[Sports correlate with positive living habits. Results from the population survey the Swiss MONICA project].
Exercise is associated with positive health habits: Findings from the populations survey of the Swiss MONICA-project. Relatively little is known on population-wide relations of habitual exercise to relevant health factors such as diet, cigarette smoking and overweight. Data from a population-based sample of approximately 800 men and women each, aged 25-64, collected in western Switzerland as a part of an international WHO-project, were used to examine cross-sectionally the interrelationships between different lifestyle factors. Men and women training regularly (i.e. greater than or equal to 2 times/wk) exhibited consistently and highly significantly more favourable health habits, regarding diet (i.e. trimming visible fat, higher intake of fruits, salad and vegetables, yogurt and cottage cheese), nonsmoking, and weight control. Men and women with at least some regular physical activity during leisure-time had in turn more favourable health habits than their sedentary counterparts. In both sexes, educational level was directly related to exercise and a healthy diet, and inversely related to smoking and relative weight. Regularly training men and women also had a significantly improved lipid profile compared to inactive ones. It is concluded from this study that leisure-time physical activity and exercise are related to a positive health behaviour including diet, nonsmoking and efficient weight control. This may suggest that exercise should possibly be integrated into any population-wide attempts and efforts to promote health to enhance primary prevention.


Pericardial effusion due to hypothyroidism in Down syndrome: report of four cases.
Pericardial effusion may be the first sign of congenital or acquired hypothyroidism and will completely resolve after thyroxin therapy. Hypothyroidism is more common in Down syndrome population than normal population. In this report we present four infants with Down syndrome who have pericardial effusion due to congenital hypothyroidism. All of these children with Down syndrome were admitted to our clinic with pericardial effusion. Pericardial effusion was completely resolved with thyroxin therapy without pericardiosentesis. Any child with Down syndrome who present with dyspnea and cardiomegaly should be suspected of having pericardial effusion due to hypothyroidism and echocardiography examination should be performed immediately. Pericardial effusion due to hypothyroidism will completely resolve with L-thyroxin therapy without pericardiosentesis. In conclusion, since a delayed diagnosis of hypothyroidism is likely and may favor the development of massive pericardial effusion and because of the difficult diagnosis of the hypothyroidism in Down syndrome, periodic follow-up of thyroid function tests are important.


A 12-month randomized, open-label study of the metabolic effects of olanzapine and risperidone in psychotic patients: influence of valproic acid augmentation.
Longitudinal data comparing the metabolic effects of olanzapine and risperidone with or without valproic acid supplementation in schizophrenic and bipolar patients are lacking. This study compares the metabolic effects of olanzapine and risperidone in a prospective, randomized, open-label trial in 160 patients with DSM-IV-TR schizophrenia, schizoaffective disorder, or bipolar disorder after 1, 3, 6, and 12 months' treatment. The study was conducted between 2000 and 2006. The primary analysis compared all patients randomized to olanzapine or risperidone; the primary outcome measure was changes in triglycerides (TG), and TG/high density lipoprotein cholesterol (HDL-C) ratio, a risk factor for ischemic cardiovascular disease. Secondary analyses included the effect of concomitant valproic acid. Significantly greater increases in weight (F(4,434) = 4.7), body mass index (BMI) (F(4,424) = 5.1), glycosylated hemoglobin (HgbA1c) (F(4,427) = 4.3), total cholesterol (F(4,429) = 4.4), TG (F(4,426) = 5.9), and TG/HDL-C ratio (F(4,426) = 4.3) (P < .005 for all drug × time interaction effects) were observed at all but the initial time points in the olanzapine- compared to the risperidone patients. Olanzapine/+valproic acid produced significantly greater increases in HgbA1c, BMI, weight, TG, and TG/HDL-C than olanzapine/-valproic acid at 3 and 6 months, while risperidone/+valproic acid produced significantly smaller increases in HgbA1c, BMI, and weight at 1, 3, and 6 months than risperidone/-valproic acid. The olanzapine/+valproic acid group had significantly greater BMI, and weight at 1, 3, and 6 months, and greater HgbA1c at 3 and 6 months, compared with the risperidone/+valproic acid group. There were too few patients treated with mood stabilizers other than valproic acid to analyze effects of any other mood stabilizer separately. Metabolic effects did not differ significantly by diagnostic category (schizophrenia/schizoaffective disorder vs bipolar disorder). Further study of the metabolic effects of adjunctive valproic acid is indicated, as valproic acid may produce markedly different metabolic effects when combined with various antipsychotic drugs. clinicaltrials.gov Identifier: NCT00179062.


Broadening the heterologous cross-neutralizing antibody inducing ability of porcine reproductive and respiratory syndrome virus by breeding the GP4 or M genes.
Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important swine pathogens, which causes reproductive failure in sows and respiratory disease in piglets. A major hurdle to control PRRSV is the ineffectiveness of the current vaccines to confer protection against heterologous strains. Since both GP4 and M genes of PRRSV induce neutralizing antibodies, in this study we molecularly bred PRRSV through DNA shuffling of the GP4 and M genes, separately, from six genetically different strains of PRRSV in an attempt to identify chimeras with improved heterologous cross-neutralizing capability. The shuffled GP4 and M genes libraries were each cloned into the backbone of PRRSV strain VR2385 infectious clone pIR-VR2385-CA. Three GP4-shuffled chimeras and five M-shuffled chimeras, each representing sequences from all six parental strains, were selected and further characterized in vitro and in pigs. These eight chimeric viruses showed similar levels of replication with their backbone strain VR2385 both in vitro and in vivo, indicating that the DNA shuffling of GP4 and M genes did not significantly impair the replication ability of these chimeras. Cross-neutralization test revealed that the GP4-shuffled chimera GP4TS14 induced significantly higher cross-neutralizing antibodies against heterologous strains FL-12 and NADC20, and similarly that the M-shuffled chimera MTS57 also induced significantly higher levels of cross-neutralizing antibodies against heterologous strains MN184B and NADC20, when compared with their backbone parental strain VR2385 in infected pigs. The results suggest that DNA shuffling of the GP4 or M genes from different parental viruses can broaden the cross-neutralizing antibody-inducing ability of the chimeric viruses against heterologous PRRSV strains. The study has important implications for future development of a broadly protective vaccine against PRRSV.


[Adequacy of the special category antibiotics prescriptions in the Emergency Department of a third level urban Hospital].
The aim of the study was to analyze the adequacy of the special category antibiotics prescriptions in the Emergency Department (ED) of a third level urban Hospital. A random sample of 100 different patients who were started with a special category antibiotic along 2018 in the ED was selected. The research team reviewed the medical history of the emergency and admission episode. The independent factors associated with the degree of adequacy of the treatment were determined by logistic regression. A total of 97 prescriptions were analyzed of which 66 (68%) met the criteria of adequate prescription, 23 (24%) adequate prescription, but with equally recommended alternatives and 8 (8%) were inappropriate prescriptions. The degree of adequacy was 70% if the infection was related to healthcare and 75% if the patient had risk factors for mul-tiresistant (MR) microorganisms' infection. The percentage of adequacy was higher in the cases in which the focus of the infection (72%) and the severity of the episode (73%) were specified. The independent variables that were associated with an adequate prescription were: the presence of risk factors for MR microorganisms' infection (OR: 2.35 95% CI: 1.65 - 3.17 p: 0.01), if the focus of the infection (OR: 3.79 95% CI: 1.72 - 4.22 p: 0.02) and the severity of the episode (OR: 3.09 95% CI: 1.12 - 3.09 p: 0.03) were specified. The prescription of special category antibiotics in ED is appropriate if the clinical guidelines are followed and if the setting of infection acquisition, the risk factors of MR microorganisms, the focus and the severity of infection are taken into account in clinical picture.


Association between vaginal birth after cesarean delivery and primary cesarean delivery rates.
To estimate the association between vaginal birth after cesarean delivery (VBAC) rates and primary cesarean delivery rates in California hospitals. Hospital VBAC rates were calculated using birth certificate and discharge data from 2009, and hospitals were categorized by quartile of VBAC rate. Multivariable logistic regression analysis was performed to estimate the odds of cesarean delivery among low-risk nulliparous women with singleton pregnancies at term in vertex presentation (nulliparous term singleton vertex) by hospital VBAC quartile while controlling for many patient-level and hospital-level confounders. There were 468,789 term singleton births in California in 2009 at 255 hospitals, 125,471 of which were low-risk nulliparous term singleton vertex. Vaginal birth after cesarean delivery rates varied between hospitals, with a range of 0-44.6%. Rates of cesarean delivery among low-risk nulliparous term singleton vertex women declined significantly with increasing VBAC rate. When adjusted for maternal and hospital characteristics, low-risk nulliparous term singleton vertex women who gave birth in hospitals in the highest VBAC quartile had an odds ratio of 0.55 (95% confidence interval 0.46-0.66) of cesarean delivery compared with women at hospitals with the lowest VBAC rates. Each percentage point increase in a hospital's VBAC rate was associated with a 0.65% decrease in the low-risk nulliparous term singleton vertex cesarean delivery rate. Hospitals with higher rates of VBAC have lower rates of primary cesarean delivery among low-risk nulliparous women with singleton pregnancies at term in vertex presentation. II.


Systematic Review of Hospital Readmissions Among Patients With Cancer in the United States.
To review the existing literature on readmission rates, predictors, and reasons for readmission among adults with cancer. . U.S.-based empirical studies reporting readmission rates from January 2005 to December 2015 were identified using four online library databases-PubMed, CINAHL®, EconLit, and the online bibliography of the National Cancer Institute's Surveillance Epidemiology and End Results Program. Some articles were identified by the authors outside the database and bibliography searches. . Of the 1,219 abstracts and 271 full-text articles screened, 56 studies met inclusion criteria. The highest readmission rates were observed in patients with bladder, pancreatic, ovarian, or liver cancer. Significant predictors of readmission included comorbidities, older age, advanced disease, and index length of hospital stay. Common reasons for readmission included gastrointestinal and surgical complications, infection, and dehydration. . Clinical efforts to reduce the substantial readmission rates among adults with cancer may target high-rate conditions, infection prevention, proactive management of nausea and vomiting, and nurse-led care coordination interventions for older adult patients with multiple comorbid conditions and advanced cancer. . Commonly reported reasons for readmission were nursing-sensitive patient outcomes (NSPOs), amenable to nursing intervention in oncology settings. These findings underscore the important role oncology nurses play in readmission prevention by implementing evidence-based interventions to address NSPOs and testing their impact in future research.


