Localization of substance P- and enkephalin-like immunoreactivity in relation to catecholamine-containing cell bodies in the cat dorsolateral pontine tegmentum: an immunofluorescence study.
The distribution of tyrosine hydroxylase-, substance P- and enkephalin-immunoreactive neurons in the cat dorsolateral pons was studied using the indirect immunofluorescence method of Coons. To allow for the visualization of substance P- and enkephalin-immunoreactive cell bodies, colchicine was injected either in the ventricular space or in the cerebral tissue. The distribution of the tyrosine hydroxylase-immunoreactive cell bodies corresponded with the well-known distribution of catecholamine cells in this area of the brain. The observation of adjacent sections treated separately with tyrosine hydroxylase- and enkephalin-antiserum revealed that most catecholaminergic cells contain enkephalin-immunoreactivity. In addition to this catecholamine-enkephalin cell population, a moderate number of substance P-immunoreactive cell bodies was found in dorsolateral pons. The peribrachial nuclei were found to be densely supplied with substance P- and enkephalin-immunoreactive fibers, whereas the medial subdivisions, which contain the majority of the catecholamine cells in the dorsolateral pons, display a moderate number of immunoreactive fibers. These results are suggestive of interactions between peptide-containing and catecholaminergic neurons and also between-peptide-containing and non-catecholamine-containing neurons in the cat dorsolateral pons.


Effective screening methods to prevent surgical site infections in orthopedic surgery: an observational study.
The bacterial source of surgical-site infections (SSIs) can have either endogenous and/or exogenous origins, and some studies have revealed that endogenous transmission is an important pathway for SSIs in orthopedic surgery. However, since the frequency of SSIs is low (0.5-4.7%), screening all surgery patients is labor-intensive and cost-prohibitive. The goal of this study was to better understand how to improve the efficacy of nasal culture screening in preventing SSIs. Nasal cultures for 1616 operative patients over a 3-year period were evaluated for the presence of nasal bacterial microbiota and the species identity. We also investigated the medical factors that influence colonization and evaluated the ratio of agreement between nasal cultures and SSI-causing bacteria. In a survey of 1616 surgical cases, 1395 (86%) were normal microbiota (NM), 190 (12%) were MSSA carriers, and 31 (2%) were MRSA carriers. The risk factors for MRSA carriers were significantly higher than the NM group in patients with a history of hospitalization (13 [41.9%], p = 0.015), patients who had been admitted to a nursing facility (4 [12.9%], p = 0.005), and patients who were > 75 years of age (19 [61.3%], p = 0.021). The incidence of SSIs was significantly higher in the MSSA group (17/190 [8.4%]) than the NM group (10/1395 [0.7%], p = 0.00). The incidence of SSIs in the MRSA group (1/31 [3.2%]) tended to be higher than that in the NM group, but there was no statistically significant difference (p = 0.114). The concordance rate between causative bacteria of SSI and species present in nasal cultures was 53% (13/25 cases). The results of our study suggest screening patients with a history of past hospitalization, a history of admission in a long-term care facility, and older than 75 to reduce SSIs. This study was approved by the institutional review board of the authors' affiliated institutions (the ethics committee of Sanmu Medical Center, 2016-02).


The role of work-related and personal factors in diabetes self-management.
The aim of this study was to investigate how factors in the workplace and personal factors are related to the frequency with which people with diabetes perform self-management activities and the degree to which they do or do not experience the performing of self-management activities as a burden. Two hundred and ninety-two employees with insulin-treated diabetes completed questionnaires on socio-demographic and illness-related background variables, work experience, diabetes self-efficacy, social support outside of work, coping styles and self-management activities. The results indicate that employees who reported a high workload were more likely to perceive injecting insulin as a burden. The level of social support was positively related to the frequency of dietary self-management in type 2 diabetes and negatively related to the sense of being burdened by dietary self-management in type 1 diabetes. With respect to personal factors, we found that a diabetes avoidance coping style was associated particularly with infrequent blood glucose monitoring and a high sense of being burdened by blood glucose monitoring. Individuals with a low level of self-efficacy were more likely to perceive all types of self-management activities as a burden. These results may guide health professionals when counseling individuals with diabetes.


Long-term changes of synaptic transmission induced by arachidonic acid in the CA1 subfield of the rat hippocampus.
The effects induced by arachidonic acid upon excitatory synaptic transmission were investigated in the CA1 subfield of rat hippocampal slices. Perfusion with medium containing 50 microM of arachidonic acid induced in 12 of 19 experiments a long-lasting potentiation of the stratum radiatum-induced responses recorded in the cell body and in the apical dendritic layers. In 5 of 19 experiments, arachidonic acid evoked a depression of the same responses. Both effects were antagonized by nordihydroguaiaretic acid which is an inhibitor of lipoxygenase enzymes. These results demonstrate that one or more than one of the arachidonic acid metabolites of the lipoxygenase pathways might be involved in the long-term modulation of synaptic transmission in the hippocampus.


Pigmentary traits, sun exposure, and risk of non-Hodgkin's lymphoma/chronic lymphocytic leukemia: A study within the French E3N prospective cohort.
To investigate whether risk factors for keratinocyte carcinomas (KCs), namely pigmentary traits and sun exposure, are associated with risk of non-Hodgkin's lymphomas (NHL) and chronic lymphocytic leukemia (CLL). E3N is a prospective cohort of French women aged 40-65 years at inclusion in 1990. Cancer data were collected at baseline and updated every 2-3 years. Hazard Ratios (HRs) and 95% confidence intervals (CIs) for associations between pigmentary traits and sun exposure, and risk of CLL/NHL were estimated using Cox models. With a median follow-up of 24 years, 622 incident cases of CLL/NHL were ascertained among the 92,097 included women. The presence of nevi was associated with CLL/NHL risk: HR for "many or very many nevi" relative to "no nevi": 1.56 [1.15; 2.11]. Such association with number of nevi appears to be mostly limited to risk of CLL: HR for "many or very many nevi": 3.00 [1.38; 6.52]; versus 1.32 [0.94; 1.84] for NHL. Women whose skin was highly sensitive to sunburn also had a higher risk of CLL: HR = 1.96 [1.21; 3.18], while no increase in risk of NHL was observed. Skin or hair color, number of freckles, and average daily ultraviolet (UV) dose during spring and summer in location of residence at birth or at inclusion (kJ/m2 ) were not associated with CLL/NHL risk. Some pigmentary traits (presence of nevi and skin sensitivity), but not sun exposure, were associated with CLL/NHL. These observations suggest that CLL may share some constitutional risk factors with keratinocyte cancers.


Exploring causes and consequences of early discontinuation of durvalumab after chemoradiotherapy for non-small cell lung cancer.
For most locally advanced non-small cell lung cancer (LA-NSCLC) patients who complete definitive chemoradiotherapy (CRT) and do not experience disease progression, one year of adjuvant durvalumab is recommended. Here, we explore causes and consequences of early durvalumab discontinuation. We reviewed patients treated for LA-NSCLC with definitive CRT who began adjuvant durvalumab between 2017 and 2021. Duration of durvalumab receipt and causes for early discontinuation were tabulated. Logistic regression models were utilized to evaluate predictors of early durvalumab discontinuation. Landmark analyses were performed to explore associations between early durvalumab discontinuation and clinical outcomes (progression-free survival (PFS), overall survival (OS)). Fifty-nine patients were included. Forty-one patients (69%) discontinued durvalumab early, most commonly for disease progression (n = 14) or lung toxicity (n = 10). Multivariable analysis revealed mean heart radiotherapy dose (MHD) was associated with risk of durvalumab discontinuation from progression (HR = 2.34 per 10 Gy, p = 0.052), and there was a trend suggesting an association between MHD and risk of durvalumab discontinuation from lung toxicity (HR = 2.16 per 10 Gy, p = 0.126). Median PFS duration following durvalumab initiation was 14 months, and median OS duration was 32 months. Landmark analyses that excluded patients with progression or death within one year of durvalumab initiation demonstrated improved outcomes for patients who completed one year of durvalumab (2-year PFS 100% v. 40%, p < 0.001; 2-year OS 100% v. 67%, p = 0.862). Improved outcomes were observed for patients who received MHD below the cohort median (9.3 Gy) compared to patients with higher MHD (median PFS 32 months v. 8 months, p < 0.001; 2-year OS 69% v. 44%, p = 0.088). For LA-NSCLC patients treated with CRT followed by immunotherapy, extent of cardiac irradiation may be a risk factor for immunotherapy discontinuation, disease recurrence, and death.


Modifications of an immunodominant peptide antigen induce different anti-polyoma tumor responses in two separate mouse strains.
An immunodominant polyoma peptide antigen MT162-176 was modified with regard to amino acid (aa) composition in an attempt to analyze its immunogenicity in detail. Twelve modifications of peptide MT162-176, 3 overlapping peptides and 9 peptides with point mutations, were synthesized and used for immunizations of (A.CA x C57BL/6)F1 and CBA mice against the syngeneic polyoma tumors SECA and SEBA. All 3 overlapping peptides MT162-176, MT165-174 and MT170-176, were immunogenic in (A.CA x C57BL/6)F1 mice against SECA, indicating that possibly more than one immunogenic epitope may be recognized within the MT162-176 sequence. In CBA mice, the 2 peptides covering the C-terminal half were immunogenic against SEBA, while the N-terminal peptide was possibly somewhat less efficient. The peptides with aa point mutations induced different anti-tumor responses in the 2 mouse strains. In CBA mice, only one mutant, MT162-176.28, was immunogenic. For (A.CA x C57BI)F1 3 different mutants, MT162-176.29, MT162-176.35 and MT162-176.36 were immunogenic against SECA, while the remaining 6 had lost their activity. These results suggest that a different emphasis of recognition of peptide MT162-176 exists with regard to the 2 mouse strains examined. Furthermore, different immunization procedures were tested. We found that repeated immunizations with peptide without Freund's adjuvant was the most efficient.


