The prognostic value of positron emission tomography/computed tomography in rheumatoid arthritis patients with methotrexate-associated lymphoproliferative disorders.
Recently, methotrexate-associated lymphoproliferative disorders (MTX-LPDs) in rheumatoid arthritis (RA) have been found to commonly occur in association with iatrogenic immunodeficiency. Several factors have been reported to be related to the prognosis. We herein investigate the efficacy of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in predicting the prognosis of MTX-LPD. We performed a retrospective analysis of the clinical features, characteristics, and outcomes of 18 patients with MTX-LPDs who were treated from 2004 to 2015. All of the patients were diagnosed with MTX-LPD based on the histological examination of biopsy specimens. Spontaneous regression was detected after the cessation of MTX in 5 of 18 cases (28%). The maximum standardized uptake value (SUVmax) of the FDG uptake on PET/CT was significantly lower, and the maximum size of the LPD-associated tumor was significantly smaller among the patients who showed spontaneous regression (p = 0.01, p = 0.04, respectively). Both the SUVmax and the maximum tumor size were related to better overall survival (p = 0.02, p = 0.04, respectively). Thus, PET/CT can be used to predict spontaneous regression and the prognosis at the diagnosis of MTX/LPD. Cases that showed spontaneous regression never relapsed during the follow-up period, despite the usage of several anti-rheumatoid arthritis drugs, including biological agents. The early detection of LPDs and the early cessation of MTX are important for the management of RA patients. An evaluation by F-FDG-PET/CT can be useful for predicting spontaneous regression and the prognosis.


Self-rated health in Brazilian adults and elderly: data from the National Household Sample Survey 2008.
To investigate prevalence of poor self-rated health and its association with individual and household-level characteristics among adults and elderly in Brazil. Cross-sectional study with Brazilian National Household Sample Survey 2008 (n=257 816). Crude and multilevel-adjusted Poisson regression models were fitted. After adjusted analysis, poor self-rated health was significantly associated with higher household income, living alone, not having piped water nor garbage collection, lower education, not having health insurance, female sex, higher age, being a current or previous smoker, physical inactivity, having chronic diseases, having physical impairment. Subjects living in rural areas also had higher prevalence of poor self-rated health. The factors most strongly associated with the outcome were physical impairment and reporting three or more chronic diseases. Socioeconomic, health related behaviors, and physical health were associated with poor self-rated health.


Navigating being a young adult with cerebral palsy: a qualitative study.
Young adults with cerebral palsy (CP) face potential challenges. The transition to young adulthood is characterized by significant changes in roles and responsibilities. Furthermore, young adults with chronic conditions face a transfer from pediatric care to adult healthcare. This study explores how living with CP affects young adults in general, and specifically which psychosocial, medical and healthcare needs are particularly important during this phase of life. A qualitative study with data from individual, semi-structured, in-depth interviews with six young adults with CP (ages 21-31 years) were transcribed verbatim and analyzed. The participants were selected to provide a maximum variation in age, gender, Gross Motor Function Classification System score and educational background. A descriptive thematic analysis was used to explore patterns and identify themes. Three themes were identified: "Being a Young Adult", "Development in Physical Disability and New Challenges in Adulthood" and "Navigating the Healthcare System". The three themes emerged from 15 sub-themes. Our findings emphasized that young adults with CP faced psychosocial challenges in social relationships, participation in education and work settings and striving towards independence. The transition to young adulthood led to a series of new challenges that the young adults were not prepared for. Medical challenges included managing CP-related physical and cognitive symptoms and navigating adult health care services, where new physicians with insufficient knowledge regarding CP were encountered. The young adults with CP were not prepared for the challenges and changes they faced during their transition into adulthood. They felt that they had been abandoned by the healthcare system and lacked a medical home. Better transitional care is urgently needed to prepare them for the challenges in young adulthood.


[Phase structure of cardiac activity and the function of renal vessels in nephrogenic hypertension].
A total of 25 patients with renal affections, in whom an elevated arterial pressure had been ascertained clinically, were examined for the phasic structure of the cardiac action and for the functional state of the renal vessels by employing rheography. Of these patients 8 had urolithiasis, 6-tuberculosis, 7-polycystosis and 4-renal tumours. Their systolic pressure averaged 160-220 mm and diastolic-80-110 mm. In patients with nephrogenic hypertension the tone of systemic vessels and the peripheral resistance are shown to go up. The changes are accompanied by a phasic syndrome of a high diastolic pressure. A complex investigation into the phasic structure of the cardiac activity and the functional condition of the renal vessels by employing rheography makes it possible to disclose the sequential lesion of the vessels in patients suffering from nephrogenic hypertension.


Suicidal ideation in Pakistani college students.
Suicidal behavior includes ideation, attempts and completed suicides. Information on suicidal behavior from Pakistan, a conservative South Asian Islamic country, is lacking. To address the issue, a pilot study was carried out to assess the prevalence of suicidal ideation in Pakistani college students. Suicidal ideation was assessed on the basis of responses to four questions contained in the depression subscale of the General Health Questionnaire-28. Of the total 217 completed questionnaires, the overall rate of suicidal ideation was 31.4%. While there was no significant difference between genders, more females (33%) than males (29.2%) responded positively. Respondents belonging to single parent families and those living at home, compared to those using hostel facilities, reported higher rates. The reported rate in our sample is higher than similar studies conducted elsewhere. There is the need for more information in this important area of suicidal behavior, including studying such feelings in school going children as well as in a larger community sample. The findings of such studies can contribute to our understanding of the suicidal process in the Pakistani population and to address it at various levels.


Clinical impact versus factor analysis for quality of life questionnaire construction.
We have compared two philosophically different methods for selecting items for a disease-specific quality of life questionnaire. The impact method selects items that are most frequently perceived as important by patients whereas the psychometric method (factor analysis) selects items primarily according to their relationships with one another. 150 adults with symptomatic asthma and a wide range of disease severity were enrolled from asthma clinics and notices in the local media. From a list of 152 items that are potentially troublesome to patients with asthma, the patients identified those items they had experienced in the previous year and scored the importance of each on a five-point scale. For the impact method, items that were identified most frequently and that scored the highest were included in the final instrument. For the psychometric method, factor analysis was performed after highly skewed items had been removed. Items with high factor loading were included in the final instrument. The impact method resulted in a 32-item instrument and psychometric analysis in one with 36 items. Twenty items were common to both instruments. The psychometric approach discarded the highest impact emotional function and environmental items and included in their place lower impact items mainly associated with fatigue. Although some items were the same for both methods, there were also some important differences. Different approaches to item reduction led to appreciably different instruments.


Current-voltage-temperature characteristics of DNA origami.
The temperature dependences of the current-voltage characteristics of a sample of triangular DNA origami deposited in a 100 nm gap between platinum electrodes are measured using a probe station. Below 240 K, the sample shows high impedance, similar to that of the substrate. Near room temperature the current shows exponential behavior with respect to the inverse of temperature. Sweep times of 1 s do not yield a steady state; however sweep times of 450 s for the bias voltage secure a steady state. The thermionic emission and hopping conduction models yield similar barriers of approximately 0.7 eV at low voltages. For high voltages, the hopping conduction mechanism yields a barrier of 0.9 eV and the thermionic emission yields 1.1 eV. The experimental data set suggests that the dominant conduction mechanism is hopping in the range 280-320 K. The results are consistent with theoretical and experimental estimates of the barrier for related molecules.


Quantitative Proteomics Reveals the Regulatory Networks of Circular RNA CDR1as in Hepatocellular Carcinoma Cells.
Circular RNAs (circRNAs), a class of widespread endogenous RNAs, play crucial roles in diverse biological processes and are potential biomarkers in diverse human diseases and cancers. Cerebellar-degeneration-related protein 1 antisense RNA (CDR1as), an oncogenic circRNA, is involved in human tumorigenesis and is dysregulated in hepatocellular carcinoma (HCC). However, the molecular mechanisms underlying CDR1as functions in HCC remain unclear. Here we explored the functions of CDR1as and searched for CDR1as-regulated proteins in HCC cells. A quantitative proteomics strategy was employed to globally identify CDR1as-regulated proteins in HCC cells. In total, we identified 330 differentially expressed proteins (DEPs) upon enhanced CDR1as expression in HepG2 cells, indicating that they could be proteins regulated by CDR1as. Bioinformatic analysis revealed that many DEPs were involved in cell proliferation and the cell cycle. Further functional studies of epidermal growth factor receptor (EGFR) found that CDR1as exerts its effects on cell proliferation at least in part through the regulation of EGFR expression. We further confirmed that CDR1as could inhibit the expression of microRNA-7 (miR-7). EGFR is a validated target of miR-7; therefore, CDR1as may exert its function by regulating EGFR expression via targeting miR-7 in HCC cells. Taken together, we revealed novel functions and underlying mechanisms of CDR1as in HCC cells. This study serves as the first proteome-wide analysis of a circRNA-regulated protein in cells and provides a reliable and highly efficient method for globally identifying circRNA-regulated proteins.


Mitochondria-lysosome membrane contacts are defective in GDAP1-related Charcot-Marie-Tooth disease.
Mutations in the GDAP1 gene cause Charcot-Marie-Tooth (CMT) neuropathy. GDAP1 is an atypical glutathione S-transferase (GST) of the outer mitochondrial membrane and the mitochondrial membrane contacts with the endoplasmic reticulum (MAMs). Here, we investigate the role of this GST in the autophagic flux and the membrane contact sites (MCSs) between mitochondria and lysosomes in the cellular pathophysiology of GDAP1 deficiency. We demonstrate that GDAP1 participates in basal autophagy and that its depletion affects LC3 and PI3P biology in autophagosome biogenesis and membrane trafficking from MAMs. GDAP1 also contributes to the maturation of lysosome by interacting with PYKfyve kinase, a pH-dependent master lysosomal regulator. GDAP1 deficiency causes giant lysosomes with hydrolytic activity, a delay in the autophagic lysosome reformation, and TFEB activation. Notably, we found that GDAP1 interacts with LAMP-1, which supports that GDAP1-LAMP-1 is a new tethering pair of mitochondria and lysosome membrane contacts. We observed mitochondria-lysosome MCSs in soma and axons of cultured mouse embryonic motor neurons and human neuroblastoma cells. GDAP1 deficiency reduces the MCSs between these organelles, causes mitochondrial network abnormalities, and decreases levels of cellular glutathione (GSH). The supply of GSH-MEE suffices to rescue the lysosome membranes and the defects of the mitochondrial network, but not the interorganelle MCSs nor early autophagic events. Overall, we show that GDAP1 enables the proper function of mitochondrial MCSs in both degradative and nondegradative pathways, which could explain primary insults in GDAP1-related CMT pathophysiology, and highlights new redox-sensitive targets in axonopathies where mitochondria and lysosomes are involved.


