Expression of Hypoxia-Inducible Factor-1α in the Infiltrative Belt Surrounding Hepatic Alveolar Echinococcosis in Rats.
Our main aims were to investigate hypoxia inducible factor-1α (HIF-1α) expression in the surrounding invasion range of hepatic alveolar echinococcosis (HAE) lesions and determine the pathological basis of angiogenesis. In total, 23 Wistar rats with hepatic echinococcus multilocularis infection were killed and their livers, which contained 27 HAE lesions, obtained. Specimen segments were generated from 119 paraffin blocks. Comparative analysis of the tissue samples containing HAE nodules and hepatic parenchyma of the surrounding region was performed with the immunohistochemical SP method in this animal experiment. Expression patterns of HIF-1α in the surrounding invasion range and the hepatic parenchyma were compared. The HIF-1α positive expression rate was 97.5% (116/119 samples). Expression of HIF-1α in the actively multiplying infiltrative region of the HAE lesions was significantly higher than that in hepatic parenchyma (P < 0.05). Overexpression of HIF-1α in the actively multiplying infiltrative region of HAE lesions in rats is closely related to angiogenesis and microvasculature. The sensitivity of HIF-1α facilitates its application as a representative maker of HAE. Our data indicate that the invasion range of HAE lesions is based on extrusion and compression, and induces anoxia and ischemia in hepatic tissue. Thus, HIF-1α provides a valuable index for evaluating HAE activity, and induces anoxia and ischemia in hepatic tissue.


Amyloid precursor protein processing and A beta42 deposition in a transgenic mouse model of Alzheimer disease.
The PDAPP transgenic mouse, which overexpresses human amyloid precursor protein (APP717V-->F), has been shown to develop much of the pathology associated with Alzheimer disease. In this report, levels of APP and its amyloidogenic metabolites were measured in brain regions of transgenic mice between 4 and 18 months of age. While absolute levels of APP expression likely contribute to the rate of amyloid beta-peptide (Abeta) deposition, regionally specific factors also seem important, as homozygotic mice express APP levels in pathologically unaffected regions in excess of that measured in certain amyloid plaque-prone regions of heterozygotic mice. Regional levels of APP and APP-beta were nearly constant at all ages, while A beta levels dramatically and predictably increased in brain regions undergoing histochemically confirmed amyloidosis, most notably in the cortex and hippocampus. In hippocampus, A beta concentrations increase 17-fold between the ages of 4 and 8 months, and by 18 months of age are over 500-fold that at 4 months, reaching an average level in excess of 20 nmol of A beta per g of tissue. A beta1-42 constitutes the vast majority of the depositing A beta species. The similarities observed between the PDAPP mouse and human Alzheimer disease with regard to A beta42 deposition occurring in a temporally and regionally specific fashion further validate the use of the model in understanding processes related to the disease.


The effects of child maltreatment and polymorphisms of the serotonin transporter and dopamine D4 receptor genes on infant attachment and intervention efficacy.
This investigation examined the extent to which polymorphisms of the serotonin transporter linked promoter region (5-HTTLPR) and the dopamine receptor D4 (DRD4) genes differentially influenced the development of attachment security and disorganization in maltreated and nonmaltreated infants at age 13 months, and the extent to which the efficacy of preventive interventions to promote attachment security were influenced by genetic variation. The sample consisted of 106 infants from maltreating families, participating in a randomized control trial evaluating the efficacy of two interventions, child-parent psychotherapy and psychoeducational parenting intervention, and 47 infants from nonmaltreating families. DNA samples were genotyped for polymorphisms of 5-HTTLPR, DRD4 exon III variable number tandem repeat, and DRD4-521. Attachment organization at age 1 and at age 2 was assessed with the Strange Situation for all participants, prior to and following the completion of the interventions. High rates of disorganized attachment were observed in the maltreatment compared to the nonmaltreatment group, and both interventions resulted in increased rates of attachment security at age 2. Genetic variation did not influence improvement in attachment organization among maltreated infants. Among maltreated infants, genetic variation had minimal effect on attachment organization. In contrast, among nonmaltreated infants, 5-HTTLPR and DRD4 polymorphisms influenced attachment security and disorganization at age 2 and the stability of attachment disorganization over time.


Vascular smooth muscle cell calcification is mediated by regulated exosome secretion.
Matrix vesicles (MVs), secreted by vascular smooth muscle cells (VSMCs), form the first nidus for mineralization and fetuin-A, a potent circulating inhibitor of calcification, is specifically loaded into MVs. However, the processes of fetuin-A intracellular trafficking and MV biogenesis are poorly understood. The objective of this study is to investigate the regulation, and role, of MV biogenesis in VSMC calcification. Alexa488-labeled fetuin-A was internalized by human VSMCs, trafficked via the endosomal system, and exocytosed from multivesicular bodies via exosome release. VSMC-derived exosomes were enriched with the tetraspanins CD9, CD63, and CD81, and their release was regulated by sphingomyelin phosphodiesterase 3. Comparative proteomics showed that VSMC-derived exosomes were compositionally similar to exosomes from other cell sources but also shared components with osteoblast-derived MVs including calcium-binding and extracellular matrix proteins. Elevated extracellular calcium was found to induce sphingomyelin phosphodiesterase 3 expression and the secretion of calcifying exosomes from VSMCs in vitro, and chemical inhibition of sphingomyelin phosphodiesterase 3 prevented VSMC calcification. In vivo, multivesicular bodies containing exosomes were observed in vessels from chronic kidney disease patients on dialysis, and CD63 was found to colocalize with calcification. Importantly, factors such as tumor necrosis factor-α and platelet derived growth factor-BB were also found to increase exosome production, leading to increased calcification of VSMCs in response to calcifying conditions. This study identifies MVs as exosomes and shows that factors that can increase exosome release can promote vascular calcification in response to environmental calcium stress. Modulation of the exosome release pathway may be as a novel therapeutic target for prevention.


Use of anionic denaturing detergents to purify insoluble proteins after overexpression.
Many proteins form insoluble protein aggregates, called "inclusion bodies", when overexpressed in E. coli. This is the biggest obstacle in biotechnology. Ever since the reversible denaturation of proteins by chaotropic agents such as urea or guanidinium hydrochloride had been shown, these compounds were predominantly used to dissolve inclusion bodies. Other denaturants exist but have received much less attention in protein purification. While the anionic, denaturing detergent sodiumdodecylsulphate (SDS) is used extensively in analytical SDS-PAGE, it has rarely been used in preparative purification. Here we present a simple and versatile method to purify insoluble, hexahistidine-tagged proteins under denaturing conditions. It is based on dissolution of overexpressing bacterial cells in a buffer containing sodiumdodecylsulfate (SDS) and whole-lysate denaturation of proteins. The excess of detergent is removed by cooling and centrifugation prior to affinity purification. Host- and overexpressed proteins do not co-precipitate with SDS and the residual concentration of detergent is compatible with affinity purification on Ni/NTA resin. We show that SDS can be replaced with another ionic detergent, Sarkosyl, during purification. Key advantages over denaturing purification in urea or guanidinium are speed, ease of use, low cost of denaturant and the compatibility of buffers with automated FPLC. Ionic, denaturing detergents are useful in breaking the solubility barrier, a major obstacle in biotechnology. The method we present yields detergent-denatured protein. Methods to refold proteins from a detergent denatured state are known and therefore we propose that the procedure presented herein will be of general application in biotechnology.


Leasing can add flexibility to asset management.
Better management of high-technology assets begins with an understanding of a healthcare organization's goals and the equipment it needs to meet them. Under the right conditions, leasing can shift economic and technological risks of equipment obsolescence from healthcare organizations to leasing companies. Steps involved in a leasing decision include reviewing a hospital's equipment acquisition plans; conducting cost-benefit analyses, determining useful and product lives of desired equipment; and watching the market for potential technology changes.


Family history of premature coronary heart disease, child cardio-metabolic risk factors and left ventricular mass.
In a prospective cohort of 181 individuals followed up since childhood--when aged 9, 12 and 15 years--patients with a family history of premature coronary heart disease (n=18) had higher left ventricular mass index in adulthood--at mean age of 31 years--compared with those without (mean±standard error 39.1±1.9 versus 34.6±0.7 g/m(2.7), p=0.04). The correlation between adult left ventricular mass index and child triglycerides (r=0.66, p=0.04 versus r=-0.03, p=0.75; p(diff)=0.02) and diastolic blood pressure (r=0.65, p=0.02 versus r=0.16, p=0.07; p(diff)=0.05) was stronger among those with a family history of coronary heart disease than in those without. Although preliminary, these data suggest that the higher left ventricular mass index among adults with a family history might be explained by their increased susceptibility to child cardio-metabolic risk factors.


Induction with rATG versus No-induction in Deceased Donor Renal Transplantation - A Retrospective Observational Study.
Deceased donor renal transplantation (DDRT) poses special immunological challenges; particularly in resource-poor scenarios. There is substantial evidence that rabbit antithymocyte globulin (rATG) is superior to interleukin-2 receptor blocker and placebo among patients at high immunological risk. However, due to the lack of randomized controlled trials, this remains controversial in DDRT maintained on tacrolimus/mycophenolic acid/steroids. Here, in this study, we compared the clinical outcomes of induction with rATG therapy to no-induction therapy. The study was a single-center, retrospective cohort study. A total of 62 patients were divided into two groups, based on induction immunosuppression; induction with rATG (N = 25) and no-induction group (N = 37). Both groups received tacrolimus/mycophenolate mofetil sodium/prednisolone as maintenance immunosuppression. The main outcomes were incidence of acute rejection (AR) within the first year and graft survival at the end of 1 year. The AR at the end of 1-year was reported as 8% and 27% for the induction and no-induction groups (P = 0.07), respectively. A total of 15 patients died. Patient survival rates at 12 months were 83.8% (no-induction) and 64.0% (induction; P = 0.094). Death-censored graft survival rates, 12 months after transplantation, were similar in both treatment groups (83.7% vs. 83.5%, P = 0.972). The incidence of death with functioning graft was significantly high in the induction group (28% vs. 5.4%, P = 0.045). The incidence of AR was less in patients who received rATG induction compared with patients who did not receive any form of induction. An added advantage of induction with ATG in terms of reduced incidence of AR must be weighed against high incidence of infection, death with functioning graft, and death.