Molecular characterization of echovirus 30 isolates from Poland, 1995-2015.
Echovirus 30 (E30) is one of the most frequently identified enterovirus and a major cause of meningitis in children and adults. To investigate the genetic variability and relationship of E30 isolated from specimens of aseptic meningitis cases that occurred in Poland over a period of 20 years, sequences of VP1 gene were determined and genetic analysis was performed. From 1995 to 2015, 124 E30 were isolated using RD cells, and 58 isolates were sequenced and characterized by phylogenetic analysis of partial VP1 region (793 nt). In general, nucleotide sequence divergence in pairwise comparisons among Polish E30 isolates ranged from 0.0 to 15.0 %. The phylogenetic analysis revealed that E30 circulating in Poland since 1995 belong to two unique groups: Group I, characterized by high divergence (up to 13.1 %), segregated in four subgroups, and showed strong temporal circulation of E30. Group II, detected in Poland in 2013-2014, was closely correlated with two meningitis outbreaks and formed a separate genetically homogeneous group. Phylogenetic analysis revealed that strains from Poland had the closest genetic relationship with not only the isolates previously identified in Europe (Belarus, France, Germany, Italy, Russia) but also those in other parts of the world (Australia, China). Sequences of outbreak isolates were grouped in group II together with those from Russia and China isolated during 2010-2013. The identification of five distinct viral lineages during 1995-2015 confirmed the high E30 genetic diversity which may be an essential precondition for the emergence of new strains responsible for further potential aseptic meningitis outbreaks.


Cancer of the urinary bladder and pyelonephritis.
Successful treatment of cancer of the urinary bladder consists not only in elimination of the tumour process, but also in prophylaxis of various complications. Among complications caused by the tumour process as well as by the applied methods of its therapy a certain place belongs to pyelonephritis. Pyelonephritis develops in consequence of the disturbance of the function of the urinary bladder after hemicystectomy resulting from the change of the bladder's form. With the view of preserving the anatomo-physiological function of the urinary bladder and preventing complications the author suggests a method of reconstruction of the bladder consisting in shaping it in a spherical form after hemicystectomy. Such shape of the urinary bladder ensures nearly normal conditions for both urination act and urinary flow from the upper urinary pathways, this being the prophylaxis of pyelonephritis.


Extravesical ureteroneocystostomy in renal transplantation.
From October 1970 to January 1986, 808 patients underwent renal transplant ureteroneocystostomy by an extravesical technique. Complications related to the anastomosis and/or ureter were reviewed. There were 23 total complications, for an over-all urological complication rate of 2.8 per cent. Of these complications 17 were related to the ureteroneocystostomy, for an anastomotic complication rate of 2.1 per cent. Complications were almost universally repaired by another operation. Two patients died and 1 lost the allograft because of urological complications.


A bacterial one-hybrid system for determining the DNA-binding specificity of transcription factors.
The DNA-binding specificities of transcription factors can be used to computationally predict cis-regulatory modules (CRMs) that regulate gene expression. However, the absence of specificity data for the majority of transcription factors limits the widespread implementation of this approach. We have developed a bacterial one-hybrid system that provides a simple and rapid method to determine the DNA-binding specificity of a transcription factor. Using this technology, we successfully determined the DNA-binding specificity of seven previously characterized transcription factors and one novel transcription factor, the Drosophila melanogaster factor Odd-skipped. Regulatory targets of Odd-skipped were successfully predicted using this information, demonstrating that the data produced by the bacterial one-hybrid system are relevant to in vivo function.


Unplanned 30-day readmission, comorbidity, and impact on mortality after incident atrial fibrillation hospitalization in Western Australia, 2001-2015.
The healthcare burden of atrial fibrillation (AF) is dominated by hospitalizations, but data on 30-day unplanned readmissions after AF hospitalization and impact on mortality are limited. To assess causes and trends of 30-day unplanned readmission in incident (first-ever) hospitalized AF patients, and the risk of readmission for subsequent all-cause mortality. Patients aged 25-94 years, with an incident AF hospitalization (principal diagnosis) between 2001 and 2015, and surviving 30 days post discharge, were identified from linked Western Australian hospitalization and mortality data. Unplanned 30-day readmissions were categorized by principal diagnosis. Multivariable logistic and Cox regression analyses determined the independent predictors of readmission and the hazard ratio (HR) with 95% confidence intervals (CI) of readmission for subsequent 1-year mortality. Of 22,814 patients, 57.7% male, mean age 67.8 ± 13.8 (standard deviation) years, 9.5% experienced 1 or more 30-day unplanned readmissions, with standardized rates increasing 2.0% annually (95% CI, 1.0%-3.1%). Among all readmissions, 64.8% were cardiovascular-related, with AF (31.7%), coronary events (12.2%), and heart failure (8.5%) being the most frequent. In 30-day survivors, 4.3% died within 1 year. Patients with any cardiovascular or noncardiovascular readmission (vs none) had a multivariable-adjusted mortality HR of 2.12 (95% CI, 1.82-2.45). Coexistent comorbidities were independently associated with 30-day unplanned readmission and 1-year mortality. Following incident AF hospitalization, 30-day unplanned readmissions were common, mostly cardiovascular-related, but any readmission, regardless of cause, was associated with a 2-fold higher adjusted mortality risk. Our findings also support the importance of comorbidity optimization within an integrated care pathway to reduce adverse outcomes in AF patients.


Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists.
Modification of a phenolic lead structure based on lessons learned from increasing the potency of steroidal glucocorticoid agonists lead to the discovery of exceptionally potent, nonsteroidal, indazole GR agonists. SAR was developed to achieve good selectivity against other nuclear hormone receptors with the ultimate goal of achieving a dissociated GR agonist as measured by human in vitro assays. The specific interactions by which this class of compounds inhibits GR was elucidated by solving an X-ray co-crystal structure.


Improved surgical safety after laparoscopic compared to open surgery for apparent early stage endometrial cancer: results from a randomised controlled trial.
To compare Total Laparoscopic Hysterectomy (TLH) and Total Abdominal Hysterectomy (TAH) with regard to surgical safety. Between October 2005 and June 2010, 760 patients with apparent early stage endometrial cancer were enroled in a multicentre, randomised clinical trial (LACE) comparing outcomes following TLH or TAH. The main study end points for this analysis were surgical adverse events (AE), hospital length of stay, conversion from laparoscopy to laparotomy, including 753 patients who completed at least 6 weeks of follow-up. Postoperative AEs were graded according to Common Toxicity Criteria (V3), and those immediately life-threatening, requiring inpatient hospitalisation or prolonged hospitalisation, or resulting in persistent or significant disability/incapacity were regarded as serious AEs. The incidence of intra-operative AEs was comparable in either group. The incidence of post-operative AE CTC grade 3+ (18.6% in TAH, 12.9% in TLH, p 0.03) and serious AE (14.3% in TAH, 8.2% in TLH, p 0.007) was significantly higher in the TAH group compared to the TLH group. Mean operating time was 132 and 107 min, and median length of hospital stay was 2 and 5 days in the TLH and TAH group, respectively (p<0.0001). The decline of haemoglobin from baseline to day 1 postoperatively was 2g/L less in the TLH group (p 0.006). Compared to TAH, TLH is associated with a significantly decreased risk of major surgical AEs. A laparoscopic surgical approach to early stage endometrial cancer is safe.


Qualitative and quantitative risk assessment for human salmonellosis due to multi-resistant Salmonella Typhimurium DT104 from consumption of Danish dry-cured pork sausages.
Salmonella Typhimurium DT104 (DT104) is unwanted in products for human consumption due to its antibiotic resistance and ability to cause disease. We intended to set up an improved monitoring and management program to aid in deciding when to use pork contaminated with DT104 for production of sausages without jeopardizing consumer safety. We started by carrying out two assessments of the risk for human health associated with consumption of sausages produced by: (1) Danish pork from average slaughter days; (2) imported pork (IMP) with average prevalence of DT104. The assessments showed that, if Salmonella is present, it is usually in lower numbers (< or =50 per 400 cm(2) surface). Additionally, during processing, the numbers will be reduced by at least 2 log-units. In Danish (DK) pork, DT104 constitutes 0.2-1.0% of the Salmonella isolates reported, while in imported pork (IMP), 18%. We estimated that out of one million, 25 g servings of DK dry-cured sausages, up to two DT104 bacteria could be found in each of 245 servings. Out of one million servings of 25 g IMP dry-cured sausages, up to two DT104 bacteria would occur in each of 19,260 servings.


Parietal wound drainage in abdominal surgery.
A prospective randomized study of wound drainage in 250 surgical abdominal wounds was undertaken to determine (a) what effect wound drains had on clean surgical wounds; (b) whether wound drains reduced infection in potentially contaminated wounds; (c) whether wound drainage was an acceptable alternative to the use of topical antibiotics in frankly contaminated wounds. Ten per cent of clean wounds which had been drained became infected, compared with 2 per cent of control wounds in the same group (P less than 0.002). Infection was also more common in potentially and frankly contaminated wounds in the presence of a drain. Skin organisms were grown from 8 drained and 2 nondrained wounds in this group (P less than 0.005), suggesting contamination by the drains. Drains were, however, associated with a lower infection rate in 23 obese patients with frankly contaminated wounds.


Factors associated with psychosocial problems in Korean nursing and non-nursing students during the COVID-19 pandemic.
The coronavirus disease 2019 (COVID-19) pandemic has changed our lives in many ways, including school closures and social distancing practices. These abrupt life changes may have led to psychosocial problems in college students. This study aimed to identify the factors associated with psychosocial problems in South Korean nursing and non-nursing students. This descriptive cross-sectional survey was conducted with 139 nursing and 147 non-nursing students (N = 286) between August 6 and October 30, 2020. We investigated participants' general characteristics (that is, sociodemographic and health-promoting behaviors), sensitivity to COVID-19 infection, COVID-19 pandemic response indicators, and psychosocial problems. The factors associated with psychosocial problems were determined using multiple regression analysis. Among the COVID-19 pandemic response indicators, perceived health status during the COVID-19 pandemic was verified as a factor associated with psychosocial problems in nursing (β = - 5.831, p < .001) and non-nursing students (β = - 8.513, p < .001). Perceived stress (β = 1.263, p = .045), trust in policy (β = .892, p < .001), and religion (β = - 1.424, p = .004) were verified as correlates of psychosocial problems in non-nursing students. As the COVID-19 pandemic continues, the stakeholders can use our study results to identify students experiencing psychosocial problems and subsequently as a theoretical background for developing intervention programs for those at a high risk of psychosocial problems. Additionally, it can be used as primary data for future research and practice regarding COVID-19 guidelines among students.