A randomized trial to assess the effectiveness of an infant home safety programme.
The aim of this study was to test an intervention aimed at addressing the risk of injury in infants 2 - 12 months of age. A non-blinded, randomized controlled trial was conducted, whereby parents were randomly assigned to either a control or one of two intervention groups. Parents completed questionnaires regarding safety behaviours and injuries at the 2 (baseline), 6 and 12 month immunization visit at the community health unit. During the 2 month visit to the health unit, the two intervention groups received a home safety kit containing nine items, an instructional brochure and a risk assessment checklist. Subjects randomized to the safety kit plus home visit group also received a standardized home visit from a community health nurse. Two of the 14 parental safety behaviours showed a significant increase in use among parents in the intervention groups. Neither of the interventions was associated with a reduction in parent-reported injuries among children. It was concluded that home visitation may provide a beneficial adjunct to the provision of safety devices and may increase use by parents.


Configuration of biological wastewater treatment line and influent composition as the main factors driving bacterial community structure of activated sludge.
The structure of microbial consortia in wastewater treatment facilities is a resultant of environmental conditions created by the operational parameters of the purification process. In the research, activated sludge from nine Polish wastewater treatment plants (WWTPs) was investigated at a molecular level to determine the impact of the complexity of biological treatment line and the influent composition on the species structure and the diversity of bacterial consortia. The community fingerprints and technological data were subjected to the canonical correspondence and correlation analyses. The number of separated biological processes realized in the treatment line and the presence of industrial wastewater in the influent were the key factors determining the species structure of total and ammonia-oxidizing bacteria in biomass. The N2O-reducers community composition depended significantly on the design of the facility; the highest species richness of denitrifiers was noted in the WWTPs with separated denitrification tanks. The contribution of industrial streams to the inflow affected the diversity of total and denitrifying bacterial consortia and diminished the diversity of ammonia oxidizers. The obtained data are valuable for engineers since they revealed the main factors, including the design of wastewater treatment plant, influencing the microbial groups critical for the stability of purification processes.


Efficacy and Safety of AbobotulinumtoxinA (Dysport) for the Treatment of Hemiparesis in Adults With Upper Limb Spasticity Previously Treated With Botulinum Toxin: Subanalysis From a Phase 3 Randomized Controlled Trial.
To assess the efficacy and safety of abobotulinumtoxinA in adults with upper limb spasticity previously treated with botulinum toxin A (BoNT-A). A post hoc analysis from a Phase 3, prospective, double-blind, randomized, placebo-controlled study (NCT01313299). A total of 34 neurology or rehabilitation clinics in 9 countries. Adults aged 18-80 years with hemiparesis, ≥6 months after stroke or traumatic brain injury. This analysis focused on a subgroup of subjects with previous onabotulinumtoxinA or incobotulinumtoxinA treatment (n = 105 of 243 in the total trial population) in the affected limb. The mean age was 52 years, and 62% were male. Study subjects were randomized 1:1:1 to receive a single injection session with abobotulinumtoxinA 500 or 1000 U or with placebo in the most hypertonic muscle group among the elbow, wrist, or finger flexors (primary target muscle group [PTMG]), and ≥2 additional muscle groups from the upper limb. Efficacy and safety measures were assessed, including muscle tone (Modified Ashworth Scale [MAS] in the PTMG), Physician Global Assessment (PGA), perceived function, spasticity, active movement, and treatment-emergent adverse events. At week 4, more subjects had ≥1 grade improvement in MAS for the PTMG with abobotulinumtoxinA versus placebo (abobotulinumtoxinA 500 U, 81.1%; abobotulinumtoxinA 1000 U, 75.0%; placebo, 25.0%). PGA scores ≥1 were achieved by 75.7% and 87.5% of abobotulinumtoxinA 500 and 1000 U subjects versus 41.7% with placebo. Perceived function (Disability Assessment Scale), spasticity angle (Tardieu Scale), and active movement were also improved with abobotulinumtoxinA. There were no treatment-related deaths or serious adverse events. The efficacy and safety of abobotulinumtoxinA in subjects previously treated with BoNT-A were consistent with those in the total trial population. Hence, abobotulinumtoxinA is a treatment option in these patients, and no difference in initial dosing appears to be required compared to that in individuals not treated previously. III.


Cross-reaction of synthetic alpha-(1----3)-branched glucans with rabbit anti-N4 dextran.
Cross-reactions of four synthetic branched glucans (3-O-alpha-D-glucopyranosyl-(1----6)-alpha-D-glucopyranans: V39, V17, V37, and V32, each containing one unit glucose branches amounting to 11-12%, 33-43%, 50-54%, and 71-100%, respectively) with rabbit anti-N4 dextran were examined. All four samples precipitated antibodies raised in rabbits by injecting N4 dextran-concanavalin A conjugate. The ability of glucans to precipitate antibody depended on the quantity of branches, samples with more branches precipitating less antibody nitrogen under the same conditions. This may indicate an inhibitory effect of the branches on precipitation. Oligosaccharide inhibition assay showed that the precipitation reactions were specific for (1----6)-alpha-D-glucopyranosyl linkages, and the maximum size of the alpha-(1----6)-specific antibody combining site corresponded to isomaltopentaose. Determination of antibody nitrogen and glucan in the precipitates indicated that the ratios of one combining site of antibody to numbers of glucose residues were 1:9 (V39), 1:11 (V17), and 1:16 (V37) in the extreme antibody excess region. A synthetic sample of manno-glucan ((1----6)-alpha-D-glucopyranan containing about 27% of randomly linked 3-O-alpha-D-mannopyranosyl side chains) also reacted with the same antibody.


Migrants and Service Providers' Perspectives of Barriers to Accessing Mental Health Services in South Australia: A Case of African Migrants with a Refugee Background in South Australia.
International mobility has increased steadily in recent times, bringing along a myriad of health, social and health system challenges to migrants themselves and the host nations. Mental health issues have been identified as a significant problem among migrants, with poor accessibility and underutilisation of the available mental health services (MHSs) repeatedly reported, including in Australia. Using a qualitative inquiry and one-on-one in-depth interviews, this study explored perspectives of African migrants and service providers on barriers to accessing MHSs among African migrants in South Australia. The data collection took place during the COVID-19 pandemic with lockdown and other measures to combat the pandemic restricting face to face meetings with potential participants. Online platforms including Zoom and/or WhatsApp video calls were used to interview 20 African migrants and 10 service providers. Participants were recruited from community groups and/or associations, and organisations providing services for migrants and/or refugees in South Australia using the snowball sampling technique. Thematic framework analysis was used to guide the data analysis. Key themes centred on personal factors (health literacy including knowledge and the understanding of the health system, and poor financial condition), structural factors related to difficulties in navigating the complexity of the health system and a lack of culturally aware service provision, sociocultural and religious factors, mental health stigma and discrimination. The findings provide an insight into the experiences of African migrants of service provision to them and offer suggestions on how to improve these migrants' mental health outcomes in Australia. Overcoming barriers to accessing mental health services would need a wide range of strategies including education on mental health, recognising variations in cultures for effective service provision, and addressing mental health stigma and discrimination which strongly deter service access by these migrants. These strategies will facilitate help-seeking behaviours as well as effective provision of culturally safe MHSs and improvement in access to MHSs among African migrants.


An amphioxus LIM-homeobox gene, AmphiLim1/5, expressed early in the invaginating organizer region and later in differentiating cells of the kidney and central nervous system.
A LIM-homeobox gene, AmphiLim1/5, from the Florida amphioxus (Branchiostoma floridae) encodes a protein that phylogenetic analysis positions at the base of a clade comprising vertebrate Lim1 and Lim5. Amphioxus AmphiLim1/5 is expressed in domains that are a composite of those of vertebrate Lim1 and Lim5, which evidently underwent subfunctionalization after duplication of an ancestral protochordate Lim1/5. During amphioxus development, transcription is first detected in the ectoderm of the blastula. Then, in the gastrula, a second expression domain appears in the mesendoderm just within the dorsal lip of the blastopore, a region known to have organizer properties in amphioxus. This mesendodermal expression corresponds to Lim1 expression in the Spemann organizer of vertebrates. At least one of the functions of vertebrate Lim1 in the organizer is to control the transcription of genes involved in cell and tissue movements during gastrulation, and a comparable early function seems likely for AmphiLim1/5 during gastrular invagination of amphioxus. Later embryos and larvae of amphioxus express AmphiLim1/5 in clusters of cells, probably motoneurons, in the anterior part of the central nervous system, in the hindgut, in Hatschek's right diverticulum (a rudiment of the rostral coelom), and in the wall of the first somite on the left side (a precursor of Hatschek's nephridium). In the early larva, expression continues in neural cells, in Hatschek's nephridium, in the wall of the rostral coelom, in the epidermis of the upper lip, and in mesoderm cells near the opening of the second gill slit. The developmental expression in Hatschek's nephridium is especially interesting because it helps support the homology between this amphioxus organ and the vertebrate pronephros.