Middle cerebral artery circulation during carotid surgery. A transcranial Doppler study.
Perioperative carotid cross-clamping might induce low stump pressures as well as hypoperfusion of the middle cerebral artery. In this study blood flow velocities in the middle cerebral artery were compared with intraoperative measurements of the poststenotic carotid blood pressure. Forty-one patients with internal carotid artery stenosis were operated on without shunting, under general anesthesia. Poststenotic carotid pressures and middle cerebral artery flow velocities were measured before and during cross-clamping. The hemodynamic responses to preoperative carotid compressions and intraoperative cross-clamping were evaluated. In seven patients the poststenotic carotid blood pressure decreased on clamping despite unchanged or even increased middle cerebral artery blood flow velocities. In all other patients, pressure changes were significantly correlated to the decrease in middle cerebral artery blood flow velocities. Autoregulatory blood flow velocity responses after preoperative common carotid artery compression were not reproducible by cross-clamping. Stump blood pressure measurements may not reflect middle cerebral artery perfusion in about 20% of thrombendarterectomies performed under general anesthesia. A possible explanation might be dimished cerebral autoregulation and changes in collateral flow distributions.


WEBINO and the return of the King's Speech.
We present a 69 year-old man with hypertension who developed the sudden onset of horizontal binocular diplopia and stuttering of speech. On examination, bilateral exotropia (i.e. 'wall-eyed') was observed in the primary position. Attempted horizontal saccades revealed bilateral internuclear ophthalmoplegia; all consistent with the wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) syndrome. Convergence, vertical saccades and vestibular ocular reflexes were likewise impaired. Pupillary and levator palpebrae superioris functions were intact. Mild left-sided dysmetria, intention tremor and dysdiadochokinesia were elicited. Conspicuously, further characterization of the patient's history revealed that he had stuttered as a child, but it had resolved in adolescence. Brain MRI revealed an acute infarction of the mesencephalic and upper pontine tegmentum involving the periaqueductal gray region and the medial longitudinal fasciculus bilaterally with greater involvement of the left. Like the WEBINO syndrome, re-emergent developmental stuttering is a rare neurologic phenomenon. To our knowledge, this is the first case report of a mesencephalic and upper pontine infarction causing both syndromes. We discuss the pathobiological underpinnings of the WEBINO syndrome and neurogenic stuttering and in relationship to this unusual case.


[Gene rearrangement of immunoglobulins and of the T-cell receptor for antigens and its significance in the diagnosis of lymphoproliferative diseases].
The blot-hybridization method for detecting gene rearrangement of Ig and T-cell receptor for antigen is briefly described. The results obtained by this method in various lymphoproliferative diseases offer new insights in the diagnosis of monoclonal lymphocyte expansion and in the determination of the lineage of proliferating cells. The ability of revealing oligoclonal lymphocyte proliferation and discriminating benign and malignant forms of angioimmunoblastic lymphadenopathy, T gamma-lymphocytosis, and some other disorders makes this method a useful tool for investigating diseases with lymphocyte proliferation.


Future liasing of the lockdown during COVID-19 pandemic: The dawn is expected at hand from the darkest hour.
The lockdown during COVID-19 pandemic has converted the world into new experimental laboratories, which may reveal temporal or spatial comparative analysis data. However, some startling information is gathered in terms of reduced premature mortality cases associated with air and water quality improvement, enhanced e-learning on a broader platform, work from home, and successful e-health. The decline in vehicular density on roads and congestion leads to reduced energy consumption and associated greenhouse gases (GHG) and other pollutants emission. The lockdown has also been identified as a possible emergency measure to combat severe air pollution episodes. Similarly, industrial pollution has been recognized as one of the primary causes of water resource pollution and would, therefore, bring change in policy vis-à-vis groundwater pollution control. Our findings suggest that the results of successful e-learning and work from home would be a permanent shift from conventional modes in the near future due to a drastic reduction in socio-economic cost. Our critical analysis also highlights that with such temporary lockdown measures acute/chronic ill-effects of anthropogenic perturbations on planet earth can be effectively estimated through sociocultural, socioeconomical and socio-political/sociotechnological nexus.


Metabolic Signaling into Chromatin Modifications in the Regulation of Gene Expression.
The regulation of cellular metabolism is coordinated through a tissue cross-talk by hormonal control. This leads to the establishment of specific transcriptional gene programs which adapt to environmental stimuli. On the other hand, recent advances suggest that metabolic pathways could directly signal into chromatin modifications and impact on specific gene programs. The key metabolites acetyl-CoA or S-adenosyl-methionine (SAM) are examples of important metabolic hubs which play in addition a role in chromatin acetylation and methylation. In this review, we will discuss how intermediary metabolism impacts on transcription regulation and the epigenome with a particular focus in metabolic disorders.


Development and Pilot Test of the Competency Assessment for Sexual Assault Prevention Practitioners.
Sexual assault is a preventable problem that is widespread and particularly prevalent for certain populations (e.g., female college students, Native American women). Despite the gravity of this public health priority, most individuals tasked with the primary prevention of sexual assault are not adequately trained for the job (e.g., professionals often trained solely in sexual assault response). To achieve optimal outcomes, professionals responsible for implementing sexual assault prevention must possess certain core competencies, or knowledge and skills essential for job performance, which include those needed for any primary prevention effort in addition to those specific to sexual assault prevention. The purpose of this study was to develop and assess the construct validity of a competency assessment tool for sexual assault prevention practitioners. An existing assessment tool, which was designed for injury and violence prevention practitioners, was tailored to reflect competencies needed by sexual assault prevention practitioners as informed by the literature. The newly tailored measure was pilot tested with 33 individuals with varying levels of expertise with sexual assault prevention. These individuals were categorized into three groups based on self-rated sexual assault prevention expertise (low, medium, or high) to assess group differences. As expected, the high expertise group rated higher knowledge in all the competencies than the medium and low expertise groups (except for the competency pertaining to developing and maintaining competency). Data collection and analyses were conducted in 2020. Implications for how the assessment tool can be used to identify gaps among individual practitioners and teams of practitioners are discussed.


Hand hygiene compliance in a universal gloving setting.
The use of gloves for every patient contact (ie, universal gloving) has been suggested as an infection prevention adjunct and alternative to contact precautions. However, gloves may carry organisms unless they are changed properly. In addition, hand hygiene is required before donning and after removing gloves, and there are scarce data regarding glove changing and hand hygiene in a universal gloving setting. This nonrandomized observational before-after study evaluated the effect of education and feedback regarding hand hygiene. Compliance with hand hygiene and glove use was directly observed in a universal gloving setting at a 10-bed intensive care unit in a Japanese tertiary care university teaching hospital. A total of 6,050 hand hygiene opportunities were identified. Overall, hand hygiene compliance steadily increased from study period 1 (16.1%) to period 5 (56.8%), although there were indication-specific differences in the baseline compliance, the degree of improvement, and the reasons for noncompliance. There were decreases in the compliance with universal gloving and the incidence of methicillin-resistant Staphylococcus aureus. It is difficult to properly perform glove use and hand hygiene in a universal gloving setting, given its complexity. Direct observation with specific feedback and education may be effective in improving compliance.


[International trade in health services and the medical industrial complex: implications for national health systems].
Health services have increasingly proven to be an innovative sector, gaining prominence in the medical industrial complex through expansion to public and international markets. International trade can foster economic development and redirect the resources and infrastructure available for healthcare in different countries in favorable or unfavorable directions. Wherever private providers play a significant role in government-funded healthcare, GATS commitments may restrict health policy options in subscribing countries. Systematic information on the impacts of electronic health services, medical tourism, health workers' migration, and foreign direct investment is needed on a case-by-case basis to build evidence for informed decision-making, so as to maximize opportunities and minimize risks of GATS commitments.


A Variance Distribution Model of Surface EMG Signals Based on Inverse Gamma Distribution.
Objective: This paper describes the formulation of a surface electromyogram (EMG) model capable of representing the variance distribution of EMG signals. Methods: In the model, EMG signals are handled based on a Gaussian white noise process with a mean of zero for each variance value. EMG signal variance is taken as a random variable that follows inverse gamma distribution, allowing the representation of noise superimposed onto this variance. Variance distribution estimation based on marginal likelihood maximization is also outlined in this paper. The procedure can be approximated using rectified and smoothed EMG signals, thereby allowing the determination of distribution parameters in real time at low computational cost. Results: A simulation experiment was performed to evaluate the accuracy of distribution estimation using artificially generated EMG signals, with results demonstrating that the proposed model's accuracy is higher than that of maximum-likelihood-based estimation. Analysis of variance distribution using real EMG data also suggested a relationship between variance distribution and signal-dependent noise. Conclusion: The study reported here was conducted to examine the performance of a proposed surface EMG model capable of representing variance distribution and a related distribution parameter estimation method. Experiments using artificial and real EMG data demonstrated the validity of the model. Significance: Variance distribution estimated using the proposed model exhibits potential in the estimation of muscle force.Objective: This paper describes the formulation of a surface electromyogram (EMG) model capable of representing the variance distribution of EMG signals. Methods: In the model, EMG signals are handled based on a Gaussian white noise process with a mean of zero for each variance value. EMG signal variance is taken as a random variable that follows inverse gamma distribution, allowing the representation of noise superimposed onto this variance. Variance distribution estimation based on marginal likelihood maximization is also outlined in this paper. The procedure can be approximated using rectified and smoothed EMG signals, thereby allowing the determination of distribution parameters in real time at low computational cost. Results: A simulation experiment was performed to evaluate the accuracy of distribution estimation using artificially generated EMG signals, with results demonstrating that the proposed model's accuracy is higher than that of maximum-likelihood-based estimation. Analysis of variance distribution using real EMG data also suggested a relationship between variance distribution and signal-dependent noise. Conclusion: The study reported here was conducted to examine the performance of a proposed surface EMG model capable of representing variance distribution and a related distribution parameter estimation method. Experiments using artificial and real EMG data demonstrated the validity of the model. Significance: Variance distribution estimated using the proposed model exhibits potential in the estimation of muscle force.


