Influence of structural properties and kinetic constraints on Bacillus cereus growth.
The influence of structural properties and kinetic constraints on the behavior of Bacillus cereus was investigated on agar media. Dimensional criteria were used to study the growth in bacterial colonies. The architecture of the agar gel as modified by the agar content was found to influence the colony size, and smaller colonies were observed on media containing 50 to 70 g of agar liter-1. Except at low nutrient levels, colonies responded to nutrient gradients by decreasing in size the farther away they were from the nutrient source, and the decrease in colony size was influenced by the agar content. The diffusivities of glucose and a protein (insulin-like growth factor) were not affected by the gel architecture, suggesting that other factors, such as mechanical factors, could influence microbial growth in the agar systems used. Increasing the viscosity of the liquid phase of the agar media by adding polyvinylpyrrolidone resulted in a reduction in colony size. When the agar concentration was increased, the colony areas were not influenced by the viscosity of the system.


Annexin-like alpha giardins: a new cytoskeletal gene family in Giardia lamblia.
Through a genome survey and phylogenetic analysis, we have identified and sequenced 14 new coding regions for alpha-giardins in Giardia lamblia. These proteins are related to annexins and comprise a multi-gene family with 21 members. Many alpha giardins are highly expressed proteins that are very immunogenic during acute giardiasis in humans. However, little is known about the function of these proteins. By using PCR with different combinations of gene-specific primers, we demonstrated that several of the genes localised to the same chromosomal fragment. These data point towards a molecular evolution through gene duplication and subsequent functional divergence. Semi-quantitative reverse transcriptase-PCR analysis of the Giardia life cycle revealed large differences in mRNA expression levels of the alpha giardins. Epitope tagging of the alpha-giardins localised them to different cytoskeletal components, such as the flagella and the adhesive disc, but also to the plasma membrane. These localisation experiments suggest alpha-giardins play a role in cell motility, attachment and membrane stability.


Comparison of calculated and measured free thyroid hormones in serum in health and in abnormal states.
To evaluate a theoretical model for calculating free thyroid hormones, based on the law of mass action, we compared values for both calculated and measured free thyroxin and free triiodothyronine in a group of normal subjects. To determine whether the concentrations of circulating free hormones were also predictable from equilibrium considerations in abnormal states, we compared calculated and measured free thyroid hormone values in an additional population including pregnant women and hyperthyroid, hypothyroid, and "sick euthyroid" patients. Predictions based on the model were accurate in all these states except pregnancy, where there was some discrepancy between calculated and measured values for both hormones. In pregnant women with large abnormalities in thyroid-hormone-binding proteins, euthyroidism was accompanied by significantly lower free hormone concentrations, leading us to conclude that, in pregnancy, equilibrium may be reached at concentrations lower than those in other healthy subjects. Values for calculated and measured free thyroid hormones in "sick euthyroids" showed no discrepancy; however, we cannot exclude the possibility that non-dialyzable compounds are present that interfere with the hormone-protein binding.


Metrizamide shuntography for evaluation of shunt malfunction in hydrocephalus.
Ventricular shunts were evaluated by a shuntographic technique using metrizamide for the contrast material and delayed spot films and computed tomography (CT) to evaluate shunt function. Thirty hydrocephalic patients were studied who had clinical presentations of shunt malfunction. Fifty-two shuntograms were obtained; most demonstrated the cause of shunt malfunction. No contrast-related complications resulted from the procedure. Diagnostic accuracy was greatly improved by this method, since both anatomic and functional evaluations could be performed. In patients with normal studies, unnecessary surgery was eliminated; in abnormal shuntograms, the duration of surgery and the likelihood of complications were reduced because the surgeons knew the exact anatomic derangements to be corrected.


c-FLIP downregulation contributes to apoptosis induction by the novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me) in human lung cancer cells.
The novel synthetic triterpenoid methyl-2-cyano-3, 12-dioxooleana-1, 9-dien-28-oate (CDDO-Me) induces apoptosis of cancer cells, enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis, and exhibits potent anticancer activity in animal models with a favorable pharmacokinetic profile. Thus, CDDO-Me is being tested in Phase I clinical trials. In an effort to understand the mechanism by which CDDO-Me induces apoptosis, particularly in human lung cancer cells, we previously demonstrated that CDDO-Me induces apoptosis involving c-Jun N-terminal kinase (JNK)-dependent upregulation of death receptor 5 (DR5) expression. In the current work, we determined the modulatory effects of CDDO-Me on the levels of c-FLIP, a major inhibitor of death receptor-mediated caspase-8 activation, and its impact on CDDO-Me-induced apoptosis and enhancement of TRAIL-induced apoptosis in human lung cancer cells. CDDO-Me rapidly and potently decreased c-FLIP levels including both long (FLIP(L)) and short (FLIP(S)) forms of c-FLIP in multiple human lung cancer cell lines. The presence of the proteasome inhibitor MG132, but not the JNK inhibitor SP600125, prevented CDDO-Me-induced c-FLIP reduction. Moreover, CDDO-Me increased ubiquitination of c-FLIP. Thus, CDDO-Me induces ubiquitin/proteasome-dependent c-FLIP degradation independently of JNK activation. Importantly, overexpression of c-FLIP (e.g., FLIP(L)) protected cells not only from CDDO-Me-induced apoptosis, but also from induction of apoptosis by the combination of CDDO-Me and TRAIL. Accordingly, silencing of c-FLIP with c-FLIP siRNA sensitized cancer cells to CDDO-Me. Collectively, these results indicate that c-FLIP downregulation contributes to CDDO-Me-initiated apoptosis and also to enhancement of TRAIL-induced apoptosis by CDDO-Me.