Identifying preferences for mobile health applications for self-monitoring and self-management: focus group findings from HIV-positive persons and young mothers.
Self-management of risk behaviors is a cornerstone of future population health interventions. Using mobile phones for routine self-monitoring and feedback is a cost-efficient strategy for self-management and ecological momentary interventions (EMI). However, mobile health applications need to be designed to be highly attractive and acceptable to a broad range of user groups. To inform the design of an adaptable mobile health application we aimed to identify the dimensions and range of user preferences for application features by different user groups. Five focus group interviews were conducted: two (n=9; n=20) with people living with HIV (PLH) and three with young mothers (n=6; n=8; n=10). Thematic analyses were conducted on the focus group sessions' notes and transcripts. Both groups considered customization of reminders and prompts as necessary, and goal setting, motivational messaging, problem solving, and feedback as attractive. For PLH, automated and location-based reminders for medication adherence and sharing data with healthcare providers were both acceptable and attractive features. Privacy protection and invasiveness were the primary concerns, particularly around location tracking, illegal drug use, and sexual partner information. Concerns were ameliorated by use scenario or purpose, monetary incentives, and password protection. Privacy was not a major concern to mothers who considered passwords burdensome. Mothers' preferences focused on customization that supports mood, exercise and eating patterns, and especially using the mobile phone camera to photograph food to increase self-accountability. Individualization emerged as the key feature and design principle to reduce user burden and increase attractiveness and acceptability. Mobile phone EMI uniquely enables individualization, context-aware and real-time feedback, and tailored intervention delivery.


Quality of life as a prognostic indicator of survival: A pooled analysis of individual patient data from canadian cancer trials group clinical trials.
The aims of this study were to externally validate an established association between baseline health-related quality of life (HRQOL) scores and survival and to assess the added prognostic value of HRQOL with respect to demographic and clinical indicators. Pooled data were analyzed from 17 randomized controlled trials opened by the Canadian Cancer Trials Group between 1991 and 2004; they included survival and baseline HRQOL data from 3606 patients with 8 different cancer sites. The models included sex, age (≤60 vs >60 years), World Health Organization performance status (0 or 1 vs 2-4), distant metastases (no vs yes), and 15 European Organization for Research and Treatment of Cancer (EORTC) Core Quality-of-Life Questionnaire (QLQ-C30) scales. Analyses were conducted with multivariate Cox proportional hazards models and were stratified by cancer site. Harrell's discrimination C-index was used to calculate the predictive accuracy of the model when HRQOL parameters were added to clinical and demographic variables. The added value of adding HRQOL scales to clinical and demographic variables was illustrated with Kaplan-Meier curves. In the stratified, multivariate model, HRQOL parameters-global health status (hazard ratio [HR], 0.97; 95% confidence interval [CI], 0.95-1.00; P < . 0001), dyspnea (HR, 1.04; 95% CI, 1.02-1.06; P < . 0002), and appetite loss (HR, 1.06; 95% CI, 1.04-1.08; P < . 0001)-were independent prognostic factors in addition to the demographic and clinical variables (all P values < .05). Adding these HRQOL variables to the clinical variables resulted in an added relative prognostic value for survival of 5%. These results confirm previous findings showing that baseline HRQOL scores on the EORTC QLQ-C30 provide prognostic information in addition to information from clinical measures. However, the impact of specific domains may differ across studies. Cancer 2018. © 2018 American Cancer Society.


[Relationship between lymph node metastasis and pathologic features of invasive micropapillary carcinoma of breast].
To investigate the relationship between lymph node metastasis and pathologic features of invasive micropapillary carcinoma (IMPC) of the breast. Histopathologic features and status of lymph node metastasis of fifty-one cases of IMPC were studied by microscopic examination, immunohistochemical staining (VEGF-C and VEGFR-3) and analysis of lymphatic vessel density. (1) The number of positive lymph nodes in histologic grade II/III IMPCs was significantly higher (mean 12.5) than that in histologic grade I tumors (mean 4.0). (2) The incidence of nodal metastases in IMPCs with lymphocyte infiltration (+)/(++) was significantly higher (27/28, 96.4%) than that in tumors with no or minimal lymphocyte infiltration (-)/(+/-) (14/23, 60.9%), and the number of positive nodes was also higher (mean 14.4) in tumors with lymphocyte infiltration compared with those without (mean 4.6). (3) In IMPCs with histologic grade II/III, the expression of VEGF-C was significantly higher than that of histologic grade I tumors (P = 0.03). VEGF-C expression was in positive correlation with lymph node metastasis (P = 0.006) and lymphatic vessel density (P = 0.009). Lymph node metastasis was also correlated with lymphatic vessel density (P = 0.007). (4) The percentage of IMPC component in the tumor did not correlate with nodal metastasis. The metastatic foci in lymph node were all IMPC or mainly IMPC. (5) Fourteen of twenty-eight cases (14/28, 50%) of IMPC containing ductal carcinoma in-situ (DCIS) were DCIS of micropapillary type. The histologic grade, lymphatic vessel density and lymphocyte infiltration are key histological features that are correlated with lymph node metastasis of IMPC. The expression of VEGF-C and VEGFR-3 may play an important role in the development of lymph node metastasis of IMPC. Micropapillary type DCIS may be the early stage of IMPC.


A randomized, double-blind, comparative study of standard-dose rabeprazole and high-dose omeprazole in gastro-oesophageal reflux disease.
Rabeprazole has a faster onset of antisecretory action than omeprazole, and it is of interest to determine whether this translates into faster symptom relief in patients with gastro-oesophageal reflux disease. To assess the relief from heartburn after 3 days of treatment with standard-dose rabeprazole or high-dose omeprazole (primary end-point). Secondary end-points included the decrease in score for other symptoms of gastro-oesophageal reflux disease, healing rates and quantification of antacid use. Patients with endoscopically confirmed erosive oesophagitis were randomized to receive 4 weeks of double-blind treatment with rabeprazole (20 mg) or omeprazole (40 mg). Patients who were not healed after 4 weeks received a further 4 weeks of treatment. Two hundred and seventy-four patients were screened, 251 patients were randomized and 230 patients completed the trial. The numbers of patients with relief from heartburn on day 4 were similar in the two groups (84% for rabeprazole; 95% confidence interval, 76-90%; 83% for omeprazole; 95% confidence interval, 75-89%). There were no significant differences between the treatments in the relief from other gastro-oesophageal reflux disease symptoms or in healing rates. The number of reports of severe heartburn during the first 3 days was higher in the omeprazole group (daytime heartburn: 4.7% for rabeprazole vs. 10.3% for omeprazole, P=0.005; night-time heartburn: 4.7% for rabeprazole vs. 9.8% for omeprazole, P=0.01; statistical comparisons defined post hoc). Standard-dose rabeprazole was as effective as high-dose omeprazole in relieving symptoms by day 4 of treatment and in healing oesophageal lesions, but had a faster onset of action in patients with severe heartburn. This suggests that the improved pharmacological properties of rabeprazole translate into a clinically relevant advantage.


Liver disease and the PI ElembergM phenotype of alpha 1-antitrypsin.
The purpose of this article is to document clinical and pathologic observations concerning liver disease associated with the PI ElembergM phenotype of alpha 1-antitrypsin. Deposits of alpha 1-antitrypsin that were periodic acid-Schiff positive and stained with an antiserum to alpha 1-antitrypsin were found in the liver of a markedly jaundiced, terminally ill patient with Stage IV primary biliary cirrhosis. A biopsy performed three years earlier failed to reveal alpha 1-antitrypsin deposits. The phenotype PI ElembergM was verified by both acid starch gel electrophoresis and isoelectric focusing in agarose. The deposits of alpha 1-antitrypsin in the liver appear to be a consequence of the patient's disease and age and not due to an association with the PI*Elemberg allele. Accumulation of alpha 1-antitrypsin in the liver of this patient may be due to an accelerated synthesis of this protease inhibitor exceeding the liver's capacity for glycosylation or other steps in its secretion.


Xbra functions as a switch between cell migration and convergent extension in the Xenopus gastrula.
During Xenopus gastrulation, the dorsal mesoderm exhibits two different cell behaviors in two different regions: active cell migration of prechordal mesoderm and convergent extension of chordamesoderm. Although many genes involved in specification and differentiation of the dorsal mesoderm have been studied, the role of these genes in controlling cell behaviors is poorly understood. To understand better the link between the development and cell behaviors of the dorsal mesoderm, we have examined these behaviors in dissociated cells and explants, where activin protein can induce both active cell migration and convergent extension. We find that Xbra, a transcription factor necessary for convergent extension, actively inhibits cell migration, both in animal cap explant assays and in the endogenous dorsal mesoderm. In addition, Xbra appears to inhibit cell migration by inhibiting adhesion to fibronectin. We propose that Xbra functions as a switch to keep cell migration and convergent extension as mutually exclusive behaviors during gastrulation.


Stimulation of enzyme and cytokine production by methyl mercaptan in human gingival fibroblast and monocyte cell cultures.
The volatile sulphur compound methyl mercaptan (CH3SH) is a by-product of protein metabolism and a principal component of oral malodour. This investigation examines the effect of CH3SH on the enzymatic activities of cathepsins B and G and elastase, and on the production by human gingival fibroblasts of two key factors, prostaglandin E (PGE) and cAMP, of the PGE2-cAMP-dependent pathway, which may contribute to the increased production of collagenase and tissue destruction in human periodontal disease. The results demonstrate that CH3SH alone, or in combination with interleukin-1 (IL-1) or lipopolysaccharide, can significantly enhance the secretion of PGE2, cAMP and procollagenase by human gingival fibroblasts. CH3SH also stimulated mononuclear cells to produce IL-1, which can increase cAMP production, and act in synergism with the direct effect of CH3SH on cAMP. CH3SH also significantly enhanced the activity of cathepsin B, moderately suppressed that of cathepsin G, but did not significantly affect elastase. These results provide evidence that CH3SH could be a contributing factor in the enzymatic and immunological cascade of events leading to tissue degradation in periodontal diseases.


Nurse education program on meaninglessness in terminally ill cancer patients: a randomized controlled study of a novel two-day workshop.
Fostering patients' sense of meaning is an essential task for palliative care clinicians. Few studies have reported the effects on nurses of a short-term training program aimed at improving skills to relieve feelings of meaninglessness in terminally ill cancer patients. The primary aim of this study was to determine the impact on nurses of a novel two-day education program focusing on care that addresses patients' feelings of meaninglessness. Measured were impacts on nurses' confidence, self-reported practice, attitudes toward caring for such patients, burnout, meaning of life, and knowledge. This study was a randomized controlled trial using the waiting list control. Intervention consisted of a two-day interactive education program. A total of 76 nurses randomly allocated to two groups completed the study. Outcome measures included confidence scale; self-reported practice scale; scales of nursing attitudes toward caring for patients who experience feelings of meaningless (willingness to help, positive appraisal, helplessness, nurse-perceived value of being, and nurse-perceived value of patients' inner power); Maslach burnout scale, Functional Assessment of Chronic Illness Therapy-Spiritual, and knowledge scale. There were significant intervention effects in nurse-reported confidence and nurse-perceived value of patients' inner power. Nurse-reported helplessness showed marginally significant improvement after intervention (p=0.067). No significant intervention effects were observed in the self-reported practice scale; attitudes toward caring for patients (willingness to help, positive appraisal, and nurse-perceived value of being); burnout scale, meaning of life; and knowledge score. The percentages of nurses who evaluated this program as useful or very useful were 95% (understanding the conceptual framework) and 85% (helping to learn how to provide care for patients feeling meaninglessness in clinical practice). This short-term educational intervention had a significant beneficial effect on nurses' confidence and modest effects on attitudes.