Efficacy and tolerance of antihypertensive treatment in men and women with stage 1 diastolic hypertension. Results of the Treatment of Mild Hypertension Study.
To explore the sex-specific benefits and risks of treatment of stage 1 diastolic hypertension. Participants were African-American and white hypertensive men (n = 557) and women (n = 345) (age range, 45 to 69 years) with a diastolic blood pressure less than 100 mm Hg. Participants were randomized to treatment with placebo, chlorthalidone (15 mg/d), acebutolol hydrochloride (400 mg/d), doxazosin mesylate (2 mg/d), amlodipine besylate (5 mg/d), or enalapril maleate (5 mg/d); all were given nutritional-hygienic intervention. After 4 years, women who were randomized to lifestyle intervention only were less likely to be receiving step 1 therapy alone (placebo) than men who were randomized to placebo therapy (46% vs 66%, respectively, P < .01). There were significantly greater decreases in the mean systolic blood pressure in both men and women who were assigned to treatment with active drugs compared with those participants who were receiving placebo therapy; differences among treatments with active drugs were similar between men and women. Men experienced larger falls in their total and low-density lipoprotein cholesterol and triglyceride levels regardless of the treatment assignment than did women; however, there were no significant sex-by-treatment interactions. Quality-of-life indexes were generally improved with active drug treatment compared with placebo therapy in both sexes; there was a sex-by-treatment interaction for the general health index. The relative risk (RR) for combined clinical events was similar in women (RR, 0.64; 95% confidence interval [CI], (0.36 to 1.16) and in men (RR, 0.67; 95% CI, 0.40 to 1.14) who were assigned to treatment with all active drugs combined, compared with those who were receiving placebo therapy. In these exploratory analyses, men and women who were assigned to treatment with active drugs experienced greater and generally similar benefits from treatment than those participants who were assigned to lifestyle intervention only.


Factors affecting smallholder farmers' technical and non-technical adaptation responses to drought in Iran.
Farmers adopt a range of technical and non-technical adaptation behaviors (TANAB) to alleviate the negative effects of drought. Understanding this adaptation behavior and its determinants is essential for improving adaptation capacity and promoting sustainable agriculture. In this study, we investigated the factors affecting TANAB using the Health Belief Model (HBM) as a theoretical framework. A survey was conducted of 320 farmers in Dashtestan County, Bushehr Province, southern Iran, on the shores of Persian Gulf. We used multi-stage stratified random sampling to select the research samples and applied structural equation modeling to analyze the determinants of TANAB. The findings revealed that the self-efficacy variable is the most important predictor of TANAB. As well as self-efficacy, other determinants of technical adaptation behaviors (TAB) are perceived barriers, severity, and susceptibility. Self-efficacy and cue to action were found to determine non-technical adaptive behaviors (NAB). This study indicates the differences between the determinants of TAB and NAB and emphasizes the key role of self-efficacy. The results of this study have implications for policymakers in the agricultural sector and can help in the development of interventionist policies to improve rural development in response to environmental crises. Governments and policymakers need to reinforce capacity-building potential for agricultural extension systems and adaptation training through information and communication technologies. This investment in education is critical for sustainable agricultural development and encourages farmers to adopt appropriate drought strategies aiming reducing farmers' vulnerability.


Seroepidemiology of Burkholderia pseudomallei, Etiologic Agent of Melioidosis, in the Ouest and Sud-Est Departments of Haiti.
Burkholderia pseudomallei, the etiological agent of melioidosis, has been hypothesized to be endemic throughout the Caribbean, including the impoverished nation of Haiti. However, because of the protean clinical manifestations, presence of asymptomatic infections, and limited medical diagnostic capacity, the identification of active melioidosis cases remains challenging. A seroepidemiological study was conducted using a novel enzyme-linked immunosorbent assay (ELISA) to detect antibodies toward B. pseudomallei in the native population. The performance of an indirect ELISA with purified lipopolysaccharide (LPS) from B. pseudomallei was evaluated using serum collected from rhesus macaques exposed to aerosolized B. pseudomallei. After optimization, serum collected from asymptomatic population members (n = 756) was screened for polyvalent (immunoglobulin M [IgM]/ immunoglobulin G [IgG]/ immunoglobulin A) and monoclonal (IgG or IgM) immunoglobulins against B. pseudomallei LPS. The population seroprevalence was 11.5% (95% confidence interval [CI]: 9.2, 13.8) for polyvalent immunoglobulins, 9.8% (95% CI: 7.7, 11.9) for IgG, and 1.7% (95% CI: 0.8, 2.6%) for IgM. The seroprevalence was not significantly different by gender (P = 0.16), but increased significantly (P < 0.001) with age, yielding an estimated annual seroconversion rate of 1.05% (95% CI: 0.81, 1.3). The detection of both recent (IgM+) and previous (IgG+) exposure to B. pseudomallei provides serological evidence that melioidosis is endemic in Haiti.


Human-on-a-chip design strategies and principles for physiologically based pharmacokinetics/pharmacodynamics modeling.
Advances in maintaining multiple human tissues on microfluidic platforms has led to a growing interest in the development of microphysiological systems for drug development studies. Determination of the proper design principles and scaling rules for body-on-a-chip systems is critical for their strategic incorporation into physiologically based pharmacokinetic (PBPK)/pharmacodynamic (PD) model-aided drug development. While the need for a functional design considering organ-organ interactions has been considered, robust design criteria and steps to build such systems have not yet been defined mathematically. In this paper, we first discuss strategies for incorporating body-on-a-chip technology into the current PBPK modeling-based drug discovery to provide a conceptual model. We propose two types of platforms that can be involved in the different stages of PBPK modeling and drug development; these are μOrgans-on-a-chip and μHuman-on-a-chip. Then we establish the design principles for both types of systems and develop parametric design equations that can be used to determine dimensions and operating conditions. In addition, we discuss the availability of the critical parameters required to satisfy the design criteria, consider possible limitations for estimating such parameter values and propose strategies to address such limitations. This paper is intended to be a useful guide to the researchers focused on the design of microphysiological platforms for PBPK/PD based drug discovery.


Cephalic phase responses, craving and food intake in normal subjects.
Cephalic phase responses (CPRs) are elicited during exposure to food cues. They gear up the body to optimize digestion or they compensate for unwanted changes during a meal. The cue reactivity model of binge eating predicts that CPRs are experienced as craving for food, thereby increasing food intake and playing a role in abnormal eating behaviour. The present experiment was designed to measure CPRs in normal women and to examine its relationship with craving, food intake and restraint. Results show that normal subjects do react to food exposure with changes in heart rate, heart rate variability (HRV), salivation, blood pressure, skin conductance and gastric activity. These CPRs presumably gear up the body and presumably do not reflect compensatory responses. Significant correlations between restraint and blood pressure, between blood pressure and craving, and between craving and food intake were also found. These results are in line with the cue reactivity model and suggest that research into physiological CPRs and craving in the field of eating disorders is valuable.


The Use of the Medical Dictionary for Regulatory Activities in the Identification of Mitochondrial Dysfunction in HIV-Infected Children.
To demonstrate the utility of a medical terminology-based method for identifying cases of possible mitochondrial dysfunction (MD) in a large cohort of youths with perinatal HIV infection and to describe the scoring algorithms. Medical Dictionary for Regulatory Activities (MedDRA)® version 6 terminology was used to query clinical criteria for mitochondrial dysfunction by two published classifications, the Enquête Périnatale Française (EPF) and the Mitochondrial Disease Classification (MDC). Data from 2,931 participants with perinatal HIV infection on PACTG 219/219C were analyzed. Data were qualified for severity and persistence, after which clinical reviews of MedDRA-coded and other study data were performed. Of 14,000 data records captured by the EPF MedDRA query, there were 3,331 singular events. Of 18,000 captured by the MDC query, there were 3,841 events. Ten clinicians blindly reviewed non MedDRA-coded supporting data for 15 separate clinical conditions. We used the Statistical Analysis System (SAS) language to code scoring algorithms. 768 participants (26%) met the EPF case definition of possible MD; 694 (24%) met the MDC case definition, and 480 (16%) met both definitions. Subjective application of codes could have affected our results. MedDRA terminology does not include indicators of severity or persistence. Version 6.0 of MedDRA did not include Standard MedDRA Queries, which would have reduced the time needed to map MedDRA terms to EPF and MDC criteria. Together with a computer-coded scoring algorithm, MedDRA terminology enabled identification of potential MD based on clinical data from almost 3000 children with substantially less effort than a case by case review. The article is accessible to readers with a background in statistical hypothesis testing. An exposure to public health issues is useful but not strictly necessary.


Synthetic Biology to Engineer Bacteriophage Genomes.
Recent advances in the synthetic biology field have enabled the development of new molecular biology techniques used to build specialized bacteriophages with new functionalities. Bacteriophages have been engineered toward a wide range of applications, including pathogen control and detection, targeted drug delivery, or even assembly of new materials.In this chapter, two strategies that have been successfully used to genetically engineer bacteriophage genomes will be addressed: the bacteriophage recombineering of electroporated DNA (BRED) and the yeast-based phage-engineering platform.


Modulating donor-acceptor transition energies in phosphorus-boron co-doped silicon nanocrystals via X- and L-type ligands.
In this work, we explore the effect of ligand binding groups on the visible and NIR photoluminescent properties within phosphorus-boron co-doped silicon nanocrystals (PB:Si NCs) by exploiting both the X-type (covalent) and L-type (Lewis donor molecule) bonding interactions. We find that the cooperative nature of both X- and L-type bonding from alkoxide/alcohol, alkylamide/alkylamine, and alkylthiolate/alkylthiol on PB:Si NCs results in photoluminescence (PL) energy blue shifts from the as-synthesized, hydride-terminated NCs (PB:Si-H) in excess of 0.4 eV, depending on the surface termination. These PL blue shifts appear greatest in the most strongly confined samples with diameters <4 nm where the surface-to-volume ratio is high and, therefore, the ligand effects are most pronounced. A correlation between the donor group strength (either X-type or L-type) and the degree of D-A state modulation is found, and the proportion of the PL blue shift from the X- and L-type interactions is quantified. Raman spectroscopy is used to provide additional evidence of the strength of the L-type donor groups. Additionally, we probe how the nature of the ligand chemistry affects the radiative lifetime and PL efficiency and find that the ligands do not significantly change the D-A emission dynamics, and all samples retain the long 50-130 μs lifetimes characteristic of these transitions. Finally, we describe three mechanisms that operate to affect the D-A recombination energies: (1) X-type ligands that modulate the PB:Si-X NC wavefunction; (2) L-type ligands that perturb the donor and acceptor states via a molecular orbital theory picture; and (3) X- and L-type ligands that cause a dielectric increase around the PB:Si NC core, which provides Coulomb screening and modulates the donor and acceptor states even further.