A Longitudinal Epigenetic Aging and Leukocyte Analysis of Simulated Space Travel: The Mars-500 Mission.
Astronauts undertaking long-duration space missions may be vulnerable to unique stressors that can impact human aging. Nevertheless, few studies have examined the relationship of mission duration with DNA-methylation-based biomarkers of aging in astronauts. Using data from the six participants of the Mars-500 mission, a high-fidelity 520-day ground simulation experiment, we tested relationships of mission duration with five longitudinally measured blood DNA-methylation-based metrics: DNAmGrimAge, DNAmPhenoAge, DNA-methylation-based estimator of telomere length (DNAmTL), mitotic divisions (epigenetic mitotic clock [epiTOC2]), and pace of aging (PoA). We provide evidence that, relative to baseline, mission duration was associated with significant decreases in epigenetic aging. However, only decreases in DNAmPhenoAge remained significant 7 days post-mission. We also observed significant changes in estimated proportions of plasmablasts, CD4T, CD8 naive, and natural killer (NK) cells. Only decreases in NK cells remained significant post-mission. If confirmed more broadly, these findings contribute insights to improve the understanding of the biological aging implications for individuals experiencing long-duration space travel.


An unusual appearance of a left adrenal mass on computed tomography.
A case of carcinoma of the left adrenal gland in which computed tomography (CT) demonstrated posterior displacement of the splenic vessels and tail of the pancreas is reported.


Soil carbon dynamics in cropland and rangeland.
Most soils in the Midwestern USA have lost 30 to 50% of their original pool, or 25 to 40 Mg C/ha, upon conversion from natural to agricultural ecosystems. About 60 to 70% of the C thus depleted can be resequestered through adoption of recommended soil and crop management practices. These practices include conversion from plow till to no till, frequent use of winter cover crops in the rotation cycle, elimination of summer fallow, integrated nutrient management along with liberal use of biosolids and biological nitrogen fixation, precision farming to minimize losses and enhance fertilizer use efficiency, and use of improved varieties with ability to produce large root biomass with high content of lignin and suberin. The gross rate of soil organic carbon (SOC) sequestration ranges from 500 to 800 kg/ha/year in cold and humid regions and 100 to 300 kg/ha/year in dry and warm regions. The rate of SOC sequestration can be measured with procedures that are cost effective and credible at soil pedon level, landscape level, regional or national scale. In addition to SOC, there is also a large potential to sequester soil inorganic carbon (SIC) in arid and semi-arid regions. Soil C sequestration has numerous ancillary benefits. It is truly a win-win situation: extremely cost-effective, and a bridge to the future until alternative energy options take effect.


National Trends in the Management of Lower Urinary Tract Symptoms Associated with Benign Prostatic Hyperplasia.
To gain an understanding of current practices in the management of lower urinary tract symptoms (LUTSs) in the setting of benign prostatic hyperplasia (BPH). Including both medication therapy and emerging minimally invasive options including peri-procedure considerations, expected outcomes, and value-based considerations. Medical therapy, primarily alpha blockers (ABs), and 5 alpha reductase inhibitors (5-ARI) remain the most commonly utilized intervention for LUTS associated with BPH. Several minimally invasive surgical treatments (MISTs) have emerged to provide efficacious and durable results, while largely sparing men from the sexual adverse effects of more invasive surgical options. The introduction of value-based health care has led to more cost-conscious medical care and is poised to influence the landscape of LUTS associated with BPH treatment. As the population-based and societal needs continue to influence medical care for men with LUTS associated with BPH, a paradigm shift in management is expected.


Secondary prevention of cervical cancer.
Cervical cancer affects women in their reproductive ages. Screening is an important secondary prevention strategy. The long process of carcinogenic transformation from human papillomavirus (HPV) infection to invasive cancer provides ample opportunities to detect the disease at a stage when treatment is highly effective. Suitable screening tests are cytology, visual inspection after acetic acid application and HPV detection tests. Evidence of effectiveness of the tests to reduce cervical cancer mortality and the cost-effectiveness of screening programs have been demonstrated. Cervical intraepithelial neoplasia grade 2 and grade 3 are the high-grade cervical cancer precursors and need to be treated. Treatment is safe and effective with ablative or excisional techniques. The World Health Organization recommends screening women at least once in a lifetime between 30 and 49 years of age and ensuring effective treatment of the detected abnormalities. Combination of HPV vaccination and population-based screening will be instrumental in eliminating cervical cancer.


[Intraclonal and interclonal differences of ploidy in transplantable rat rhabdomyosarcoma RA-2 detected using DNA flow cytometry].
DNA contents were determined using flow cytometry in cells of 71 clones of the rat transplantable rhabdomyosarcoma passed through more than 70 cycles of selection for increased malignancy. 58 clones (82%) consisted of cells with diploid DNA content, whereas 13 clones (18%) displayed not only diploid, but also near tetraploid cell subpopulations, the latter covering from 20 to 60% of the total number of cells measured. The data obtained show the existence of intra- and interclonal karyotypic heterogeneity in populations of tumor clonogenic cells.


Systematic Analysis of Survival-Associated Alternative Splicing Signatures in Gastrointestinal Pan-Adenocarcinomas.
Gastrointestinal pan-adenocarcinomas, which mainly include adenocarcinomas of the esophagus, stomach, colon, and rectum, place a heavy burden on society owing to their poor prognoses. Since aberrant alternative splicing (AS) are starting to be considered as efficacious signatures for tumor prognosis predicting and therapeutic targets, systematic analysis of AS events is urgent. Prognosis-related AS events were selected by using univariate COX regression analysis. Gene functional enrichment analysis revealed the pathways enriched by prognosis-related AS. Then, prognostic signatures based on AS events were developed for prognosis prediction. Potential mechanism to regulate splicing events by splicing factors was analyzed via Pearson correlation and regulatory networks were constructed. A total of 967, 918, 674, and 406 AS events were identified as prognosis-related AS events in esophagus, stomach, colon, and rectum adenocarcinomas, respectively. Survival-associated AS events were distinguishing in the four subtypes of adenocarcinoma. Furthermore, computational algorithm results indicated that perturbation of ribosome and ubiquitin-mediated proteolysis pathways were the potential molecular mechanisms corresponding to inferior prognoses. Most notably, several prognostic signatures based on AS events displayed moderate performance in prognosis predicting. The area under curve values of the time-dependent receiver operating characteristic were 0.961, 0.871, 0.870, and 0.890 in esophagus, stomach, colon, and rectum adenocarcinomas. Survival-associated splicing factors were submitted to construct the AS regulatory network, which could be an underlying mechanism of AS events. AS may could be ideal indiactors in the prognosis of gastrointestinal pan-adenocarcinomas. Exploring interesting splicing regulatory networks is conducive to solve the puzzles of AS.


Reaction mode between Si and Fe and evaluation of optimal species in poly-silicic-ferric coagulant.
A kind of Fe-polysilicate polymer, poly-silicic-ferric (PSF) coagulant was prepared by co-polymerization (hydroxylation of mixture of Fe3+ and fresh polysilicic acid (PS)), in which PSF0.5, PSF1 or PSF3 denotes Si/Fe molar ratio of 0.5, 1 or 3, respectively. The effects of Si/Fe ratio and reaction time (co-polymerization time or aging time) on the reaction mode between Si and Fe were studies, and the optimal species of PSF was evaluated by pH change during the preparation of PSF and coagulation tests. The results showed that the characteristics of PSF are largely affected by both reaction time and Si/Fe ratio. PSF is found to be a essential complex of Si, Fe, and many other ions. The reaction mode between Si and Fe differs with various Si/Fe ratios. The pH of PSF0.5, PSF1 or PSF3 tended to be stable when reaction time is 10, 25 or 55 min, respectively, which is almost consistent with the time reaching the relative stable morphology that is just the optimal species of higher coagulation efficiency. The optimal reaction time reaching optimal species can be evaluated by measuring the pH change during the polymerization process.


Calsequestrin. Structure, function, and evolution.
Calsequestrin is the major Ca2+ binding protein in the sarcoplasmic reticulum (SR), serves as the main Ca2+ storage and buffering protein and is an important regulator of Ca2+ release channels in both skeletal and cardiac muscle. It is anchored at the junctional SR membrane through interactions with membrane proteins and undergoes reversible polymerization with increasing Ca2+ concentration. Calsequestrin provides high local Ca2+ at the junctional SR and communicates changes in luminal Ca2+ concentration to Ca2+ release channels, thus it is an essential component of excitation-contraction coupling. Recent studies reveal new insights on calsequestrin trafficking, Ca2+ binding, protein evolution, protein-protein interactions, stress responses and the molecular basis of related human muscle disease, including catecholaminergic polymorphic ventricular tachycardia (CPVT). Here we provide a comprehensive overview of calsequestrin, with recent advances in structure, diverse functions, phylogenetic analysis, and its role in muscle physiology, stress responses and human pathology.


Reorganization of the nuclear envelope during open mitosis.
The nuclear envelope (NE) provides a selective barrier between the nuclear interior and the cytoplasm and constitutes a central component of intracellular architecture. During mitosis in metazoa, the NE breaks down leading to the complete mixing of the nuclear content with the cytosol. Interestingly, many NE components actively participate in mitotic progression. After chromosome segregation, the NE is reassembled around decondensing chromatin and the nuclear compartment is reestablished in the daughter cells. Here, we summarize recent progress in deciphering the molecular mechanisms underlying NE dynamics during cell division.


Persistent pain and depression: a biopsychosocial perspective.
This review highlights recent research findings on the relationship between persistent pain and depression and discusses the implications of these findings for future research in persons who suffer from both pain and depression. First, we briefly discuss advances in theories of pain that underscore the important role that depression can play in the chronic pain experience. Second, we discuss depression in persons suffering from chronic pain from a biopsychosocial perspective that takes into account both biological and psychosocial mechanisms linking pain and depression. Third, we address biomedical, psychosocial, and combined medical-psychosocial approaches to treatment in persons with persistent pain and depression. We conclude by highlighting future directions for research related to screening and diagnosis of depression in persons having persistent pain, treatment of comorbid pain and depression, and individual and subgroup differences in the experience of persistent pain and depression.


Neonatal appendicitis: ischemic infarction in incarcerated inguinal hernia.
A premature 12-day-old infant with ischemic infarction of the appendix due to hernial incarceration is presented. Literature review (1901-1975) of 106 cases of acute appendicitis in the first 30 days of life permitted tabulation of some clinical aspects in 94 cases. Overt manifestations mandating surgical intervention and isolation of the inflammatory process in the inguinoscrotal region are important factors responsible for the significantly better prognosis for neonatal hernial versus intraabdominal appendicitis.