Peptide neuromodulation of synaptic dynamics in an oscillatory network.
Although neuromodulation of synapses is extensively documented, its consequences in the context of network oscillations are not well known. We examine the modulation of synaptic strength and short-term dynamics in the crab pyloric network by the neuropeptide proctolin. Pyloric oscillations are driven by a pacemaker group which receives feedback through the inhibitory synapse from the lateral pyloric (LP) to pyloric dilator (PD) neurons. We show that proctolin modulates the spike-mediated and graded components of the LP to PD synapse. Proctolin enhances the graded component and unmasks a surprising heterogeneity in its dynamics where there is depression or facilitation depending on the amplitude of the voltage waveform of the presynaptic LP neuron. The spike-mediated component is influenced by the baseline membrane potential and is also enhanced by proctolin at all baseline potentials. In addition to direct modulation of this synapse, proctolin also changes the shape and amplitude of the presynaptic voltage waveform which additionally enhances synaptic output during ongoing activity. During ongoing oscillations, proctolin reduces the variability of cycle period but only when the LP to PD synapse is functionally intact. Using the dynamic clamp technique we find that the reduction in variability is a direct consequence of modulation of the LP to PD synapse. These results demonstrate that neuromodulation of synapses involves complex and interacting influences that target different synaptic components and dynamics as well as the presynaptic voltage waveform. At the network level, modulation of feedback inhibition can result in reduction of variability and enhancement of stable oscillatory output.


The Mammalian circadian clock gene per2 modulates cell death in response to oxidative stress.
Living in the earth's oxygenated environment forced organisms to develop strategies to cope with the damaging effects of molecular oxygen known as reactive oxygen species (ROS). Here, we show that Per2, a molecular component of the mammalian circadian clock, is involved in regulating a cell's response to oxidative stress. Mouse embryonic fibroblasts (MEFs) containing a mutation in the Per2 gene are more resistant to cytotoxic effects mediated by ROS than wild-type cells, which is paralleled by an altered regulation of bcl-2 expression in Per2 mutant MEFs. The elevated survival rate and alteration of NADH/NAD(+) ratio in the mutant cells is reversed by introduction of the wild-type Per2 gene. Interestingly, clock synchronized cells display a time dependent sensitivity to paraquat, a ROS inducing agent. Our observations indicate that the circadian clock is involved in regulating the fate of a cell to survive or to die in response to oxidative stress, which could have implications for cancer development and the aging process.


Temsirolimus targets multiple hallmarks of cancer to impede mesothelioma growth in vivo.
The mechanistic target of rapamycin (mTOR) promotes cancer cell proliferation and survival, transduces pro-angiogenic signals and regulates immune cell differentiation and function. We hypothesized that temsirolimus, an mTOR inhibitor, would curtail experimental mesothelioma progression in vivo by limiting tumour cell growth, abrogating tumour angiogenesis and modulating immune/inflammatory tumour milieu. We produced flank and pleural syngeneic murine mesotheliomas by delivering AE17 and AB1 murine mesothelioma cells into the right flank or the pleural space of C57BL/6 and BALB/c mice, respectively. Animals were given five times/week intraperitoneal injections of 20 mg/kg temsirolimus or vehicle and were sacrificed on day 26 (flank) or on day 15 (pleural) post-tumour cell propagation. Temsirolimus limited mesothelioma growth in vivo by stimulating tumour cell apoptosis, inhibiting tumour angiogenesis, enhancing tumour lymphocyte abundance and blocking pro-tumour myeloid cell recruitment. Pleural fluid accumulation was significantly mitigated in AE17 but not in AB1 mesotheliomas. In vitro, temsirolimus hindered mesothelioma cell growth, NF-kappaB activation and macrophage migration. In conclusion, temsirolimus apart from inducing tumour cell apoptosis, targets tumour angiogenesis and influences inflammatory tumour microenvironment to halt experimental mesothelioma growth in vivo.


Photophysical and photobiological studies of a silicon tribenzonaphthoporphyrazinato incorporated into liposomes for photodynamic therapy use.
Nanostructured drug delivery systems (NDDS), such as liposomes, represent a growing area in biomedical research. These microheterogeneous media can be used in many biological systems to provide appropriate drug levels with a specific biodistribution. The photophysical properties of a silicon derivative of tribenzonaphthoporphyrazinato (Si-tri-PcNc) incorporated into liposome were studied by steady-state techniques, time-resolved fluorescence and laser flash photolysis. All the spectroscopy measurements performed allowed us to conclude that Si-tri-PcNc in liposome is a promising NDDS for PDT. The in vitro experiments with liposomal NDDS showed that the system is not cytotoxic in darkness, but exhibits a substantial phototoxicity at 1 microM of photosensitizer concentration and 10.0 J/cm2 of light. These conditions are sufficient to kill about 80% of the cells.


A high-resolution chronology of rapid forest transitions following polynesian arrival in New Zealand.
Human-caused forest transitions are documented worldwide, especially during periods when land use by dense agriculturally-based populations intensified. However, the rate at which prehistoric human activities led to permanent deforestation is poorly resolved. In the South Island, New Zealand, the arrival of Polynesians c. 750 years ago resulted in dramatic forest loss and conversion of nearly half of native forests to open vegetation. This transformation, termed the Initial Burning Period, is documented in pollen and charcoal records, but its speed has been poorly constrained. High-resolution chronologies developed with a series of AMS radiocarbon dates from two lake sediment cores suggest the shift from forest to shrubland occurred within decades rather than centuries at drier sites. We examine two sites representing extreme examples of the magnitude of human impacts: a drier site that was inherently more vulnerable to human-set fires and a wetter, less burnable site. The astonishing rate of deforestation at the hands of small transient populations resulted from the intrinsic vulnerability of the native flora to fire and from positive feedbacks in post-fire vegetation recovery that increased landscape flammability. Spatially targeting burning in highly-flammable seral vegetation in forests rarely experiencing fire was sufficient to create an alternate fire-prone stable state. The New Zealand example illustrates how seemingly stable forest ecosystems can experience rapid and permanent conversions. Forest loss in New Zealand is among the fastest ecological transitions documented in the Holocene; yet equally rapid transitions can be expected in present-day regions wherever positive feedbacks support alternate fire-inhibiting, fire-prone stable states.


MET and PI3K/mTOR as a potential combinatorial therapeutic target in malignant pleural mesothelioma.
Malignant pleural mesothelioma (MPM) is an aggressive disease with a poor prognosis. Studies have shown that both MET and its key downstream intracellular signaling partners, PI3K and mTOR, are overexpressed in MPM. Here we determined the combinatorial therapeutic efficacy of a new generation small molecule inhibitor of MET, ARQ 197, and dual PI3K/mTOR inhibitors NVP-BEZ235 and GDC-0980 in mesothelioma cell and mouse xenograft models. Cell viability results show that mesothelioma cell lines were sensitive to ARQ 197, NVP-BEZ235 and GDC-0980 inhibitors. The combined use of ARQ 197 with either NVP-BEZ235 or GDC-0980, was synergistic (CI<1). Significant delay in wound healing was observed with ARQ 197 (p<0.001) with no added advantage of combining it with either NVP-BEZ235 or GDC-0980. ARQ 197 alone mainly induced apoptosis (20±2.36%) that was preceded by suppression of MAPK activity, while all the three suppressed cell cycle progression. Both GDC-0980 and NVP-BEZ235 strongly inhibited activities of PI3K and mTOR as evidenced from the phosphorylation status of AKT and S6 kinase. The above observation was further substantiated by the finding that a majority of the MPM archival samples tested revealed highly active AKT. While the single use of ARQ 197 and GDC-0980 inhibited significantly the growth of MPM xenografts (p<0.05, p<0.001 respectively) in mice, the combination of the above two drugs was highly synergistic (p<0.001). Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than the use of the drugs singly in suppressing MPM tumor growth and motility and therefore merit further translational studies.


Subchondral stem cell therapy versus contralateral total knee arthroplasty for osteoarthritis following secondary osteonecrosis of the knee.
Total knee arthroplasty (TKA) implanted in patients with secondary osteonecrosis (ON) related to corticosteroids have relatively poor outcome (20% revision rate) at a mean follow-up of only eight years. With the hypothesis that subchondral bone marrow injection might improve knees in these patients, we evaluated 30 patients who had bilateral knee osteoarthritis with severe joint space narrowing and received TKA in one knee and subchondral bone marrow concentrate injection in the contralateral knee. A prospective randomized controlled clinical trial was carried out in 60 knees of 30 patients (mean age 28 years, 18-41) who presented bilateral osteoarthritis secondary to knee ON related to corticosteroids in relation with different severe medical conditions. During the same anesthesia, one knee received TKA; for the other knee, a bone marrow graft containing an average of 6500 MSCs/mL (counted as CFU-F, range 3420 to 9830) was delivered to the subchondral bone of the femur and tibia. The length of anesthesia related to each procedure (bone marrow aspiration and subchondral injection of concentrated bone marrow versus total knee arthroplasty) was measured. Peri-operative outcomes, morbidity, complications, and safety of the two procedures were compared. Subsequent admissions for revision surgery were identified. At the most recent follow-up (average of 12 years, range 8 to 16 years), clinical outcomes of the patient (Knee Society score) were obtained along with radiological imaging outcomes (MRIs for knees with subchondral bone marrow injection). Anesthesia related to the TKA side was longer than for the cell therapy group. Medical and surgical complications were more frequent after TKA. A higher number of thrombophlebitis was observed on the side with TKA (15%) versus none on the side with cell therapy (0%). At the most recent follow-up (average of 12 years, range 8 to 16 years), six (out of 30) TKA knees needed subsequent surgery versus only one with cell therapy. The Knee Score had improved and remained similar in the TKA and cell therapy groups (respectively 80.3 points ± 11 versus 78.3 ± 23); 21 patients preferred the knee with cell therapy and 9 preferred the knee with TKA. Knees with cell therapy had improvement on cartilage and bone marrow lesions observed at the site of bone marrow subchondral injection. Subchondral autologous bone marrow concentrate was an effective procedure for treating young patients with knee osteoarthritis following secondary ON of the knee related to corticosteroids with a lower complication rate and a quicker recovery as compared with TKA.