Isatis indigotica induces hepatocellular cancer cell death via caspase-independent apoptosis-inducing factor translocation apoptotic pathway in vitro and in vivo.
Isatis indigotica is a biennial herbaceous cruciferous medical herb with antipyretic, antiviral, anti-inflammatory, and anti-endotoxin activity. This study explored the chemotherapeutic potential of I indigotica on human hepatoma cells and investigated the mechanism by which metabolites from I indigotica inhibit hepatoma cell growth. Antitumor activity was discovered in dried I indigotica leaf chloroform extracts (CEDLI). In nude mice xenotransplanted with human hepatoma cells, CEDLI supplementation inhibited tumor growth by ~40% compared with nonsupplemented animals without affecting body weight/food intake. CEDLI induced sub-G1 cell cycle arrest and apoptosis in hepatoma cells. Furthermore, CEDLI activates p53 and Bax, reduces Bcl-2 expression, and causes mitochondrial stress and the release of apoptosis-inducing factor into the cytosol followed by its translocation into the nucleus, resulting in hepatoma cell apoptosis. This study provides novel in vivo evidence of I indigotica's antitumor activity. The chemotherapeutic activity against human hepatoma tumorigenesis was because of a distinguished caspase-independent apoptotic pathway.


The 10 basic requirements for a scientific paper reporting antioxidant, antimutagenic or anticarcinogenic potential of test substances in in vitro experiments and animal studies in vivo.
There is increasing evidence that chemicals/test substances cannot only have adverse effects, but that there are many substances that can (also) have a beneficial effect on health. As this journal regularly publishes papers in this area and has every intention in continuing to do so in the near future, it has become essential that studies reported in this journal reflect an adequate level of scientific scrutiny. Therefore a set of essential characteristics of studies has been defined. These basic requirements are default properties rather than non-negotiables: deviations are possible and useful, provided they can be justified on scientific grounds. The 10 basic requirements for a scientific paper reporting antioxidant, antimutagenic or anticarcinogenic potential of test substances in in vitro experiments and animal studies in vivo concern the following areas: (1) Hypothesis-driven study design; (2) The nature of the test substance; (3) Valid and invalid test systems; (4) The selection of dose levels and gender; (5) Reversal of the effects induced by oxidants, carcinogens and mutagens; (6) Route of administration; (7) Number and validity of test variables; (8) Repeatability and reproducibility; (9) Statistics; and (10) Quality Assurance.


Risk factors for trachoma: 6-year follow-up of children aged 1 and 2 years.
The authors investigated the long-term stability of risk factors in predicting the presence of active trachoma and severe inflammatory trachoma in 176 children in Kongwa, Tanzania, who were aged 1 and 2 years in 1989 and were available for follow-up in 1995. Familial cattle ownership, living more than 2 hours away from a water source, and facial cleanliness at both time points were associated with the presence of active trachoma at both time points (odds ratio (OR) = 2.58, 95% confidence interval (CI): 1.15, 5.79; OR = 3.07, 95% CI: 1.23, 7.64; and OR = 0.52, 95% CI: 0.26, 1.03, respectively). An association of familial cattle ownership with facial cleanliness and water accessibility was observed. Having a clean face at both time points was associated with lower odds of active trachoma at both time points for children in non-cattle-herding families (OR = 0.40, 95% CI: 0.18, 0.87). Living more than 2 hours away from a water source at both time points increased the odds of active trachoma at both time points in children of cattle-herding families (OR = 8.00, 95% CI: 1.99, 32.10). Noticeably, severe inflammatory trachoma at baseline predicted mortality in children from villages in which trachoma was less common (OR = 3.75, 95% CI: 1.09, 12.98). The results suggest that risk factor reduction could diminish persistent disease.


A combination of cis and trans control can solve the hotspot conversion paradox.
There is growing evidence that in a variety of organisms the majority of meiotic recombination events occur at a relatively small fraction of loci, known as recombination hotspots. If hotspot activity results from the DNA sequence at or near the hotspot itself (in cis), these hotspots are expected to be rapidly lost due to biased gene conversion, unless there is strong selection in favor of the hotspot itself. This phenomenon makes it very difficult to maintain existing hotspots and even more difficult for new hotspots to evolve; it has therefore come to be known as the "hotspot conversion paradox." I develop an analytical framework for exploring the evolution of recombination hotspots under the forces of selection, mutation, and conversion. I derive the general conditions under which cis- and trans-controlled hotspots can be maintained, as well as those under which new hotspots controlled by both a cis and a trans locus can invade a population. I show that the conditions for maintenance of and invasion by trans- or cis-plus-trans-controlled hotspots are broader than for those controlled entirely in cis. Finally, I show that a combination of cis and trans control may allow for long-lived polymorphisms in hotspot activity, the patterns of which may explain some recently observed features of recombination hotspots.


Population analysis of pharmacogenetic polymorphisms related to acute lymphoblastic leukemia drug treatment.
This study aimed to evaluate in the Brazilian population, the genotypes and population frequencies of pharmacogenetic polymorphisms involved in the response to drugs used in treatment of acute lymphoblastic leukemia (ALL), and to compare the data with data from the HapMap populations. There was significant differentiation between most population pairs, but few associations between genetic ancestry and SNPs in the Brazilian population were observed. AMOVA analysis comparing the Brazilian population to all other populations retrieved from HapMap pointed to a genetic proximity with the European population. These associations point to preclusion of the use of genetic ancestry as a proxy for predicting drug response. In this way, any study aiming to correlate genotype with drug response in the Brazilian population should be based on pharmacogenetic SNP genotypes.


Nail psoriasis: a review of the literature.
Nails are considered epidermal appendages, and as such, are commonly affected in patients with psoriasis, 80% of whom are likely to develop nail psoriasis as a result of their condition. Two patterns of nail disorders have been shown to be caused by psoriasis. Nail matrix involvement can result in features such as leukonychia, pitting (punctures or cupuliform depressions), red spots in the lunula and crumbling. Nail bed involvement, on the other hand, can cause onycholysis, salmon or oil-drop patches, subungual hyperkeratosis and splinter hemorrhages. Nail disease causes aesthetic and functional impairment, and is indicative of more severe forms of psoriasis as well as of joint involvement. The treatment for nail psoriasis involves behavioral interventions, topical medications, or systemic therapy in case of extensive skin or joint involvement. This article presents a review of the main features of nail psoriasis, its clinical presentation, diagnostic and assessment methods, clinical repercussions, and of its available treatment options.


Treatment of posttraumatic stress disorder with phenytoin: an open-label pilot study.
Phenytoin is an anticonvulsant used in the treatment of epilepsy. Its mechanism of action is incompletely understood but most likely involves modulation of glutamatergic transmission. The neurobiology of posttraumatic stress disorder (PTSD) has been hypothesized to involve, at least in part, alterations in glutamatergic transmission in the hippocampus and possibly other brain regions. The purpose of this study was to assess the effects of phenytoin on symptoms of PTSD. Phenytoin was administered in an open-label fashion for 3 months to 9 adult male and female patients with DSM-IV PTSD related to a variety of traumas including childhood abuse, combat, and car accidents. Dosage was adjusted to maintain the therapeutic blood levels used in the treatment of epilepsy. Subjects were assessed before, during, and after treatment for PTSD with standardized dimensional measures of disease severity including the Clinician Administered PTSD Scale (CAPS), the Hamilton Rating Scale for Depression (HAM-D), and the Hamilton Rating Scale for Anxiety (HAM-A). Data were collected from November 2001 through June 2003. Phenytoin treatment resulted in a significant decrease in PTSD symptoms as measured with the CAPS (mean score = 65 pretreatment vs. 38 posttreatment) with reductions in each of the symptom clusters of intrusions, avoidance, and hyperarousal (p < .05). There were no significant decreases in symptoms of depression severity as measured with the HAM-D or anxiety severity as measured with the HAM-A. These findings suggest that phenytoin may be efficacious in the treatment of PTSD, possibly mediated through its antiglutamatergic effects. Randomized, controlled, double-blind clinical trials are indicated to further evaluate this medication in the treatment of PTSD.


What sort of follow-up services would Australian breast cancer survivors prefer if we could no longer offer long-term specialist-based care? A discrete choice experiment.
Early diagnosis and improved treatment outcomes have increased breast cancer survival rates that, in turn, have led to increased numbers of women undergoing follow-up after completion of primary treatment. The current workload growth is unsustainable for breast cancer specialists who also provide care for women newly diagnosed or with a recurrence. Appropriate and acceptable follow-up care is important; yet, currently we know little about patient preferences. The aim of this study was to explore the preferences of Australian breast cancer survivors for alternative modes of delivery of follow-up services. A self-administered questionnaire (online or paper) was developed. The questionnaire contained a discrete choice experiment (DCE) designed to explore patient preferences with respect to provider, location, frequency and method of delivery of routine follow-up care in years 3, 4 and 5 after diagnosis, as well as the perceived value of 'drop-in' clinics providing additional support. Participants were recruited throughout Australia over a 6-month period from May to October 2012. Preference scores and choice probabilities were used to rank the top 10 most preferred follow-up scenarios for respondents. A total of 836 women participated in the study, of whom 722 (86.4%) completed the DCE. In the absence of specialist follow-up, the 10 most valued surveillance scenarios all included a Breast Physician as the provider of follow-up care. The most preferred scenario is a face-to-face local breast cancer follow-up clinic held every 6 months and led by a Breast Physician, where additional clinics focused on the side effects of treatment are also provided. Beyond the first 2 years from diagnosis, in the absence of a specialist led follow-up, women prefer to have their routine breast cancer follow-up by a Breast Physician (or a Breast Cancer Nurse) in a dedicated local breast cancer clinic, rather than with their local General Practitioner. Drop-in clinics for the management of treatment related side effects and to provide advice to both develop and maintain good health are also highly valued by breast cancer survivors.