Seizures after very mild head or spine trauma.
Traumatic brain injury (TBI) is a major cause of seizures in the general population. Several studies have shown an increased risk of epilepsy after traumatic brain injury, depending on risk factors, such as severity and time post trauma. The aim of our study was to evaluate the appearance of late seizures after a very mild head trauma or whiplash injury. All patients admitted to the emergency room after a very mild head trauma or whiplash injury during 2008-2010 were evaluated prospectively within 24 hours of the event and followed up 1 year later for evaluation of seizure appearance. The appearance of seizures in the head trauma or whiplash injury group was compared to a control group of orthopedic injury patients. A total of 2999 patients were included in the study--2005 patients with involvement of head and spine trauma and 994 in an orthopedic control group. Three patients (0.1%) out of the whole study group developed seizures: 2 (0.18%) in the head trauma group and 1 (0.1%) in the control group. The conclusion of the study was that post trauma seizure incidence is not significantly different in patients with very mild head or spine trauma and is similar respective to subjects with no non-head or cervical spine injury. This may have medico-legal repercussions.


Family studies in glaucoma.
Two groups of patients with a family history of chronic open-angle glaucoma were compared with a normal population of 5919 individuals studied during the Bedford Glaucoma Survey. The mean screening intraocular pressure was significantly raised in both groups with a family history of chronic open-angle glaucoma. The prevalence rate of a raised intraocular pressure was 3.81 times that found in the normal population. This relationship was maintained when age-dependent prevalence rates were evaluated. No correlation between raised intraocular pressure and type of familial involvement could be determined. A 10- to 12-year follow-up of one group with a family history for open-angle glaucoma (101 patients) showed that 3% developed confirmed glaucoma, while an additional 5.9% were diagnosed as suspected chronic open-angle glaucoma. A letter survey of this group showed that 9 out of 63 respondents knew of additional family members who developed glaucoma over this 10-12-year period.


Retrospective review of endoscopic plantar fasciotomy. 1994 through 1997.
In the September 1996 issue of the Journal of the American Podiatric Medical Association, the authors published a retrospective review of their experiences with and results of plantar fasciotomy from 1992 through 1994. Since then, patients who underwent endoscopic plantar fasciotomy from 1994 through 1997 have been reviewed by utilizing materials and methods identical to those used in the original study. This article provides an update of the results of endoscopic plantar fasciotomy and compares them with the results described in the 1996 study.


Molecularly Imprinted Dispersive Solid-Phase Extraction for the Determination of Triazine Herbicides in Grape Seeds by High-Performance Liquid Chromatography.
Molecular imprinting technique, regarded as one of the current state-of-the-art researches, was incorporated with the simple dispersive solid-phase extraction (MI-DSPE) in this work for the extraction of triazine herbicides in grape seeds. The atrazine molecularly imprinted polymers (MIPs) were successfully prepared and characterized by scanning electron microscopy and Fourier transform infrared spectroscopy. The imprinting particles were used as the adsorbent in DSPE. Thus, a simple, rapid and selective method based on MIPs coupled with DSPE was established for the simultaneous cleaning-up and quantitative extraction of four triazine herbicides in grape seeds. The experiment parameters, including type of washing solvents, washing time and type of eluting solvents, were investigated and optimized. The performance of the present method was validated by high-performance liquid chromatography. Good linear responses were obtained in concentration range of 0.010-5.0 µg g(-1)with correlation coefficients (r(2)) higher than 0.9993. The recoveries at two spiked levels (1.0 and 2.0 µg g(-1)) were between 81.2 and 113.0% with relative deviations ranging from 1.2 to 10.7%. The limits of detection were ranged between 0.006 and 0.013 µg g(-1), which were lower than the values required by European regulations.


Placental Transcriptome Profiling in Subtypes of Diabetic Pregnancies Is Strongly Confounded by Fetal Sex.
The placenta is a temporary organ with a unique structure and function to ensure healthy fetal development. Placental dysfunction is involved in pre-eclampsia (PE), fetal growth restriction, preterm birth, and gestational diabetes mellitus (GDM). A diabetic state affects maternal and fetal health and may lead to functional alterations of placental metabolism, inflammation, hypoxia, and weight, amplifying the fetal stress. The placental molecular adaptations to the diabetic environment and the adaptive spatio-temporal consequences to elevated glucose or insulin are largely unknown (2). We aimed to identify gene expression signatures related to the diabetic placental pathology of placentas from women with diabetes mellitus. Human placenta samples (n = 77) consisting of healthy controls, women with either gestational diabetes mellitus (GDM), type 1 or type 2 diabetes, and women with GDM, type 1 or type 2 diabetes and superimposed PE were collected. Interestingly, gene expression differences quantified by total RNA sequencing were mainly driven by fetal sex rather than clinical diagnosis. Association of the principal components with a full set of clinical patient data identified fetal sex as the single main explanatory variable. Accordingly, placentas complicated by type 1 and type 2 diabetes showed only few differentially expressed genes, while possible effects of GDM and diabetic pregnancy complicated by PE were not identifiable in this cohort. We conclude that fetal sex has a prominent effect on the placental transcriptome, dominating and confounding gene expression signatures resulting from diabetes mellitus in settings of well-controlled diabetic disease. Our results support the notion of placenta as a sexual dimorphic organ.


End of study transition from study drug to open-label vitamin K antagonist therapy: the ROCKET AF experience.
To evaluate the previously reported excess of thromboembolic events during the 30 days after the end of study (EOS) visit when participants transitioned from blinded therapy to open-label vitamin K antagonist. At the EOS visit, open-label vitamin K antagonist was recommended, and the international normalized ratio (INR) was not to be measured until 3 days later to preserve blinding. We analyzed transition strategies, clinical outcomes, and INR values. Event rates are per 100 patient-years. A total of 9248 (65%) participants were taking study drug at EOS, and, between days 3 and 30, an excess of stroke and systemic embolic events were observed in participants assigned to rivaroxaban (rivaroxaban 22 events, event rate 6.42; warfarin 6 events, event rate 1.73; hazard ratio, 3.72; 95% confidence interval, 1.51-9.16; P=0.0044). No INR values were reported for ≈5% of participants transitioned to warfarin. By 30 days after EOS, 83% of the warfarin group and 52% of the rivaroxaban group had ≥1 therapeutic INR value. Median time to first therapeutic INR was 3 days in the warfarin group and 13 days in the rivaroxaban group. The excess of events at EOS was likely because of a period of inadequate anticoagulation in rivaroxaban participants switched to vitamin K antagonist therapy. If transition from rivaroxaban to vitamin K antagonist is needed, timely monitoring and careful dosing should be used to ensure consistent and adequate anticoagulation.


