion scores during withdrawal after EtOH inhalation, but did not differ in terms of EtOH withdrawal-induced anxiety. In humans, we found a significant association of the rs356219 SNP with a high level of anxiety (Beck Anxiety Inventory score >15) and the rs356200 SNP with a positive familial history of AUD. Our translational study highlights a significant role of α-synuclein in components of AUD.


Constipation: a frequent iatrogenic complication in cancer patients receiving narcotics.
Many patients who are receiving opiates develop a problem with constipation. Constipation can be prevented in most patients who are receiving narcotics by judicious and routine use of laxatives contributing to the comfort of the patients. In general the responsibility for bowel management is delegated to the nursing staff, but joint responsibility between the nursing and medical staff is recommended. The author defines constipation, highlights its incidence, and gives a short overview of its numerous causes, including the effects of narcotics on the gut. He suggests a protocol for bowel management, lists the different types of laxatives, and discusses rectal measures, such as suppositories, enemas, and manual disimpaction. A stepladder approach, which has proven to be effective and simple, is outlined.


Pursuit and saccadic tracking exhibit a similar dependence on movement preparation time.
Data from previous human and primate studies on saccadic and smooth pursuit eye movements suggest that there are shared internal inputs (for example, perception, attention, expectation, and memory) for the initiation of the two types of movements. Additional reports examining the effect of preparation time on movement responses have shown that when ample time is allowed subjects usually generate long-latency "reactive" responses. When the time allowed to prepare a movement is short, however, subjects respond with reduced latency and often anticipate the stimulus ("predictive" response). Based on these findings, we believe that the shared internal inputs at early stages of movement preparation may result in saccade and pursuit eye movements demonstrating the same dependence on preparation time despite acting through different neural pathways further downstream. Previously we demonstrated a behavioral "phase transition" when normal subjects tracked alternating targets with saccades. When preparation time was long (low-frequency pacing) subjects made reactive saccades (latency approximately 180 ms). As preparation time monotonically decreased (pacing frequency increased), there was an abrupt transition to a predictive response (latency <100 ms). In the present study we show that a similar transition exists in smooth pursuit tracking and that the point of transition between the two behaviors is the same for both systems. In other words, the same behavior (reactive versus predictive) is selected when pursuit and saccade tracking are tested under the same time constraints. This provides further evidence that the two types of movements are different motor outcomes of a common decision process.


Influence of bedspacing on outcomes of hospitalised medicine service patients: a retrospective cohort study.
Specialty wards cohort hospitalised patients to improve outcomes and lower costs. When demand exceeds capacity, patients overflow and are "bedspaced" to alternate wards. Some studies have demonstrated that bedspacing among medicine service patients is associated with adverse patient-centred outcomes, however, results have been inconsistent and have primarily been performed within national health systems. The objective of this study was to assess the association of bedspacing with patient-centred outcomes among United States patients admitted to general medicine services. We performed a retrospective cohort study of internal medicine, family medicine and geriatric service patients who were bedspaced vs cohorted for the entirety of their hospital stay within three large, urban United States hospitals (quaternary referral centre, tertiary referral centre and community hospital, with different patient demographics and case-mixes) in 2014 and 2015. We performed quantile regression to determine differences in length of stay (LOS) between bedspaced vs cohorted patients and logistic regression for in-hospital mortality and discharge to home. Among 18 802 patients in 33 wards, 6119 (33%) patients were bedspaced. Bedspaced patients had significantly longer LOS compared with cohorted patients at the 25th (0.1 days, 95% CI: 0.05 to 0.2, p=0.001), 50th (0.2 days, 95% CI: 0.1 to 0.3, p=0.003) and 75th (0.3 days, 95% CI: 0.2 to 0.5, p<0.001) percentiles; and no statistically significant differences in odds of mortality (OR=0.9, 95% CI: 0.6 to 1.3, p=0.5) or discharge to home (OR=0.9, 95% CI: 0.9 to 1.0, p=0.06) in adjusted analyses. Bedspacing is associated with adverse patient-centred outcomes. Future work is needed to confirm these findings, understand mechanisms contributing to adverse outcomes and identify factors that mitigate these adverse effects in order to provide high-value, patient-centred care to hospitalised patients.