General Practitioners' Experiences of, and Responses to, Uncertainty in Prostate Cancer Screening: Insights from a Qualitative Study.
Prostate-specific antigen (PSA) testing for prostate cancer is controversial. There are unresolved tensions and disagreements amongst experts, and clinical guidelines conflict. This both reflects and generates significant uncertainty about the appropriateness of screening. Little is known about general practitioners' (GPs') perspectives and experiences in relation to PSA testing of asymptomatic men. In this paper we asked the following questions: (1) What are the primary sources of uncertainty as described by GPs in the context of PSA testing? (2) How do GPs experience and respond to different sources of uncertainty? This was a qualitative study that explored general practitioners' current approaches to, and reasoning about, PSA testing of asymptomatic men. We draw on accounts generated from interviews with 69 general practitioners located in Australia (n = 40) and the United Kingdom (n = 29). The interviews were conducted in 2013-2014. Data were analysed using grounded theory methods. Uncertainty in PSA testing was identified as a core issue. Australian GPs reported experiencing substantially more uncertainty than UK GPs. This seemed partly explainable by notable differences in conditions of practice between the two countries. Using Han et al's taxonomy of uncertainty as an initial framework, we first outline the different sources of uncertainty GPs (mostly Australian) described encountering in relation to prostate cancer screening and what the uncertainty was about. We then suggest an extension to Han et al's taxonomy based on our analysis of data relating to the varied ways that GPs manage uncertainties in the context of PSA testing. We outline three broad strategies: (1) taking charge of uncertainty; (2) engaging others in managing uncertainty; and (3) transferring the responsibility for reducing or managing some uncertainties to other parties. Our analysis suggests some GPs experienced uncertainties associated with ambiguous guidance and the complexities of their situation as professionals with responsibilities to patients as considerably burdensome. This raises important questions about responsibility for uncertainty. In Australia in particular they feel insufficiently supported by the health care system to practice in ways that are recognisably consistent with 'evidence based' professional standards and appropriate for patients. More work is needed to clarify under what circumstances and how uncertainty should be communicated. Closer attention to different types and aspects of the uncertainty construct could be useful.


The impact of vasculitis on patients' social participation and friendships.
Our objective is to explore how vasculitis affects patients' friendships and social participation. Vasculitis patients (n=221) completed an online questionnaire that asked if, and how, relationships with friends have changed since receiving a vasculitis diagnosis. Participants' written responses were imported into Atlas.ti, and two independent researchers used both structured and unstructured coding to identify themes. After reaching 100% consensus on the themes present in each participant's responses, the coders determined how themes were interrelated across participants. Over half of patients (52%) expressed that vasculitis negatively impacted their friendships and 25% noted a negative impact on their social participation. At times, this negative impact was related to structural changes in patients' social networks due to loss of friendships. Reduced social participation was also associated with friends' inability to understand vasculitis and its effects, vasculitis-related fatigue, and lifestyle changes such as not being able to drink alcohol and avoiding infection-prone events. Additionally, patients withdrew from social engagements due to fatigue or because of physical symptoms and side effects. The unique circumstances associated with a rare chronic illness like vasculitis can create significant barriers to friendships, including loss of these relationships. Interventions designed to help patients cope with the social impact of vasculitis are implicated, especially if they increase patients' ability to engage in dialogue about their illness with their friends.


To what extent residual alveolar ridge can be preserved by implant? A systematic review.
It has been reported that the load for (or to) implant-supported restoration may lead to bone remodeling as bone resorption and/or formation. While many authors supported the process of bone resorption, others elaborated bone apposition and increasing bone density close and remote to implant body (or fixture). This may suggest the role of the implant to reserve alveolar ridge from physiologic/pathologic resorption. The aim of this systematic review was to predict to how extend dental implants can preserve the residual alveolar ridge based on previous clinical investigations. This systematic review based on the retrospective and prospective studies, randomized clinical trial, and case reports. The process of searching for proposed articles included PubMed, Ovid, and Web of Science databases, with specific inclusion and exclusion criterion. A total 2139 citations were identified. After expunging the repeated articles between databases and application of exclusion and inclusion criteria, 18 articles were found to meet the topic of this systematic review. Many of the articles reported bone preservation with implant-assisted restorations, and the rest denoted noticeable bone apposition. According to the published clinical studies, the behavior of bone remodeling around implant predicts a sort of residual alveolar bone preservation.


Characterization of recombinant soybean leghemoglobin a and apolar distal histidine mutants.
The cDNA for soybean leghemoglobin a (Lba) was cloned from a root nodule cDNA library and expressed in Escherichia coli. The crystal structure of the ferric acetate complex of recombinant wild-type Lba was determined at a resolution of 2.2 A. Rate constants for O2, CO and NO binding to recombinant Lba are identical with those of native soybean Lba. Rate constants for hemin dissociation and auto-oxidation of wild-type Lba were compared with those of sperm whale myoglobin. At 37 degrees C and pH 7, soybean Lba is much less stable than sperm whale myoglobin due both to a fourfold higher rate of auto-oxidation and to a approximately 600-fold lower affinity for hemin. The role of His61(E7) in regulating oxygen binding was examined by site-directed mutagenesis. Replacement of His(E7) with Ala, Val or Leu causes little change in the equilibrium constant for O2 binding to soybean Lba, whereas the same mutations in sperm whale myoglobin cause 50 to 100-fold decreases in K(O2). These results show that, at neutral pH, hydrogen bonding with His(E7) is much less important in regulating O2 binding to the soybean protein. The His(E7) to Phe mutation does cause a significant decrease in K(O2) for Lba, apparently due to steric hindrance of the bound ligand. The rate constants for O2 dissociation from wild-type and native Lba decrease significantly with decreasing pH. In contrast, the O2 dissociation rate constants for mutants with apolar E7 residues are independent of pH, suggesting that hydrogen bonding to the distal histidine residue in the native protein is enhanced under acid conditions. All of these results support the hypothesis that the high affinity of Lba for oxygen and other ligands is determined primarily by enhanced accessibility and reactivity of the heme group.


Assessment and management of sport-related concussions in United States high schools.
Little existing data describe which medical professionals and which medical studies are used to assess sport-related concussions in high school athletes. To describe the medical providers and medical studies used when assessing sport-related concussions. To determine the effects of medical provider type on timing of return to play, frequency of imaging, and frequency of neuropsychological testing. Descriptive epidemiology study. All concussions recorded by the High School Reporting Information Online (HS RIO) injury surveillance system during the 2009 to 2010 academic year were included. χ(2) analyses were conducted for categorical variables. Fisher exact test was used for nonparametric data. Logistic regression analyses were used when adjusting for potential confounders. Statistical significance was considered for P < .05. The HS RIO recorded 1056 sport-related concussions, representing 14.6% of all injuries. Most (94.4%) concussions were assessed by athletic trainers (ATs), 58.8% by a primary care physician. Few concussions were managed by specialists. The assessment of 21.2% included computed tomography. Computerized neuropsychological testing was used for 41.2%. For 50.1%, a physician decided when to return the athlete to play; for 46.2%, the decision was made by an AT. After adjusting for potential confounders, no associations between timing of return to play and the type of provider (physician vs AT) deciding to return the athlete to play were found. Concussions account for nearly 15% of all sport-related injuries in high school athletes. The timing of return to play after a sport-related concussion is similar regardless of whether the decision to return the athlete to play is made by a physician or an AT. When a medical doctor is involved, most concussions are assessed by primary care physicians as opposed to subspecialists. Computed tomography is obtained during the assessment of 1 of every 5 concussions occurring in high school athletes.


Preoperative Chronic Kidney Disease Status is an Independent Prognostic Factor in Patients with Renal Cell Carcinoma.
Preoperative chronic kidney disease (CKD) status may affect disease outcomes in patients with renal cell carcinoma (RCC). This study evaluated the influence of preoperative CKD status on clinicopathological features and prognosis in patients with RCC. Between 1999 and 2011, a total of 1855 patients underwent radical nephrectomy at various centers throughout Korea. Of these patients, 1655 had an estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m(2) (non-CKD group) and 200 patients had an eGFR ≥30 but <60 ml/min/1.73 m(2) (CKD group). To reduce the effects of selection bias and potential confounding factors, 600 patients in the non-CKD group were selected by propensity-score matching. The median age of all patients was 57.3 years (range 20-94 years) and the median follow-up was 35.0 months (range 1-154 months). Comparisons of the propensity-score-matched cohorts showed that T and N stages were more advanced and tumor size was larger in the CKD group than in the non-CKD group (p < 0.05 each). Kaplan-Meier analyses showed that recurrence-free survival, cancer-specific survival (CSS), and overall survival (OS) were significantly lower in the CKD group (p < 0.01 each). Multivariate regression analysis showed that preoperative CKD status was an independent predictor of CSS and OS in patients with RCC (p < 0.05 each). Preoperative CKD may be associated with more aggressive features and poorer prognosis in patients with RCC. RCC patients with preoperative CKD should be carefully and frequently followed-up after nephrectomy.


Hepatoprotective effect of feeding celery leaves mixed with chicory leaves and barley grains to hypercholesterolemic rats.
Celery, chicory leaves, and barley grains are valuable in weight loss diets and regulate lipid metabolism. They may reduce risk of fatty liver. The present study aimed to investigate the effect of diet supplementation with celery, chicory, and barley powder on liver enzymes and blood lipids in rats fed with cholesterol-enriched diet. This study used four groups of rats fed with 3% cholesterol were supplemented diet to induce hypercholesterolemia and one group was fed on cholesterol-free basal diet. The dry powder of celery leaves, chicory leaves, and barley grains was separately added to the basal diet at 10% concentration or in combination of three plants at 15% for four weeks. Biochemical analyses of serum liver enzymes and blood lipids as well as histopathological examination of liver were performed. Feeding of diet supplemented with 10% of celery, 10% chicory, and 10% of barley lowered the elevated serum level of liver enzymes and blood lipids in rats. Feeding plant combination of celery, chicory, and barley at 15% concentration (5% from each) was more effective in decreasing the elevation of liver enzymes (aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) and blood lipids. The histopathological lesions seen in the livers of hypercholesterolemic rats were ameliorated by feeding this plant mixture. This study recommends that dietary intake of plant mixture of celery; chicory, and barley at 15% (5% of each) concentration can be beneficial to patients suffering from hypercholesterolemia and liver diseases.


Combining External Beam Radiation and Radionuclide Therapies: Rationale, Radiobiology, Results and Roadblocks.
The emergence of effective radionuclide therapeutics, such as radium-223 dichloride, [177Lu]Lu-DOTA-TATE and [177Lu]Lu-PSMA ligands, over the last 10 years is driving a rapid expansion in molecular radiotherapy (MRT) research. Clinical trials that are underway will help to define optimal dosing protocols and identify groups of patients who are likely to benefit from this form of treatment. Clinical investigations are also being conducted to combine new MRT agents with other anticancer drugs, with particular emphasis on DNA repair inhibitors and immunotherapeutics. In this review, the case is presented for combining MRT with external beam radiotherapy (EBRT). The technical and dosimetric challenges of combining two radiotherapeutic modalities have impeded progress in the past. However, the need for research into the specific radiobiological effects of radionuclide therapy, which has lagged behind that for EBRT, has been recognised. This, together with innovations in imaging technology, MRT dosimetry tools and EBRT hardware, will facilitate the future use of this important combination of treatments.