Safety and Outcomes of Peripherally Administered Vasopressor Infusion in Patients Admitted with Shock to an Intensive Cardiac Care Unit-A Single-Center Prospective Study.
Vasopressors are frequently utilized for blood pressure stabilization in patients with cardiogenic shock (CS), although with a questionable benefit. Obtaining central venous access is time consuming and may be associated with serious complications. Hence, we thought to evaluate whether the administration of vasopressors through a peripheral venous catheter (PVC) is a safe and effective alternative for the management of patients with CS presenting to the intensive cardiovascular care unit (ICCU). A prospective single-center study was conducted to compare the safety and outcomes of vasopressors administered via a PVC vs. a central venous catheter (CVC) in patients presenting with CS over a 12-month period. A total of 1100 patients were included; of them, 139 (12.6%) required a vasopressor treatment due to shock, with 108 (78%) treated via a PVC and 31 (22%) treated via a CVC according to the discretion of the treating physician. The duration of the vasopressor administration was shorter in the PVC group compared with the CVC group (2.5 days vs. 4.2 days, respectively, p < 0.05). Phlebitis and the extravasation of vasopressors occurred at similar rates in the PVC and CVC groups (5.7% vs. 3.3%, respectively, p = 0.33; 0.9% vs. 3.3%, respectively, p = 0.17). Nevertheless, the bleeding rate was higher in the CVC group compared with the PVC group (3% vs. 0%, p = 0.03). The administration of vasopressor infusions via PVC for the management of patients with CS is feasible and safe in patients with cardiogenic shock. Further studies are needed to establish this method of treatment.


Atherosclerotic disease of the middle cerebral artery.
Three hundred and fifty-two patients with atherosclerotic middle cerebral artery stenosis (MCAS, 53%) or occlusion (MCAO, 47%) have been systematically studied. The study involved all patients entered into the EC/IC Bypass Study with isolated MCA disease or a tandem lesion predominating in the MCA ipsilateral to the ischemic events (18 patients with a tandem lesion of greater magnitude in the internal carotid artery were not included). The Asian patients represented 58% of all Asians entered into the EC/IC Bypass Study, whereas the white patients represented 18% of all whites and the black patients 34% of all blacks. Isolated TIAs were less frequent in MCAO (12%) than in MCAS (34%). Warning TIAs before a stroke occurred in one third of the cases. Presentation with stroke or isolated TIA was not influenced by sex, age, level of MCA obstruction, collateral circulation nor associated carotid disease. In MCAS, no major difference in presentation was found between severe and moderate stenosis. Pure motor hemiparesis occurred in 15% and pure sensory stroke in 2% of the patients with stroke and 30% of the MCA territory infarcts were small and limited to the lenticulocapsular area, confirming that so-called lacunar infarcts may be due to large vessel disease. During follow-up (42 months) of 164 medically-treated patients, further cerebrovascular events (TIA and stroke) occurred in 11.7% of the patients per year. In MCAO the stroke rate was 10.1% per patient-year and the ipsilateral infarct rate was 7.1% per patient-year. In MCAS, the stroke rate was 9.5% per patient-year and the ipsilateral stroke rate was 7.8% per patient-year.(ABSTRACT TRUNCATED AT 250 WORDS)


Improved outcomes for stem cell transplant recipients requiring pediatric intensive care.
Survival for hematopoietic stem cell transplant patients requiring pediatric intensive care unit admission may be improving. This study was conducted to review outcomes for patients undergoing hematopoietic stem cell transplantation requiring admission to our pediatric intensive care unit and to identify variables impacting survival. Retrospective database review. Pediatric intensive care unit and bone marrow transplant service of a children's hospital. Patients undergoing hematopoietic stem cell transplantation at our center from July 2004 through June 2010 requiring pediatric intensive care unit admission during the same period. Thirty-five percent of patients (155 of 448) undergoing hematopoietic stem cell transplantation required 319 admissions over this period. Of these 155 patients, 63% (97 of 155) were discharged alive following their most recent admission with a 100-day survival of 51% (79 of 155). Forty-five percent (69 of 155) of patients were still alive on long-term follow-up. Intubation and mechanical ventilation were required for 57% (88 of 155) of patients, with 39% (34 of 88) of patients surviving their last pediatric intensive care unit admission. Renal support was utilized for 25% (38 of 155) of patients with 34% (13 of 38) survival to pediatric intensive care unit discharge. Admissions surviving to pediatric intensive care unit discharge had significantly lower Pediatric Risk of Mortality II scores, shorter pediatric intensive care unit length of stay, lower utilization of intubation and mechanical ventilation with fewer ventilator days, and lower use of renal support when compared to nonsurvivors. Of note, each prior pediatric intensive care unit admission significantly reduced the odds of pediatric intensive care unit survival. We report a 63% survival to pediatric intensive care unit discharge, with 45% surviving at a median follow-up of over 2 yrs for all hematopoietic stem cell transplantation patients admitted to our pediatric intensive care unit over a 6-yr period. Our data suggest improved survival outcomes for this high risk patient population.