The association of age, sense of control, optimism, and self-esteem with emotional distress.
The aim of this study was to test a model of emotional distress, which incorporates the potential mediator role of positive resources (sense of control, self-esteem, and optimism) in the association of age with emotional distress. The study used a cross-sectional design with intentional sampling and the voluntary participation of 325 adults between 18 and 87 years (M = 46.8 ± 19.10). The results show that emotional distress was negatively associated with age. Psychological resources also varied according to age, with older subjects presenting higher optimism and external control as well as lower internal control. The association between internal control and emotional distress was mediated by optimism and self-esteem. Moreover, the combined association of these 3 personal resources significantly increased the relationship between age and lower emotional distress. The results suggest that optimism and self-esteem are powerful resources in relieving emotional distress. The data provide potentially useful information for the design of psychological interventions aimed at reducing emotional distress. (PsycINFO Database Record


Optimizing the outcome of surgery in patients with rectal cancer and synchronous liver metastases.
This study evaluated the outcome of patients treated for rectal cancer and synchronous hepatic metastases in the era of effective induction radiotherapy and chemotherapy. All patients undergoing surgical treatment of rectal cancer and synchronous liver metastases between 2000 and 2007 were identified retrospectively from a prospectively collected database. Three approaches were followed: the classical staged, the simultaneous and the liver-first approach. Of 57 patients identified, the primary tumour was resected first in 29 patients (group 1), simultaneous resection was performed in eight patients (group 2), and 20 patients underwent a liver-first approach (group 3). The overall morbidity rate was 24.6 per cent; there was no in-hospital mortality. Median in-hospital stay was significantly shorter for the simultaneous approach (9 days versus 18 and 15 days for groups 1 and 3 respectively; P < 0.001). The overall 5-year survival rate was 38 per cent, with an estimated median survival of 47 months. Long-term survival can be achieved using an individualized approach, with curative intent, in patients with rectal cancer and synchronous liver metastases. Simultaneous resections as well as the liver-first approach are attractive alternatives to traditional staged resections.


mRNA vaccines: the most recent clinical applications of synthetic mRNA.
Synthetic mRNA has been considered as an emerging biotherapeutic agent for the past decades. Recently, the SARS-CoV-2 pandemic has led to the first clinical use of synthetic mRNA. mRNA vaccines showed far surpassing influences on the public as compared to other vaccine platforms such as viral vector vaccines and recombinant protein vaccines. It allowed rapid development and production of vaccines that have never been achieved in history. Synthetic mRNA, called in vitro transcribed (IVT) mRNA, is the key component of mRNA vaccines. It has several advantages over conventional gene-expressing systems such as plasmid DNA and viral vectors. It can translate proteins in the cytoplasm by structurally resembling natural mRNA and exhibit various protein expression patterns depending on how it is engineered. Another advantage is that synthetic mRNA enables fast, scalable, and cost-effective production. Therefore, starting with the mRNA vaccine, synthetic mRNA is now in the spotlight as a promising new drug development agent. In this review, we will summarize the latest IVT mRNA technology such as new mRNA structures or large-scale production. In addition, the nature of the innate immunogenicity of IVT mRNA will be discussed along with its roles in the development of vaccines. Finally, the principles of the mRNA vaccine and the future direction of synthetic mRNA will be provided.


Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila.
Aging is characterized by a growing risk of disease and death, yet the underlying pathophysiology is poorly understood. Indeed, little is known about how the functional decline of individual organ systems relates to the integrative physiology of aging and probability of death of the organism. Here we show that intestinal barrier dysfunction is correlated with lifespan across a range of Drosophila genotypes and environmental conditions, including mitochondrial dysfunction and dietary restriction. Regardless of chronological age, intestinal barrier dysfunction predicts impending death in individual flies. Activation of inflammatory pathways has been linked to aging and age-related diseases in humans, and an age-related increase in immunity-related gene expression has been reported in Drosophila. We show that the age-related increase in expression of antimicrobial peptides is tightly linked to intestinal barrier dysfunction. Indeed, increased antimicrobial peptide expression during aging can be used to identify individual flies exhibiting intestinal barrier dysfunction. Similarly, intestinal barrier dysfunction is more accurate than chronological age in identifying individual flies with systemic metabolic defects previously linked to aging, including impaired insulin/insulin-like growth factor signaling, as evidenced by a reduction in Akt activation and up-regulation of dFOXO target genes. Thus, the age-dependent loss of intestinal integrity is associated with altered metabolic and immune signaling and, critically, is a harbinger of death. Our findings suggest that intestinal barrier dysfunction may be an important factor in the pathophysiology of aging in other species as well, including humans.