CALCULATIONS OF BIOELECTRIC POTENTIALS : IV. SOME EFFECTS OF CALCIUM ON POTENTIALS IN NITELLA.
In Nitella the substitution of KCl for NaCl changes the P.D. in a negative direction. In some cases this change is lessened by adding solid CaCl(2) to the solution of KCl. This may be due to lessening the partition coefficient of KCl or to decreasing the solubility of an organic substance which sensitizes the cell to the action of KCl. Little or no correlation exists between this effect of calcium and its ordinary antagonistic action in producing a balanced solution which preserves the life of the cell indefinitely. CaCl(2) is negative to NaCl but positive to KCl. The effects of mixtures of KCl, NaCl, and CaCl(2) are discussed. The concentration effect of a mixture of KCl + CaCl(2) shows certain peculiarities due to action currents: these resemble those found with pure KCl. These studies and others on Nitella, Valonia, and Halicystis indicate that mobilities and partition coefficients are variable and can be brought under experimental control.


Human fetal bone marrow early progenitors for T, B, and myeloid cells are found exclusively in the population expressing high levels of CD34.
Experimentation on human stem cells is hampered by the relative paucity of this population and by the lack of assays identifying multilineage differentiation, particularly along the lymphoid lineages. In our current study, phenotypic analysis of low-density fetal bone marrow cells showed two distinct populations of CD34+ cells: those expressing a high density of CD34 antigen on their surface (CD34hi) and those expressing an intermediate level of CD34 antigen (CD34lo). Multiple tissues were used to characterize the in vitro and in vivo potential of these subsets and showed that only CD34hi cells support long-term B lymphopoiesis and myelopoiesis in vitro and mediate T, B, and myeloid repopulation of human tissues implanted into SCID mice. CD34lo cells repeatedly failed to provide long-term hematopoietic activity in vivo or in vitro. These results indicate that a simple fractionation based on well-defined CD34 antigen levels can be used to reproducibly isolate cells highly enriched for in vivo long-term repopulating activity and for multipotent progenitors, including T- and B-cell precursors. Additionally, given the limited variability in the results and the high correlation between in vitro and in vivo hematopoietic potential, we propose that the CD34hi population contains virtually all of the stem cell activity in fetal bone marrow and therefore is the population of choice for future studies in hematopoietic stem cell development and gene therapy.


VEGFR tyrosine kinase inhibitor II (VRI) induced vascular insufficiency in zebrafish as a model for studying vascular toxicity and vascular preservation.
In ischemic disorders such as chronic wounds and myocardial ischemia, there is inadequate tissue perfusion due to vascular insufficiency. Besides, it has been observed that prolonged use of anti-angiogenic agents in cancer therapy produces cardiovascular toxicity caused by impaired vessel integrity and regeneration. In the present study, we used VEGFR tyrosine kinase inhibitor II (VRI) to chemically induce vascular insufficiency in zebrafish in vivo and human umbilical vein endothelial cells (HUVEC) in vitro to further study the mechanisms of vascular morphogenesis in these pathological conditions. We also explored the possibility of treating vascular insufficiency by enhancing vascular regeneration and repair with pharmacological intervention. We observed that pretreatment of VRI induced blood vessel loss in developing zebrafish by inhibiting angiogenesis and increasing endothelial cell apoptosis, accompanied by down-regulation of kdr, kdrl and flt-1 genes expression. The VRI-induced blood vessel loss in zebrafish could be restored by post-treatment of calycosin, a cardiovascular protective isoflavone. Similarly, VRI induced cytotoxicity and apoptosis in HUVEC which could be rescued by calycosin post-treatment. Further investigation of the underlying mechanisms showed that the PI3K/AKT/Bad cell survival pathway was a main contributor of the vascular regenerative effect of calycosin. These findings indicated that the cardiovascular toxicity in anti-angiogenic therapy was mainly caused by insufficient endothelial cell survival, suggesting its essential role in vascular integrity, repair and regeneration. In addition, we showed that VRI-induced blood vessel loss in zebrafish represented a simple and effective in vivo model for studying vascular insufficiency and evaluating cancer drug vascular toxicities.


Investigation of 18F-FDG PET in the selection of patients with breast cancer as candidates for sentinel node biopsy after neoadjuvant therapy.
The main objective of this study was to determine the role of [(18)F]-2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) in the selection of patients with breast cancer as candidates for sentinel node biopsy (SNB) after neoadjuvant therapy. Forty-four patients with primary breast cancer clinically classified as cT2, cT3 or cT4(a-c) cN0-N2 or cN3 M0 and with a baseline FDG PET scan positive both in the site of primary tumour and axillary lymph nodes underwent neoadjuvant therapy and then a second FDG PET scan. In the case of axillary FDG PET uptake, patients underwent axillary lymph node dissection (ALND). If the second FDG PET scan was negative for axillary involvement, SNB was performed in order to evaluate axillary lymph node status. Only in the case of SN positivity did total ALND follow. Specificity and positive predictive value of FDG PET for detection of axillary lymph node metastases after neoadjuvant therapy were as high as 83% (95% confidence interval: 51-97%) and 85% (95% confidence interval: 54-97%), respectively, whereas sensitivity, negative predictive value and diagnostic accuracy were inadequate for a correct staging (34, 32 and 48%, respectively). The poor sensitivity of FDG PET in detecting axillary lymph node metastases makes SNB mandatory in cases of a negative scan. The relatively high positive predictive value seems to suggest a role of FDG PET in selecting patients who, after neoadjuvant therapy, are candidates for ALND, avoiding SNB. However, this issue requires confirmation in a larger series of patients.


Zaleplon and triazolam in humans: acute behavioral effects and abuse potential.
Zaleplon, a pyrazolopyrimidine that is under development as a hypnotic, produces its pharmacological effects at the benzodiazepine-recognition site on the GABA(A) benzodiazepine-receptor complex. Unlike most benzodiazepines, zaleplon binds selectively to the BZ1 (omega1) subtype of the benzodiazepine receptor. The present study compared the acute subject-rated effects, performance-impairing effects, and abuse potential of zaleplon and triazolam, a triazolobenzodiazepine hypnotic, in 14 healthy volunteers with histories of drug abuse. Zaleplon (25, 50, and 75 mg), triazolam (0.25, 0.5, and 0.75 mg) and placebo were administered orally in this double-blind, crossover study. Zaleplon and triazolam produced comparable dose-related effects on several subject-rated drug-effect questionnaires. Zaleplon and triazolam also produced comparable dose-dependent decrements on several performance tasks including balance, circular lights, digit-enter and recall, DSST, picture recall/recognition and repeated acquisition. Same-day and next-day subject-rated measures reflecting abuse potential (e.g., drug liking, good effects, and monetary street value) also suggest that zaleplon and triazolam were comparable. The only notable between-drug difference observed in the present study was that the time-action function of zaleplon differed from that of triazolam. The onset time, time to maximum drug effect, and duration of action were shorter with zaleplon than triazolam. Thus, despite its non-benzodiazepine structure and unique benzodiazepine-receptor binding profile, the behavioral pharmacological profile of zaleplon is similar to that of triazolam.


Demonstration of a spatial filtering amplifier for high-order harmonics.
We report what is to our knowledge the first demonstration of spatial filtering of a high-order harmonic beam into a soft-x-ray laser plasma amplifier at 32.8 nm. After amplification the seed energy is enhanced by a factor of 50, and the beam profile of the amplified beam exhibits an Airy-like shape due to the spatial filtering by the optical field ionized plasma. Moreover, the transverse coherence of the spatially filtered amplified beam is strongly enhanced, resulting in the generation of a peak coherent power of 0.9 x 10(5) to 1.8 x 10(5) W.


Glucocorticoid and mineralocorticoid receptor mRNA expression in rat brain.
In the rat brain, the binding of corticosterone is mediated through two receptor types, the type I receptor and the type II receptor, which are presumed to be encoded by genes designated as MR and GR, respectively. We have studied the regulation of these receptors by glucocorticoids, utilizing a cytosol receptor binding assay. In addition, we have employed molecular probes for the GR and the MR to measure receptor mRNAs. The level of type II receptor binding is uniform across several brain regions, as is the expression of GR (type II) mRNA. In contrast, type I receptor binding is concentrated in the hippocampus, and the MR (type I) mRNA similarly shows a higher level of expression in hippocampus than in the other brain regions studied. Removal of endogenous glucocorticoids by adrenalectomy (ADX) induces an increase, and corticosterone administration results in a decrease, in the level of type I and type II binding in the hippocampus; however, no significant changes in the MR (type I) or GR (type II) mRNA levels are seen with these treatments. The diurnal variation of serum corticosterone in intact rats is correlated with a circadian regulation of type I receptor binding in the hippocampus, while MR (type I) mRNA expression is unaffected. Thus, the changes in type I and type II receptor binding capacity elicited by differing steroid conditions cannot be attributed to modulation of the steady state levels of MR (type I) or GR (type II) mRNA.