Screening to prevent polyoma virus nephropathy: a medical decision analysis.
Polyomavirus nephropathy (PVN) is an emerging medical dilemma in kidney transplantation. Methods to screen before clinical disease are available and early immunosuppression reduction may change the natural history of progression. However, the consequences of an increase in rejection may limit the benefits. In a simulation model a 'screen' versus 'no-screen' strategy was compared. Baseline PVN cumulative incidence was assumed to be 4%. Patients with PVN were modeled to have 4-fold higher risk of graft loss. In the screen strategy, patients positive for blood DNA PCR had their immunosuppression reduced. This pre-emptive change was modeled to reduce progression to overt PVN by 80%. Therapy reduction was associated with a 10% risk of precipitating acute rejection and greater risk of chronic allograft loss. In the baseline case, screening saved 1912 dollars (discounted) and produced 0.020 more quality adjusted life years (QALYs) than not screening. Screening resulted in decreased net QALYs if the false positive viremia rate was >9.5% and the PVN incidence was <2.1%. Much of the cost savings of screening relate to savings from immunosuppression reduction in the screened arm. Screening may well be cost-effective if not cost saving in centers with high PVN rates. There remain significant areas of uncertainty.


Pharmacokinetic-pharmacodynamic modeling of the hydroxy lerisetron metabolite L6-OH in rats: an integrated parent-metabolite model.
The twofold aim of this study was to characterize in vivo in rats the pharmacokinetics (PK) and pharmacodynamics (PD) of L6-OH, a metabolite of lerisetron with in vitro pharmacological activity, and evaluate the extent to which L6-OH contributes to the overall effect. The PK of L6-OH was determined directly postmetabolite i.v. dose (PK-1), and also simultaneously for L (lerisetron concentration) and for generated L6-OH after lerisetron dose (200 microg kg(-1), i.v.), using Nonlinear Mixed Effects Modeling with an integrated parent-metabolite PK model (PK-2). Surrogate effect was measured by inhibition of serotonin-induced bradycardia. Protein binding was assayed via ultrafiltration and all quantification was performed via liquid chromatography-electrospray ionization-mass spectrometry. L6-OH showed elevated plasma and renal clearances, and volume of distribution (PK-1). The in vivo potency (PD) of L6-OH was high (EC(50) = 0.098 ng mL(-1) and EC(50unbound) = 0.040 ng mL(-1)). Total clearance for L (PK-2) in the presence of generated L6-OH (CL(L) = CL(-->L6-OH) + CL(n)) was 0.0139 L min(-1). Most of this clearance was L6-OH formation (F(c) = 99.6%), but only an 8.6% fraction of L6-OH was released into the bloodstream. The remainder undergoes biliar and fecal elimination. The parameters estimated from PK-2 were used to predict concentrations of L6-OH (Cp(L6)) generated after a lerisetron therapeutic dose (10 microg kg(-1)) in the rat. These concentrations are needed for the PD model and are below the quantification limit. Cp(L6max) was less than the EC(50) of L6-OH. We conclude that after lerisetron administration, L6-OH is extensively formed in the rat but it is quickly eliminated; therefore, besides being equipotent with the parent drug, the L6-OH metabolite does not influence the effect of lerisetron.


Cloning plants by seeds: Inheritance models and candidate genes to increase fundamental knowledge for engineering apomixis in sexual crops.
Apomixis is desirable in agriculture as a reproductive strategy for cloning plants by seeds. Because embryos derive from the parthenogenic development of apomeiotic egg cells, apomixis excludes fertilization in addition to meiotic segregation and recombination, resulting in offspring that are exact replicas of the parent. Introgression of apomixis from wild relatives to crop species and transformation of sexual genotypes into apomictically reproducing ones are long-held goals of plant breeding. In fact, it is generally accepted that the introduction of apomixis into agronomically important crops will have revolutionary implications for agriculture. This review deals with the current genetic and molecular findings that have been collected from model species to elucidate the mechanisms of apomeiosis, parthenogenesis and apomixis as a whole. Our goal is to critically determine whether biotechnology can combine key genes known to control the expression of the processes miming the main components of apomixis in plants. Two natural apomicts, as the eudicot Hypericum perforatum L. (St. John's wort) and the monocot Paspalum spp. (crowngrass), and the sexual model species Arabidopsis thaliana are ideally suited for such investigations at the genomic and biotechnological levels. Some novel views and original concepts have been faced on this review, including (i) the parallel between Y-chromosome and apomixis-bearing chromosome (e.g., comparative genomic analyses revealed common features as repression of recombination events, accumulation of transposable elements and degeneration of genes) from the most primitive (Hypericum-type) to the most advanced (Paspalum-type) in evolutionary terms, and (ii) the link between apomixis and gene-specific silencing mechanisms (i.e., likely based on chromatin remodelling factors), with merging lines of evidence regarding the role of auxin in cell fate specification of embryo sac and egg cell development in Arabidopsis. The production of engineered plants exhibiting apomictic-like phenotypes is critically reviewed and discussed.


[Maternal anxiety related to how the pediatrician provided prenatal information about preterm birth].
Women hospitalized for preterm labor require clear information about prematurity. This study assessed whether or not specific written information about prematurity delivered at admission to the unit combined with an oral explanation from a pediatrician would decrease women's anxiety compared to an oral explanation alone. This was a prospective, single-center observational study. Women were included in the high-risk pregnancies department and distributed into two groups: receiving "only oral" information for a prenatal clinical consultation with a senior pediatrician or receiving "combined" oral information+a booklet about prematurity given to the women at admission. The primary endpoint was the change in anxiety-state (before and after the information procedure) evaluated by the State Trait Anxiety Inventory-Y (STAI-Y). The anxiety score before receiving information did not differ between the two groups (STAI-Y-A "combined" group: 46.7±3.0 vs. "only oral" group: 42.7±2.74; P=0.55). After consultation with a pediatrician, the acute anxiety-state score STAI-Y-A decreased significantly in the "combined" group (-6.7±1.9) compared to the "only oral" group (-2.5±4.6; P<0.05). A booklet about prematurity combined with oral information from a pediatrician reduced patients' anxiety more than oral information alone. Given that the psychology of the mother interacts with the pregnancy, it is necessary to provide clear and adapted information. Giving a booklet appears to be one of the modalities to improve information. Other modalities such as video documents have to be studied.


Pericarditis due to Campylobacter coli infection: a case report.
Campylobacter spp. is a gram-negative bacillus that causes infectious enteritis and consists of several species, including Campylobacter jejuni, Campylobacter coli, and Campylobacter fetus. Although C. jejuni and C. coli cause infectious enteritis primarily in immunocompetent hosts, C. fetus causes extraintestinal infections such as septicemia, meningitis, and perinatal infections in immunocompromised hosts, as well as myopericarditis in rare cases. Only a few cases of infectious myo(peri)carditis associated with C. coli in immunocompetent hosts have been reported. These studies concentrated on antecedent C. coli enterocolitis and never demonstrated a positive culture in the pericardial fluid.A 72-year-old Japanese man presented with a 2-week fever, cough, and vomiting lasting. He was on hemodialysis for polycystic kidney disease, as well as medication for diabetes and hypertension. A chest computed tomography (CT) scan and a transthoracic echocardiogram revealed bilateral pleural fluid and large pericardial fluid at the time of admission. C. coli was identified from blood culture samples and blood-tinged pericardial fluid. He was successfully treated with antibacterial chemotherapy as well as pericardial fluid drainage and was discharged from the hospital with no complications.In this case, the presence of C. coli in the pericardial fluid confirmed the diagnosis of C. coli pericarditis. C. coli may cause septic pericarditis in immunocompromised hosts, despite typically causing only enteritis.


Enhanced antitumor activity of irofulven in combination with thiotepa or mitomycin C.
Irofulven (6-hydroxymethylacylfulvene, MGI 114, NSC 683863) is a semisynthetic derivative of illudin S, a toxin present in the Omphalotus mushroom. Irofulven has demonstrated activity against a broad range of solid tumors in both xenograft models and human trials. The potential application of administering irofulven in combination with aziridine-containing chemotherapeutic agents was evaluated in this study. Human lung carcinoma MV522 cells and BALB/c athymic mice bearing the human lung carcinoma MV522 xenograft were used to evaluate the activity of irofulven in combination with aziridine-containing drugs. Irofulven in combination with either thiotepa or mitomycin C demonstrated a strong synergistic (supraadditive) activity both in vitro and in vivo, that exceeded results obtained with monotherapy at the same or higher doses of these agents. The majority of xenograft-bearing animals that received subtoxic doses of irofulven, and either thiotepa or mitomycin C, demonstrated a complete cure. In contrast, there was no detectable synergistic activity between irofulven and other aziridine-containing drugs, including AZQ and thiotepa metabolites such as TEPA or AZD. These results indicate that the therapeutic activity of irofulven is enhanced when combined with mitomycin C or thiotepa, and further evaluation of these combinations is therefore warranted.


Luteinizing hormone stimulation of in vitro ovulation in brook trout (Salvelinus fontinalis) involves follicle contraction and activation of proteolytic genes.
Luteinizing hormone (LH) is an essential hormone for the stimulation of the ovulatory process in vertebrates. However, little is known in fish regarding the different mechanisms induced by LH during ovulation that facilitate the rupture of the follicle wall and the subsequent expulsion of the mature oocyte. In this study, the effects of salmon LH (sLH) on in vitro ovulation were investigated in brook trout (Salvelinus fontinalis) isolated follicles. sLH significantly stimulated in vitro ovulation and contraction of brook trout preovulatory follicles. In order to investigate the possible involvement of proteolytic events in the ovulatory action of LH, the expression of genes known to have a crucial role in the degradation of follicle wall structure was examined. Our results show that sLH clearly stimulated the mRNA expression levels of matrix metalloproteinases (MMPs; including mmp2 and mmp19) and other enzymes with proteolytic action during ovulation, such as a disintegrin and metalloproteinase with thrombospondin-like motifs 1 (adamts1) and plasminogen (plg), in brook trout preovulatory follicles. In addition, the expression of mmp2, adamts1 and plg increased in brook trout follicles during the progression of LH-induced ovulation. Interestingly, the expression of tissue inhibitor of matrix metalloproteinase 2 (timp2), a known regulator of MMP2 activity, paralleled that of mmp2, suggesting the existence of a controlled mechanism of MMP2 action. Therefore, the known increase in proteolytic activity during ovulation in fish could be the result of the stimulation of the expression of proteolytic enzymes by LH in preovulatory follicles. We propose that LH may stimulate ovulation in brook trout follicles by stimulating proteolysis of the follicle wall and by stimulating follicle contraction.