Cch1 restores intracellular Ca2+ in fungal cells during endoplasmic reticulum stress.
Pathogens endure and proliferate during infection by exquisitely coping with the many stresses imposed by the host to prevent pathogen survival. Recent evidence has shown that fungal pathogens and yeast respond to insults to the endoplasmic reticulum (ER) by initiating Ca(2+) influx across their plasma membrane. Although the high affinity Ca(2+) channel, Cch1, and its subunit Mid1, have been suggested as the protein complex responsible for mediating Ca(2+) influx, a direct demonstration of the gating mechanism of the Cch1 channel remains elusive. In this first mechanistic study of Cch1 channel activity we show that the Cch1 channel from the model human fungal pathogen, Cryptococcus neoformans, is directly activated by the depletion of intracellular Ca(2+) stores. Electrophysiological analysis revealed that agents that enable ER Ca(2+) store depletion promote the development of whole cell inward Ca(2+) currents through Cch1 that are effectively blocked by La(3+) and dependent on the presence of Mid1. Cch1 is permeable to both Ca(2+) and Ba(2+); however, unexpectedly, in contrast to Ca(2+) currents, Ba(2+) currents are steeply voltage-dependent. Cch1 maintains a strong Ca(2+) selectivity even in the presence of high concentrations of monovalent ions. Single channel analysis indicated that Cch1 channel conductance is small, similar to that reported for the Ca(2+) current I(CRAC). This study demonstrates that Cch1 functions as a store-operated Ca(2+)-selective channel that is gated by intracellular Ca(2+) depletion. The inability of cryptococcal cells that lacked the Cch1-Mid1 channel to survive ER stress suggests that Cch1 and its co-regulator, Mid1, are critical players in the restoration of Ca(2+) homeostasis.


Children's Autonomic Nervous System Reactivity Moderates the Relations between Family Adversity and Sleep Problems in Latino 5-Year Olds in the CHAMACOS Study.
Sleep problems are common for young children especially if they live in adverse home environments. Some studies investigate if young children may also be at a higher risk of sleep problems if they have a specific biological sensitivity to adversity. This paper addresses the research question, does the relations between children's exposure to family adversities and their sleep problems differ depending on their autonomic nervous system's sensitivity to challenges? As part of a larger cohort study of Latino, low-income families, we assessed the cross-sectional relations among family demographics (education, marital status), adversities [routines, major life events (MLE)], and biological sensitivity as measured by autonomic nervous system (ANS) reactivity associated with parent-rated sleep problems when the children were 5 years old. Mothers were interviewed in English or Spanish and completed demographic, family, and child measures. The children completed a 15-min standardized protocol while continuous cardiac measures of the ANS [respiratory sinus arrhythmia (RSA), preejection period (PEP)] were collected during resting and four challenge conditions. Reactivity was defined as the mean of the responses to the four challenge conditions minus the first resting condition. Four ANS profiles, co-activation, co-inhibition, reciprocal low RSA and PEP reactivity, and reciprocal high RSA and PEP reactivity, were created by dichotomizing the reactivity scores as high or low reactivity. Logistic regression models showed there were significant main effects for children living in families with fewer daily routines having more sleep problems than for children living in families with daily routines. There were significant interactions for children with low PEP reactivity and for children with the reciprocal, low reactivity profiles who experienced major family life events in predicting children's sleep problems. Children who had a reciprocal, low reactivity ANS profile had more sleep problems if they also experienced MLE than children who experienced fewer MLE. These findings suggest that children who experience family adversities have different risks for developing sleep problems depending on their biological sensitivity. Interventions are needed for young Latino children that support family routines and reduce the impact of family adversities to help them develop healthy sleep practices.


[Clinical and morphological characteristics of thyroid adenomatosis].
Surgical (374 cases) and puncture (6148 cases) material from patients with multinodular goiter was studied. Definitions and a working classification characterizing morphological and cytological signs of adenomatous goiter were formulated. Prognostic significance of thyroid adenomatosis and approaches to its treatment in multinodular goiter are shown.


The importance of walking to public health.
There is clear evidence that physical activity, including walking, has substantial benefits for health. This article, prepared as part of the proceedings of a conference on walking and health, discusses the type of walking that produces substantial health benefits, considers several methodological issues pertinent to epidemiologic studies investigating the association of walking and health, and reviews some of the reasons for the large public health importance of walking. Review of the available literature. Due to space constraints, this is not intended to be a comprehensive review; instead, selected studies are cited to illustrate the points raised. Walking as a healthful form of physical activity began to receive attention in the 1990s due to new recommendations that emphasized moderate-intensity physical activity. The main example of moderate-intensity activity in the 1995 Centers for Disease Control/American College of Sports Medicine recommendation was brisk walking at 3 to 4 mph. Evidence for the health benefits of walking comes largely from epidemiologic studies. When interpreting the data from such studies, it is necessary to consider several methodological issues, including the design of the study, confounding by other lifestyle behaviors, and confounding by other kinds of physical activity. Walking has the potential to have a large public health impact due to its accessibility, its documented health benefits, and the fact that effective programs to promote walking already exist. Walking is a simple health behavior that can reduce rates of chronic disease and ameliorate rising health care costs, with only a modest increase in the number of activity-related injuries.


Long-term outcomes of Absorb bioresorbable vascular scaffold using predilation, sizing, and postdilation protocol in a real-world patient population.
Bioresorbable vascular scaffolds (BVSs) have been a disappointment in the evolution of drug-eluting stents used in percutaneous coronary intervention because an excessive number of thrombotic complications have been reported. The aim of this study was to evaluate long-term clinical outcomes of the Absorb BVS in patients treated using a predilation, proper sizing, and post-dilation implantation technique. The records of 110 patients who had a total of 150 Absorb BVSs implanted were retrospectively analyzed. The rate of major adverse cardiovascular events (MACEs), defined as the composite of cardiac death, target vessel myocardial infarction (MI), and target-lesion revascularization were studied using quantitative coronary angiography. Of the study population, 80% were male and the mean age was 60±11.3 years. The most common diagnosis was stable angina (84%). The median length of follow-up was 53 months (range: 46-59 months). The rate of predilation and postdilation was 100%, and 95%, respectively. The 4-year rate of MACEs was 20%: cardiac death in 3 patients (2.7%), target vessel MI in 9 (8.2%), and target lesion revascularization in 20 (18.2%). Definite device thrombosis occurred in 6 of 110 patients (5.5%). One case of very late scaffold thrombosis was observed at 47 months. A small BVS diameter (2.5 mm) was found to be the most powerful independent predictor of a MACE (p=0.05). The Absorb BVS was associated with an increased risk of adverse events, including late and very late device thrombosis, despite the use of a good implementation protocol.


Close relationship between strict blood glucose control, including suppression of blood glucose variability, and mortality reduction in acutely ill patients with glucose intolerance investigated by means of a bedside-type artificial pancreas.
The purpose of this study was to elucidate the relationship between strict control of blood glucose (BG) and mortality reduction with the use of an artificial pancreas (AP). Patients were evaluated in the (1) early phase (E phase: mean 3.3 ± 2.6 days after admission, n = 84) and in the (2) late phase (L phase: mean 9.9 ± 3.3 days, n = 88), and were classified into a (1) group with a higher daily mean BG level (BGm) (BGmXa: BGm above Xmg/dl) and a (2) group with a lower BGm (BGmXb: BGm below Xmg/dl). Each group was classified into a (1) subgroup with a higher daily standard deviation of the BG levels (BGsd) and a (2) subgroup with a lower BGsd. In the E phase, the (1) mortality of the BGm200a group was significantly higher than that of the BGm200b group (56 vs. 29%, p < 0.05), and (2) in the BGm200b group, the mortality of the subgroup with a BGsd above 14 mg/dl was significantly higher than that with a BGsd below 14 mg/dl (46 vs. 17%, p < 0.025). In the L phase, the mortality of the BGm175a group was significantly higher than that of the BGm175b group (50 vs. 28%, p < 0.05). In conclusion, (1) a higher BGm and (2) higher BGsd in the E phase were prognostic risk factors. Based on the findings, it was considered that the target for BG control should be set at (1) BGm below 200 mg/dl and BGsd below 14 mg/dl in the E phase, and (2) BGm below 175 mg/dl in the L phase.


Gender differences in pathways to care for early psychosis.
Gender is a critical demographic determinant in first-episode psychosis research. We used data from the ACE Pathways to Care Project, which examined pathways to care in African-origin, Caribbean-origin and European-origin participants, to investigate the role of gender in pathways to early intervention programmes. A qualitative approach was used to examine gender differences in the routes to care. We conducted four focus groups and four individual in-depth interviews with 25 service users of early intervention services from African-origin, Caribbean-origin and European-origin populations. Gender stereotypes negatively influence the first service contact for women, and the early phase of the help seeking process for men. Women reported trying to seek care. However, family members and service providers often questioned their calls for help. Men described having difficulties in talking about their symptoms, as the act of seeking help was perceived as a sign of weakness by peers. The findings of this study suggest that gender stereotypes shape the journey to specialized care in different ways for men and women. Awareness of the impact that gender stereotypes have when a young person is seeking care for psychosis could help to promote a shift in attitudes among health-care providers and the provision of more compassionate and patient-centred care during this critical time.


Open peer review: a randomised controlled trial.
Most scientific journals practise anonymous peer review. There is no evidence, however, that this is any better than an open system. To evaluate the feasibility of an open peer review system. Reviewers for the British Journal of Psychiatry were asked whether they would agree to have their name revealed to the authors whose papers they review; 408 manuscripts assigned to reviewers who agreed were randomised to signed or unsigned groups. We measured review quality, tone, recommendation for publication and time taken to complete each review. A total of 245 reviewers (76%) agreed to sign. Signed reviews were of higher quality, were more courteous and took longer to complete than unsigned reviews. Reviewers who signed were more likely to recommend publication. This study supports the feasibility of an open peer review system and identifies such a system's potential drawbacks.