Considering low-rank, sparse and gas-inflow effects constraints for accelerated pulmonary dynamic hyperpolarized 129Xe MRI.
Dynamic hyperpolarized (HP) 129Xe MRI is able to visualize the process of lung ventilation, which potentially provides unique information about lung physiology and pathophysiology. However, the longitudinal magnetization of HP 129Xe is nonrenewable, making it difficult to achieve high image quality while maintaining high temporal-spatial resolution in the pulmonary dynamic MRI. In this paper, we propose a new accelerated dynamic HP 129Xe MRI scheme incorporating the low-rank, sparse and gas-inflow effects (L + S + G) constraints. According to the gas-inflow effects of HP gas during the lung inspiratory process, a variable-flip-angle (VFA) strategy is designed to compensate for the rapid attenuation of the magnetization. After undersampling k-space data, an effective reconstruction algorithm considering the low-rank, sparse and gas-inflow effects constraints is developed to reconstruct dynamic MR images. In this way, the temporal and spatial resolution of dynamic MR images is improved and the artifacts are lessened. Simulation and in vivo experiments implemented on the phantom and healthy volunteers demonstrate that the proposed method is not only feasible and effective to compensate for the decay of the magnetization, but also has a significant improvement compared with the conventional reconstruction algorithms (P-values are less than 0.05). This confirms the superior performance of the proposed designs and their ability to maintain high quality and temporal-spatial resolution.


Phase-contrast breast CT: the effect of propagation distance.
X-ray phase imaging has the potential to dramatically improve soft tissue contrast sensitivity, which is a crucial requirement in many diagnostic applications such as breast imaging. In this context, a program devoted to perform in vivo phase-contrast synchrotron radiation breast computed tomography is ongoing at the Elettra facility (Trieste, Italy). The used phase-contrast technique is the propagation-based configuration, which requires a spatially coherent source and a sufficient object-to-detector distance. In this work the effect of this distance on image quality is quantitatively investigated scanning a large breast surgical specimen at three object-to-detector distances (1.6, 3, 9 m) and comparing the images both before and after applying the phase-retrieval procedure. The sample is imaged at 30 keV with a [Formula: see text] pixel pitch CdTe single-photon-counting detector, positioned at a fixed distance of 31.6 m from the source. The detector fluence is kept constant for all acquisitions. The study shows that, at the largest distance, a 20-fold SNR increase can be obtained by applying the phase-retrieval procedure. Moreover, it is shown that, for phase-retrieved images, changing the object-to-detector distance does not affect spatial resolution while boosting SNR (four-fold increase going from the shortest to the largest distance). The experimental results are supported by a theoretical model proposed by other authors, whose salient results are presented in this paper.


Array electrode design for transcutaneous electrical stimulation: a simulation study.
Array electrodes are a promising technology that is likely to bring transcutaneous electrical stimulation (TES) a step forward. The dynamic adaptation of electrode size and position helps to simplify the use of electrical stimulation systems and to increase their clinical efficacy. However, up to now array electrodes were built by trial and error and it is unclear how, for example, the gaps between the array elements or the resistivity of the electrode-skin interface material influence the current distribution. A TES model that comprises a finite element model and a nerve model has been used to analyze the influence of array electrode gaps and gel resistivities on nerve activation. Simulation results indicate that the resistivity of the electrode-skin interface layer should be adapted depending on the size of the gaps between the array elements. Furthermore, the gap sizes should be smaller than 3mm in order to keep losses small.


Return to sport activities after medial displacement calcaneal osteotomy and flexor digitorum longus transfer.
Medial displacement calcaneal osteotomy with flexor digitorum longus transfer is a common treatment for the management of the adult flatfoot associated with posterior tibial tendon dysfunction. In the literature, there is a paucity of information regarding the ability of patients to return to sport and recreational activities after this surgical procedure. The purpose of this retrospective clinical study was to assess the rate and type of athletic activities that patients participated in before and after medial displacement calcaneal osteotomy with flexor digitorum longus transfer. A consecutive series of 42 patients with a mean age at surgery of 41 years (range 19-74 years) was evaluated with a minimum follow-up of 24 months (range 18-31 months). Pre- and post-operative sporting activities were assessed. At final follow-up, patients were asked to complete a Sports Athlete Foot and Ankle Score (SAFAS). Each patient was also evaluated with weight-bearing radiographs of the foot before surgery and at final follow-up. Preoperatively, 27 of 42 (64.3 %) patients were engaged in athletic activities, participating in an average of 1.4 h/week (range 0-6 h/week); post-operatively, 36/42 (85.7 %) participated in sport and recreational activities for an average of 3.5 h/week (range 0-15 h/week). Meary's angle improved significantly from 11.5 ± 6.2 degrees preoperatively to 7.0 ± 5.7 degrees at final follow-up (p < 0.01); calcaneal pitch improved significantly from 16.5 ± 4.6 degrees to 19.0 ± 5.0 degrees (p < 0.01). At final follow-up, patients demonstrated good SAFASs in symptom tolerance (86.4 %), pain tolerance (89.0 %), daily living performance (96.1 %), and sports performance (86.7 %). The majority of patients returned to sports and recreational activity after medial displacement calcaneal osteotomy and flexor digitorum longus for the treatment of adult flatfoot associated with posterior tibial tendon dysfunction. III.


Children's refractions and visual activities in the school year and summer.
To investigate the association of children's refractive errors with their visual activities assessed by questionnaire in the school year and summer break (June, July, and August). The parents of 147 children aged 6 to 18 years participating in a longitudinal study of refraction and visual function filled out a questionnaire in 1999 listing the number of weekly hours outside of school that the children read for pleasure, studied, watched TV, used the computer/played video games, and engaged in sports/outdoor activities. They also provided hours for these activities during the summer break. Refractions were measured annually by non-cycloplegic distance retinoscopy. Myopes refer to subjects who were myopic (spherical equivalent < -0.5 diopter) at the time of the survey and non-myopes (spherical equivalent refraction > or = -0.5 diopter) were emmetropic or in a few cases hyperopic at survey time. During the school year, myopes spent significantly fewer hours (8.25 +/- 6.24 h/week) than non-myopes (10.95 +/- 5.95 h/week) in sports/outdoor activity (p < 0.05). In addition, myopes (12.78 +/- 9.28 h/week) watched more television than non-myopes (8.91 +/- 5.95 h/week) (p = 0.02). No significant refractive group differences were found for other activities. During the summer break, no significant differences were found between refractive groups in any visual activity times. No significant correlations between sports/outdoor activity and TV time were found. Overall, the biggest differences between summer and school activity times were found in outdoor activity (21.76 +/- 13.80 vs.10.34 +/- 6.10 h/week; p < 0.001) and studying (1.69 +/- 3.71 vs. 9.51 +/- 6.96 h/week; p < 0.001). In agreement with other studies, the non-myopes had more hours of sports/outdoor activity during the school year, which may protect against myopia development. A new finding is the high number of sports/outdoor activity hours for both myopes and non-myopes during the summer break, which may contribute to slowed eye growth in all children during these 3 months.


Motivational processing of food cues in anorexia nervosa: a pilot study.
Current literature suggests an increased attentional bias toward food stimuli in eating-disordered individuals compared to healthy controls. In line with these research efforts, the present study aims to investigate the processing of food stimuli (enriched by emotional stimuli) between patients diagnosed for anorexia nervosa (AN) and healthy controls by means of electroencephalography. Twenty-two female adolescents (eleven AN patients vs. eleven healthy controls) were investigated. Positive event-related potentials "P300" and "late positive potential" (LPP) reflecting attentional processing (caused by motivationally relevant stimuli) were investigated during passive viewing of the food cue picture stream. This method was used for the first time in a sample of individuals with AN. As a main result, AN patients exhibited a higher amount of attentional bias in P300 and LPP, while watching food stimuli. Moreover, AN patients rated food stimuli as less pleasant. For a conclusion, there is substantial evidence pointing to an abnormal attentional brain reactivity to food pictures in AN. Therefore, food stimuli seem to be more motivationally relevant for AN patients than for healthy controls. By broadening existing knowledge, these findings might bear some implications for the treatment for AN. However, further research is recommended in order to confirm the results coming from rather limited data.


A primer on dichotic listening as a paradigm for the assessment of hemispheric asymmetry.
Dichotic listening is a well-established method to non-invasively assess hemispheric specialization for processing of speech and other auditory stimuli. However, almost six decades of research also have revealed a series of experimental variables with systematic modulatory effects on task performance. These variables are a source of systematic error variance in the data and, when uncontrolled, affect the reliability and validity of the obtained laterality measures. The present review provides a comprehensive overview of these modulatory variables and offers both guiding principles as well as concrete suggestions on how to account for possible confounding effects and avoid common pitfalls. The review additionally provides guidance for the evaluation of past studies and help for resolving inconsistencies in the available literature.


Significance of anti-A and anti-B isohemagglutinins in cord blood of ABO incompatible newborn infants: correlation with hyperbilirubinemia.
Transcutaneous bilirubin index measurements (TcBI) were determined in ABO-incompatible term white newborn infants who had an indirect Coombs' test for detection of ABO incompatibility (ABO test) performed on cord blood. Serial transcutaneous measurements in the first 72 hours of life in 63 ABO test positive (group I) and 31 ABO test negative (group II) infants were compared with a control group of 109 term ABO compatible infants (group III). During the first phase of this study, the accuracy of TcBI was confirmed in 33 infants who had serum bilirubin determinations demonstrating a correlation coefficient of r = 0.93 between the jaundice meter index reading and total serum bilirubin. Determination of total serum bilirubin using TcBI did not show any statistically significant differences when groups I, II, and III were compared for maximum serum bilirubin values. These results reveal that a positive ABO test does not increase the predictive value of hyperbilirubinemia in ABO-incompatible white newborn infants.