HBV seroprevalence after 25 years of universal mass vaccination and management of non-responders to the anti-Hepatitis B vaccine: An Italian study among medical students.
According to international guidelines, healthcare workers and medical students immunized against HBV are periodically tested for anti-HBs IgG. Subjects who show an anti-HBs titre <10 mUI/mL must receive additional vaccine doses to induce a measurable antibody response. This study aimed to evaluate the long-time immunogenicity of anti-hepatitis B vaccination in a sample of medical students and residents of the University of Bari who attended the Hygiene Department for biological risk assessment (April 2014-June 2017). The strategy for the management of nonresponder subjects was evaluated. A total of 3676 students and residents were invited for testing according to a standardized protocol. Anti-HBs IgG was tested for in 3140 (85.4%) subjects: 1174/3140 (37.7%) subjects were negative. 14.6% (128/808) of subjects who received the vaccine during their 12th year of life and 45.8% (1056/2305) of subjects immunized during the first year of life (P < 0.0001) were negative. 1005/1174 (85.6%) seronegative subjects received a booster dose, and 903/1005 (89.9%) were tested for anti-HBs 1 month after the booster dose: 82/903 (9.1%) subjects were still negative. Of these, 56/82 (68.3%) received 2 additional doses of vaccine and 52/56 (92.9%) were tested 1 month after the third dose: 50/52 subjects (96.2%) developed a positive titre. In conclusion, several medical students, immunized at birth or at young age against HBV, did not develop protective titres against the virus. Our management strategy (booster retest; for negative subjects, 2 doses and retest) seems consistent with the purpose of evidencing immunological memory.


[Haemodynamics in retinal branch vein obstruction (author's transl)].
A branch vein obstruction in a 44-years-old woman recovered with in 7 months without any clinical residuals. The evaluation of fluorescein angiograms performed during thrombosis and after recovery showed significantly reduced retinal circulation times in around the thrombosis. The results indicate an increased blood flow ranging between 50 and 200% around the obstructed area of the retina. The haemodynamic situation of the retinal circulation during branch vein obstruction and its therapeutic consequences (photocoagulation) are discussed.


Effects of capsazepine against capsaicin- and proton-evoked excitation of single airway C-fibres and vagus nerve from the guinea-pig.
We have examined the effects of low pH and the selectivity of the capsaicin antagonist capsazepine on single sensory fibres innervating the guinea-pig trachea in vitro, and on the whole isolated vagus nerve. Application of a pH 5 solution for 1 min to the exposed receptive fields of single fibres caused excitation of all C-fibres tested but had no effect on A delta-fibres. Capsazepine (1 microM) perfused onto the receptive field for 5 min produced a reversible inhibition of both low pH- and capsaicin (60 nM)-evoked firing of C-fibres. In contrast, capsazepine had no effect on responses of C-fibres to bradykinin (0.1 microM) or of A delta-fibres to hypertonic saline. Perfusion of tissues with zero-calcium Krebs' solution containing trypsin produced denudation of the epithelium. In these tissues responses to low pH and capsaicin were unchanged and, moreover, the inhibitory effect of capsazepine against low pH and capsaicin was maintained. C- and A delta-fibre responses to bradykinin and hypertonic saline were similarly unaffected by epithelium removal. Perfusion of the whole guinea-pig vagus nerve with capsaicin (0.3 microM) or pH 5 buffer caused depolarization. However, in this preparation prior perfusion with capsazepine (1 microM) abolished responses to capsaicin whilst low pH-evoked depolarization was unchanged. These data show that capsazepine is a specific antagonist of proton- and capsaicin-evoked activation of the peripheral endings of sensory nerves in the guinea-pig airways, and suggest the release by protons of an endogenous ligand for the capsaicin receptor that does not originate from the epithelium.


A global study of transcriptome dynamics in canola (Brassica napus L.) responsive to Sclerotinia sclerotiorum infection using RNA-Seq.
The necrotrophic phytopathogen, Sclerotinia sclerotiorum, causes Sclerotinia stem rot, which is a serious constraint to canola (Brassica napus L.) production worldwide. To understand the detailed molecular mechanisms underlying host response to Sclerotinia infection, we analyzed the transcript level changes in canola post-infection with S. sclerotiorum in a time course of a compatible interaction using strand specific whole transcriptome sequencing. Following infection, 161 and 52 genes (P≤0.001) were induced while 24 and 23 genes were repressed at 24h post-inoculation (hpi) and 48hpi, respectively. This suggests that, a gradual increase in host cell lyses and increase virulence of the pathogen led to the expression of only a fewer host specific genes at the later stage of infection. We observed rapid induction of key pathogen responsive genes, including glucanases, chitinases, peroxidases and WRKY Transcription factors (TFs) within 24hpi, indicating early detection of the pathogen by the host. Only 16 genes were significantly induced at both the time points suggesting a coordinated suppression of host responses by the pathogen. In addition to genes involved in plant-pathogen interactions, many novel disease responsive genes, including various TF sand those associated with jasmonate (JA) and ethylene (ET) signalling were identified. This suggests that canola adopts multiple strategies in mediating plant responses to the pathogen attack. Quantitative real time PCR (qRT-PCR) validation of a selected set of genes demonstrated a similar trend as observed by RNA-Seq analysis and highlighted the potential involvement of these genes by the host to defend itself from pathogen attack. Overall, this work presents an in-depth analysis of the interaction between host susceptibility and pathogen virulence in the agriculturally important B. napus-S. sclerotiorum pathosystem.


A comprehensive review on sustainable coastal zone management in Bangladesh: Present status and the way forward.
Bangladesh, a coastal developing nation with a diverse sustainable biodiversity of natural resources is currently focused upon by international communities as a result of its high potential of the coastal zone (CZ) with natural gas. Sustainable Coastal Zone Management (SCZM) is key to its national development. SCZM refers to the management of coastal resources in order to provide secure and alternative livelihoods, as well as to manage all types of coastal hazards and social and cultural well-being in order to ensure long-term productivity and minimize environmental impact. This paper aims to delineate the current initiatives and status of coastal management in Bangladesh, highlighting key issues such as climate changes, sea level rise, tropical cyclones, coastal and marine pollution, coastal erosions, saltwater intrusions, and mangrove degradations as well as the future trend in Bangladesh which will facilitate sustainable development by emphasizing the social, ecological, and economic pillars of sustainability. Unsustainable coastal development practices in Bangladesh are going to damage the coastal ecosystems, particularly mangrove forests and coral reefs, which provide protection against tropical cyclones caused by global climate change and coastal erosions. The paper concludes by outlining a roadmap toward achieving SCZM in Bangladesh. The road to achieving SCZM requires collaboration, integration of scientific research, policy frameworks, community engagement, capacity building, and long-term commitment from all stakeholders involved. So, it is required to address all kinds of coastal issues and reframes all existing coastal management practices to ensure a healthy productive ecosystem to achieve SCZM as well as the sustainable development of the country.


Endoscopic double stenting for the treatment of malignant biliary and duodenal obstruction due to pancreatic cancer.
The purpose of the present study was to retrospectively evaluate endoscopic double stenting by endoscopic retrograde cholangiopancreatography-guided biliary drainage (ERCP-BD) and by endoscopic ultrasonography-guided biliary drainage (EUS-BD) for the treatment of non-resectable malignant biliary and duodenal obstruction. Medical records of 11 patients that underwent endoscopic double stenting from January 2008 to September 2012 were analyzed retrospectively. Technical success rate was 100%, clinical success rate was 100%, early complication rate was 0% and late complication rate was 27.3% (cholangitis: two, perforation: one). Mean survival time from double stenting was 76.5 ± 67.8 days, mean patent period of the duodenal stent was 73.5 ± 69.7 days, and mean patent period of the biliary stent was 62.6 ± 60.4 days. Three (27.3%) patients were discharged (mean duration of hospitalization, 21.3 days). All patients could take food orally, and mean Gastric Outlet Obstruction Scoring System score after double stenting was 2.2 ± 0.9 points. ERCP-BD and EUS-BD were done in three and eight patients, respectively. There was no statistically significant difference between ERCP-BD and EUS-BD in terms of success rate and complication rate. Our study revealed that endoscopic double stenting appears to be feasible and useful for the treatment of non-resectable malignant biliary and duodenal obstruction. In terms of selection criteria of ERCP-BD patients and EUS-BD patients, further prospective studies are mandatory.


Hypsarhythmia or Hypsarrhythmia?
Hypsarhythmia was originally spelled with one 'r' by Drs Frederick and Erna Gibbs when they coined the term in 1952.


Activation of ERK during DNA damage-induced apoptosis involves protein kinase Cdelta.
We have previously shown that protein kinase C (PKC) acts upstream of caspases to regulate cisplatin-induced apoptosis. Since extracellular signal-regulated kinases (ERKs) have also been implicated in DNA damage-induced apoptosis, we have examined if ERK signaling pathway acts downstream of PKC in the regulation of cisplatin-induced apoptosis. PKC activator PDBu induced ERK1/2 phosphorylation which was inhibited by general PKC inhibitor bisindolylmaleimide and Gö 6983 as well as the MEK inhibitor U0126 but not by the PKCdelta inhibitor rottlerin. Cisplatin caused a concentration-dependent activation of ERK1/2 in HeLa cells. The level of ERK2 was decreased in HeLa cells that acquired resistance to cisplatin (HeLa/CP). The MEK inhibitor U0126 inhibited cisplatin-induced ERK activation and attenuated cisplatin-induced cell death. Inhibition of PKCdelta by rottlerin or depletion of PKCdelta by siRNA inhibited cisplatin-induced ERK activation. These results suggest that cisplatin-induced DNA damage results in activation of ERK1/2 via PKCdelta.


Correlation between segmental mobility and the location of antigenic determinants in proteins.
Most continuous antigenic determinants of tobacco mosaic virus protein (TMVP), myoglobin and lysozyme correspond to those surface regions in the protein structure, as determined by X-ray crystallography, which possess a run of high-temperature factors along the polypeptide backbone, that is, a high segmental mobility. The mobility of an antigenic determinant may make it easier to adjust to a pre-existing antibody site not fashioned to fit the exact geometry of a protein. The correlation found between temperature factors and antigenicity is better than that between hydrophilicity and antigenicity.