The rupture of a single liquid aluminium alloy film.
The present study is based on the idea of understanding the rupture of films in metal foams by studying free standing metallic films as a model system. Liquid dynamics, the velocity of the rupturing material as well as the behaviour of ceramic particles inside the melt were analysed optically ex situ and by synchrotron X-ray radiography in situ. It was found that the resistance of films to rupture is mainly based on the interaction between solid particles and an immobile oxide skin, the formation of which depends on the oxygen content of the surrounding atmosphere and the presence of magnesium.


Changes in kinetics of cerebral auto-regulation with head-down bed rest.
Thoraco-cephalic fluid shift induced by weightlessness may influence cerebral autoregulation. Our objective was to assess effects of simulated weightlessness by a 7-day head-down bed rest (HDBR) on the kinetics of cerebral blood flow (CBF) autoregulation in eight healthy women (27.9 +/- 0.9 years). This was studied by transcranial Doppler (TCD) of the middle cerebral artery (MCA) during the sudden decrease in blood pressure (BP) induced by quickly deflating thigh cuff aftera 4-min arterial occlusion before (D - 3), during (D2, D5) and after the HDBR (D + 1). BP (Finapres) and MCA maximal blood flow velocity were continuously recorded. Cerebrovascular resistance (CR) was expressed as the ratio of mean BP to mean MCA velocity. The CR slope was defined as changes in CR per second during the BP decrease. The magnitude of the relative decrease in mean BP and MCA velocity as well as the CR slope did not differ significantly before, during and after the HDBR, showing no major impairment of cerebral autoregulation during short-term HDBR. The time to maximum decrease in CR (T1 in s), corresponding to the maximum vasodilation was reduced on D2 (7-2 +/- 0.6) versus D - 3 (9.9 +/- 1-3), D5 (9-6 +/- 0.8) and R + 1 (11.7 +/- 11) probably as a result of the fluid shift. We also looked if the responses during the thigh cuff release differed in women according to their tolerance to the 10 min stand test performed after the HDBR: T1 was larger in the five women who presented orthostatic intolerance suggesting that some differences in cerebral autoregulatory responses may be related to orthostatic intolerance.


Does a change in psychosocial work factors lead to a change in employee health?
The aim was to identify psychosocial factors at work that promote positive changes in employee health and factors that prevent negative changes in employee health. This study is part of a large longitudinal study and includes 1212 employees. Data for psychosocial work factors and self rated health was collected in 2000 and 2003. A modified Poisson regression was used to find factors of relevance for positive and negative changes in health. A negative change in leadership, organizational commitment and reporting job strain increased the risk for negative change in health. Improved leadership and social climate increased the chance for positive changes in health. By improving psychosocial factors at work, it is possible to promote employee health as well as prevent employee ill-health.


Nutritional evaluation of Glutenol: a co-product of ethanol production.
The objective of this study was to evaluate the nutritional value of Glutenol, a new coproduct of the ethanol industry. Glutenol was produced by Quality Technology International, Elgin, IL, in a modified wet-milling plant using a hybrid process, NextGenFrac, which fractionates the corn kernel components prior to fermentation without the use of sulfur dioxide. Glutenol was analyzed to contain 52.3% CP, 1.7% Met + Cys, 1.32% Lys, 1.69% Thr, and 2.23% Val on a DM basis. Two precision-fed rooster assays with conventional and cecectomized roosters were conducted to determine TMEn and standardized digestibility of amino acids (AA), respectively. The TMEn of Glutenol was determined to be 3,256 kcal/kg DM. Standardized digestibility values for Lys, Met, Cys, Thr, and Val were 80.1%, 90.4%, 80.1%, 74.1%, 81.1%, and 84.9%, respectively. In addition, a 3-wk broiler chick assay was conducted with increasing levels of dietary Glutenol. Diet 1 was a standard corn/soybean meal diet with 0% Glutenol. Diets 2, 3, and 4 had increasing levels of Glutenol at 4%, 8%, and 12%, respectively. Diets were fed from 3 to 22 d post-hatch and all diets were formulated to be equal in TMEn and digestible AA. Weight gain, feed intake, and gain/feed ratio were measured. No differences in growth performance were observed among dietary treatments. In conclusion, Glutenol can be fed up to at least 12% in the diet of broiler chickens if diets are formulated to be equal in ME and digestible AA.


[Treatment strategy toward Fontan completion in hypoplastic left heart syndrome].
The Norwood procedure with right ventricle-pulmonary artery (RV-PA) conduit is thought to improve post-operative hemodynamics in hypoplastic left heart syndrome( HLHS). Prematurity( GA<37 weeks), body weight less than 2.5 kg and tricuspid regurgitation( TR)2+ or more were associated with mortality. For requiring better outcome, paralyzed ventilation, inherent N2 are indicated, to avoid preoperative high pulmonary blood flow followed by progressive TR. Rapid staged bilateral pulmonary artery banding( PAB) might improve the outcome for this high mortality group. As operative improvement, the distal neoaortic reconstruction was completed without any patch materials in most case. For achievement this, it is important that aortic arch and ascending aorta just opposite the site of the innominate artery were sutured inferiorly to extend the width of the aortic arch. Also we have developed a modified strategy to control RV-PA shunt flow, which is partial clipping on the ePTFE graft. Because significant TR associated with mortality, TR should be surgically treated at any sage of reconstruction. At bidirectional Glenn operation, 70% of patient were left the RV-PA conduit as additional flow. Hospital mortality after Fontan completion for HLHS is excellent with short averaging more than 95%. Extracardiac conduit with fenestration is indicated in all HLHS patients.


Mechanisms of vascular damage in SSc--implications for vascular treatment strategies.
Vascular abnormalities are a major component of SSc, but little is known about the events or mechanisms that initiate vascular injury and prevent its repair. In SSc, angiogenesis is incomplete or lacking despite the increased expression of a large array of pro-angiogenic factors such as VEGF. Conflicting results have recently been published concerning the presence and role of vasculogenesis and circulating endothelial progenitor cells in SSc. It remains to be established if these endothelial progenitor cells are a marker of endothelial disease or a cause of insufficient vascular repair. Human mesenchymal stem cells (MSCs) may be an alternative source for endothelial progenitor cells, and it has been observed that the angiogenic potential of endothelial-like MSCs is reduced. Other mechanisms of vascular damage include oxidative stress and factors released from activated platelets. In addition, growth factors such as ET-1 and PDGF induce proliferation of vascular smooth muscle cells resulting in intimal thickening. For the development of new therapeutic strategies, it is important to realize that the different vascular pathologies--uncompensated loss of capillaries on one hand and vascular remodelling with a proliferative vasculopathy on the other--might require different treatment approaches.


Achalasia: a new clinically relevant classification by high-resolution manometry.
Although the diagnosis of achalasia hinges on demonstrating impaired esophagogastric junction (EGJ) relaxation and aperistalsis, 3 distinct patterns of aperistalsis are discernable with high-resolution manometry (HRM). This study aimed to compare the clinical characteristics and treatment response of these 3 subtypes. One thousand clinical HRM studies were reviewed, and 213 patients with impaired EGJ relaxation were identified. These were categorized into 4 groups: achalasia with minimal esophageal pressurization (type I, classic), achalasia with esophageal compression (type II), achalasia with spasm (type III), and functional obstruction with some preserved peristalsis. Clinical and manometric variables including treatment response were compared among the 3 achalasia subtypes. Logistic regression analysis was performed using treatment success as the dichotomous dependent variable controlling for independent manometric and clinical variables. Ninety-nine patients were newly diagnosed with achalasia (21 type I, 49 type II, 29 type III), and 83 of these had sufficient follow-up to analyze treatment response. Type II patients were significantly more likely to respond to any therapy (BoTox [71%], pneumatic dilation [91%], or Heller myotomy [100%]) than type I (56% overall) or type III (29% overall) patients. Logistic regression analysis found type II to be a predictor of positive treatment response, whereas type III and pretreatment esophageal dilatation were predictive of negative treatment response. Achalasia can be categorized into 3 subtypes that are distinct in terms of their responsiveness to medical or surgical therapies. Utilizing these subclassifications would likely strengthen future prospective studies of treatment efficacy in achalasia.


More than a Corepressor: The Role of CoREST Proteins in Neurodevelopment.
The molecular mechanisms governing normal neurodevelopment are tightly regulated by the action of transcription factors. Repressor element 1 (RE1) silencing transcription factor (REST) is widely documented as a regulator of neurogenesis that acts by recruiting corepressor proteins and repressing neuronal gene expression in non-neuronal cells. The REST corepressor 1 (CoREST1), CoREST2, and CoREST3 are best described for their role as part of the REST complex. However, recent evidence has shown the proteins have the ability to repress expression of distinct target genes in a REST-independent manner. These findings indicate that each CoREST paralogue may have distinct and critical roles in regulating neurodevelopment and are more than simply "REST corepressors," whereby they act as independent repressors orchestrating biological processes during neurodevelopment.


Suppression of survivin promoter activity by YM155 involves disruption of Sp1-DNA interaction in the survivin core promoter.
YM155, a novel survivin suppressant, shows potent antitumor activity against various human cancers and is currently in phase II clinical trials. In this study, we investigated whether YM155 selectively inhibits survivin transcription. We hypothesize that inhibition of survivin transcription plays a role in YM155-mediated survivin inhibition. We found that YM155 inhibited survivin promoter activity, while it showed minimal inhibitory effect on four control gene promoters in transfection and luciferase activity assay experiments, indicating its selectivity. Transfection of various survivin promoter-luciferase constructs followed by luciferase assays revealed that the survivin core promoter (269 bp) plays a major role in YM155-mediated inhibitory effects. However, flow cytometry analysis indicated that inhibition of survivin promoter activity by YM155 is cell cycle-independent without G1 cell arrests. Electrophoretic mobility shift assays (EMSA) identified that YM155 abrogates nuclear proteins binding to the region of -149 to -71, in which Sp1 is a major candidate, and that YM155 treatment induces Sp1 re-subcellular localization without inhibiting its expression. Forced expression of Sp1 neutralized YM155-mediated downregulation of survivin promoter activity. Consistently, mutation of the identified Sp1 sites in the oligonucleotide probe diminished DNA-protein interactions in EMSA experiments, and mutation of the Sp1 sites in the survivin promoter-luciferase construct diminished survivin promoter activity. These findings indicate that YM155 inhibition of survivin expression is at least in part through its inhibition of survivin transcription by disruption of Sp1 interaction with the region of -149 to -71 in the survivin core promoter.