Resistance-based interval exercise acutely improves endothelial function in type 2 diabetes.
Different modes of exercise, disease, and training status can modify endothelial shear stress and result in distinct effects on endothelial function. To date, no study has examined the influence of type 2 diabetes (T2D) and training status on the acute endothelial response to different modes of interval exercise (INT). We examined the effect of a single session of resistance- and cardio-based INT compared with a time-matched control on endothelial function in 12 age-matched T2D participants, 12 untrained, and 11 trained adults (aged 56 ± 7 yr). Flow-mediated dilation (%FMD) of the brachial artery was assessed at baseline and immediately, 1, and 2 h after an acute bout of cardio interval (C-INT), resistance interval (R-INT), and seated control (CTL); these interventions were randomized and separated by >2 days. C-INT involved seven 1-min cycling intervals at 85% of peak power with 1-min recovery between. R-INT involved the same pattern of seven 1-min intervals using leg resistance exercises. Endothelial function (%FMD) was improved after R-INT in all groups (Condition × Time interaction, P < 0.01), an effect that was most robust in T2D where %FMD was higher immediately (+4.0 ± 2.8%), 1 h (+2.5 ± 2.5%), and 2 h (+1.9 ± 1.9%) after R-INT compared with CTL (P < 0.01 for all). C-INT improved %FMD in T2D at 1-h postexercise (+1.6 ± 2.2%, P = 0.03) compared with CTL. In conclusion, R-INT acutely improves endothelial function throughout the 2-h postexercise period in T2D patients. The long-term impact of resistance exercise performed in an interval pattern is warranted.


Ionic clusters vs shear viscosity in aqueous amino acid ionic liquids.
Aqueous solutions of amino acid ionic liquids (AAILs) are of high importance for applications in protein synthesis and solubilization, enzymatic reactions, templates for synthetic study, etc. This work employs molecular dynamics simulations using our own force field to investigate shear viscosity and cluster compositions of three 1-ethyl-3-methylimidazolium (emim) amino acid salts: [emim][ala], [emim][met], and [emim][trp] solutions (2, 5, 10, 20, and 30 mol %) in water at 310 K. We, for the first time, establish simple correlations between cluster composition, on one side, and viscosity, on another side. We argue that knowledge about any of these properties alone is enough to derive insights regarding the missed properties, using the reported correlations. The numerical observations and qualitative correlations are discussed in the context of the chemical structure of the amino acid anions, [ala], [met], and [trp]. The reported results will enhance progress in the efficient design and applications of AAILs and their solutions.


Computational Characterization of the mtORF of Pocilloporid Corals: Insights into Protein Structure and Function in Stylophora Lineages from Contrasting Environments.
More than a decade ago, a new mitochondrial Open Reading Frame (mtORF) was discovered in corals of the family Pocilloporidae and has been used since then as an effective barcode for these corals. Recently, mtORF sequencing revealed the existence of two differentiated Stylophora lineages occurring in sympatry along the environmental gradient of the Red Sea (18.5°C to 33.9°C). In the endemic Red Sea lineage RS_LinB, the mtORF and the heat shock protein gene hsp70 uncovered similar phylogeographic patterns strongly correlated with environmental variations. This suggests that the mtORF too might be involved in thermal adaptation. Here, we used computational analyses to explore the features and putative function of this mtORF. In particular, we tested the likelihood that this gene encodes a functional protein and whether it may play a role in adaptation. Analyses of full mitogenomes showed that the mtORF originated in the common ancestor of Madracis and other pocilloporids, and that it encodes a transmembrane protein differing in length and domain architecture among genera. Homology-based annotation and the relative conservation of metal-binding sites revealed traces of an ancient hydrolase catalytic activity. Furthermore, signals of pervasive purifying selection, lack of stop codons in 1830 sequences analyzed, and a codon-usage bias similar to that of other mitochondrial genes indicate that the protein is functional, i.e., not a pseudogene. Other features, such as intrinsically disordered regions, tandem repeats, and signals of positive selection particularly in StylophoraRS_LinB populations, are consistent with a role of the mtORF in adaptive responses to environmental changes.