When trade-offs interact: balance of terror enforces dominance discovery trade-off in a local ant assemblage.
1. Trade-offs underpin local species coexistence. Trade-offs between interference and exploitative competitive ability provie a mechanism for explaining species coexistence within guilds that exploit overlapping resources. 2. Omnivorous, leaf litter ants exploit a shared food base and occur in species-rich assemblages. In these assemblages, species that excel at usurping food items from other species are poor at finding food items first. In assemblages where some members are attacked by phorid fly parasitoids, host species face an additional trade-off between defending themselves against parasitic attack and maximizing their competitive abilities. Host species thus face two trade-offs that interact via the trait-mediated indirect interaction generated by phorid defence behaviour. 3. In this study we test for the existence of these trade-offs and evaluate the predictions of a model for how they interact in an assemblage of woodland ants in which two behaviourally dominant members are attacked by phorid fly parasitoids as they attempt to harvest food resources. 4. The major findings are that unparasitized species in the assemblage follow a dominance-discovery trade-off curve. When not subject to attack by phorid flies, host species violate that trade-off by finding resources too quickly for their level of behavioural dominance. In contrast, when attacked by their phorid parasitoids, the host species dominance drops such that they fall into the assemblage trade-off. 5. These results match the predictions of the balance of terror model, which derives the optimal host response to parasitism, indicating that the host species balance the competing fitness costs of reduced competitive dominance and loss of workers to parasitism. This result supports the view that understanding the structure of ecological communities requires incorporating the indirect effects created by trait plasticity.


Lung volume reduction surgery for diffuse emphysema.
Lung volume reduction surgery (LVRS) performed to treat patients with severe diffuse emphysema was reintroduced in the nineties. Lung volume reduction surgery aims to resect damaged emphysematous lung tissue, thereby increasing elastic properties of the lung. This treatment is hypothesised to improve long-term daily functioning and quality of life, although it may be costly and may be associated with risks of morbidity and mortality. Ten years have passed since the last version of this review was prepared, prompting us to perform an update. The objective of this review was to gather all available evidence from randomised controlled trials comparing the effectiveness of lung volume reduction surgery (LVRS) versus non-surgical standard therapy in improving health outcomes for patients with severe diffuse emphysema. Secondary objectives included determining which subgroup of patients benefit from LVRS and for which patients LVRS is contraindicated, to establish the postoperative complications of LVRS and its morbidity and mortality, to determine which surgical approaches for LVRS are most effective and to calculate the cost-effectiveness of LVRS. We identified RCTs by using the Cochrane Airways Group Chronic Obstructive Pulmonary Disease (COPD) register, in addition to the online clinical trials registers. Searches are current to April 2016. We included RCTs that studied the safety and efficacy of LVRS in participants with diffuse emphysema. We excluded studies that investigated giant or bullous emphysema. Two independent review authors assessed trials for inclusion and extracted data. When possible, we combined data from more than one study in a meta-analysis using RevMan 5 software. We identified two new studies (89 participants) in this updated review. A total of 11 studies (1760 participants) met the entry criteria of the review, one of which accounted for 68% of recruited participants. The quality of evidence ranged from low to moderate owing to an unclear risk of bias across many studies, lack of blinding and low participant numbers for some outcomes. Eight of the studies compared LVRS versus standard medical care, one compared two closure techniques (stapling vs laser ablation), one looked at the effect of buttressing the staple line on the effectiveness of LVRS and one compared traditional 'resectional' LVRS with a non-resectional surgical approach. Participants completed a mandatory course of pulmonary rehabilitation/physical training before the procedure commenced. Short-term mortality was higher for LVRS (odds ratio (OR) 6.16, 95% confidence interval (CI) 3.22 to 11.79; 1489 participants; five studies; moderate-quality evidence) than for control, but long-term mortality favoured LVRS (OR 0.76, 95% CI 0.61 to 0.95; 1280 participants; two studies; moderate-quality evidence). Participants identified post hoc as being at high risk of death from surgery were those with particularly impaired lung function, poor diffusing capacity and/or homogenous emphysema. Participants with upper lobe-predominant emphysema and low baseline exercise capacity showed the most favourable outcomes related to mortality, as investigators reported no significant differences in early mortality between participants treated with LVRS and those in the control group (OR 0.87, 95% CI 0.23 to 3.29; 290 participants; one study), as well as significantly lower mortality at the end of follow-up for LVRS compared with control (OR 0.45, 95% CI 0.26 to 0.78; 290 participants; one study). Trials in this review furthermore provided evidence of low to moderate quality showing that improvements in lung function parameters other than forced expiratory volume in one second (FEV1), quality of life and exercise capacity were more likely with LVRS than with usual follow-up. Adverse events were more common with LVRS than with control, specifically the occurrence of (persistent) air leaks, pulmonary morbidity (e.g. pneumonia) and cardiovascular morbidity. Although LVRS leads to an increase in quality-adjusted life-years (QALYs), the procedure is relatively costly overall. Lung volume reduction surgery, an effective treatment for selected patients with severe emphysema, may lead to better health status and lung function outcomes, specifically for patients who have upper lobe-predominant emphysema with low exercise capacity, but the procedure is associated with risks of early mortality and adverse events.


Sub-4 nm Nanodiamonds from Graphene-Oxide and Nitrated Polycyclic Aromatic Hydrocarbons at 423 K.
Nanodiamonds are interesting materials from the point of view of their biocompatibility and their chemical, spectroscopic, and mechanical properties. Current synthetic methods for nanodiamonds involve harsh environments, which are potentially hazardous in addition to being expensive. We report a low-temperature (423 K) hydrothermal approach to form nanodiamonds by using graphene-oxide or nitrated polycyclic aromatic hydrocarbons (naphthalene, anthracene, phenanthrene, or pyrene) as a starting material. The reaction products contain single-crystalline or twinned nanodiamonds with average diameters in the 2-3 nm range. Theoretical calculations prove that, at the nanoscale, sub-4 nm nanodiamonds may adopt a structure that is more stable than graphene-oxide and nitrated polycyclic aromatic hydrocarbons. Our findings show that sp2 carbon in the polycyclic aromatic precursor can be converted to sp3 carbon under unexpectedly moderate temperature conditions by using nanoscale precursors and thus offer a low-temperature approach for the synthesis of sub-4 nm nanodiamonds.


Is edaravone harmful? (A placebo is not a control).
Edaravone is delivered by long-term daily intravenous infusions, yet the risk of infusion was not considered in the design or analysis of studies examining the efficacy of edaravone in ALS. A reappraisal of the pivotal edaravone study (Study 19) on which claims of efficacy are based suggests that this risk cannot be dismissed, that the efficacy of edaravone may be over-estimated, and that some differences between edaravone and placebo may not implicate the ALS disease process. When trial conditions may be harmful to both arms of a placebo-controlled trial, not only is it necessary that treatment prove superior to placebo, but also that treatment is better than no intervention. In Study 19, edaravone performed better than placebo, but both placebo and edaravone likely did worse than no intervention, an interpretation more in keeping with previous trial experience of drugs with similar mechanisms of action, and with previous trial experience with edaravone. Edaravone, as presently delivered, may be both ineffective and harmful.


A comparative study: tongue muscle performance in weightlifters and runners.
Exercise mode (i.e., resistance training, endurance training) is known to yield mode-specific effects on strength and endurance of muscles that are directly targeted during the exercise. Such mode-specific effects can also be observed in indirectly involved (i.e., nontargeted) muscles. Mode-specific muscle performance changes of nontargeted muscles, however, have only been investigated within the skeletal system. Therefore, as a first step, this study aimed to determine if bulbar muscle performance (tongue strength [TS], tongue endurance [TE]) differs between weightlifters and runners and if group differences are tongue region-specific. The Iowa Oral Performance Instrument (IOPI) was used to measure TS and TE of the anterior and posterior tongue regions in 21 weightlifters and 23 runners. In weightlifters anterior TS was significantly greater than posterior TS (P = 0.008), whereas in runners anterior and posterior TS were comparable. Furthermore, weightlifters produced significantly greater anterior TS than runners (P = 0.001). Finally, TE was overall significantly greater in runners than in weightlifters (P = 0.001). Findings suggest that exercise mode may differentially impact performance patterns of nontargeted bulbar muscles. More research is warranted to better understand the mechanisms underlying tongue muscle performance differences between weightlifters and runners.


Cultivating scholarship in the clinical setting.
Many clinical nursing departments have added scholarly activity as a goal, expecting staff development personnel to implement the needed programs for research utilization, professional presentations, and clinical investigations. In this article, the author provides specific strategies for starting a research program and nurturing its development, addressing the emotional needs as well as the knowledge and resource needs of the learner. These strategies provide a blueprint for building the research utilization, initiation, and publication productivity in a clinical setting.


Inhibition of translation in liver polyribosomes by a new substituted thiopseudourea with antitumour action.
A new thiopseudourea, S-(10-undecen-1-yl)isothiouronium iodide (compound AHR-1911), was tested for antitumour action and shown to inhibit considerably the growth of the Walker carcinoma in rats. The mechanism of its effect on protein and nucleic acid synthesis was then studied with systems in vitro from rat liver. In incubations of liver slices, 1.4mm-compound AHR-1911 decreased by 96% the incorporation of [(14)C]leucine into microsomal proteins, and mitochondrial protein synthesis measured in the presence of cycloheximide was decreased by 44%. At lower doses, translation, as well as the incorporation of [(3)H]uridine into RNA, was also considerably impaired, compound AHR-1911 being the most active of all the thiopseudoureas tested whereas undecylenic acid and thiourea by themselves showed practically no inhibition. Protein synthesis by cytoplasmic ribosomes (microsomes and C-polyribosomes) was inhibited by compound AHR-1911 at different concentrations (72% at 0.42mm), and again the other related compounds were much less effective, with the exception of one antileukaemic thiopseudourea. The same occurred with the poly(U)-stimulated incorporation of phenylalanine. The puromycin reaction with pulse-labelled C-ribosomes was strongly inhibited, particularly when preincubation with compound AHR-1911 preceded the addition of puromycin, with no release of nascent chains by the thiopseudourea alone. In the presence of GTP and pH5 fraction, to induce translocation and transform all the ribosomes to the donor state, the percentage inhibition remained the same. The ribosomes incubated with the drug are aggregated, as shown by the polyribosome profile, but, when excess of inhibitor was removed, the activity in protein synthesis and the puromycin reaction was restored, indicating that the inhibition is not due to the polyribosomal aggregation. These results suggest that the effect on translation with both 55S and 80S ribosomes is derived from inhibition of chain elongation at the level of transpeptidation and not translocation, probably together with the interference with transcription playing a role in the antitumour activity.