The dual role of the DREAM/G2M pathway in non-tumorigenic immortalization of senescent cells.
Anti-aging and tumorigenesis share common genes and pathways, and thus targeting these genes as part of anti-aging interventions carries the risk of tumorigenesis. It is essential to understand the gene signatures which balance tumorigenesis and aging. To achieve this goal, we analyzed RNA-seq data from three non-tumorigenic immortalized cell lines that spontaneously escaped from senescence. By ssGSEA and GSEA analysis, we found that both cell growth signaling (E2F targets, MYC targets) and tumor surveillance mechanisms (DNA repair, G2M checkpoint, mitotic spindle) were up-regulated in all three cell lines, suggesting these genes as potential signatures for non-tumorigenic immortalization. Further analysis revealed that the 182 commonly up-regulated genes in these three cell lines overlapped with the DREAM/G2M pathway, which is known to be the upstream regulator of E2F, Myc targets, DNA repair, G2M checkpoint, and mitotic spindle pathways, in its cell cycle activation or inhibitory form. By Western blot, qPCR and co-immunoprecipitation, we verified that both forms of the DREAM pathway are up-regulated in all three cell lines; this pathway facilitates control of cell cycle progression, supporting a new mechanism for non-tumorigenic immortalization. Thus, we propose that the DREAM/G2M pathway plays important dual roles in preventing tumorigenesis in the process of immortalization. Our data might serve as the basis for the identification of new signature pathways or gene biomarkers for non-tumorigenic immortalization, and may aid in the discovery of new targets for tumor-free anti-aging drug screening.


Subscapularis tendon integrity: an examination of shoulder index tests.
The systematic review focused on various index tests for the shoulder. We concentrated on the subscapularis tendon results to determine the accuracy of reported index tests for clinically diagnosing subscapularis integrity. Studies were identified by an OVID search using MEDLINE, SPORTDiscus, and CINHAL databases (1966-2006) and a hand search by 2 authors (E.J.H. and S.C.). Primary search terms were shoulder, examination, and diagnosis. In addition to the database searches, personal files were hand searched by one of the authors (E.J.H.) for publications, posters, and abstracts. The reference lists in review articles were cross-checked, and all individual names of each special test were queried using MEDLINE and PubMed. The search was limited to English-language journals. Studies were eligible for inclusion if the criterion standard was surgery, magnetic resonance imaging, or injection (subacromial or acromioclavicular joint); at least 1 physical examination test or special test was studied; and one of the paired statistics of sensitivity and specificity was reported or could be determined. Excluded were studies in which the index test was performed under anesthesia or in cadavers, studies in which the index test was assigned the status of composite physical examination, and review articles. Studies were grouped according to the subscapularis index test assessed: lift off, internal-rotation lag sign, Napoleon sign, bear hug, belly off, and belly press. Studies were selected in a 2-stage process. First, all abstracts and articles found through the search process were independently reviewed by 2 authors (E.J.H. and S.C.). Disagreement on inclusion of an article was resolved by consensus. Second, each selected study was assessed by each reviewer independently. A third reviewer made the final decision on any disagreements for the selected studies. The primary outcome measures were sensitivity and specificity and positive and negative likelihood ratios. The quality of a study was determined by assessing its internal and external validity. Validity was determined by the primary author (E.J.H.) using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) statement. Our work required data extraction from the original articles, which we used to generate 2 x 2 contingency tables for each index test. Pooled indices of clinical usefulness were then determined for each index test. The specific search criteria identified 922 articles for review. Of these, 4 met the inclusion and exclusion criteria for subscapularis tendon tears, resulting in the number of studies assessing each index test as follows: 4 for lift off, 2 for internal-rotation lag sign, 2 for Napoleon sign, 1 for bear hug, 1 for belly off, and 1 for belly press. Subscapularis tears were identified by the criterion standard of surgery to visually assess the torn fibers. Across all 4 studies, a total of 304 shoulders were examined, 95 of which had a subscapularis tear (45 full thickness, 50 partial thickness), and 106 were injury free. Indices of clinical usefulness for full-thickness and partial-thickness subscapularis tears are reported in Tables 1 and 2 , respectively.


Valproic acid potentiates the anticancer activity of capecitabine in vitro and in vivo in breast cancer models via induction of thymidine phosphorylase expression.
The prognosis of patients with metastatic breast cancer remains poor, and thus novel therapeutic approaches are needed. Capecitabine, which is commonly used for metastatic breast cancer in different settings, is an inactive prodrug that takes advantage of elevated levels of thymidine phosphorylase (TP), a key enzyme that is required for its conversion to 5-fluororacil, in tumors. We demonstrated that histone deacetylase inhibitors (HDACi), including low anticonvulsant dosage of VPA, induced the dose- and time-dependent up-regulation of TP transcript and protein expression in breast cancer cells, but not in the non-tumorigenic breast MCF-10A cell line. Through the use of siRNA or isoform-specific HDACi, we demonstrated that HDAC3 is the main isoform whose inhibition is involved in the modulation of TP. The combined treatment with capecitabine and HDACi, including valproic acid (VPA), resulted in synergistic/additive antiproliferative and pro-apoptotic effects in breast cancer cells but not in TP-knockout cells, both in vitro and in vivo, highlighting the crucial role of TP in the synergism observed. Overall, this study suggests that the combination of HDACi (e.g., VPA) and capecitabine is an innovative antitumor strategy that warrants further clinical evaluation for the treatment of metastatic breast cancer.


Strategies to expand the donor pool for pancreas transplantation.
Our organ procurement organization has been forced to liberalize the donor criteria in order to expand the donor pool for pancreas transplantation. In this report, we describe our experience using whole organ pancreatic grafts from "marginal" donors, which include grafts obtained from donors over 45 years of age and from donors who were identified to be hemodynamically unstable at the time of organ retrieval. A prospective study was performed between July 1994 and March 1998, during which time 137 pancreas transplants were performed at our center using organs procured by our own surgeons (organs sent by other teams were excluded). The rapid en bloc technique was used exclusively. The use of pancreatic grafts from marginal donors was analyzed for short-term and overall graft survival, and for delayed graft function and complications. Overall pancreas graft survival for our series was 83%, with a mean follow-up of 23 months. There were 22 pancreas grafts from donors over 45 years of age, 13 of whom were greater than 50 years of age. The actual graft survival rate of the over-45 donor group was 86%. Fifty-one grafts were removed from hemodynamically unstable donors on high-dose vasopressors. The actual graft survival in this group was 86%. There was no significant difference found in graft survival between recipients of pancreatic grafts from marginal and nonmarginal donors. Delayed graft function was exhibited by more recipients of grafts from donors on high-dose vasopressors (P<0.05), but this had no effect on long-term graft survival and endocrine function. Recipients of marginal donor grafts did not have higher rates of complication compared to recipients of nonmarginal grafts. Based on our results, we currently employ a graft selection strategy not limited by donor age or hemodynamic stability. Our selection of pancreas organs for transplantation is based on careful inspection of the pancreas and determination of the adequacy of the ex vivo flush. Our results suggest that the current pancreas donor pool may be expanded substantially.


[Minimal early childhood brain damage and the compensation capacity of the nervous system].
The concept of infantile cerebral lesion with later behavioral and learning disorders remains unclear and controversial, despite the voluminous literature on the subject. Neuropathologic data are lacking and the neurologic findings are often hard to interpret. Indirect access to this problem is provided by animal experiments in which the sequelae (neurologic and behavioral) of early and late, circumscribed cerebral lesions are compared. They have provided evidence that early--usually neonatal--lesions in particular areas of the central nervous system can be largely compensated. This may involve assumption of the function by the undamaged contralateral side, or sprouting of intact axons reinnervates denervated neurons. In this process, incorrect "switching" is not out of the question. Moreover, subcortical areas may retain their functions if cortical areas which normally take over their functions are damaged. Compensation following early lesions frequently produces intact, but biologically different, nervous systems. For this reason the behavior they generate may diverge from the norm. In many cases these deviations are apparent only in quite specific situations and otherwise remain latent.


Adjuvant and neoadjuvant treatment of resectable, locally advanced, rectal carcinoma with radiation therapy and chemotherapy.
Patients who undergo apparently curative low anterior or abdominal-perineal resection of locally advanced carcinoma of the rectum have a significant rate of local pelvic recurrence and death from cancer in the years following surgery. Pre- and postoperative irradiation and chemotherapy in various combinations and schedules have been recommended to improve the outcome for these patients. Several randomized trials have evaluated the effectiveness of adjuvant and neoadjuvant treatments in improving survival and reducing the rate of pelvic recurrence with a combination of radiation and chemotherapy. There is some evidence that preoperative treatment with radiation is more effective than postoperative treatment. The treatment program preferred at Ochsner is described.


Mothers' knowledge and practices on breastfeeding and complementary feeding in an urban slum area and rural area in Kenya: A cross-sectional interview study.
Maternal breastfeeding and complementary feeding knowledge is an important determinant of childrens' long-term health and development. This study aims to account for associations between knowledge and practices in Kenya and report the food consumption of children from birth to 18 months. In 2015 mother-child pairs were recruited from Mother-and-Child Health Centers; 415 in an urban slum in Nairobi and 364 in rural Machakos. Knowledge and practice scores were calculated from questionnaire variables and 24-h food frequency questionnaire. The associations of knowledge and practices were studied with regression analysis. Breastfeeding knowledge (Nairobi 6.3/9, Machakos 5.9/9) and practices (Nairobi 7.5/8, Machakos 7.2/8) were good in both areas. Complementary feeding knowledge was not as good (Nairobi 7.5/14, Machakos 7.1/14). Minimum meal frequency was reached by almost 80% of the children but dietary diversity was low (Nairobi 2.7 [SD 1.4], Machakos 2.4. [SD 1.3]). Only 27% of children in Nairobi and 13% in Machakos were fed a minimum acceptable diet. The complementary feeding knowledge score was associated only with minimum dietary diversity in Nairobi (OR: 1.29; 95% CI: 1.105-1.514). Infant and young child feeding knowledge and practices were on a similar level in both areas. Future interventions should focus on improving dietary diversity.