Impact of cathepsin B on the interstitial fluid proteome of murine breast cancers.
Carcinomas establish a molecular cross talk between malignant tumor cells and the activated non-malignant cells of the tumor stroma. This cell-cell communication in tumor-stroma interaction includes soluble, secreted proteins that act in a paracrine or autocrine manner. Proteases are crucial factors in tumor-stroma interaction by degrading or truncating secreted bioactive proteins. The cysteine protease cathepsin B is frequently overexpressed in several cancer types, including breast cancer. Its abundance often correlates with poor prognosis. In the murine polyoma virus middle T oncogene (PyMT) breast cancer model, cathepsin B is equally pro-tumorigenic. In this study, we investigate how cathepsin B shapes the secreted proteome of PyMT breast cancers. We employed a novel strategy to harvest tumor interstitial fluid (IF) in combination with chemical stable isotope tagging for quantitative proteomic comparison of IF stemming from PyMT tumors from wild-type mice, mice lacking cathepsin B, and mice over-expressing human cathepsin B. In three biological replicates, we achieve good proteome coverage (∼1700 proteins), with a large content (>70%) of secreted proteins. This characterizes IF as a robust source for the investigation of cancer secretomes. We also identified a large number of shed ectodomains, thus highlighting the importance of tumor-contextual cell surface proteolysis. Furthermore, IF contained >190 proteases and protease inhibitors, which span the entire range of absolute protein abundances; an observation testifying for an important role of proteolysis in tumor-stroma interaction. The cathepsin B genotype consistently affected proteins including alpha-1B-glycoprotein and major urinary proteins 11 and 8 (MUP8). Our study establishes tumor IF as a rich source for the investigation of secreted proteins in tumor biology and sheds light on complex proteolytic networks in the breast cancer secretome.


The genetic basis of inhibitor development in haemophilia A.
Inhibitor development is now the main complication of replacement therapy in haemophilia A. Given that most severely affected patients make no detectable factor VIII, it is perhaps surprising that only approximately 30% actually mount an immune response to factor VIII as a foreign antigen. Those that do mostly have major factor VIII gene lesions. The association of HLA genotype with inhibitors in patients with identical mutations is weak. Environmental factors may be more important than genetic in antibody response to factor VIII.


Genome Sequence of the Aerobic Arsenate-Reducing Bacterium Pantoea sp. Strain IMH.
We here report the draft assembly for the genome of Pantoea sp. strain IMH, isolated from arsenic-contaminated soil in Inner Mongolia, China, with the ability to aerobically reduce arsenate to arsenite. The genome sequence will allow for the characterization of the molecular mechanisms of arsenate reduction.


Ralstonia mannitollylitica endocarditis: A case report.
Ralstonia mannitolilytica (R. mannitolilytica.) is an emerging aerobic Gram-negative bacteria causing infection among immunocompromised patients. R. mannitolilytica, has been described in hospital outbreaks, mainly as bloodstream infection, but also as meningitis, hemoperitoneum infection and post renal transplant infection. We describe the first reported case of R. mannitolilytica infective endocarditis.


KTP laser destruction of dysplasia and early cancer in columnar-lined Barrett's esophagus.
The rising incidence of esophageal adenocarcinoma in western countries requires a new strategy in the management of dysplasia in Barrett's esophagus. Esophagectomy, which has high morbidity and mortality rates, has been recommended to treat patients with severe dysplasia. Strictly superficial laser coagulation with tissue ablation therefore is a desirable option for the management of dysplasia in Barrett's esophagus because the tissue to be ablated is only about 2 mm thick. Potassium-titanyl-phosphate (KTP) laser light with a wavelength of 532 nm is preferentially absorbed by hemoglobin and therefore combines excellent coagulation with limited tissue penetration. We report first clinical results with KTP laser superficial vaporization of dysplasia and early cancer in Barrett's esophagus. Eight men and 2 women 43 to 84 years of age with short segments of Barrett's esophagus or traditional Barrett's esophagus and histologically proved low-grade (n = 4) and high-grade (n = 4) dysplasia or early adenocarcinoma (n = 2) were selected for this pilot study. For all patients thermal endoscopic destruction was conducted with a frequency-doubled neodymium:yttrium-aluminum-garnet (Nd:YAG) KTP laser system. Laser therapy was performed by means of the free-beam method with coaxial insufflation of gas. An average of 2.4 sessions per patient were required for ablation of the Barrett's mucosa. Two to three days after laser treatment the response of the ablated mucosa was assessed with endoscopy and biopsy. Samples taken showed fibrinoid necrosis of the mucosal layer. A complete response was obtained for all 10 patients. Replacement by normal squamous cell epithelium was induced in combination with acid suppression therapy of up to 80 mg omeprazole daily. No complications occurred. In two patients biopsy showed specialized mucosa beneath the restored squamous cell epithelial layer. Follow-up times were as long as 15 months (mean value 10.6 months). KTP laser destruction of Barrett's esophagus induced mucosal regeneration with normal squamous cell epithelium in combination with acid suppression. Limitation of the depth of thermal destruction in Barrett's esophagus minimizes risk for perforation or stricture formation. KTP laser ablation of Barrett's esophagus seems to be feasible and safe in short segments of Barrett's esophagus with dysplasia or early cancer.


Perforated ileal diverticulitis. An atypical presentation with definitive diagnosis by laparoscopy.
An atypical presentation of ileal diverticulosis definitively diagnosed and treated with laparoscopy is presented. While jejunoileal diverticula are often asymptomatic, they may lead to chronic or acute symptoms. The large majority of complications secondary to small-bowel diverticulitis present with an acute abdomen similar to appendicitis but they also may appear with atypical symptoms. As a result, identification of jejunoileal diverticulosis can be quite difficult and surgery is often required in order to reach an absolute diagnosis. Surgical exploration, resection of the involved segment, and primary reanastomosis may be indicated in instances of symptomatic diverticular disease of the small bowel. Current laparoscopic techniques make this procedure well suited for both diagnosis and treatment of jejunoileal diverticula. In this report, the surgical incision was directed and limited under laparoscopic guidance while still allowing the benefit of thorough examination of the abdominal contents.


Detection of HIV-1 p24 antigen in patients with varying degrees of viremia using an ELISA with a photochemical signal amplification system.
We describe a photochemical signal amplification method (PSAM) for increasing the sensitivity of enzyme-linked immunosorbent assays (ELISAs) for the detection of HIV-1 p24 antigen, and present a preliminary validation study on ELISA+PSAM technology for detection of HIV-1 p24 antigen in clinical samples. ELISA+PSAM is compatible with commercially available microtiter plate readers, employs an inexpensive illumination device and the amplification takes around 10 min. The PSAM technology not only increases the analytical sensitivity for detection of HIV-1 p24 antigen by approximately 40 times, but also significantly increases the clinical sensitivity of the ELISA: in instances where viral RNA load is <3000 copies/ml, conventional heat mediated immune complex disruption ELISA (HM-ELISA) cannot detect any HIV positive samples whereas HM-ELISA+PSAM can detect HIV infection in approximately half of the samples (clinical sensitivity is 52.63%). For viral RNA loads between 3000 and 30,000 copies/ml, the clinical sensitivities of the HM-ELISA and HM-ELISA+PSAM are 32.6% and 91.3%, and for that >30,000 copies/ml, clinical sensitivities of HM-ELISA and HM-ELISA+PSAM are 52.3% and 100%, respectively. The HM-ELISA+PSAM represents an advancement in monitoring HIV-1 disease progression and treatment in the global healthcare setting.


Learning-induced synaptic potentiation in implanted neural precursor cell-derived neurons.
Neuronal loss caused by neurodegenerative diseases, traumatic brain injury and stroke results in cognitive dysfunctioning. Implantation of neural stem/precursor cells (NPCs) can improve the brain function by replacing lost neurons. Proper synaptic integration following neuronal differentiation of implanted cells is believed to be a prerequisite for the functional recovery. In the present study, we characterized the functional properties of immortalized neural progenitor HiB5 cells implanted into the rat hippocampus with chemically induced lesion. The implanted HiB5 cells migrated toward CA1 pyramidal layer and differentiated into vGluT1-positive glutamatergic neurons with morphological and electrophysiological properties of endogenous CA1 pyramidal cells. Functional synaptic integration of HiB5 cell-derived neurons was also evidenced by immunohistochemical and electrophysiological data. Lesion-caused memory deficit was significantly recovered after the implantation when assessed by inhibitory avoidance (IA) learning. Remarkably, IA learning preferentially produced long-term potentiation (LTP) at the synapses onto HiB5 cell-derived neurons, which occluded paring protocol-induced LTP ex vivo. We conclude that the implanted HiB5 cell-derived neurons actively participate in learning process through LTP formation, thereby counteracting lesion-mediated memory impairment.


Patient perceptions of quality in discharge instruction.
The present study investigates patient perceptions of the quality of discharge instruction by assessing inpatients' ratings of care and service in the United States over the past 5 years (1997-2001) (n = 4,901,178). As expected, patients' ratings of "instructions given about how to care for yourself at home" showed a strong, consistent positive relationship with overall patient satisfaction from 1997 through 2001. Nevertheless, patient satisfaction with discharge instructions decreased significantly each year (p < 0.001). Patients gave lower ratings to the quality of discharge instruction than to the overall quality of their hospital stay which indicates a failure to match the quality delivered among other services within the hospital. Patient assessments of discharge instruction quality varied systematically among conditions. Patients with musculoskeletal diseases and disorders (MDC-8) rated discharge instruction considerably lower than all other patient groups. Patients' age, sex, self-described health status and length of stay did not predict patients' evaluations of discharge instructions. U.S. hospitals may not be meeting existing AMA and JCAHO standards for patient education and discharge.


Financial implications of male circumcision scale-up for the prevention of HIV and other sexually transmitted infections in a sub-Saharan African community.
The financial implications of male circumcision (MC) scale-up in sub-Saharan Africa associated with reduced HIV have been evaluated. However, no analysis has incorporated the expected reduction of a comprehensive set of other sexually transmitted infections including human papillomavirus, herpes simplex virus type 2, genital ulcer disease, bacterial vaginosis, and trichomoniasis. A Markov model tracked a dynamic population undergoing potential MC scale-up, as individuals experienced MC procedures, procedure-related adverse events, and MC-reduced sexually transmitted infections and accrued any associated costs. Rakai, Uganda, was used as a prototypical rural sub-Saharan African community. Monte Carlo microsimulations evaluated outcomes under 4 alternative scale-up strategies to reach 80% MC coverage among men aged 15 to 49 years, in addition to a baseline strategy defined by current MC rates in central Uganda. Financial outcomes included direct medical expenses only and were evaluated over 5 and 25 years. Costs were discounted to the beginning of each period, coinciding with the start of MC scale-up, and expressed in US $2012. Cost savings from infections averted by MC vary from US $197,531 after 5 years of a scale-up program focusing on adolescent/adult procedures to more than US $13 million after 25 years, under a strategy incorporating increased infant MCs. Over a 5-year period, reduction in HIV contributes to 50% of cost savings, and for 25 years, this contribution rises to nearly 90%. Sexually transmitted infections other than HIV contribute to cost savings associated with MC scale-up. Previous analyses, focusing exclusively on the financial impact through averted HIV, may have underestimated true cost savings by 10% to 50%.