Cooperation of c-raf-1 and c-myc protooncogenes in the neoplastic transformation of simian virus 40 large tumor antigen-immortalized human bronchial epithelial cells.
Overexpression of c-raf-1 and the myc family of protooncogenes is primarily associated with small cell carcinoma, which accounts for approximately 25% of human lung cancer. To determine the functional significance of the c-raf-1 and/or c-myc gene expression in lung carcinogenesis and to delineate the relationship between protooncogene expression and tumor phenotype, we introduced both protooncogenes, alone or in combination, into human bronchial epithelial cells. Two retroviral recombinants, pZip-raf and pZip-myc, containing the complete coding sequences of the human c-raf-1 and murine c-myc genes, respectively, were constructed and transfected into simian virus 40 large tumor antigen-immortalized bronchial epithelial cells (BEAS-2B); this was followed by selection for G418 resistance. BEAS-2B cells expressing both the transfected c-raf-1 and c-myc sequences formed large cell carcinomas in athymic nude mice with a latency of 4-21 weeks, whereas either pZip-raf- or pZip-myc-transfected cells were nontumorigenic after 12 months. Cell lines established from tumors (designated RMT) revealed the presence of the cotransfected c-raf-1 and c-myc sequences and expressed morphological, chromosomal, and isoenzyme markers, which identified BEAS-2B cells as the progenitor line of the tumors. A significant increase in the mRNA levels of neuron-specific enolase was detected in BEAS-2B cells containing both the c-raf-1 and c-myc genes and derived tumor cell lines. The data demonstrate that the concomitant expression of the c-raf and c-myc protooncogenes causes neoplastic transformation of human bronchial epithelial cells resulting in large cell carcinomas with certain neuroendocrine markers. The presented model system should be useful in studies of molecular events involved in multistage lung carcinogenesis.


[Hypertrophic basal pachymeningitis presenting as Tolosa-Hunt syndrome].
We examined 6 patients with hypertrophic basal pachymeningitis using clinical, laboratory and instrumental methods. The clinical presentations were similar to Tolosa-Hunt syndrome although the differences were noted. One case is described in-depth. Based on literature and own observations, we considered the etiology, pathogenesis, diagnostic features and treatment of hypertrophic basal pachymeningitis.


Automated Alignment of Multi-Modal Plant Images Using Integrative Phase Correlation Approach.
Modern facilities for high-throughput phenotyping provide plant scientists with a large amount of multi-modal image data. Combination of different image modalities is advantageous for image segmentation, quantitative trait derivation, and assessment of a more accurate and extended plant phenotype. However, visible light (VIS), fluorescence (FLU), and near-infrared (NIR) images taken with different cameras from different view points in different spatial resolutions exhibit not only relative geometrical transformations but also considerable structural differences that hamper a straightforward alignment and combined analysis of multi-modal image data. Conventional techniques of image registration are predominantly tailored to detection of relative geometrical transformations between two otherwise identical images, and become less accurate when applied to partially similar optical scenes. Here, we focus on a relatively new technical problem of FLU/VIS plant image registration. We present a framework for automated alignment of FLU/VIS plant images which is based on extension of the phase correlation (PC) approach - a frequency domain technique for image alignment, which relies on detection of a phase shift between two Fourier-space transforms. Primarily tailored to detection of affine image transformations between two structurally identical images, PC is known to be sensitive to structural image distortions. We investigate effects of image preprocessing and scaling on accuracy of image registration and suggest an integrative algorithmic scheme which allows to overcome shortcomings of conventional single-step PC by application to non-identical multi-modal images. Our experimental tests with FLU/VIS images of different plant species taken on different phenotyping facilities at different developmental stages, including difficult cases such as small plant shoots of non-specific shape and non-uniformly moving leaves, demonstrate improved performance of our extended PC approach within the scope of high-throughput plant phenotyping.


Combination of iCVD and porous silicon for the development of a controlled drug delivery system.
We describe a pH responsive drug delivery system which was fabricated using a novel approach to functionalize biodegradeable porous silicon (pSi) by initiated chemical vapor deposition (iCVD). The assembly involved first loading a model drug (camptothecin, CPT) into the pores of the pSi matrix followed by capping the pores with a thin pH responsive copolymer film of poly(methacrylic acid-co-ethylene dimethacrylate) (p(MAA-co-EDMA)) via iCVD. Release of CPT from uncoated pSi was identical in two buffers at pH 1.8 and pH 7.4. In contrast, the linear release rate of CPT from the pSi matrix with the p(MAA-co-EDMA) coating was dependent on the pH; release of CPT was more than four times faster at pH 7.4 (13.1 nmol/(cm(2) h)) than at pH 1.8 (3.0 nmol/(cm(2) h)). The key advantage of this drug delivery approach over existing ones based on pSi is that the iCVD coating can be applied to the pSi matrix after drug loading without degradation of the drug because the process does not expose the drug to harmful solvents or high temperatures and is independent of the surface chemistry and pore size of the nanoporous matrix.


Toward efficient biomechanical-based deformable image registration of lungs for image-guided radiotherapy.
Both accuracy and efficiency are critical for the implementation of biomechanical model-based deformable registration in clinical practice. The focus of this investigation is to evaluate the potential of improving the efficiency of the deformable image registration of the human lungs without loss of accuracy. Three-dimensional finite element models have been developed using image data of 14 lung cancer patients. Each model consists of two lungs, tumor and external body. Sliding of the lungs inside the chest cavity is modeled using a frictionless surface-based contact model. The effect of the type of element, finite deformation and elasticity on the accuracy and computing time is investigated. Linear and quadrilateral tetrahedral elements are used with linear and nonlinear geometric analysis. Two types of material properties are applied namely: elastic and hyperelastic. The accuracy of each of the four models is examined using a number of anatomical landmarks representing the vessels bifurcation points distributed across the lungs. The registration error is not significantly affected by the element type or linearity of analysis, with an average vector error of around 2.8 mm. The displacement differences between linear and nonlinear analysis methods are calculated for all lungs nodes and a maximum value of 3.6 mm is found in one of the nodes near the entrance of the bronchial tree into the lungs. The 95 percentile of displacement difference ranges between 0.4 and 0.8 mm. However, the time required for the analysis is reduced from 95 min in the quadratic elements nonlinear geometry model to 3.4 min in the linear element linear geometry model. Therefore using linear tetrahedral elements with linear elastic materials and linear geometry is preferable for modeling the breathing motion of lungs for image-guided radiotherapy applications.


The Roles of IL-22 and Its Receptor in the Regulation of Inflammatory Responses in the Brain.
Interleukin (IL)-22 is a potent mediator of inflammatory responses. The IL-22 receptor consists of the IL-22Rα and IL-10Rβ subunits. Previous studies have shown that IL-22Rα expression is restricted to non-hematopoietic cells in the skin, pancreas, intestine, liver, lung, and kidney. Although IL-22 is involved in the development of inflammatory responses, there have been no reports of its role in brain inflammation. Here, we used RT-PCR, Western blotting, flow cytometry, immunohistochemical, and microarray analyses to examine the role of IL-22 and expression of IL-22Rα in the brain, using the microglial cell line, hippocampal neuronal cell line, and inflamed mouse brain tissue. Treatment of BV2 and HT22 cells with recombinant IL-22 increased the expression levels of the pro-inflammatory cytokines IL-6 and TNF-α, as well as cyclooxygenase (COX)-2 and prostaglandin E2. We also found that the JNK and STAT3 signaling pathways play an important role in IL-22-mediated increases in inflammatory mediators. Microarray analyses revealed upregulated expression of inflammation-related genes in IL-22-treated HT22 cells. Finally, we found that IL-22Rα is spontaneously expressed in the brain and is upregulated in inflamed mouse brain. Overall, our results demonstrate that interaction of IL-22 with IL-22Rα plays a role in the development of inflammatory responses in the brain.


Laparoscopic management and clinical outcome of emphysematous cholecystitis.
As opposed to acute, chronic, and acalculus cholecystitis, emphysematous cholecystitis (EC) is associated with significant morbidity and mortality. Only a few studies have specifically reviewed the operative management and clinical outcome of EC. This study documents the operative management and clinical outcome of EC at the Cleveland Clinic Foundation. Between January 1996 and June 1999, 18 consecutive patients underwent cholecystectomy for emphysematous cholecystitis at our institution. All charts were reviewed retrospectively, and patients undergoing concurrent procedures were excluded. Mean values +/- standard deviation (SD) of the mean were calculated for patient demographics, preoperative white blood cell count (WBC), bilirubin, alkaline phosphatase, and length of hospital stay. Operative procedure (laparoscopic, converted, or open), preoperative imaging studies, operative time, ICU stay, morbidity, and mortality were reviewed. Patients presented with a mean age of 53.4 years (range, 18-80) and a male/female ratio of 3.5 (14/4). There were no differences between groups in terms of patient demographics. Mean WBC on admission was 14.2 K/mL (range, 5.4-19.7). Mean alkaline phosphatase and total bilirubin were 115 U/L (range, 45-428) and 1.4 mg/dl (range, 0.5-3.4), respectively. Thirteen patients (72%) were completed laparoscopically, two patients (11%) were converted to an open procedure, and three patients (17%) had open surgery. Overall mean length of hospital stay was 5 days (range, 1-18). Two patients from the open group ultimately died 1 year later due to progression of preexisting illness. One of these patients had congestive heart failure and chronic renal failure; the other had metastatic malignant melanoma. None of the patients died in the immediate perioperative period. There were five complications (27.8%). Two patients presented with bleeding secondary to heparin and coumadin therapy. One developed sepsis, and another developed leakage from the cystic duct stump, necessitating an endoscopic retrograde cholangiopancreatogram (ERCP) with stent decompression. The fifth complication, ileus, required readmission 3 days postoperatively, but the patient responded to conservative management. Complications were evenly distributed between the three groups. There were two complications in the laparoscopic group, two in the open group, and one in the conversion group. All other patients were alive at the time of this publication. Using current techniques, patients with EC can be managed successfully utilizing laparoscopy. Morbidity and mortality appear to be slightly higher than published reports for acute, chronic, and acalculus cholecystitis. Conversion rates are comparable to patients with acute and chronic cholecystitis who undergo laparoscopic cholecystectomy. Based on these data, laparoscopic cholecystectomy should be considered the first-line treatment for patients with known or suspected EC.