A Case Report of a Challenging Disease: Immunoglobulin G4-Related Disease With Acute Kideny Injury.
Immunoglobulin G4-related disease (IgG4-RD), which was initially identified as a type of autoimmune pancreatitis around the year 2000, is now widely acknowledged to be a systemic sickness. Based on both general and organ-specific criteria, alongside laboratory measurements of IgG4-subtype, the diagnosis is made. The diagnosis requires, however, a heightened index of suspicion, especially given the nonspecific clinical presentation. In addition to this, the symptoms may be "disseminated" in time and the multitude of organ-system involvement may seem initially unrelated. Furthermore, IgG4 levels may be falsely normal especially during the first presentation of IgG4-RD. We report a case of a 33-year-old male who was referred by his general practitioner (GP) to the fast access nephrology clinic due to elevated creatinine and fatigue, which was found after the patient had undergone some investigations at the GP office. He had history of atopic dermatitis and a prior admission for acute pancreatitis of unknown cause and recent bilateral anterior uveitis treated with steroid eyedrops. His urinalysis showed one to two granular casts per high-power field (HPF), and his creatinine was 262 µmol/L (previously normal). Three main differential diagnoses were considered given the patient's history: sarcoidosis, tubulointerstitial nephritis with uveitis (TINU) and IgG4-related disorder. Investigations were undertaken in that regard showing elevated serum IgG4 levels (2.7 times upper-limit of normal). Renal biopsy demonstrated tubulointerstitial nephritis (TIN) with 30 IgG4-positive plasma cells per HPF. Given the patient's presentation over time, a diagnosis of IgG4-TIN was considered. The patient was treated with high-dose steroids and has shown signs of improvement of both his renal and ocular problems. The uniqueness of the case is reflected through the fact that IgG4-renal disease is usually diagnosed in patients with an already established manifestation of another organ, whilst in our patient the renal involvement led to establishing IgG4-RD. It is also important to note that, in spite of initially negative serum IgG4 levels, the diagnosis still needs to be considered especially if multisystem involvement is present (as in this case).


Galactokinase: evidence for a new racial polymorphism.
Activities of galactokinase and galactose-1-phosphate uridyltransferase in red cells were assayed in a mixed racial population of 645 pregnant women. The distribution of individual transferase activities for black subjects was the same as that for whites. In contrast, the distributions of individual galactokinase activities differed significantly in blacks and whites, the mean for the black population being 30 percent lower than the mean for the white population. The same racial difference was found when red cell galactokinase activity was examined in males and in newborns. Because low-, intermediate-, and high-galactokinase activities appear to segregate within several black families, this observed difference suggests a new, racially determined enzyme polymorphism.


Sodium channel gating currents in frog skeletal muscle.
Charge movements similar to those attributed to the sodium channel gating mechanism in nerve have been measured in frog skeletal muscle using the vaseline-gap voltage-clamp technique. The time course of gating currents elicited by moderate to strong depolarizations could be well fitted by the sum of two exponentials. The gating charge exhibits immobilization: at a holding potential of -90 mV the proportion of charge that returns after a depolarizing prepulse (OFF charge) decreases with the duration of the prepulse with a time course similar to inactivation of sodium currents measured in the same fiber at the same potential. OFF charge movements elicited by a return to more negative holding potentials of -120 or -150 mV show distinct fast and slow phases. At these holding potentials the total charge moved during both phases of the gating current is equal to the ON charge moved during the preceding prepulse. It is suggested that the slow component of OFF charge movement represents the slower return of charge "immobilized" during the prepulse. A slow mechanism of charge immobilization is also evident: the maximum charge moved for a strong depolarization is approximately doubled by changing the holding potential from -90 to -150 mV. Although they are larger in magnitude for a -150-mV holding potential, the gating currents elicited by steps to a given potential have similar kinetics whether the holding potential is -90 or -150 mV.


Trajectories of relationship stress and inflammatory processes in adolescence.
Researchers have identified cross-sectional links between interpersonal stress and inflammation. Little is known, however, about how these dynamics unfold over time, what underlying immune pathways might exist, or whether moderators such as race could alter the strength of the connection between interpersonal stress and inflammatory processes. We examined whether adolescent girls whose relationship trajectories were characterized by chronic stress would exhibit a proinflammatory phenotype marked by systemic inflammation, heightened cytokine responses to bacterial challenges, and resistance to the anti-inflammatory properties of cortisol. Significant Stress × Race interactions revealed that family stress trajectories predicted glucocorticoid sensitivity and peer stress trajectories predicted cytokine production for White but not Asian girls. Relationship stress trajectories were not associated with systemic inflammation, however. These findings suggest that particular subgroups of adolescent girls who face chronic and elevated stress in their close relationships may be at risk for disruptions to the immune system.