[Correlation of morphological criteria with the rate of growth in cancer of the breast].
Prognosis of carcinoma of the breast depends on a number of factors. Besides tumour staging, these parameters include the number of axillary lymph nodes with metastatic growths, the status of the hormonal receptors, and the histological type of the tumour, especially the tumour grading and the rate of growth correlated therewith. The first few of these criteria are relatively easy to determine. The tumour duplication time has so far been determined only by means of serial mammographies. Only few studies have been conducted on the correlation of the morphological parameters connected with the dynamics of growth of carcinomas of the breast. In a group of 61 patients with carcinoma of the breast and known tumour duplication time determined by serial mammography, it is shown that broadening of the conventional tumour grading by means of additional histopathological malignancy criteria (frequency of mitosis, incidence of nuclear hyperchromasias, formation of tubules and nuclear irregularities) correlates with the growth dynamics of the tumours. This makes it seem possible to draw prospective conclusions on the growth performance of carcinomas of the breast even without resorting to serial mammographies.


A randomised controlled feasibility study of interpersonal art psychotherapy for the treatment of aggression in people with intellectual disabilities in secure care.
Rates of aggression in inpatient secure care are higher than in other psychiatric inpatient settings. People with intellectual disabilities in secure care require adapted psychological treatments. Interpersonal art psychotherapy incorporates the use of creative art making approaches by participants, thus reducing sole reliance upon verbal interactions during psychotherapy for people who may have communication difficulties. During interpersonal art psychotherapy, participants are individually supported by their therapist to consider how they conduct relationships. This includes the influence and impact of interpersonal issues resulting in repeated patterns of conflict. The key feasibility objectives were to assess recruitment and retention rates, follow-up rates and trial procedures such as randomisation, allocation and identifying any practical or ethical problems. In addition, a preliminary 'signal' for the intervention was considered and an indicative sample size calculation completed. The acceptability of a potential third trial arm attentional control condition, mindful colouring-in, was assessed using four single-case design studies and a UK trial capacity survey was conducted. Adult patients with intellectual disabilities in secure care were recruited and randomised to either interpersonal art psychotherapy or delayed treatment in this multi-site study. Outcomes were assessed using weekly observations via the Modified Overt Aggression Scale and a range of self-report measures. Within study reporting processes, qualitative interviews and a survey were completed to inform trial feasibility. Recruitment procedures were successful. The target of recruiting 20 participants to the trial from multiple sites was achieved within 8 months of the study opening. All participants recruited to the treatment arm completed interpersonal art psychotherapy. Between-group differences of interpersonal art psychotherapy versus the delayed treatment control showed a 'signal' effect-size of .65 for total scores and .93 in the verbal aggression sub-scale. There were no amendments to the published protocol. The assessment of key feasibility objectives were met and the trial procedures were acceptable to all involved in the research. This study suggested that a randomised controlled trial of interpersonal art psychotherapy is acceptable and feasible. ISRCTN14326119 (Retrospectively Registered).


Age-related patterns in clinical presentations and gluten-related issues among children and adolescents with celiac disease.
Celiac disease (CD) is common and often cited as an "iceberg" phenomenon (i.e., an assumed large number of undiagnosed cases). Recently, atypical or asymptomatic manifestations are becoming more commonly described in older children and adolescents. Moreover, CD diagnosis in children can be complicated by several factors, including its diverse clinical presentations, delay in recognizing CD signs and symptoms, and premature dietary gluten avoidance before the formal diagnosis of CD. To date, few studies have directly examined age-related differences in clinical characteristics and gluten-related issues among children with CD. The aim of this study was to determine age-related patterns in clinical characteristics and gluten-related issues among children with confirmed CD. We performed a structured medical record review of biopsy-proven CD patients, aged 0-19 years, between 2000 and 2010 at a large Boston teaching hospital. Data collection included demographics, medical history, gluten-related issues, and diagnostic investigations (CD-specific serology, upper gastrointestinal endoscopy, and small intestinal biopsy). The first positive duodenal biopsy with Marsh III classification defined age of diagnosis. Patients were divided into three age groups for comparisons of the aforementioned characteristics: infant-preschool group (0-5 years), school-aged group (6-11 years), and adolescence group (12-19 years). Among 411 children with biopsy-proven CD, the mean age was 9.5 (s.d. 5.1) years. Most were female (63%) and white (96%). All children had positive CD-specific serology. Most children presented with either abdominal complaints or bowel movement changes. Overall, boys were more common among infant-preschool group compared with the other age groups. More distinct clinical manifestations (vomiting, bowel movement changes, and weight issues) were apparent in the youngest group, whereas school-aged children had more subjective abdominal complaints at the initial presentation. Conversely, the adolescents were most likely to present without any gastrointestinal (GI) symptoms, but not when this was combined with absence of weight issues. Age of diagnosis was not associated with atypical extraintestinal CD presentations. Regarding the gluten-related issues, 10% of school-aged children avoided dietary gluten before the formal CD diagnosis, and 27% of the adolescents reported dietary gluten transgression within the first 12 months of diagnosis, significantly higher than the other age groups. Age differences in histopathology were also found. Whereas the infant-preschool group had a higher proportion of total villous atrophy, the older children were more likely to have gross duodenal abnormalities and chronic duodenitis suggestive of CD at the time of diagnosis. Children and adolescents with CD have age-related patterns in both the clinical presentations and gluten-related issues. More pronounced clinical and histological features were determined in younger children, whereas older children more commonly presented with solely subjective abdominal complaints or even without any GI symptoms. However, silent and atypical extraintestinal CD presentations were comparable between age groups. In addition to the aforementioned presentations, the higher rates of dietary gluten avoidance and transgression in older children make CD diagnosis and management particularly challenging. These age-related patterns may further increase awareness, facilitate early diagnosis, and improve patient care of pediatric CD.