Sensitivity, specificity, and vaccine efficacy.
We study the effects of imperfect sensitivity and specificity on estimation of vaccine efficacy (VE). We show that a specificity of <1.0 (i.e., some noncases are classified as cases) can reduce the value of the estimate of VE. One may attempt to adjust the estimate by accounting for the values of sensitivity and specificity. This increases the variance of the estimate of VE and leads to larger sample size requirements. Alternatively, one may adopt the diagnosis method as the disease definition.


Incremental evaluation of exercise capacity as an independent predictor of coronary artery disease presence and extent.
To determine the independent incremental value of exercise capacity (METS) concerning the presence and extent of coronary artery disease, we analyzed data from 800 patients with suspected coronary disease who underwent both exercise testing and coronary angiography. We performed logistic regression analysis of clinical and exercise test data with an incremental design to mimic the usual flow of data acquisition. Separate analyses were performed concerning coronary disease presence (> or = 1 vessel with a > or = 50% lesion) and extent (three-vessel/left main disease). Diagnostic accuracy was determined by calculating receiver operating characteristic (ROC) curve areas. When considered alone, METS was a significant predictor of both presence and extent of disease. Multivariate analysis revealed that METS was an independent predictor of disease extent but not presence. However, comparison of ROC curve areas failed to show any loss of accuracy when METS was removed from the coronary disease extent analysis. Despite the strong univariate relationship between exercise capacity and coronary disease presence and extent and the independence of exercise capacity as a predictor of coronary disease extent, the lack of an additional incremental accuracy attributed to its consideration virtually cancels its value as a diagnostic variable for assessing both coronary disease presence and extent.


Carcinoma in situ of germ cells and subsequent development of an invasive seminoma in a hyperprolactinaemic man.
A 25-year-old man was first seen complaining of impotence and found to have a pituitary tumour and hyperprolactinaemia. Both testes were small and atrophic, but a testicular tumour was not apparent. Biopsy of the right testis was performed, and the pathology report described thickening of the seminiferous tubule walls and impaired spermatogenesis. The patient refused to undergo an operation for his pituitary tumour and was lost to follow-up. 5 years later, the same patient presented with enlargement of his right testis, and this and the pituitary tumour were excised. The testicular tumour was classified as seminoma, and the pituitary tumour as an adenoma with low malignancy. Re-examination of the previous specimen of his right testis revealed foci of carcinoma-in-situ. This is an additional example of the growth of an invasive germ cell tumour from non-invasive carcinoma-in-situ of the testis.


Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway.
Survivin is an inhibitor of apoptosis protein, which is over-expressed in most tumors. Aberrant expression of survivin and loss of wild-type p53 in many tumors prompted us to investigate a possible link between these two events. Here we show that wild-type p53 represses survivin expression at both mRNA and protein levels. Transient transfection analyses revealed that the expression of wild-type p53, but not mutant p53, was associated with strong repression of the survivin promoter in various cell types. The over-expression of exogenous survivin protein rescues cells from p53-induced apoptosis in a dose-dependent manner, suggesting that loss of survivin mediates, at least, in part the p53-dependent apoptotic pathway. In spite of the presence of two putative p53-binding sites in the survivin promoter, deletion and mutation analyses suggested that neither site is required for transcriptional repression of survivin expression. This was confirmed by chromatin immunoprecipitation assays. Further analyses suggested that the modification of chromatin within the survivin promoter could be a molecular explanation for silencing of survivin gene transcription by p53.


Simultaneous balloon occlusion of the renal artery and hypothermic perfusion in in situ surgery of the kidney.
Renal ischemia and cooling may be achieved by intraluminal balloon occlusion and intermittent hypothermic perfusion using a double lumen, balloon-tipped catheter introduced into the renal artery percutaneously. This technique was used successfully in 26 of 31 extensive nephrolithotomies, eliminating the need for dissection and clamping of the renal artery and intricate surface cooling. Intrarenal operations could be performed as effectively as with clamp occlusion. Despite a mean ischemia time of 54 minutes the individual 131I-hippuran clearance of the operated kidneys was only reduced to a mean 78.4 per cent of the preoperative value 2 to 3 weeks postoperatively and increased to 92.2 per cent after 3 to 6 months, with a tendency toward further improvement.


Left ventricular mechanical dyssynchrony by phase analysis of gated single photon emission computed tomography in end-stage renal disease.
The presence and degree of left ventricular (LV) dyssynchrony in patients with end-stage renal disease (ESRD) has not been well studied. We hypothesized that these patients would be more likely to have mechanical dyssynchrony than a control cohort. The indexes of LV mechanical dyssynchrony were measured by automated analysis of gated single photon emission computed tomography myocardial perfusion imaging in 290 patients with ESRD and 109 control patients. Only patients with normal myocardial perfusion imaging findings and a narrow QRS duration were included. The following variables were derived: LV ejection fraction (EF), volume, mass, and 2 indexes of dyssynchrony, the standard deviation and bandwidth. The standard deviation and bandwidth were significantly greater in those with ESRD (23° ± 13° vs 15° ± 6° and 65° ± 40° vs 42° ± 14°, respectively, p <0.001 for each). The LV volumes and LV mass were significantly lower and LVEF significantly greater in the control group than in the patients with ESRD (p <0.001 for each). The subgroup of 217 patients with ESRD and normal LVEF also had a significantly greater standard deviation and bandwidth than did the control group (21° ± 12° and 57° ± 35°, p <0.001 for each). However, their values were lower than those of the 73 patients with ESRD and a LVEF <50% (30° ± 13° and 90° ± 45°, p <0.001 for each). Finally, 25 patients (9%) with ESRD and none of the control group had a standard deviation >43° (p = 0.01). In conclusion, patients with ESRD had significantly more mechanical dyssynchrony than did the control group, even in absence of electrical dyssynchrony and abnormal LV perfusion or function.


Immunohistomorphologic and molecular cytogenetic analysis of a carcinosarcoma of the urinary bladder.
Carcinosarcomas of the urinary bladder are malignant biphasic tumors with an epithelial and a spindle cell component. For the histogenesis of the two components, a biclonal and a monoclonal origin are discussed. We present the immunomorphology and molecular cytogenetics of such a case. The immunohistology of biopsies of the urinary bladder revealed a poorly differentiated urothelial carcinoma (GIII) and a co-existing pleomorphic, spindle cell leiomyosarcoma (GIII). The two components were microdissected and further analyzed for gains and losses of chromosomal material using comparative genomic hybridization. In addition, loss of heterozygosity analyses were included. The tumor components revealed as overlapping core aberrations losses on the short arm of chromosome 9 and on the long arm of chromosome 11. However, both components showed additional aberrations exclusively detected in one of the components. The occurrence of overlapping aberrations strongly argues for a monoclonal origin of this tumor with a common ancestor. The additional aberrations of the components point to an independent and divergent course of tumor progression in both components.


Comparison of periodontal ligament and gingiva-derived mesenchymal stem cells for regenerative therapies.
Tissue-engineering therapies using undifferentiated mesenchymal cells (MSCs) from intra-oral origin have been tested in experimental animals. This experimental study compared the characteristics of undifferentiated mesenchymal stem cells from either periodontal ligament or gingival origin, aiming to establish the basis for the future use of these cells on regenerative therapies. Gingiva-derived mesenchymal stem cells (GMSCs) were obtained from de-epithelialized gingival biopsies, enzymatically digested and expanded in conditions of exponential growth. Their growth characteristics, phenotype, and differentiation ability were compared with those of periodontal ligament-derived mesenchymal stem cells (PDLMSCs). Both periodontal ligament- and gingiva-derived cells displayed a MSC-like phenotype and were able to differentiate into osteoblasts, chondroblasts, and adipocytes. These cells were genetically stable following in vitro expansion and did not generate tumors when implanted in immunocompromised mice. Furthermore, under suboptimal growth conditions, GMSCs proliferated with higher rates than PDLMSCs. Stem cells derived from gingival biopsies represent bona fide MSCs and have demonstrated genetic stability and lack of tumorigenicity. Gingiva-derived MSCs may represent an accessible source of messenchymal stem cells to be used in future periodontal regenerative therapies.


Physiological concentrations of zinc reduce taurine-activated GlyR responses to drugs of abuse.
Taurine is an endogenous ligand acting on glycine receptors in many brain regions, including the hippocampus, prefrontal cortex, and nucleus accumbens (nAcc). These areas also contain low concentrations of zinc, which is known to potentiate glycine receptor responses. Despite an increasing awareness of the role of the glycine receptor in the rewarding properties of drugs of abuse, the possible interactions of these compounds with zinc has not been thoroughly addressed. Two-electrode voltage-clamp electrophysiological experiments were performed on α1, α2 α1β and α2β glycine receptors expressed in Xenopus laevis oocytes. The effects of zinc alone, and zinc in combination with other positive modulators on the glycine receptor, were investigated when activated by the full agonist glycine versus the partial agonist taurine. Low concentrations of zinc enhanced responses of maximally-effective concentrations of taurine but not glycine. Likewise, chelation of zinc from buffers decreased responses of taurine- but not glycine-mediated currents. Potentiating concentrations of zinc decreased ethanol, isoflurane, and toluene enhancement of maximal taurine currents with no effects on maximal glycine currents. Our findings suggest that the concurrence of high concentrations of taurine and low concentrations of zinc attenuate the effects of additional modulators on the glycine receptor, and that these conditions are more representative of in vivo functioning than effects seen when these modulators are applied in isolation.