Has the relationship between wealth and HIV risk in Sub-Saharan Africa changed over time? A temporal, gendered and hierarchical analysis.
This study examines the relationship between wealth and HIV infection in Sub-Saharan Africa to determine whether and how this relationship has varied over time, within and across countries, by gender, and urban environment. The analysis draws on DHS and AIS data from 27 Sub-Saharan African countries, which spanned the 14 years between 2003 and 2016. We first use logistic regression analyses to assess the relationship between individual wealth, HIV infection and gender by country and year stratified on urban environment. We then use meta-regression analyses to assess the relationship between country level measures of wealth and the odds of HIV infection by gender and individual level wealth, stratified on urban environment. We find that there is a persistent and positive relationship between wealth and the odds of HIV infection across countries, but that the strength of this association has weakened over time. The rate of attenuation does not appear to differ between urban/rural strata. Likewise, we also find that these associations were most pronounced for women and that this relationship was persistent over the study period and across urban and rural strata. Overall, our findings suggest that the relationship between wealth and HIV infection is beginning to reverse and that in the coming years, the relationship between wealth and HIV infection in Sub-Saharan Africa may more clearly mirror the predominant global picture.


Low-frequency fluctuation amplitude analysis of resting-state fMRI in sickle cell disease.
Sickle cell disease may result in neurological damage and strokes, leading to morbidity and mortality. Currently, there are no dependable biomarkers to predict impending strokes. In this study, we analyzed neuronal processes at resting state and more particularly how this disease affects the default mode network. The amplitude of low frequency fluctuations was used to reflect areas of spontaneous BOLD signal across brain regions. We compared the activations of sickle cell disease patients to a control group using variance analysis and t-test. Significant regional differences among the two groups were observed, especially in the default mode network areas and cortical regions near large cerebral arteries. These findings suggest that sickle cell disease causes activation modifications near vessels, and these changes could be used as a biomarker of the disease.


Potassium feldspar in weekeroo station, kodaikanal, and colomera iron meteorites.
Sodium plagioclase and small amounts of potassium feldspar are common constituents of silicate inclusions in the Weekeroo Station and Colomera iron meteorites; flamboyant x-ray antiperthite is unique to Kodaikanal silicate inclusions. Enrichment of potassium, sodium, silicon, and aluminum in these inclusions indicates a higher degree of chemical differentiation than in other meteorites.


[Magnetophore therapy in the combined treatment of patients with obstructive bronchial diseases and its effect on immunological reactivity].
Follow up of 93 patients with chronic obstructive bronchitis and bronchial asthma enabled the authors to trace the effect of magnetophorotherapy combined with pathogenetic treatment on the disease progress, external respiration function, cardiovascular system, and immune responsiveness. It was shown that magnetophorotherapy is an effective therapy for bronchial obstruction, favouring the recovery and improvement of respiratory function, characteristics of the flow-volume curve. It also exerts a beneficial effect on different components of immunity.


Morphological and molecular characterization of Ptychodiscus noctiluca revealed the polyphyletic nature of the order Ptychodiscales (Dinophyceae).
The planktonic dinoflagellate Ptychodiscus noctiluca combined distinctive morphological features such as a disk-shaped anteroposteriorly compressed cell body and an apical carina, together with a flexible and tough cell covering, suggesting intermediate characteristics between thecate and naked dinoflagellates. Ptychodiscus noctiluca was examined by light, epifluorescence, and scanning electron microscopy from specimens collected in the Mediterranean Sea and the North and South Atlantic Ocean. Ptychodiscus noctiluca showed a straight apical groove that bisected the carina, a cell covering with a polygonal surface reticulum, nucleus without capsule, sulcal intrusion in the episome, sulcal ventral flange, and yellowish-green chloroplasts that are shared characters with Brachidinium/Karenia. The cell division was the typical binary fission of gymnodinioid dinoflagellates, although exceptionally in an oblique transversal axis. We examined the intraspecific variability during incubation experiments. In the fattened cells, termed as Ptychodiscus carinatus, chloroplasts transformed into dark granules, and the cell acquired the swollen and smaller stage, termed as P. inflatus. Ptychodiscus carinatus, P. inflatus, and Diplocystis antarctica are synonyms of P. noctiluca. Molecular phylogeny based on the SSU rDNA sequence revealed that Ptychodiscus branched within the short-branching dinokaryotic dinoflagellates as an independent lineage with affinity to Brachidinium/Karenia and Karlodinium/Takayama in a generally poorly resolved clade. Our results indicated that the order Ptychodiscales, established for unarmored dinoflagellates with a strongly developed pellicle, has artificially grouped thecate dinoflagellates (Kolkwitziella, Herdmania), naked dinoflagellates with thick cell covering (Balechina, Cucumeridinium) and other insufficiently known unarmored genera with typical cell coverings (Brachidinium, Ceratoperidinium).


ProsRegNet: A deep learning framework for registration of MRI and histopathology images of the prostate.
Magnetic resonance imaging (MRI) is an increasingly important tool for the diagnosis and treatment of prostate cancer. However, interpretation of MRI suffers from high inter-observer variability across radiologists, thereby contributing to missed clinically significant cancers, overdiagnosed low-risk cancers, and frequent false positives. Interpretation of MRI could be greatly improved by providing radiologists with an answer key that clearly shows cancer locations on MRI. Registration of histopathology images from patients who had radical prostatectomy to pre-operative MRI allows such mapping of ground truth cancer labels onto MRI. However, traditional MRI-histopathology registration approaches are computationally expensive and require careful choices of the cost function and registration hyperparameters. This paper presents ProsRegNet, a deep learning-based pipeline to accelerate and simplify MRI-histopathology image registration in prostate cancer. Our pipeline consists of image preprocessing, estimation of affine and deformable transformations by deep neural networks, and mapping cancer labels from histopathology images onto MRI using estimated transformations. We trained our neural network using MR and histopathology images of 99 patients from our internal cohort (Cohort 1) and evaluated its performance using 53 patients from three different cohorts (an additional 12 from Cohort 1 and 41 from two public cohorts). Results show that our deep learning pipeline has achieved more accurate registration results and is at least 20 times faster than a state-of-the-art registration algorithm. This important advance will provide radiologists with highly accurate prostate MRI answer keys, thereby facilitating improvements in the detection of prostate cancer on MRI. Our code is freely available at https://github.com/pimed//ProsRegNet.


[Recommendations for reopening elective surgery services during the SARS-CoV-2 pandemic].
Given the uncertainty that accompanies the SARS-CoV-2 pandemic and the need to respond to multiple chronic and acute health problems affecting the general population, including those requiring surgical intervention, the recommendations implemented in clinics and hospitals in Colombia are presented as a guide to achieve a reopening of elective surgery services in a safe, staggered and monitored manner in accordance with the dynamics imposed by the pandemic, national and international guidelines and the speed of production of scientific evidence related to COVID-19.


Phosphoproteomic analysis of lettuce (Lactuca sativa L.) reveals starch and sucrose metabolism functions during bolting induced by high temperature.
High temperatures induce early bolting in lettuce (Lactuca sativa L.), which decreases both quality and production. However, knowledge of the molecular mechanism underlying high temperature promotes premature bolting is lacking. In this study, we compared lettuce during the bolting period induced by high temperatures (33/25 °C, day/night) to which raised under controlled temperatures (20/13 °C, day/night) using iTRAQ-based phosphoproteomic analysis. A total of 3,814 phosphorylation sites located on 1,766 phosphopeptides from 987 phosphoproteins were identified after high-temperature treatment,among which 217 phosphoproteins significantly changed their expression abundance (116 upregulated and 101 downregulated). Most phosphoproteins for which the abundance was altered were associated with the metabolic process, with the main molecular functions were catalytic activity and transporter activity. Regarding the functional pathway, starch and sucrose metabolism was the mainly enriched signaling pathways. Hence, high temperature influenced phosphoprotein activity, especially that associated with starch and sucrose metabolism. We suspected that the lettuce shorten its growth cycle and reduce vegetative growth owing to changes in the contents of starch and soluble sugar after high temperature stress, which then led to early bolting/flowering. These findings improve our understanding of the regulatory molecular mechanisms involved in lettuce bolting.


Tropism modification of adenovirus vectors by peptide ligand insertion into various positions of the adenovirus serotype 41 short-fiber knob domain.
Recombinant adenoviruses have emerged as promising agents in therapeutic gene transfer, genetic vaccination, and viral oncolysis. Therapeutic applications of adenoviruses, however, would benefit substantially from targeted virus cell entry, for example, into cancer or immune cells, as opposed to the broad tropism that adenoviruses naturally possess. Such tropism modification of adenoviruses requires the deletion of their natural cell binding properties and the incorporation of cell binding ligands. The short fibers of subgroup F adenoviruses have recently been suggested as a tool for genetic adenovirus detargeting based on the reduced infectivity of corresponding adenovectors with chimeric fibers in vitro and in vivo. The goal of our study was to determine functional insertion sites for peptide ligands in the adenovirus serotype 41 (Ad41) short fiber knob. With a model peptide, CDCRGDCFC, we could demonstrate that ligand incorporation into three of five analyzed loops of the knob, namely, EG, HI, and IJ, is feasible without a loss of fiber trimerization. The resulting adenovectors showed enhanced infectivity for various cell types, which was superior to that of viruses with the same peptide fused to the fiber C terminus. Strategies to further augment gene transfer efficacy by extension of the fiber shaft, insertion of tandem copies of the ligand peptide, or extension of the ligand-flanking linkers failed, indicating that precise ligand positioning is pivotal. Our study establishes that internal ligand incorporation into a short-shafted adenovirus fiber is feasible and suggests the Ad41 short fiber with ligand insertion into the top (IJ loop) or side (EG and HI loops) of the knob domain as a novel platform for genetic targeting of therapeutic adenoviruses.


Medical thoracoscopy removal of a self-expandable metallic stent migration into pleural cavity.
Pleuroscopy, also known as medical thoracoscopy (MT), is an important tool for pleural disease management. Removal of foreign body (FB) by MT was reported in a few reports because it can identify the position of a FB in the pleural cavity and can be used for its urgent removal. In this study, we describe the case of a male patient with a ruptured lung abscess and a rare complication of self-expandable metallic stent (SEMS) migration into the pleural cavity via a bronchopleural fistula after the management of obstructive airway disease. An experienced pulmonologist successfully removed the SEMS from the pleural cavity using semi-rigid pleuroscopy under local anesthesia and conscious sedation in a bronchoscopy suite.