A refractory period for rejuvenating GABAergic synaptic transmission and ocular dominance plasticity with dark exposure.
Dark exposure initiated in adulthood reactivates robust ocular dominance plasticity in the visual cortex. Here, we show that a critical component of the response to dark exposure is the rejuvenation of inhibitory synaptic transmission, resulting in a decrease in functional inhibitory synaptic density, a decrease in paired-pulse depression, and a reexpression of endocannabinoid-dependent inhibitory long-term depression (iLTD). Importantly, pharmacological acceleration of the maturation of inhibition in dark-exposed adults inhibits the reexpression of iLTD and the reactivation of ocular dominance plasticity. Surprisingly, dark exposure initiated earlier in postnatal development does not rejuvenate inhibitory synaptic transmission or facilitate rapid ocular dominance plasticity, demonstrating the presence of a refractory period for the regulation of synaptic plasticity by visual deprivation.


Effect of carbocisteine on acute exacerbation of chronic obstructive pulmonary disease (PEACE Study): a randomised placebo-controlled study.
Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation, and has many components including mucus hypersecretion, oxidative stress, and airway inflammation. We aimed to assess whether carbocisteine, a mucolytic agent with anti-inflammatory and antioxidation activities, could reduce the yearly exacerbation rate in patients with COPD. We did a randomised, double-blind, placebo-controlled study of 709 patients from 22 centres in China. Participants were eligible if they were diagnosed as having COPD with a postbronchodilator forced expiratory volume in 1 s (FEV(1)) to forced vital capacity (FVC) ratio (FEV(1)/FVC) of less than 0.7 and an FEV(1) between 25% and 79% of the predicted value, were aged between 40 and 80 years, had a history of at least two COPD exacerbations within the previous 2 years, and had remained clinically stable for over 4 weeks before the study. Patients were randomly assigned to receive 1500 mg carbocisteine or placebo per day for a year. The primary endpoint was exacerbation rate over 1 year, and analysis was by intention to treat. This trial is registered with the Japan Clinical Trials Registry (http://umin.ac.jp/ctr/index/htm) number UMIN-CRT C000000233. 354 patients were assigned to the carbocisteine group and 355 to the placebo group. Numbers of exacerbations per patient per year declined significantly in the carbocisteine group compared with the placebo group (1.01 [SE 0.06] vs 1.35 [SE 0.06]), risk ratio 0.75 (95% CI 0.62-0.92, p=0.004). Non-significant interactions were found between the preventive effects and COPD severity, smoking, as well as concomitant use of inhaled corticosteroids. Carbocisteine was well tolerated. Mucolytics, such as carbocisteine, should be recognised as a worthwhile treatment for prevention of exacerbations in Chinese patients with COPD.


Homocystinuria: what about mild hyperhomocysteinaemia?
Hyperhomocysteinaemia is associated with an increased risk of atherosclerotic vascular disease and thromboembolism, in both men and women. A variety of conditions can lead to elevated homocysteine levels, but the relation between high levels and vascular disease is present regardless of the underlying cause. Pooled data from a large number of studies demonstrate that mild hyperhomocysteinaemia after a standard methionine load is present in 21% of young patients with coronary artery disease, in 24% of patients with cerebrovascular disease, and in 32% of patients with peripheral vascular disease. From such data an odds ratio of 13.0 (95% confidence interval 5.9 to 28.1), as an estimate of the relative risk of vascular disease at a young age, can be calculated in subjects with an abnormal response to methionine loading. Furthermore, mild hyperhomo-cysteinaemia can lead to a two- or three-fold increase in the risk of recurrent venous thrombosis. Elevated homocysteine levels can be reduced to normal in virtually all cases by simple and safe treatment with vitamin B6, folic acid, and betaine, each of which is involved in methionine metabolism. A clinically beneficial effect of such an intervention, currently under investigation, would make large-scale screening for this risk factor mandatory.


Sudan ebolavirus long recovered survivors produce GP-specific Abs that are of the IgG1 subclass and preferentially bind FcγRI.
Ebolavirus is a highly lethal pathogen, causing a severe hemorrhagic disease with a high fatality rate. To better understand immune correlates of protection by virus specific IgG, we investigated the evolution of the Fcγ receptors (FcγRs)-activating capabilities of antiviral IgG in serum samples of long recovered survivors. To this end, longitudinal serum samples from survivors of Sudan ebolavirus (SUDV) infection, studied over years, were examined for the presence of Ebola-GP specific IgG subclasses, and for their binding to FcγRs. We developed a cell-based reporter system to quantitate pathogen-specific antibody binding to FcγRIIIA, FcγRIIA, FcγRIIB and FcγRI. With this system, we demonstrate that anti-GP-specific stimulation of the FcγRI reporter by survivors' sera was substantially high one year after acute infection, with a slight reduction in activity over a decade post infection. We further demonstrate that GP-specific IgG1 is by far the seroprevalent subclass that retained and even enhanced its presence in the sera, over ten years post infection; the prevalence of other GP-specific IgG subclasses was considerably reduced over time. In accordance, GP-specific FcγRI reporter response and GP-specific total IgG1 subclass correlated in the studied group of Ebola survivors. These observations are important for further informing Ebola vaccine and therapeutic development.