L-carnitine ameliorates the muscle wasting of cancer cachexia through the AKT/FOXO3a/MaFbx axis.
Recent studies suggest potential benefits of applying L-carnitine in the treatment of cancer cachexia, but the precise mechanisms underlying these benefits remain unknown. This study was conducted to determine the mechanism by which L-carnitine reduces cancer cachexia. C2C12 cells were differentiated into myotubes by growing them in DMEM for 24 h (hrs) and then changing the media to DMEM supplemented with 2% horse serum. Differentiated myotubes were treated for 2 h with TNF-α to establish a muscle atrophy cell model. After treated with L-carnitine, protein expression of MuRF1, MaFbx, FOXO3, p-FOXO3a, Akt, p-Akt, p70S6K and p-p70S6K was determined by Western blotting. Then siRNA-Akt was used to determine that L-carnitine ameliorated cancer cachexia via the Akt/FOXO3/MaFbx. In vivo, the cancer cachexia model was established by subcutaneously transplanting CT26 cells into the left flanks of the BALB/c nude mice. After treated with L-carnitine, serum levels of IL-1, IL-6 and TNF-α, and the skeletal muscle content of MuRF1, MaFbx, FOXO3, p-FOXO3a, Akt, p-Akt, p70S6K and p-p70S6K were measured. L-carnitine increased the gastrocnemius muscle (GM) weight in the CT26-bearing cachexia mouse model and the cross-sectional fiber area of the GM and myotube diameters of C2C12 cells treated with TNF-α. Additionally, L-carnitine reduced the protein expression of MuRF1, MaFbx and FOXO3a, and increased the p-FOXO3a level in vivo and in vitro. Inhibition of Akt, upstream of FOXO3a, reversed the effects of L-carnitine on the FOXO3a/MaFbx pathway and myotube diameters, without affecting FOXO3a/MuRF-1. In addition to regulating the ubiquitination of muscle proteins, L-carnitine also increased the levels of p-p70S6K and p70S6K, which are involved in protein synthesis. Akt inhibition did not reverse the effects of L-carnitine on p70S6K and p-p70S6K. Hence, L-carnitine ameliorated cancer cachexia via the Akt/FOXO3/MaFbx and p70S6K pathways. Moreover, L-carnitine reduced the serum levels of IL-1 and IL-6, factors known to induce cancer cachexia. However, there were minimal effects on TNF-α, another inducer of cachexia, in the in vivo model. These results revealed a novel mechanism by which L-carnitine protects muscle cells and reduces inflammation related to cancer cachexia.


Evidence of denser MgSiO3 glass above 133 gigapascal (GPa) and implications for remnants of ultradense silicate melt from a deep magma ocean.
Ultralow velocity zones are the largest seismic anomalies in the mantle, with 10-30% seismic velocity reduction observed in thin layers less than 20-40 km thick, just above the Earth's core-mantle boundary (CMB). The presence of silicate melts, possibly a remnant of a deep magma ocean in the early Earth, have been proposed to explain ultralow velocity zones. It is, however, still an open question as to whether such silicate melts are gravitationally stable at the pressure conditions above the CMB. Fe enrichment is usually invoked to explain why melts would remain at the CMB, but this has not been substantiated experimentally. Here we report in situ high-pressure acoustic velocity measurements that suggest a new transformation to a denser structure of MgSiO(3) glass at pressures close to those of the CMB. The result suggests that MgSiO(3) melt is likely to become denser than crystalline MgSiO(3) above the CMB. The presence of negatively buoyant and gravitationally stable silicate melts at the bottom of the mantle, would provide a mechanism for observed ultralow seismic velocities above the CMB without enrichment of Fe in the melt. An ultradense melt phase and its geochemical inventory would be isolated from overlying convective flow over geologic time.


[High myopic patients: A survey of their history, feelings, beliefs and needs].
High myopia (HM), which affects 0.9 to 3.1% of the population, is a major cause of vision loss. The purpose of this investigation was to study and evaluate the impact of their high myopia on the daily lives of patients and to better understand their expectations in order to better meet their needs. The survey was conducted between February 19 and March 21, 2014. To be eligible, patients had to have myopia of at least -8 diopters and be over 40 years of age, with or without myopic complications. Patients' degree of myopia was defined as the optical prescription of their worse eye. The 123 patients included were interviewed by phone using a questionnaire developed and validated by a scientific committee composed of experts and members of the patients' Association against myopic maculopathy (AMAM). The phone interview, semi-structured, lasted 20 minutes. On average, myopia was -11.7 diopters. Women accounted for 71% of the population, 89% of patients were under 65 years and were mostly professionals (65%). Over half of the subjects reported myopic complications; 5% of patients had choroidal neovascularization (CNV). Only 29% had been informed of the risk of CNV or maculopathy. HM was a handicap in sports for 64% of patients, in leisure activities for 51%, and in professional activities for more than a quarter (28%). Only 56% of HM patients reported living perfectly well with their condition. This survey is the first study on the daily life of people with HM aiming to analyze their social and emotional environment. It shows that HM has a profound impact on the daily lives of patients and may affect social life and professional activity. Most myopic patients possess incomplete or unclear information about the nature and risk of myopic complications. They expressed the desire to be better informed about their condition earlier, before the onset of complications.


Analysis of nascent silicon phase-change gratings induced by femtosecond laser irradiation in vacuum.
The formation of periodic surface structures is a general effect of femtosecond laser irradiation of solid targets showing promising interest in material science and technology. However, the experiments are typically carried out in air, a condition in which the target surface becomes densely decorated with nanoparticles that can influence the formation of the surface structures in the early stage of the irradiation process. Here we report an investigation of structures generation on a silicon surface irradiated in vacuum (10-5 mbar) with a low number of laser pulses (N ≤ 10) that exploits several microscopy techniques (optical, atomic force, electron and Raman). Our analyses allow identifying the creation of silicon phase-change gratings consisting of alternating amorphous and crystalline periodic lines, with almost no material removal, located at the periphery of a shallow ablation crater. These gratings originate from two different kinds of defects: (i) the first is characterized by a peculiar lobed shape that is produced by the first few laser pulses; (ii) the second is provided by the one-dimensional, linear singularity defined by the ablation edge of the nascent crater. Both kind of defects lead to grating structures extending outwards the amorphous central area of the crater along the direction of the laser polarization. Comparative analysis with the surface formed in air, in the same experimental conditions, evidences the important role played by nanoparticles densely decorating the target in air and the striking variation occurring in vacuum.


Salmonellacidal antibody response to Salmonella enterica serovar Typhi in enteric fever and after vaccination with Vi capsular polysaccharide.
Serum salmonellacidal (bactericidal) antibody could be used to detect functional capacity of antibody in patients with enteric fever and after typhoid vaccination. Salmonellacidal antibody response was measured by colorimetric serum salmonellacidal assay from 70 acute and 11 convalescence sera of patients infected with Salmonella Typhi and Paratyphi A and also from 15 control and 6 Vi capsular polysaccharide vaccinated volunteer's sera. Sera from patients with typhoid and paratyphoid A showed significant (p < 0.05) levels of salmonellacidal antibody titer (549.9 ± 108.5 and 528.7 ± 187.3) compared with control (0.133 ± 0.1). Moreover, this titer increased significantly (p <0.05) in sera collected between 7 and 10 days and between 11 and 25 days of fever (titer 535.7 ± 119.2 and 794.6 ± 235.6) compared with sera collected from patients with fever for less than 7 days (136.4 ± 52.7). The mean titer significantly (p < 0.05) decreased to 5.5 ± 2.1 after 6-8 weeks onset of illness. Although, very low salmonellacidal titers (2.5 ± 1.5 and 2.3 ± 1.5) were detected after Vi CPS vaccine among the human volunteers, but mean titer was raised 15-fold from pre- to postvaccinated sera (0.166-2.5). The serum salmonellacidal antibody by colorimetric salmonellacidal assay could be used to detect acute typhoidal cases and also to monitor immune response of typhoid vaccine.


The Experimental Research (In Vitro) of Carrageenans and Fucoidans to Decrease Activity of Hantavirus.
The effect of carrageenans and fucoidans on the activity of Hantavirus is studied. It has been found that among carrageenans a significant antiviral effect is exerted by the ι-type, which decreases the viral titer by 2.5 log focus forming units per mL; among fucoidans, by a preparation from Laminaria cichorioides, which reduces the number of infected cells from 27.0 to 5.3 after pretreatment of both the macrophage culture and Hantavirus. The antiviral effect of fucoidan from Laminaria japonica is shown to grow in direct proportion to the increase of dose of the preparation.


Na(+)/H(+) antiporter (NHE1) and lactate/H(+) symporters (MCTs) in pH homeostasis and cancer metabolism.
The Na(+)/H(+)-exchanger NHE1 and the monocarboxylate transporters MCT1 and MCT4 are crucial for intracellular pH regulation, particularly under active metabolism. NHE1, a reversible antiporter, uses the energy provided by the Na(+) gradient to expel H(+) ions generated in the cytosol. The reversible H(+)/lactate(-) symporters MCT1 and 4 cotransport lactate and proton, leading to the net extrusion of lactic acid in glycolytic tumors. In the first two sections of this article we review important features and remaining questions on the structure, biochemical function and cellular roles of these transporters. We then use a fully-coupled mathematical model to simulate their relative contribution to pH regulation in response to lactate production, as it occurs in highly hypoxic and glycolytic tumor cells. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.


Performance of the Hypotension Prediction Index May Be Overestimated Due to Selection Bias.
The Hypotension Prediction Index is a proprietary prediction model incorporated into a commercially available intraoperative hemodynamic monitoring system. The Hypotension Prediction Index uses multiple features of the arterial blood pressure waveform to predict hypotension. The index publication introducing the Hypotension Prediction Index describes the selection of training and validation data. Although precise details of the Hypotension Prediction Index algorithm are proprietary, the authors describe a selection process whereby a mean arterial pressure (MAP) less than 75 mmHg will always predict hypotension. We hypothesize that the data selection process introduced a systematic bias that resulted in an overestimation of the current MAP value's ability to predict future hypotension. Since current MAP is a predictive variable contributing to Hypotension Prediction Index, this exaggerated predictive performance likely also applies to the corresponding Hypotension Prediction Index value. Other existing validation studies appear similarly problematic, suggesting that additional validation work and, potentially, updates to the Hypotension Prediction Index model may be necessary.


Hydroxyl radical scavengers inhibit TNF-alpha production in mononuclear cells but not in polymorphonuclear leukocytes.
The hydroxyl radical (HO*) scavengers dimethylthiourea (DMTU), tetramethylthiourea (TMTU), dimethylsulfoxide (DMSO) and deferoxamine (DFX), the latter being an iron chelator which prevents HO* formation by blocking the Fenton reaction, were found to inhibit TNF-alpha production in LPS-stimulated human PBMC but not in PMN. Furthermore, this effect was not LPS-specific, as TNF-alpha production was reduced by HO* radical scavengers to a similar extent upon stimulation of PBMC with immune complexes (IC), concanavalin A (Con A) and phorbol myristate acetate (PMA). Other scavengers such as glutathione (GSH), N-acetylcysteine (NAC), ascorbic acid (ASC) and mannitol (MAN) do not have effect on the production of TNF-alpha either in PBMC or PMN. These results provide evidence that the participation of ROI in the regulation of TNF-alpha production differ in different cell types. Particularly, the data presented in this work indicate that HO* radicals have a central role in the production of this inflammatory cytokine by human PBMC.