Population Genomics of Francisella tularensis subsp. holarctica and its Implication on the Eco-Epidemiology of Tularemia in Switzerland.
Whole genome sequencing (WGS) methods provide new possibilities in the field of molecular epidemiology. This is particularly true for monomorphic organisms where the discriminatory power of traditional methods (e.g., restriction enzyme length polymorphism typing, multi locus sequence typing etc.) is inadequate to elucidate complex disease transmission patterns, as well as resolving the phylogeny at high resolution on a micro-geographic scale. In this study, we present insights into the population structure of Francisella tularensis subsp. holarctica, the causative agent of tularemia in Switzerland. A total of 59 Fth isolates were obtained from castor bean ticks (Ixodes ricinus), animals and humans and a high resolution phylogeny was inferred using WGS methods. The majority of the Fth population in Switzerland belongs to the west European B.11 clade and shows an extraordinary genetic diversity underlining the old evolutionary history of the pathogen in the alpine region. Moreover, a new B.11 subclade was identified which was not described so far. The combined analysis of the epidemiological data of human tularemia cases with the whole genome sequences of the 59 isolates provide evidence that ticks play a pivotal role in transmitting Fth to humans and other vertebrates in Switzerland. This is further underlined by the correlation of disease risk estimates with climatic and ecological factors influencing the survival of ticks.


Baseline lipid levels rather than the presence of reported body shape changes determine the degree of improvement in lipid levels after switching to atazanavir.
To study factors influencing lipid changes after switching to atazanavir (ATV) and the effectiveness of ATV in maintaining virus suppression. Retrospective cohort study in patients with viral suppression, comparing patients switching to ATV with those continuing combination antiretroviral therapy (cART). Outcome measures were 48-week total (TC), high-density (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) changes, stratified for dyslipidemia and lipodystrophy and virological failure (time to first of two consecutive detectable HIV RNA). 225 patients switched to ATV (193 [85.8%] RTV boosted), and 3120 continued cART. In patients with baseline TC >6.2 mmol/L, those switching had greater mean (95% CI) TC decreases compared to those continuing cART (-1.26 [-1.63 to -0.89] and -0.54 [-0.64 to -0.44] mmol/L, p = .002). Likewise greater TG changes were observed in patients with high (>2.3 mmol/L) baseline TG (-1.44 [-2.05 to -0.83] and -0.54 [-0.70 to -0.38] mmol/L, p = .002). Effects were seen irrespective of presence of lipodystrophy. Patients switching to ATV had virological failure more often (17/224 [7.8%]) than those continuing cART (73/3100 [2.4%], p < .0001). Patients with virological suppression, including those with lipodystrophy, may benefit from switching to ATV with lipid profile improvement, especially if baseline lipid levels are high. This should be balanced against a possible higher virological failure risk.


Using outcomes data to identify best medical practice: the role of policy models.
Increasingly, physicians are attempting to incorporate best evidence into their clinical decision making. However, best evidence takes a variety of forms, including clinical trials, cohort studies, administrative data, and patient preference data. Incorporating multiple data sources in a way that informs complex clinical decisions is a substantial analytical challenge. One approach to this challenge is to develop a simulation/decision model that explicitly represents the natural history of disease and the impact of treatments on that natural history. The model should be requisite--that is, sufficient in form to address the decision problem--but not overly complex. Such a model can be of value because it (1) allows a variety of viewpoints to be considered, (2) incorporates the best scientific evidence, and (3) permits sensitivity analyses to evaluate the impact of alternative clinical scenarios and uncertainty in model inputs. The Stroke Prevention Policy Model (SPPM) illustrates this approach. The SPPM is a simulation model designed to predict the best among various treatment alternatives for preventing strokes. Similar models can be applied to treatment outcomes for liver disease.


Crystal structure of the ribonucleoprotein core of the signal recognition particle.
The signal recognition particle (SRP), a protein-RNA complex conserved in all three kingdoms of life, recognizes and transports specific proteins to cellular membranes for insertion or secretion. We describe here the 1.8 angstrom crystal structure of the universal core of the SRP, revealing protein recognition of a distorted RNA minor groove. Nucleotide analog interference mapping demonstrates the biological importance of observed interactions, and genetic results show that this core is functional in vivo. The structure explains why the conserved residues in the protein and RNA are required for SRP assembly and defines a signal sequence recognition surface composed of both protein and RNA.


Colonization of a marker and field strain of Salmonella enteritidis and a marker strain of Salmonella typhimurium in vancomycin-pretreated and nonpretreated laying hens.
This study was conducted to evaluate the influence of a vancomycin pretreatment on the ability of marker (nalidixic-acid resistant) Salmonella Enteritidis (SE(M)), field Salmonella Enteritidis (SE(E)), and marker Salmonella Typhimurium (ST(M)) strains to colonize within the intestinal and reproductive tracts and translocate to other organs of leghorn laying hens. In each of three trials, caged laying hens (76, 26, and 33 wk ofage) were divided into six groups designated to receive SE(M), SE(F), or ST(M), and half were pretreated with vancomycin (n = 11-12 hens). Vancomycin-treated hens received 10 mg vancomycin in saline/kilogram body weight orally for 5 days to inhibit Gram-positive bacteria within the intestines. On Day 6, all hens were concurrently challenged by oral, intravaginal, and intracolonal routes with Salmonella and placed into separate floor chambers by Salmonella strain. Two weeks postinoculation, all hens were euthanatized and the ceca, spleen, liver/gall bladder (LGB), upper (URT), and lower (LRT) reproductive tracts, and ovarian follicles were aseptically collected, and analyzed for Salmonella. Results did not differ for the three hen's ages and were therefore combined. The vancomycin pretreatment also had no significant effect on the colonization ability of SE(M), SE(F) or ST(M), and therefore results were combined within Salmonella strain. The marker strain of Salmonella Enteritidis was recovered from 21% of ceca, 4% of LGB, 9% of LRT, and 17% of the fecal samples. The field strain of Salmonella Enteritidis was recovered from 88% of ceca, 96% of spleen, 92% of LGB, 30% of LRT, 4% of URT, 13% of follicle, and 42% of the fecal samples. The marker strain of Salmonella Typhimurium was recovered from 100% of ceca, 74% of spleen, 91% of LGB, 30% of LRT, 9% of URT, 9% of follicle, and 100% of the fecal samples. Among ceca, spleen, LGB, and fecal samples, SE(F) and ST(M) colonization was significantly greater than SE(M) colonization. Overall prevalence of Salmonella in the reproductive tracts of challenged hens was relatively low, ranging from 4% to 30%.


Validity of the t-plot method to assess microporosity in hierarchical micro/mesoporous materials.
The t-plot method is a well-known technique which allows determining the micro- and/or mesoporous volumes and the specific surface area of a sample by comparison with a reference adsorption isotherm of a nonporous material having the same surface chemistry. In this paper, the validity of the t-plot method is discussed in the case of hierarchical porous materials exhibiting both micro- and mesoporosities. Different hierarchical zeolites with MCM-41 type ordered mesoporosity are prepared using pseudomorphic transformation. For comparison, we also consider simple mechanical mixtures of microporous and mesoporous materials. We first show an intrinsic failure of the t-plot method; this method does not describe the fact that, for a given surface chemistry and pressure, the thickness of the film adsorbed in micropores or small mesopores (< 10σ, σ being the diameter of the adsorbate) increases with decreasing the pore size (curvature effect). We further show that such an effect, which arises from the fact that the surface area and, hence, the free energy of the curved gas/liquid interface decreases with increasing the film thickness, is captured using the simple thermodynamical model by Derjaguin. The effect of such a drawback on the ability of the t-plot method to estimate the micro- and mesoporous volumes of hierarchical samples is then discussed, and an abacus is given to correct the underestimated microporous volume by the t-plot method.


Generation of stable reporter breast cancer cell lines for the identification of ER subtype selective ligands.
Estrogen signaling is mediated by two estrogen receptors (ERs), ERα and ERβ, which have unique roles in the regulation of breast cancer cell proliferation. ERα induces proliferation in response to estrogen and ERβ inhibits proliferation in breast cancer cells, suggesting that ERβ selective ligands may be beneficial for promoting the anti-proliferative action of ERβ. Subtype selective ligands can be identified using transcriptional assays, but cell lines in which ERα or ERβ are independently expressed are required. Of the available reporter cell lines, none have been generated in breast cancer cells to identify subtype selective ligands. Here we describe the generation of two isogenic breast cancer cell lines, Hs578T-ERαLuc and Hs578T-ERβLuc, with stable integration of an estrogen responsive luciferase reporter gene. Hs578T-ERαLuc and Hs578T-ERβLuc cell lines are highly sensitive to estrogenic chemicals and ER subtype selective ligands, providing a tool to characterize the transcriptional potency and subtype selectivity of estrogenic ligands in the context of breast cancer cells. In addition to measuring reporter activity, ERβ target gene expression and growth inhibitory effects of ERβ selective ligands can be determined as biological endpoints. The finding that activation of ERβ by estrogen or ERβ selective natural phytoestrogens inhibits the growth of Hs578T-ERβ cells implies therapeutic potential for ERβ selective ligands in breast cancer cells that express ERβ.


Nutritional consequences of radiotherapy.
Curative doses of radiotherapy, when directed to any portion of the gastrointestinal tract, may result in serious nutritional consequences from the effects of radiation on the altered function of normal tissues. Symptoms from radiotherapy resulting in nutritional alterations are usually dependent upon dose, time, and fractionation of radiation administered, and the volume included in the treatment field. These effects directly related to radiation may be enhanced by other associated cancer therapy, e.g., surgery or chemotherapy. Careful observation and prompt attention to supportive therapy are mandatory to minimize the nutritional consequences of radiation injury. Well-designed clinical trials are necessary to demonstrate any possible increased tolerance to radiation therapy and the preventative benefits of nutritional support.


CO2 exchange and thallus nitrogen across 75 contrasting lichen associations from different climate zones.
Aiming to investigate whether a carbon-to-nitrogen equilibrium model describes resource allocation in lichens, net photosynthesis (NP), respiration (R), concentrations of nitrogen (N), chlorophyll (Chl), chitin and ergosterol were investigated in 75 different lichen associations collected in Antarctica, Arctic Canada, boreal Sweden, and temperate/subtropical forests of Tenerife, South Africa and Japan. The lichens had various morphologies and represented seven photobiont and 41 mycobiont genera. Chl a, chitin and ergosterol were used as indirect markers of photobiont activity, fungal biomass and fungal respiration, respectively. The lichens were divided into three groups according to photobiont: (1) species with green algae, (2) species with cyanobacteria, and (3) tripartite species with green algal photobionts and cyanobacteria in cephalodia. Across species, thallus N concentration ranged from 1 to 50 mg g-1 dry wt., NP varied 50-fold, and R 10-fold. In average, green algal lichens had the lowest, cyanobacterial Nostoc lichens the highest and tripartite lichens intermediate N concentrations. All three markers increased with thallus N concentration, and lichens with the highest Chl a and N concentrations had the highest rates of both P and R. Chl a alone accounted for ca. 30% of variation in NP and R across species. On average, the photosynthetic efficiency quotient [K F=(NPmax+R)/R)] ranged from 2.4 to 8.6, being higher in fruticose green algal lichens than in foliose Nostoc lichens. The former group invested more N in Chl a and this trait increased NPmax while decreasing R. In general terms, the investigated lichens invested N resources such that their maximal C input capacity matched their respiratory C demand around a similar (positive) equilibrium across species. However, it is not clear how this apparent optimisation of resource use is regulated in these symbiotic organisms.