Toward an Optimized Staging System for Pancreatic Ductal Adenocarcinoma: A Clinically Interpretable, Artificial Intelligence-Based Model.
The American Joint Committee on Cancer (AJCC) eighth edition schema for pancreatic ductal adenocarcinoma treats T and N stage as independent factors and uses positive lymph nodes (PLNs) to define N stage, despite data favoring lymph node ratio (LNR). We used artificial intelligence-based techniques to compare PLN with LNR and investigate interactions between tumor size and nodal status. Patients who underwent pancreatic ductal adenocarcinoma resection between 2000 and 2017 at six institutions were identified. LNR and PLN were compared through shapley additive explanations (SHAP) analysis, with the best predictor used to define nodal status. We trained optimal classification trees (OCTs) to predict 1-year and 3-year risk of death, incorporating only tumor size and nodal status as variables. The OCTs were compared with the AJCC schema and similarly trained XGBoost models. Variable interactions were explored via SHAP. Two thousand eight hundred seventy-four patients comprised the derivation and 1,231 the validation cohort. SHAP identified LNR as a superior predictor. The OCTs outperformed the AJCC schema in the derivation and validation cohorts (1-year area under the curve: 0.681 v 0.603; 0.638 v 0.586, 3-year area under the curve: 0.682 v 0.639; 0.675 v 0.647, respectively) and performed comparably with the XGBoost models. We identified interactions between LNR and tumor size, suggesting that a negative prognostic factor partially overrides the effect of a concurrent favorable factor. Our findings highlight the superiority of LNR and the importance of interactions between tumor size and nodal status. These results and the potential of the OCT methodology to combine them into a powerful, visually interpretable model can help inform future staging systems.


The effect of continuous versus intermittent renal replacement therapy on the outcome of critically ill patients with acute renal failure (CONVINT): a prospective randomized controlled trial.
Acute renal failure (ARF) requiring renal replacement therapy (RRT) occurs frequently in ICU patients and significantly affects mortality rates. Previously, few large clinical trials investigated the impact of RRT modalities on patient outcomes. Here we investigated the effect of two major RRT strategies (intermittent hemodialysis (IHD) and continuous veno-venous hemofiltration (CVVH)) on mortality and renal-related outcome measures. This single-center prospective randomized controlled trial ("CONVINT") included 252 critically ill patients (159 male; mean age, 61.5 ± 13.9 years; Acute Physiology and Chronic Health Evaluation (APACHE) II score, 28.6 ± 8.8) with dialysis-dependent ARF treated in the ICUs of a tertiary care academic center. Patients were randomized to receive either daily IHD or CVVH. The primary outcome measure was survival at 14 days after the end of RRT. Secondary outcome measures included 30-day-, intensive care unit-, and intrahospital mortality, as well as course of disease severity/biomarkers and need for organ-support therapy. At baseline, no differences in disease severity, distributions of age and gender, or suspected reasons for acute renal failure were observed. Survival rates at 14 days after RRT were 39.5% (IHD) versus 43.9% (CVVH) (odds ratio (OR), 0.84; 95% confidence interval (CI), 0.49 to 1.41; P = 0.50). 14-day-, 30-day, and all-cause intrahospital mortality rates were not different between the two groups (all P > 0.5). No differences were observed in days on RRT, vasopressor days, days on ventilator, or ICU-/intrahospital length of stay. In a monocentric RCT, we observed no statistically significant differences between the investigated treatment modalities regarding mortality, renal-related outcome measures, or survival at 14 days after RRT. Our findings add to mounting data demonstrating that intermittent and continuous RRTs may be considered equivalent approaches for critically ill patients with dialysis-dependent acute renal failure. NCT01228123, clinicaltrials.gov.


Retrospective audit of clinico-pathologic features and treatment outcomes in a cohort of elderly non-Hodgkin's lymphoma patients in a tertiary cancer center.
There is limited data from India regarding elderly non-Hodgkin's lymphomas (NHL) patients. Hence, this audit was planned to study the clinic-pathological features and treatment outcomes in elderly NHL patients. Retrospective analysis of all NHL patients above age of 59 years treated at the author's institute, between December 2010 and December 2013 was done. Case records were reviewed for baseline details, staging details, prognostic factors, treatment delivered, response, toxicity and efficacy. SPSS version 16 (IBM, Newyork) was used for analysis. Descriptive statistics was performed. Kaplan-Meir survival analysis was done for estimation of progression-free survival (PFS) and overall survival (OS). Univariate analysis was done for identifying factors affecting PFS and OS. Out of 141 NHL patients, 67 patients were identified subjected to the inclusion criteria. The median age was 68 years (60-92). Majority were B-cell NHL (86.6%). The commonest subtype in B-cell was diffuse large B-cell lymphoma (55.2%). Fifty-four patients took treatment. The treatment intent was curative in 41 patients (61.2%). Among the patients receiving curative treatment, 16 patients couldn't receive treatment in accordance with NCCN guidelines due to financial issues. Two years PFS was 55%. Two years PFS for B-cell NHL and T-cell NHL were 55% and 50% respectively (P = 0.982). Two years PFS for standard Rx and nonstandard Rx were 62% and 50% respectively, but it didn't reach statistical significance (P = 0.537). Two years OS for the entire cohort was 84%. Standard treatment in accordance with guidelines can be delivered in elderly patients irrespective of age. There is a need for creating financial assistance for patients, so that potentially curative treatments are not denied.


Marital status and quality of life in patients with esophageal cancer or Barrett's esophagus: the mayo clinic esophageal adenocarcinoma and Barrett's esophagus registry study.
Patients with esophageal carcinoma (EC) report deficits in quality of life (QOL), depending on the extent of malignant disease and the goals of treatment at the time of QOL measurement. To quantify the association of marital status and changes in QOL over time in patients with EC and patients with Barrett's esophagus (BE). Eligible patients in the Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry completed QOL assessments at baseline and approximately 1 year later. QOL was determined with a ten-point linear analog self-assessment scale evaluating overall QOL and 12 subscales. Overall, 489 BE patients and 212 EC patients were evaluated. Married EC patients reported higher baseline QOL in legal concerns (8.1 vs. 7.1; p = .04) and friend and family support (9.3 vs. 8.4; p = .02) than single EC patients. Over time, married EC patients had a decrease in pain frequency QOL compared to single EC patients (-0.9 vs. +0.6; p = .02), with other QOL measures being stable. Married BE patients showed higher social activity QOL at baseline than single BE patients (7.5 vs. 6.9; p = .02); QOL was stable over time between the marital status groups. Minor, but statistically significant, changes were reported regarding QOL in two categories at baseline and over time among married and single patients with EC. Minor differences may be present between married and single EC patients regarding spiritual QOL at baseline and in overall physical well-being QOL at baseline and over time, although these differences did not reach statistical significance.


Influence of infusion methods on therapeutic drug monitoring in pediatric patients.
The purpose of this article is to emphasize the importance of infusion method on therapeutic drug monitoring in pediatric patients. Although effective serum concentrations are anticipated after intravenous infusion of drugs, studies with chloramphenicol and tobramycin have shown that the infusion method can have a profound influence on peak serum concentration and time to achieve peak concentration during therapy. Factors including infusion rate, injection site, volume of drug and fluid to be infused in the tubing, and type of infusion system should be considered for accurate drug delivery. Specific guidelines for drug infusions should be available at each institution. Since serum concentration predictions are based on the dose infused and infusion time, meaningful therapeutic monitoring data can be generated only with the understanding of the influence of infusion method on serum concentration-time profile of drugs.


Interictal EEG discharges, reproductive hormones, and menstrual disorders in epilepsy.
We evaluated reproductive endocrine function in women with unilateral temporolimbic epilepsy and normal control subjects to assess the effects of epilepsy, epilepsy laterality, and antiepileptic drug use on the cerebral regulation of hormonal secretion. The findings indicate that reproductive endocrine function differs between women with epilepsy and normal control subjects. Significant differences exist at all levels of the reproductive neuroendocrine axis, that is, hypothalamus, pituitary, and peripheral gland. Differences show significant relationships to the epilepsy itself as well as to medication use. Reproductive neuroendocrine changes occur in a stochastic manner such that the laterality of unilateral temporolimbic discharges is associated with predictable directional changes in hormonal secretion at all levels of the reproductive neuroendocrine axis. These directional changes are consistent with the finding that different reproductive disorders may develop in relation to left- and right-sided temporolimbic epilepsy. Hormonal changes can show close temporal relationship to the occurrence of interictal epileptiform discharges and may vary in relation to the laterality of the discharges. Antiepileptic drugs differ in their effects on reproductive hormone levels. There are notable differences between enzyme-inducing and noninducing drugs. Menstrual disorders are more common among women with interictal discharges as well as women with abnormal hormonal findings.


Trust, culture and communication: determinants of eye health and care among Indigenous people with diabetes in Australia.
Our study aimed to identify factors that influence access to eye care and eye health outcomes for remote Indigenous Australians living with diabetes. In collaboration with Indigenous Community-Based Researchers (CBR) and Aboriginal Community Controlled Health Services (ACCHS), a qualitative, participatory action research approach was taken, drawing on Indigenist and decolonising methodologies. The study was undertaken in four remote communities, in the Katherine region, Northern Territory and north-western New South Wales, Australia. Interviews and focus groups were undertaken with Indigenous adults aged ≥40 years living with diabetes (n=110), and primary care clinicians working in ACCHSs (n=37). A series of interviews with CBRs (n=13) were undertaken before and after data collection to add cultural insights and validation to participant accounts. Data were analysed inductively using grounded theory, in-depth discussion and NVivo V.11. More than one-third of all patients had little to no knowledge of how diabetes affects eye health. Limited access to health information and interpreters, language barriers, distrust of health providers and services, and limited cultural responsivity among non-Indigenous clinicians, were identified as determining factors in eye health and care. We outline a need to address gaps in trust and communication, through increased access to and resourcing of Indigenous language interpreters and cultural brokers, understandable and culturally sensitive diabetic eye health information and cultural responsivity training for non-Indigenous clinicians. Centring Indigenous cultures in healthcare practice will enable a shared understanding between clinicians and Indigenous patients, and subsequently more equitable eye health outcomes.