Resorufin analogs preferentially bind cerebrovascular amyloid: potential use as imaging ligands for cerebral amyloid angiopathy.
Cerebral amyloid angiopathy (CAA) is characterized by deposition of fibrillar amyloid β (Aβ) within cerebral vessels. It is commonly seen in the elderly and almost universally present in patients with Alzheimer's Disease (AD). In both patient populations, CAA is an independent risk factor for lobar hemorrhage, ischemic stroke, and dementia. To date, definitive diagnosis of CAA requires obtaining pathological tissues via brain biopsy (which is rarely clinically indicated) or at autopsy. Though amyloid tracers labeled with positron-emitting radioligands such as [11C]PIB have shown promise for non-invasive amyloid imaging in AD patients, to date they have been unable to clarify whether the observed amyloid load represents neuritic plaques versus CAA due in large part to the low resolution of PET imaging and the almost equal affinity of these tracers for both vascular and parenchymal amyloid. Therefore, the development of a precise and specific non-invasive technique for diagnosing CAA in live patients is desired. We found that the phenoxazine derivative resorufin preferentially bound cerebrovascular amyloid deposits over neuritic plaques in the aged Tg2576 transgenic mouse model of AD/CAA, whereas the congophilic amyloid dye methoxy-X34 bound both cerebrovascular amyloid deposits and neuritic plaques. Similarly, resorufin-positive staining was predominantly noted in fibrillar Aβ-laden vessels in postmortem AD brain tissues. Fluorescent labeling and multi-photon microscopy further revealed that both resorufin- and methoxy-X34-positive staining is colocalized to the vascular smooth muscle (VSMC) layer of vessel segments that have severe disruption of VSMC arrangement, a characteristic feature of CAA. Resorufin also selectively visualized vascular amyloid deposits in live Tg2576 mice when administered topically, though not systemically. Resorufin derivatives with chemical modification at the 7-OH position of resorufin also displayed a marked preferential binding affinity for CAA, but with enhanced lipid solubility that indicates their use as a non-invasive imaging tracer for CAA is feasible. To our knowledge, resorufin analogs are the fist class of amyloid dye that can discriminate between cerebrovascular and neuritic forms of amyloid. This unique binding selectivity suggests that this class of dye has great potential as a CAA-specific amyloid tracer that will permit non-invasive detection and quantification of CAA in live patients.


Sleep disturbance and risk for alcohol-related problems.
Using prospective data, the authors assessed the risk of alcohol-related problems among individuals with self-reported sleep disturbances because of worry. As part of the Epidemiologic Catchment Area program, a probability sample of Baltimore residents selected by census tracts and households completed a baseline interview in 1981. Between 1993 and 1996, the original Baltimore cohort was traced. Of the 2,633 survivors, a total of 73% were reinterviewed. After excluding individuals with alcohol-related problems or a current or prior history of alcohol abuse and/or dependence at the time of the 1981 interview, the authors identified a cohort of 1,537 individuals who were at risk for problem drinking at the time of the follow-up interview, a median of 12.6 years after the baseline interview. Logistic regression was used to assess the association between sleep disturbance because of worry and the risk for incident reports of alcohol problems. Survey respondents with sleep disturbances because of worry at the time of the baseline interview had a twofold higher risk for developing an alcohol-related problem, relative to those without these sleep disturbances (odds ratio=2.32, 95% confidence interval [CI]=1.31-4.09), with adjustment for selected demographic and clinical variables. Sleep disturbance because of worry predicted the development of alcohol problems among respondents with lifetime anxiety disorders and lifetime dysphoria (odds ratio=3.82, 95% CI=1.56-9.38, and odds ratio=2.71, 95% CI=1.25-5.91, respectively), but not among those without a history of anxiety disorders or dysphoria. Sleep disturbances because of worry may increase risk for alcohol-related problems. Risk is highest for those with sleep disturbance and co-occurring anxiety disorders or dysphoria.


Precursor-mediated synthesis of Cu2-xSe nanoparticles and their composites with TiO2 for improved photocatalysis.
The direct synthesis of copper selenide nanoparticles from the reaction of ditertiarybutyl selenide tBu2Se with copper(ii) trifluoroacetate Cu(TFA)2 under mild conditions is reported. The isolation of a molecular species during the course of this reaction, established as [Cu2(TFA)2(tBu2Se)3], by spectroscopic studies and single crystal X-ray structure analysis, confirmed that metal selenide NPs are formed via this intermediate species containing a reduced copper center. Extending this reaction in the presence of commercial TiO2 (P25) offered an easy synthesis of copper selenide-titania nanocomposites with different Cu/Ti ratios. These nanocomposites, well-characterized by powder XRD, STEM, TEM, BET, XPS, EDX and UV-Vis studies, were examined as photocatalysts for the degradation of formic acid (FA). The nCu2-xSe-TiO2 nanocomposites with low mol% of copper selenide, i.e. n = 0.1 and 0.3 mol%, displayed a superior catalytic activity over P25, which is an established benchmark for photocatalysis under UV light.


Preventing Mitochondrial Diseases: Embryo-Sparing Donor-Independent Options.
Mutant mitochondrial DNA gives rise to a broad range of incurable inborn maladies. Prevention may now be possible by replacing the mutation-carrying mitochondria of zygotes or oocytes at risk with donated unaffected counterparts. However, mitochondrial replacement therapy is being held back by theological, ethical, and safety concerns over the loss of human zygotes and the involvement of a donor. These concerns make it plain that the identification, validation, and regulatory adjudication of novel embryo-sparing donor-independent technologies remains a pressing imperative. This Opinion highlights three emerging embryo-sparing donor-independent options that stand to markedly allay theological, ethical, and safety concerns raised by mitochondrial replacement therapy.


Membrane IgE binds and activates Fc epsilon RI in an antigen-independent manner.
Interaction of secretory IgE with FcepsilonRI is the prerequisite for allergen-driven cellular responses, fundamental events in immediate and chronic allergic manifestations. Previous studies reported the binding of soluble FcepsilonRIalpha to membrane IgE exposed on B cells. In this study, the functional interaction between human membrane IgE and human FcepsilonRI is presented. Four different IgE versions were expressed in mouse B cell lines, namely: a truncation at the Cepsilon2-Cepsilon3 junction of membrane IgE isoform long, membrane IgE isoform long (without Igalpha/Igbeta BCR accessory proteins), and both epsilonBCRs (containing membrane IgE isoforms short and long). All membrane IgE versions activated a rat basophilic leukemia cell line transfected with human FcepsilonRI, as detected by measuring the release of both preformed and newly synthesized mediators. The interaction led also to Ca(2+) responses in the basophil cell line, while membrane IgE-FcepsilonRI complexes were detected by immunoprecipitation. FcepsilonRI activation by membrane IgE occurs in an Ag-independent manner. Noteworthily, human peripheral blood basophils and monocytes also were activated upon contact with cells bearing membrane IgE. In humans, the presence of FcepsilonRI in several cellular entities suggests a possible membrane IgE-FcepsilonRI-driven cell-cell dialogue, with likely implications for IgE homeostasis in physiology and pathology.