Persistent organic pollutants in the Atlantic and southern oceans and oceanic atmosphere.
Persistent organic pollutants (POPs) continue to cycle through the atmosphere and hydrosphere despite banned or severely restricted usages. Global scale analyses of POPs are challenging, but knowledge of the current distribution of these compounds is needed to understand the movement and long-term consequences of their global use. In the current study, air and seawater samples were collected Oct. 2007-Jan. 2008 aboard the Icebreaker Oden en route from Göteborg, Sweden to McMurdo Station, Antarctica. Both air and surface seawater samples consistently contained α-hexachlorocyclohexane (α-HCH), γ-HCH, hexachlorobenzene (HCB), α-Endosulfan, and polychlorinated biphenyls (PCBs). Sample concentrations for most POPs in air were higher in the northern hemisphere with the exception of HCB, which had high gas phase concentrations in the northern and southern latitudes and low concentrations near the equator. South Atlantic and Southern Ocean seawater had a high ratio of α-HCH to γ-HCH, indicating persisting levels from technical grade sources. The Atlantic and Southern Ocean continue to be net sinks for atmospheric α-, γ-HCH, and Endosulfan despite declining usage.


The relationship of NT-proBNP and dialysis parameters with outcome of incident haemodialysis patients: results from the membrane permeability outcome study.
The association of raised levels of natriuretic peptides with elevated risk of mortality was investigated in the present analysis of the Membrane Permeability Outcome study. N-terminal probrain type natriuretic peptide (NT-proBNP) was measured in 618 incident haemodialysis patients, randomised to either high-flux or low-flux. Characteristics of patients with NT-proBNP levels below or above the median were descriptively analysed and survival analysis was performed. Median NT-proBNP value was 2,124 pg/ml, with 1,854 pg/ml in the high-flux and 2,919 pg/ml in the low-flux group. Survival probability was lowest in patients with both a history of cardiovascular disease and NT-proBNP values above the median (p < 0.001). A multivariate Cox proportional hazard model showed interaction between presence of cardiovascular diseases and NT-proBNP levels above the median. NT-proBNP is an independent predictor of mortality also in incident haemodialysis patients. Lower concentrations associated with high-flux dialysis suggest a possible biological link to improved survival in this group.


Fiber optic pH sensor with self-assembled polymer multilayer nanocoatings.
A fiber-optic pH sensor based on a tilted fiber Bragg grating (TFBG) with electrostatic self-assembly multilayer sensing film is presented. The pH sensitive polymeric film, poly(diallyldimethylammonium chloride) (PDDA) and poly(acrylic acid) (PAA) was deposited on the circumference of the TFBG with the layer-by-layer (LbL) electrostatic self-assembly technique. The PDDA/PAA film exhibits a reduction in refractive index by swelling in different pH solutions. This effect results in wavelength shifts and transmission changes in the spectrum of the TFBG. The peak amplitude of the dominant spectral fringes over a certain window of the transmission spectrum, obtained by FFT analysis, has a near-linear pH sensitivity of 117 arbitrary unit (a.u.)/pH unit and an accuracy of ±1 a.u. (in the range of pH 4.66 to pH 6.02). The thickness and surface morphology of the sensing multilayer film were characterized to investigate their effects on the sensor's performance. The dynamic response of the sensor also has been studied (10 s rise time and 18 s fall time for a sensor with six bilayers of PDDA/PAA).


One slide fits all: the versatility of slide tracheoplasty with cardiopulmonary bypass support for airway reconstruction in children.
This study describes results of tracheal reconstruction in children with slide tracheoplasty with cardiopulmonary bypass and identifies predictors for adverse outcomes. Preoperative characteristics, operative variables, and outcome measures were collected for children undergoing slide tracheoplasty with cardiopulmonary bypass between April 2001 and October 2009. Predictors of worse outcomes were identified by bivariate analysis. Multiple regression analysis was performed for predictors of prolonged hospital stay. Cohort included 80 patients (median age, 8.7 months; 7 days-21 years). Forty-eight patients had associated cardiac or great vessel anomalies; 24 had simultaneous repair of cardiovascular anomaly at tracheal reconstruction. Fifty (63%) were extubated within 48 hours after operation. Median stay was 18.5 days (range, 7-119 days). Twenty-three patients (29%) required significant airway reintervention during median follow-up of 12 months (range, 4 months-7.8 years). There were 4 deaths, 2 early and 2 late. In bivariate analysis, age (P = .017), cardiopulmonary bypass duration (P = .025), and duration of mechanical ventilation (P < .05) were associated with mortality; duration of postoperative mechanical ventilation was associated with need for significant airway reintervention (P = .009). Multiple regression analysis indicated preoperative ventilatory support (P < .001), longer cardiopulmonary bypass (P = .002), previous airway operation (P = .01), and need for significant airway reintervention (P < .001) as predictors of longer hospital stay. Slide tracheoplasty with cardiopulmonary bypass can be performed with low mortality in a diverse pediatric population. This technique minimizes need for early significant airway reintervention in most cases.


Longitudinal associations between prepubertal childhood total energy and macronutrient intakes and subsequent puberty timing in UK boys and girls.
Early puberty is associated with adverse health outcomes. To identify potential modifiable factors for puberty timing, we examined the associations of prepubertal childhood macronutrient intakes with puberty timing in boys and girls. In the Avon Longitudinal Study of Parents and Children, macronutrient intakes at age 6 years were predicted using random intercepts linear regression models of dietary data at 3, 4, 7 (assessed by food frequency questionnaires) and 7.5 years (by 3-day food diaries). Timings of puberty onset (Tanner stage 2 genital or breast (B2) development) and puberty completion (voice breaking (VB) or menarche) were calculated from annual parental and child reports at 8-17 years. Age at peak height velocity (PHV) was derived from repeated height measurements at 5-20 years. Linear regression models were fit to estimate the associations of total energy (TEI) and macronutrient intakes (carbohydrate, fat, protein) with puberty timing traits, adjusting for maternal and infant characteristics. Among 3811 boys, higher TEI, but no macronutrient, was associated with earlier VB. Among 3919 girls, higher TEI was associated with earlier ages at B2, PHV, and menarche. Higher protein intake but not carbohydrate or fat intake (in energy partition models) and substitution of dietary protein for carbohydrate (in nutrient density and residual models) was associated with earlier B2, PHV, and menarche in girls. Findings were not attenuated on additional adjustment for body fat percentage during adolescence. These findings suggest habitual total energy intakes in children, and protein intakes in girls, as potential modifiable determinants of puberty timing.


Nationwide survey of partial fundoplication in Korea: comparison with total fundoplication.
Laparoscopic total fundoplication is the standard surgery for gastroesophageal reflux disease. However, partial fundoplication may be a viable alternative. Here, we conducted a nationwide survey of partial fundoplication in Korea. The Korean Anti-Reflux Surgery study group recorded 32 cases of partial fundoplication at eight hospitals between September 2009 and January 2016. The surgical outcomes and postoperative adverse symptoms in these cases were evaluated and compared with 86 cases of total fundoplication. Anterior partial fundoplication was performed in 20 cases (62.5%) and posterior in 12 (37.5%). In most cases, partial fundoplication was a secondary procedure after operations for other conditions. Half of patients who underwent partial fundoplication had typical symptoms at the time of initial diagnosis, and most of them showed excellent (68.8%), good (25.0%), or fair (6.3%) symptom resolution at discharge. Compared to total fundoplication, partial fundoplication showed no difference in the resolution rate of typical and atypical symptoms. However, adverse symptoms such as dysphagia, difficult belching, gas bloating and flatulence were less common after partial fundoplication. Although antireflux surgery is not popular in Korea and total fundoplication is the primary surgical choice for gastroesophageal reflux disease, partial fundoplication may be useful in certain conditions because it has less postoperative adverse symptoms but similar efficacy to total fundoplication.


Mediterranean diet and telomere length in high cardiovascular risk subjects from the PREDIMED-NAVARRA study.
A healthy lifestyle has been associated with longer telomeres, but whether Mediterranean Diet (MeDiet) affect telomere length (TL) has not been fully elucidated yet. Our aim was to assess the relationship between MeDiet and TL in high cardiovascular risk subjects in the context of a randomized nutritional intervention trial. We assessed 520 participants (55-80 years, 55% women) from the PREDIMED-NAVARRA trial. Leukocyte TL was measured by qPCR at baseline and after 5 years of a dietary intervention program where subjects were randomly assigned to a low-fat control diet or to two MeDiets, one supplemented with extra virgin olive oil (MeDiet-EVOO) and the other with mixed nuts (MeDiet-nuts). A validated 14-item questionnaire was used to appraise baseline adherence of participants to the MeDiet. Better adherence to MeDiet (as appraised by the 14-item score) was associated with longer basal telomeres in women in the baseline cross-sectional analysis, whereas the opposite was observed in men (P interaction = 0.036). Female subjects who scored 10 points had longer basal telomeres (0.27, 95% CI: 0.03-0.52) than women scoring ≤6 points at the beginning of the study (-0.46, 95% CI: -0.85 to -0.7) (P = 0.003). However, allocation to the MeDiet-nuts group (-0.24, 95% CI: -0.38 to -0.01) was associated with a higher risk of telomere shortening after 5 years of intervention, whereas no differences were found for the MeDiet-EVOO group (0.14, 95% CI: 0.02-0.27), in comparison with the Control group (0.07, 95% CI: -0.08 to 0.23) (P = 0.003 and P = 0.537, respectively). A greater baseline adherence to a Mediterranean dietary pattern was associated with longer telomeres only in women. No beneficial effect of the intervention with the MeDiet for the prevention of telomere shortening in comparison with a low-fat diet was observed.