Use of computerized tomography in nonsurgical management of brain abscess.
Two patients with hematogenous brain abscesses demonstrated by computerized tomographic (CT) scans were successfully treated without surgical intervention. The first patient had congenital cyanotic heart disease and multiple brain abscesses complicated by presumed rupture into the ventricles. By the time these clinical diagnoses were established, she had shown substantial improvement after antibiotic therapy alone. The second patient with bronchiectasis had a single abscess in the dominant hemisphere. Medical management was successful. Subsequent CT scans in both patients provided reassurance that clinical improvement was accompanied by anatomical healing. The use of noninvasive diagnostic techniques should encourage the formulation of new criteria for the management of cerebral abscess in carefully evaluated and closely observed patients.


Targeting Cancer Cells and Tumor Microenvironment in Preclinical and Clinical Models of Hodgkin Lymphoma Using the Dual PI3Kδ/γ Inhibitor RP6530.
Tumor-associated macrophages (TAMs) and the hyperactivation of the PI3K/AKT pathway are involved in the pathogenesis of Hodgkin lymphoma and affect disease outcome. Because the δ and γ isoforms of PI3K are overexpressed in Hodgkin/Reed-Sternberg (HRS) cells and the tumor microenvironment (TME), we propose that the PI3Kδ/γ inhibitor RP6530 might affect both HRS cells and TME, ultimately leading to an enhanced antitumor response. Hodgkin lymphoma cell lines (L-540, KM-H2, and L-428) and primary human macrophages were used to investigate the activity of RP6530 in vitro and in vivo in Hodgkin lymphoma cell line xenografts. In vitro, RP6530 besides killing and inhibiting the proliferation of Hodgkin lymphoma cells, downregulated lactic acid metabolism, switching the activation of macrophages from an immunosuppressive M2-like phenotype to a more inflammatory M1-like state. By RNA sequencing, we define tumor glycolysis as a specific PI3Kδ/γ-dependent pathway implicated in the metabolic reprogramming of cancer cells. We identify the metabolic regulator pyruvate kinase M2 as the main mediator of tumor-induced immunosuppressive phenotype of macrophages. Furthermore, we show in human tumor xenografts that RP6530 repolarizes TAMs into proinflammatory macrophages and inhibits tumor vasculature, leading to tumor regression. Interestingly, patients with Hodgkin lymphoma experiencing objective responses (complete response and partial response) in a phase I trial using RP6530 showed a significant inhibition of circulating myeloid-derived suppressor cells and an average mean reduction in serum thymus and activation-regulated chemokine levels of 40% (range, 4%-76%). Our results support PI3Kδ/γ inhibition as a novel therapeutic strategy that targets both malignant cells and the TME to treat patients with Hodgkin lymphoma.


Limitations of laser-Doppler velocimetry and reflectance spectrophotometry in estimating gastric mucosal blood flow.
This study investigated the accuracy of laser-Doppler flowmetry (LDV) and reflectance spectrophotometry (RS) measurements as an index of blood flow in the gastric mucosa of the rat, in experimental conditions such as pharmacologically induced vasoconstriction, hypoxia, hyperoxia, and acute normovolemic anemia. Hydrogen gas clearance was used as a reference method. After vasopressin infusion, LDV signal and indexes of hemoglobin (IHb) and oxygen (ISO2) content in the gastric mucosa estimated by RS significantly decreased in parallel with the reduction of gastric mucosal blood flow (GMBF). Neither hypoxia (5% O2 administration) nor hyperoxia (100% O2) affected GMBF or LDV signal. However, both IHb and ISO2 significantly decreased or increased after hypoxia or hyperoxia, respectively. Acute normovolemic anemia induced a significant increase in GMBF, while LDV signal and ISO2 remained unchanged. IHb significantly decreased in linear relationship with the decrements in the hematocrit. It is concluded that 1) in pharmacologically induced GMBF changes, LDV and RS correlate with GMBF; 2) when changes in hemoglobin saturation are induced, LDV but not RS reflects GMBF; and 3) in acute normovolemic anemia, neither LDV nor RS reflects changes in GMBF.


Hospital staffing and local pay: an investigation into the impact of local variations in the competitiveness of nurses' pay on the staffing of hospitals in France.
Spatial wage theory suggests that employers in different regions may offer different pay rates to reflect local amenities and cost of living. Higher wages may be required to compensate for a less pleasant environment or a higher cost of living. If wages in a competing sector within an area are less flexible and therefore less competitive this may lead to an inability to employ staff. This paper considers the market for nursing staff in France where there is general regulation of wages and public hospitals compete for staff with the private hospital and non-hospital sectors. We consider two types of nursing staff, registered and assistant nurses and first establish the degree of spatial variation in the competitiveness of pay of nurses in public hospitals. We then consider whether these spatial variations are associated with variation in the employment of nursing staff. We find that despite regulation of pay in the public and private sector, there are substantial local variations in the competitiveness of nurses' pay. We find evidence that the spatial variations in the competitiveness of pay are associated with relative numbers of assistant nurses but not registered nurses. While we find the influence of the competitiveness of pay is small, it suggests that nonpay conditions may be an important factor in adjusting the labour market as might be expected in such a regulated market.


[Effect of short-term space flights on the activity of the renin-angiotensin-aldosterone system and on the blood concentration of cyclic nucleotides and prostaglandins].
After short-term flights renal excretion of aldosterone increased, thus suggesting its enhanced production and metabolism. An adequate increase of aldosterone synthesis was accompanied by an increase of its concentration in blood. An inadequate activation of mineralocorticoids manifested as a lower concentration of blood aldosterone and a greater excretion of aldosterone in the urine. These differences in the mineralocorticoid activity were determined by the renin-angiotensin system whose activity was associated not only with fluid-electrolyte metabolism but also with changes in the concentration of cyclic nucleotides and prostaglandins that reflect the vascular tone and sympatho-adrenal activity. An increased activity of the renin-angiotensin system seen in most cosmonauts at an acute stage of readaptation was correlated with a higher concentration of cAMP and a lower concentration of depressor prostaglandins. The activity of the renin-angiotensin system declined in parallel with the decrease of the blood content of cAMP.


Asian Americans: an increasing reality in the population and the dental profession.
Asian Americans are one of the fastest growing minorities in the United States. The use of services by this diverse population can and is affected by a host of demographic, cultural and language factors. But little to no data on the oral conditions of this minority group are available.


CSRP2 suppresses colorectal cancer progression via p130Cas/Rac1 axis-meditated ERK, PAK, and HIPPO signaling pathways.
Metastasis is a major cause of death in patients with colorectal cancer (CRC). Cysteine-rich protein 2 (CSRP2) has been recently implicated in the progression and metastasis of a variety of cancers. However, the biological functions and underlying mechanisms of CSRP2 in the regulation of CRC progression are largely unknown. Methods: Immunohistochemistry, quantitative real-time polymerase chain reaction (qPCR) and Western blotting (WB) were used to detect the expression of CSRP2 in CRC tissues and paracancerous tissues. CSRP2 function in CRC was determined by a series of functional tests in vivo and in vitro. WB and immunofluorescence were used to determine the relation between CSRP2 and epithelial-mesenchymal transition (EMT). Co-immunoprecipitation and scanning electron microscopy were used to study the molecular mechanism of CSRP2 in CRC. Results: The CSRP2 expression level in CRC tissues was lower than in adjacent normal tissues and indicated poor prognosis in CRC patients. Functionally, CSRP2 could suppress the proliferation, migration, and invasion of CRC cells in vitro and inhibit CRC tumorigenesis and metastasis in vivo. Mechanistic investigations revealed a physical interaction between CSRP2 and p130Cas. CSRP2 could inhibit the activation of Rac1 by preventing the phosphorylation of p130Cas, thus activating the Hippo signaling pathway, and simultaneously inhibiting the ERK and PAK/LIMK/cortactin signaling pathways, thereby inhibiting the EMT and metastasis of CRC. Rescue experiments showed that blocking the p130Cas and Rac1 activation could inhibit EMT induced by CSRP2 silencing. Conclusion: Our results suggest that the CSRP2/p130Cas/Rac1 axis can inhibit CRC aggressiveness and metastasis through the Hippo, ERK, and PAK signaling pathways. Therefore, CSRP2 may be a potential therapeutic target for CRC.


Development of TIMP1 magnetic nanoformulation for regulation of synaptic plasticity in HIV-1 infection.
Although the introduction of antiretroviral therapy has reduced the prevalence of severe forms of neurocognitive disorders, human immunodeficiency virus (HIV)-1-associated neurocognitive disorders were observed in 50% of HIV-infected patients globally. The blood-brain barrier is known to be impermeable to most of antiretroviral drugs. Successful delivery of antiretroviral drugs into the brain may induce an inflammatory response, which may further induce neurotoxicity. Therefore, alternate options to antiretroviral drugs for decreasing the HIV infection and neurotoxicity may help in reducing neurocognitive impairments observed in HIV-infected patients. In this study, we explored the role of magnetic nanoparticle (MNP)-bound tissue inhibitor of metalloproteinase-1 (TIMP1) protein in reducing HIV infection levels, oxidative stress, and recovering spine density in HIV-infected SK-N-MC neuroblastoma cells. We did not observe any neuronal cytotoxicity with either the free TIMP1 or MNP-bound TIMP1 used in our study. We observed significantly reduced HIV infection in both solution phase and in MNP-bound TIMP1-exposed neuronal cells. Furthermore, we also observed significantly reduced reactive oxygen species production in both the test groups compared to the neuronal cells infected with HIV alone. To observe the effect of both soluble-phase TIMP1 and MNP-bound TIMP1 on spine density in HIV-infected neuronal cells, confocal microscopy was used. We observed significant recovery of spine density in both the test groups when compared to the cells infected with HIV alone, indicting the neuroprotective effect of TIMP1. Therefore, our results suggest that the MNP-bound TIMP1 delivery method across the blood-brain barrier can be used for reducing HIV infectivity in brain tissue and neuronal toxicity in HIV-infected patients.