Relative caries experience of sealed versus unsealed permanent posterior teeth: a three-year study.
A clinical trial has investigated the occlusal caries experience of permanent molars and premolars, following the apparent loss of occlusal sealants applied by dental students, in comparison with that of unsealed teeth erupted for time periods similar to the sealant evaluation periods. Complete retention at one, two and three years was relatively poor. Throughout the study, premolars were superior to molars in fully retaining sealants. Regardless of the clinical condition of the sealant, a statistically significant reduction in occlusal caries-experience of sealed teeth was seen in comparison with control teeth. This relative reduction was highest at one year: 72 percent for molars and 83 percent for premolars, dropping at three years to 23 percent for molars and 64 percent for premolars. At one year, molar sealant failures showed a statistically significant, relative reduction of 41 percent in occlusal caries-experience over control teeth, suggesting as ongoing caries-inhibitory effect. Thereafter, the history of a failed sealant neither enhanced nor reduced the occlusal caries susceptibility of molars, and premolars over that of control teeth.


Association between Family Dysfunction and Post-Traumatic Stress Disorder in School Students during the Second COVID-19 Epidemic Wave in Peru.
Although the effect of the COVID-19 pandemic on children and adolescents' mental health has been studied, there is still scarce evidence of the influence of nuclear family on the development of post-traumatic stress disorder (PTSD). This study aimed to determine the association between family dysfunction and PTSD in Peruvian high-school students during the COVID-19 pandemic. A cross-sectional study was conducted using a virtual survey administered to 562 high-school students in three schools in Chiclayo, Peru. The dependent variable was PTSD, which was measured with the Child PTSD Symptom Scale. Family dysfunction was the main independent variable, measured with the Family APGAR Questionnaire. Prevalence ratios (PR) and 95% confidence intervals (95% CI) were estimated with generalized linear models. Most of the students were female (88.3%) and the average age was 14.4 years. We found that 21.4% showed severe family dysfunction and 60.3% had PTSD. Students with mild and moderate family dysfunction had 37% (PR: 1.37; 95% CI: 1.14-1.65) and 26% (PR: 1.26; 95% CI: 1.04-1.54) higher PTSD prevalence, respectively. In conclusion, family dysfunction may influence the development of PTSD in adolescents. This study suggests the importance to develop a healthy family environment to help adolescents face critical situations experienced during the pandemic.


Recognition of Dimethylarginine Analogues by Tandem Tudor Domain Protein Spindlin1.
Epigenetic readout of the combinatorial posttranslational modification comprised of trimethyllysine and asymmetric dimethylarginine (H3K4me3R8me2a) takes place via biomolecular recognition of tandem Tudor-domain-containing protein Spindlin1. Through comparative thermodynamic data and molecular dynamics simulations, we sought to explore the binding scope of asymmetric dimethylarginine mimics by Spindlin1. Herein, we provide evidence that the biomolecular recognition of H3K4me2R8me2a is not significantly affected when R8me2a is replaced by dimethylarginine analogues, implying that the binding of K4me3 provides the major binding contribution. High-energy water molecules inside both aromatic cages of the ligand binding sites contribute to the reader-histone association upon displacement by histone peptide, with the K4me3 hydration site being lower in free energy due to a flip of Trp151.


Disentangling the contribution of hospitals and municipalities for understanding patient level differences in one-year mortality risk after hip-fracture: A cross-classified multilevel analysis in Sweden.
One-year mortality after hip-fracture is a widely used outcome measure when comparing hospital care performance. However, traditional analyses do not explicitly consider the referral of patients to municipality care after just a few days of hospitalization. Furthermore, traditional analyses investigates hospital (or municipality) variation in patient outcomes in isolation rather than as a component of the underlying patient variation. We therefore aimed to extend the traditional approach to simultaneously estimate both case-mix adjusted hospital and municipality comparisons in order to disentangle the amount of the total patient variation in clinical outcomes that was attributable to the hospital and municipality level, respectively. We determined 1-year mortality risk in patients aged 65 or above with hip fractures registered in Sweden between 2011 and 2014. We performed cross-classified multilevel analysis with 54,999 patients nested within 54 hospitals and 290 municipalities. We adjusted for individual demographic, socioeconomic and clinical characteristics. To quantify the size of the hospital and municipality variation we calculated the variance partition coefficient (VPC) and the area under the receiver operator characteristic curve (AUC). The overall 1-year mortality rate was 25.1%. The case-mix adjusted rates varied from 21.7% to 26.5% for the 54 hospitals, and from 18.9% to 29.5% for the 290 municipalities. The VPC was just 0.2% for the hospital and just 0.1% for the municipality level. Patient sociodemographic and clinical characteristics were strong predictors of 1-year mortality (AUC = 0.716), but adding the hospital and municipality levels in the cross-classified model had a minor influence (AUC = 0.718). Overall in Sweden, one-year mortality after hip-fracture is rather high. However, only a minor part of the patient variation is explained by the hospital and municipality levels. Therefore, a possible intervention should be nation-wide rather than directed to specific hospitals or municipalities.