A gene variant in CERS2 is associated with rate of increase in albuminuria in patients with diabetes from ONTARGET and TRANSCEND.
Although albuminuria and subsequent advanced stage chronic kidney disease are common among patients with diabetes, the rate of increase in albuminuria varies among patients. Since genetic variants associated with estimated glomerular filtration rate (eGFR) were identified in cross sectional studies, we asked whether these variants were also associated with rate of increase in albuminuria among patients with diabetes from ONTARGET and TRANSCEND-randomized controlled trials of ramipril, telmisartan, both, or placebo. For 16 genetic variants associated with eGFR at a genome-wide level, we evaluated the association with annual rate of increase in albuminuria estimated from urine albumin:creatinine ratio (uACR). One of the variants (rs267734) was associated with rate of increase in albuminuria. The annual rate of increase in albuminuria among risk homozygotes (69% of the study population) was 11.3% (95%CI; 7.5% to 15.3%), compared with 5.0% (95%CI; 3.3% to 6.8%) for heterozygotes (27% of the population), and 1.7% (95%CI; -1.7% to 5.3%) for non-risk homozygotes (4% of the population); P = 0.0015 for the difference between annual rates in the three genotype groups. These estimates were adjusted for age, sex, ethnicity, and principal component of genetic heterogeneity. Among patients without albuminuria at baseline (uACR<30 mg/g), each risk allele was associated with 50% increased risk of incident albuminuria (OR = 1.50; 95%CI 1.15 to 1.95; P = 0.003) after further adjustment for traditional risk factors including baseline uACR and eGFR. The rs267734 variant is in almost perfect linkage-disequilibrium (r2 = 0.94) with rs267738, a single nucleotide polymorphism encoding a glutamic acid to alanine change at position 115 of the ceramide synthase 2 (CERS2) encoded protein. However, it is unknown whether CERS2 function influences albuminuria. In conclusion, we found that rs267734 in CERS2 is associated with rate of increase in albuminuria among patients with diabetes and elevated risk of cardiovascular disease.


A phase 3 randomized study evaluating sialic acid extended-release for GNE myopathy.
To investigate the efficacy and safety of aceneuramic acid extended-release (Ace-ER), a treatment intended to replace deficient sialic acid, in patients with GNE myopathy. UX001-CL301 was a phase 3, double-blind, placebo-controlled, randomized, international study evaluating the efficacy and safety of Ace-ER in patients with GNE myopathy. Participants who could walk ≥200 meters in a 6-minute walk test at screening were randomized 1:1, and stratified by sex, to receive Ace-ER 6 g/d or placebo for 48 weeks and assessed every 8 weeks. The primary endpoint was change in muscle strength over 48 weeks measured by upper extremity composite (UEC) score. Key secondary endpoints included change in lower extremity composite (LEC) score, knee extensor strength, and GNE myopathy-Functional Activity Scale (GNEM-FAS) mobility domain score. Safety assessments included adverse events (AEs), vital signs, and clinical laboratory results. Eighty-nine patients were randomized (Ace-ER n = 45; placebo n = 44). Change from baseline to week 48 for UEC score between treatments did not differ (least square mean [LSM] Ace-ER -2.25 kg vs placebo -2.99 kg; LSM difference confidence interval [CI] 0.74 [-1.61 to 3.09]; p = 0.5387). At week 48, there was no significant difference between treatments for the change in key secondary endpoints: LEC LSM difference (CI) -1.49 (-5.83 to 2.86); knee extension strength -0.40 (-2.38 to 1.58); and GNEM-FAS mobility domain score -0.72 (-2.01 to 0.57). Gastrointestinal events were the most common AEs. Ace-ER was not superior to placebo in improving muscle strength and function in patients with GNE myopathy. This study provides Class I evidence that for patients with GNE myopathy, Ace-ER does not improve muscle strength compared to placebo.


Sonication assisted preparation of graphene oxide/graphitic-C₃N₄ nanosheet hybrid with reinforced photocurrent for photocatalyst applications.
Graphitic C3N4 (g-C3N4), as an advanced metal free photocatalyst, is known to be poorly exfoliated and dispersed in water from its powder form which has a layered structure, the intrinsic plane structure is not destroyed, and this has largely limited its application. In this work, we report our progress on successful sonication exfoliation of g-C3N4 nanosheets in graphene oxide (GO) aqueous solution. By making use of the substrate character of GO, g-C3N4 nanosheets of unvaried intrinsic structure were exfoliated and anchored on the GO surface, resulting in a GO/g-C3N4 hybrid. Moreover, the photocurrent of the hybrid was largely reinforced at the optimal weight fraction of GO. As a result, the corresponding photocatalytic performance of the hybrid with optimized photocurrent character was largely improved.


Amplification of KP elements associated with the repression of hybrid dysgenesis in Drosophila melanogaster.
Mobile P elements in Drosophila melanogaster cause hybrid dysgenesis if their mobility is not repressed. One type of repression, termed P cytotype, is a complex interaction between chromosomes carrying P elements and cytoplasm and is transmitted through the cytoplasm only of females. Another type of repression is found in worldwide M' strains that contain approximately 30 copies per individual of one particular P element deletion-derivative termed the KP element. This repression is transmitted equally through both sexes. In the present study we show that biparentally transmitted repression increases in magnitude together with a rapid increase in KP copy-number in genotypes starting with one or a few KP elements and no other deletion-derivatives. Such correlated increases in repression and KP number per genome occur only in the presence of complete P elements, supporting the interpretation that they are probably a consequence of the selective advantage enjoyed by flies carrying the highest numbers of KP elements. Analysis of Q strains also reveals the presence of qualitative differences in the way the repression of dysgenesis is transmitted. In general, Q strains not containing KP elements have the P cytotype mode of repression, whereas Q strains with KP elements transmit repression through both sexes. This difference among Q strains further supports the existence of at least two types of repression of P-induced hybrid dysgenesis in natural populations of D. melanogaster.


Anti-capsular antibodies activate killing of Escherichia coli O8:K87 by the alternate complement pathway in porcine serum.
Enterotoxigenic Escherichia coli (ETEC) strains that produce K88 (F4)+ fimbria are important causes of diarrhea and post-diarrheal septicemia in swine. ETEC O8:K87, a serotype represented by a number of these strains, is typically serum resistant. Strain-specific antibodies are known to activate alternative C pathway-mediated killing of other serum-resistant E. coli [Hill, A.W., Shears, A.L., Hibbitt, K.G., 1978. The requirement of specific antibody for the killing of E. coli by the alternate complement pathway in bovine serum. Immunology 34, 131-136], but their antigenic targets have not been determined. We tested the hypothesis that anti-K87 antibodies activate alternative pathway-mediated killing of ETEC O8:K87. Pigs were immunized with ETEC O8:K87 strain 2534-86 cells or purified K87 polysaccharide. Post-, but not pre-immunization sera killed 2534-86 cells, and absorption with 2534-86 cells or by K87 affinity chromatography eliminated bactericidal activity. Complementation of absorbed serum with anti-K87 antibodies restored bactericidal activity, confirming the ability of these antibodies to activate C-mediated serum killing. Serum from age-matched, non-vaccinated control pigs also killed 2534-86. This activity was eliminated by absorption with 2534-86 cells, but not K87 affinity chromatography, indicating that specific non-capsular antibodies are also able to activate C-mediated killing. In all cases, Mg-EGTA-treated serum was as effective as non-treated serum in killing, suggesting that bactericidal activity was mediated predominantly if not exclusively via the alternative C pathway.


Assessment of Fatigue and Recovery in Male and Female Athletes After 6 Days of Intensified Strength Training.
Raeder, C, Wiewelhove, T, Simola, RÁDP, Kellmann, M, Meyer, T, Pfeiffer, M, and Ferrauti, A. Assessment of fatigue and recovery in male and female athletes after 6 days of intensified strength training. J Strength Cond Res 30(12): 3412-3427, 2016-This study aimed to analyze changes of neuromuscular, physiological, and perceptual markers for routine assessment of fatigue and recovery in high-resistance strength training. Fourteen male and 9 female athletes participated in a 6-day intensified strength training microcycle (STM) designed to purposefully overreach. Maximal dynamic strength (estimated 1 repetition maximum [1RMest]; criterion measure of fatigue and recovery); maximal voluntary isometric strength (MVIC); countermovement jump (CMJ) height; multiple rebound jump (MRJ) height; jump efficiency (reactive strength index, RSI); muscle contractile properties using tensiomyography including muscle displacement (Dm), delay time (Td), contraction time (Tc), and contraction velocity (V90); serum concentration of creatine kinase (CK); perceived muscle soreness (delayed-onset muscle soreness, DOMS) and perceived recovery (physical performance capability, PPC); and stress (MS) were measured before and after the STM and after 3 days of recovery. After completing the STM, there were significant (p ≤ 0.05) performance decreases in 1RMest (%[INCREMENT] ± 90% confidence limits, ES = effect size; -7.5 ± 3.5, ES = -0.21), MVIC (-8.2 ± 4.9, ES = -0.24), CMJ (-6.4 ± 2.1, ES = -0.34), MRJ (-10.5 ± 3.3, ES = -0.66), and RSI (-11.2 ± 3.8, ES = -0.73), as well as significantly reduced muscle contractile properties (Dm, -14.5 ± 5.3, ES = -0.60; V90, -15.5 ± 4.9, ES = -0.62). After days of recovery, a significant return to baseline values could be observed in 1RMest (4.3 ± 2.8, ES = 0.12), CMJ (5.2 ± 2.2, ES = 0.28), and MRJ (4.9 ± 3.8, ES = 0.32), whereas RSI (-7.9 ± 4.5, ES = -0.50), Dm (-14.7 ± 4.8, ES = -0.61), and V90 (-15.3 ± 4.7, ES = -0.66) remained significantly reduced. The STM also induced significant changes of large practical relevance in CK, DOMS, PPC, and MS before to after training and after the recovery period. The markers Td and Tc remained unaffected throughout the STM. Moreover, the accuracy of selected markers for assessment of fatigue and recovery in relation to 1RMest derived from a contingency table was inadequate. Correlational analyses also revealed no significant relationships between changes in 1RMest and all analyzed markers. In conclusion, mean changes of performance markers and CK, DOMS, PPC, and MS may be attributed to STM-induced fatigue and subsequent recovery. However, given the insufficient accuracy of markers for differentiation between fatigue and recovery, their potential applicability needs to be confirmed at the individual level.