Cryptogenic fibrosing alveolitis with preserved lung volumes.
Cryptogenic fibrosing alveolitis (CFA) is an uncommon disorder of unknown aetiology characterised by interstitial fibrosis which typically shows a restrictive pattern on pulmonary function testing. Some patients with CFA and relative preservation of lung volumes have been described and it has been suggested that their volume preservation may be due to concomitant emphysema. In a retrospective study the relative frequency of preserved lung volumes in CFA, its relationship to emphysema determined by CT scanning, its clinical features, and its subsequent natural history were investigated. Using predefined characteristics 48 patients with CFA were identified from pulmonary function records over a three year period. Volume preservation was defined as a forced vital capacity (FVC) of > 80% predicted at presentation. Patients with relative volume preservation were compared with those with more typical pulmonary restriction and clinical data at presentation, and details of their subsequent prognosis, treatment and loss of lung function with time were obtained. Where available, computed tomographic (CT) scans for the two groups were compared in a blinded fashion to score the extent of fibrosis and the presence of concomitant emphysema. Twenty one (44%) of the patients with CFA had a FVC of > 80% predicted. They were more likely to be male (76% versus 48%) and to be current smokers (57% versus 22%) with a heavier life time cigarette consumption than the restricted patients (mean (SE) 38 (4.6) versus 25 (4.5) pack years). There were no significant differences in prognosis and subsequent treatment between the groups. Comparable HRCT scans were available in 23 subjects (seven preserved, 16 restricted). They showed no difference in extent of the pulmonary fibrosis but patients with volume preservation were more likely to show concomitant emphysema (86% versus 19%). Patients with emphysema on HRCT scans were heavier smokers (41(10) versus 21(17) pack years) than those without emphysema but there was no difference in the extent of CFA score between the two groups. In this area of high smoking prevalence a significant number of patients with CFA presented with relative preservation of lung volumes and FEV1/FVC ratio. In many of these subjects this appears to reflect coincidental emphysema. This may make interpretation of gas transfer factor used to monitor progression in CFA difficult. However, there was no evidence that lung volumes at presentation were of prognostic significance.


Muscle recruitment and stone tool use ergonomics across three million years of Palaeolithic technological transitions.
Ergonomic relationships that minimize muscle activity relative to the creation of cutting stress underpin the design of modern knives, saws, and axes. The Palaeolithic archaeological record, and the > 3 million years of technological behavior that it represents, is predominantly characterized by sharp stone implements used for cutting. To date, we do not know whether Palaeolithic hominins adhered to ergonomic principles when designing stone tools, if lithic technological transitions were linked to ease-of-use advances, or even how muscularly demanding different Palaeolithic tools are on an empirically defined relative basis. Here, we report the results of an experimental program that examines how four key stone tool types, produced between ∼ 3.3 million and ∼ 40 thousand years ago, influence muscle activation in the hominin upper limb. Using standardized laboratory-based tests designed to imitate Pleistocene cutting behaviors, surface electromyography recorded electrical activity (amplitude) in nine muscles across the hand, forearm and shoulder of modern humans during the use of replica Lomekwian, Oldowan, Acheulean and Mousterian stone tools. Results confirm digit flexors and abductors, particularly the first dorsal interosseous and flexor pollicis longus, to be the most heavily recruited muscles during the use of all tool types. Significant differences in muscle activation are, however, identified dependent on the type of stone tool used. Notably, the abductor digiti minimi, flexor pollicis longus, and biceps brachii were highly activated during handaxe use, particularly when compared to the use of Oldowan and Levallois flakes. Results are discussed in light of current understanding on the origin of Lower and Middle Palaeolithic technologies, why specific tool types were produced over others during these periods, and the extent to which early hominins produced ergonomically designed tools.


Lupeol enhances inhibitory effect of 5-fluorouracil on human gastric carcinoma cells.
Lupeol, a dietary triterpene present in many fruits and medicinal plants, has been reported to possess many pharmacological properties including cancer-preventive and anti-cancer effects in vitro and in vivo. Here, we investigated the anti-cancer efficacy and adjuvant chemotherapy action of lupeol in gastric cancer (GC) cells (SGC7901 and BGC823) and explored the underlying mechanisms. Cells were treated with lupeol and/or 5-fluorouracil (5-Fu) and subjected to cell viability, colony formation, apoptosis, western blot, semiquantitative RT-PCR, and xenograft tumorigenicity assay. Our results showed that lupeol and 5-Fu inhibited the proliferation of SGC7901 and BGC823 cells, and combination treatment with lupeol and 5-Fu resulted in a combination index < 1, indicating a synergistic effect. Co-treatment with lupeol and 5-Fu induced apoptosis through up-regulating the expressions of Bax and p53 and down-regulating the expressions of survivin and Bcl-2. Furthermore, co-treatment displayed more efficient inhibition of tumor weight and volume on BGC823 xenograft mouse model than single-agent treatment with 5-Fu or lupeol. Taken together, our findings highlight that lupeol sensitizes GC to 5-Fu treatment, and combination treatment with lupeol and 5-Fu would be a promising therapeutic strategy for human GC treatment.