Talonavicular joint abnormalities and walking ability of patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) is often associated with deformities of the feet, and foot pain often arises in the talonavicular joint of patients with RA. The object of this study was to assess the relationship between magnetic resonance imaging (MRI) findings of the talonavicular joint and walking ability. The subjects were 35 RA patients (10 feet in 5 males and 56 feet in 30 females) aged 34-87 years (mean: 70 years +/- 12.1), with a disease duration from 1-54 years (mean: 14 years +/- 12.1). MRI findings were classified as follows: Grade 1, almost normal; Grade 2, early articular destruction; Grade 3, moderate articular destruction; Grade 4, severe articular destruction; and Grade 5, bony ankylosis dislocation. Walking ability was classified into one of 9 categories ranging from normal gait to bedridden status according to the system of Fujibayashi. As the grade of MRI images became higher the walking ability decreased, and these parameters showed a correlation by Spearman's rank correlation coefficient analysis (P = 0.003). Thus, in the present cohort group of patients with RA, the deterioration of walking ability increased with the severity of destruction of the talonavicular joint.


Difference in signalling between various hormone therapies in endometrium, myometrium and upper part of the vagina.
Combined hormone treatments in post-menopausal women have different clinical responses on uterus and vagina; therefore, we investigated differences in steroid signalling between various hormone therapies in these tissues. A total of 30 post-menopausal women scheduled for hysterectomy were distributed into four subgroups: control-group (n = 9), Tibolone-group (n = 8); estradiol (E(2))-group (n = 7); E(2) + medroxyprogesterone acetate (MPA)-group (n = 6). Medication was administered orally every day for 21 days prior to removal of uterus and upper part of the vagina. Tissue RNA was isolated, and gene expression profiles were generated using GeneChip technology and analysed by cluster analysis and significance analysis of microarrays. Apoptosis and cell proliferation assays, as well as immunohistochemistry for hormone receptors were performed. 21-days of treatment with E(2), E(2) + MPA or tibolone imposes clear differential gene expression profiles on endometrium and myometrium. Treatment with E(2) only results in the most pronounced effect on gene expression (up to 1493 genes differentially expressed), proliferation and apoptosis. Tibolone, potentially metabolized to both estrogenic and progestagenic metabolites, shows some resemblance to E(2) signalling in the endometrium and, in contrast, shows significant resemblance to E(2) + MPA signalling in the myometrium. In the vagina the situation is entirely different; all three hormonal treatments result in regulation of a small number (4-73) of genes, in comparison to signalling in endometrium and myometrium. Endometrium and myometrium differentially respond to the hormone therapies and use completely different sets of genes to regulate similar biological processes, while in this experiment the upper part of the vagina is hardly hormone responsive.


A Case of Salicylate Toxicity Presenting with Acute Focal Neurologic Deficit in a 61-Year-Old Woman with a History of Stroke.
BACKGROUND Over-the-counter medications that contain aspirin are widely used, and patients generally regard them as safe. However, the side effects of salicylate toxicity can be severe, and delay in the diagnosis may increase the risk of mortality. Neurologic symptoms are a common presenting feature of salicylate toxicity in the elderly, and their recognition may allow earlier diagnosis. This report is of a case of a 61-year-old woman who presented with acute focal neurologic deficit associated with salicylate toxicity and who had a previous history of stroke. CASE REPORT A 61-year-old woman presented to the Emergency Department after awakening with left-sided weakness. She had a history of ischemic stroke with an associated seizure disorder. The patient denied recent seizure, and brain magnetic resonance imaging (MRI) showed no evidence of an acute stroke. Following her arrival, she became acutely confused and complained of tinnitus, shortness of breath, and blurred vision. On direct questioning, she gave a history of excessive use of salicylate for the previous two to three weeks. Her initial serum salicylate level was significantly increased at 78.1 mg/dl (upper therapeutic limit, 19.9 mg/dl). She recovered completely following treatment with oral activated charcoal, intravenous sodium bicarbonate, and potassium replacement. CONCLUSIONS This case demonstrates that physicians should consider salicylate toxicity as a possible cause of exacerbation of neurological deficit in elderly patients.


Staging of rectal carcinoma: MDCT, MRI or EUS. Single center experience.
To retrospectively compare the efficacy of multidetector computed tomography (MDCT), magnetic resonance imaging (MRI) and endosonography (EUS) in the staging of rectal carcinoma. A total of 50 patients (36 male, 14 female) were included in the study. The data from surgical staging were used as reference for comparing the yield of EUS, MRI, and MDCT in preoperative T and N staging of rectal carcinoma. Comparisons were based on the chi-square test. The mean age+SD of the patients were 60±12 years (range; 28-80). The distribution of rectal tumors according to the T and N staging in surgical pathology was as following: T1 (n:2), T2 (n:15), T3 (n:22), T4 (n:11); N0 (n:22), N1-2 (n:28). The accuracy rate of EUS was statistically higher than that of MDCT (92% vs 64%; p<0.01) and that of MRI (92% vs 72%; p<0.01) for T2 tumors. For T3 tumors, EUS had statistically better accuracy of staging compared to MDCT (90% vs 58%; p<0.01) and MRI (90% vs 60%; p<0.01). As for T4 tumors, the accuracy rate of EUS was higher compared to MRI (98% vs 80%; p<0.01). There was no statistical difference in accuracy rates for detection of lymph nodes across the modalities (EUS, 84%; MDCT 76%; MRI 70%; p=not significant). EUS appears more accurate in T staging compared to MDCT and MRI in rectal carcinoma. Regarding nodal staging, performance of EUS, MDCT and MRI are similar.


Improvements in survival after follicular lymphoma by race/ethnicity and socioeconomic status: a population-based study.
A recent report suggested improvements in survival after follicular lymphoma (FL), but not for all racial/ethnic groups. To better understand the reasons for these FL survival differences, we examined the joint influences of diagnostic period, race/ethnicity, and neighborhood socioeconomic status (SES) on survival in a large population-based case series. All patients (n = 15,937) diagnosed with FL between 1988 and 2005 in California were observed for vital status through November 2007. Overall and FL-specific survival were analyzed with Kaplan-Meier and Cox proportional hazards regression. Neighborhood SES was assigned from United States Census data using residence at diagnosis. Overall and FL-specific survival improved 22% and 37%, respectively, from 1988 to 1997 to 1998 to 2005, and were observed in all racial/ethnic groups. Asian/Pacific Islanders had better survival than non-Hispanic white, Hispanic, and black patients who had similar outcomes. Lower neighborhood SES was associated with worse survival in patients across all stages of disease (P for trend < .01). Patients with the lowest SES quintile had a 49% increased risk of death from all causes (hazard ratio [HR] = 1.49, 95% CI, 1.30 to 1.72) and 31% increased risk of death from FL (HR = 1.31; 95% CI, 1.06 to 1.60) than patients with the highest SES. Evolving therapies have likely led to improvements in survival after FL. Although improvements have occurred within all racial/ethnic groups, lower neighborhood SES was significantly associated with substantially poorer survival.


Functional equivalence and rescue among group 11 Hox gene products in vertebral patterning.
Hoxa-11 and Hoxd-11 are paralogous genes required for proper development of the vertebral column, the limbs, and the urogenital system. To further explore the functional relationship between these genes, as well as the potential rescue of one function by the other, we have introduced a Hoxd-11-expressing transgene into Hoxa-11/Hoxd-11 mutant genetic backgrounds. A range of phenotypes was observed, with transgenic mice displaying as few as four lumbar vertebrae while double mutant mice had as many as eight. When transgenic, double homozygote mutant animals showed six lumbar vertebrae, instead of the eight usually observed. The phenotypic rescue of these genotypes shows that the Hoxa-11 and Hoxd-11 products are functionally equivalent and that extra doses of Hoxd-11 can rescue Hoxa-11 loss of function.


Dynamic atomic-level rearrangements in small gold particles.
Small metal particles (<5 nanometers), which are widely used in catalysis, have physical and chemical properties that are markedly different from those of the bulk metal. The differences are related to crystal structure, and it is therefore significant that structral rearrangements in small particles have been observed in real time by using high-resolution electron microscopy. A detailed investigation at the atomic level has been made of the factors affecting the dynamic activity of small gold crystals that are supported on thin films of amorphous carbon, silicon, and germanium. The rate of activity depends mainly on the current density of the incident electron beam and the degree of contact of the particle with the substrate, but this rate decreases rapidly as the particle size is increased. The activity of the particles is very similar on either carbon or silicon, but it is generally less marked on germanium because of increased contact between the particle and the substrate. The electron beam effectively heats the particles, and it appears that their dynamic behavior depends on their thermal contact with the substrate.


MxA Is a Novel Regulator of Endosome-Associated Transcriptional Signaling by Bone Morphogenetic Proteins 4 and 9 (BMP4 and BMP9).
There is confusion about the role that IFN-α plays in the pathogenesis of pulmonary arterial hypertension (PAH) with different investigators reporting a causative or a protective role. There is now clear evidence in PAH pathogenesis for the involvement of BMP4 and BMP9 signaling, and its disruption by mutations in BMPR2. In the present study, we investigated MxA, an IFN-α-inducible cytoplasmic dynamin-family GTPase for effects on BMP4/9 signaling, including in the presence of PAH-disease-associated mutants of BMPR2. In human pulmonary arterial endothelial cells (HPAECs), IFN-α-induced endogenous as well as exogenously expressed MxA was associated with endosomes that aligned alongside microtubules and tubules of the endoplasmic reticulum (ER). Moreover, IFN-α and MxA stimulated basal and BMP4/9 signaling to a Smad1/5/8-responsive pBRE-Luc reporter. In HEK293T cells, immunoelectron microscopy confirmed the association of MxA with endosomes, and immunofluorescence methods showed these to be positive for early endosome markers (early endosomal antigen 1, clathrin light chain and Rab5) and RSmad1/5/8. Functionally, using different genetic and inhibitor approaches, we observed that clathrin-mediated endocytosis enhanced and caveolin-mediated endocytosis inhibited the transcriptional response to BMP4 and BMP9. MxA produced a further 3-4-fold enhancement of the BMP-induced response in a clathrin-endocytosis dependent manner. The microtubule inhibitor nocodazole and stabilizer paclitaxel respectively attenuated and enhanced the effect of MxA, implicating microtubule integrity in this process. MxA enhanced BMP-induced signaling in the presence of wild-type BMPR2, and partially rescued signaling from some PAH-disease-associated BMPR2 mutants. Taken together, the data identify MxA as a novel stimulator of BMP4 and BMP9 transcriptional signaling, and suggest it to be a candidate IFN-α-inducible mechanism that might have a protective role against development of PAH and other vascular diseases.