[Continuous bilateral sacral neuromodulation as a minimally invasive implantation technique in patients with functional bladder changes].
Up to 50% of patients with bladder dysfunctions undergoing sacral neuromodulation treatment are non-responders. The most common treatment method today is the implantable neuromodulation system described by Tanagho and Schmidt; which allows unilateral sacral nerve stimulation. Our aim was to increase the number of responders and to improve the general efficiency of chronic sacral neuromodulation; therefore we have developed the bilateral electrode implantation by minimally invasive laminectomy. PNE-tests were carried out to assess which patients were likely to be good responders. Thirty patients (16 with detrusor instability, 14 with hypocontractile detrusors) were subjected to minimally invasive laminectomy and received implants of bilateral electrodes. In those patients with a hyopcontractile detrusor, the level of residual urine of initially 350 ml was reduced to 58 ml, and the maximum detrusor pressure during micturition increased from initially 12 cMH2O to 34 cmH2O. In the other patient group with detrusor instability, the average number of incontinence incidences could be reduced from initially 7.2 to 1 per day, while the bladder capacity rose from 198 ml to 348 ml. The modulation effect did not show any signs of deteriorating in any of the patients. The follow-up period was 28 months on average. Clinical experience has shown that optimal neuromodulation in patients with bladder dysfunction can be achieved by this new approach involving bilateral electrode implantation. Moreover, the laminectomy implantation method guarantees a minimum of invasive trauma and enables optimal placement and fixation of the electrode.


Comparative analyses between radically re-resected incidental gallbladder carcinoma and primary radically resected gallbladder carcinoma: a single-center experience in China.
The current study was performed to comparatively evaluate the similarities and differences between cases with radically re-resected incidental gallbladder carcinoma (RRIGBC) and those with primary radically resected gallbladder carcinoma (PRGBC). Comparative analysis between patients with RRIGBC and those with PRGBC were performed in terms of clinic-pathological features and long-terms survival. A total of 330 surgically treated GBC patients with 110 patients with IGBC were identified. PRGBCs were generally in a more advanced tumor stage, sharing more aggressive tumor biological features and worse prognosis than those with RRIGBC. Subgroup analyses indicated a comparable prognosis among T1-2 patients between RRIGBC and PRGBC groups. However, among T3-4 patients, patients in the PRGBC group shared a much worse prognosis. Moreover, IGBC itself can be regarded as a prognostic factor but cannot be regarded as an independent prognostic factor. It is the tumor stage which really determined the overall prognosis. Patients with RRIGBC were generally in a much earlier tumor stage and shared a much better prognosis than those with PRGBC. IGBC itself can be regarded as a prognostic factor but cannot be regarded as the independent prognostic factors. It is the tumor stage which really determine the overall prognosis.


The ferret as a model for inner ear research.
Viral infections have long been suspected to be causative agents in a number of inner ear dysfunctions. With few exceptions, the virus has not been demonstrated as the direct agent leading to hearing loss and/or vertigo. Selective inner ear changes have been observed recently in sensory and nonsensory epithelial cells in the ferret model for Reye's syndrome after intranasal inoculation with influenza B combined with aspirin administration and the creation of an arginine deficiency. Such findings suggest that these agents act synergistically on the inner ear, particularly on cells that are metabolically active, and that the ferret may now be a useful model to examine the role of certain upper respiratory tract viruses implicated in inner ear disorders, singly and in combination with other agents that may cause metabolic alterations.


Management of ischemic stroke: Part 2. The inpatient stay.
Acute ischemic stroke is commonly encountered by the hospitalist. There have been dramatic changes in our ability to care for these patients both acutely and in secondary prevention. The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) primary stroke center certification has become progressively more important to institutions nationally and emphasizes many elements of the inpatient stay and discharge process. After admission, the focus changes to avoidance of complications and the appropriate initiation of allied therapies and secondary prevention. Primary trials, current guidelines. The hospitalist is well-positioned to play a major role in the treatment of stroke patients as well as the systems work that aids in the management of this population.


Human egasyn binds beta-glucuronidase but neither the esterase active site of egasyn nor the C terminus of beta-glucuronidase is involved in their interaction.
Lysosomal beta-glucuronidase shows a dual localization in mouse liver, where a significant fraction is retained in the endoplasmic reticulum (ER) by interaction with an ER-resident carboxyl esterase called egasyn. This interaction of mouse egasyn (mEg) with murine beta-glucuronidase (mGUSB) involves binding of the C-terminal 8 residues of the mGUSB to the carboxylesterase active site of the mEg. We isolated the recombinant human homologue of the mouse egasyn cDNA and found that it too binds human beta-glucuronidase (hGUSB). However, the binding appears not to involve the active site of the human egasyn (hEg) and does not involve the C-terminal 18 amino acids of hGUSB. The full-length cDNA encoding hEg was isolated from a human liver cDNA library using full-length mEg cDNA as a probe. The 1941-bp cDNA differs by only a few bases from two previously reported cDNAs for human liver carboxylesterase, allowing the anti-human carboxylesterase antiserum to be used for immunoprecipitation of human egasyn. The cDNA expressed bis-p-nitrophenyl phosphate (BPNP)-inhibitable esterase activity in COS cells. When expressed in COS cells, it is localized to the ER. The intracellular hEg coimmunoprecipitated with full-length hGUSB and with a truncated hGUSB missing the C-terminal 18-amino-acid residue when extracts of COS cells expressing both proteins were treated with anti-hGUSB antibody. It did not coimmunoprecipitate with mGUSB from extracts of coexpressing COS cells. Unlike mEg, hEg was not released from the hEg-GUSB complex with BPNP. Thus, hEg resembles mEg in that it binds hGUSB. However, it differs from mEg in that (i) it does not appear to use the esterase active site for binding since treatment with BPNP did not release hEg from hGUSB and (ii) it does not use the C terminus of GUSB for binding, since a C-terminal truncated hGUSB (the C-terminal 18 amino acids are removed) bound as well as nontruncated hGUSB. Evidence is presented that an internal segment of 51 amino acids between 228 and 279 residues contributes to binding of hGUSB by hEg.


Trust in Health Information Sources among Underserved and Vulnerable Populations in the U.S.
The purpose of this study was to examine trust in health information sources among underserved and vulnerable populations. Data (N=8,759) were from the Health Information National Trends Survey. Differences were assessed across the following subgroups: ethnoracial minorities, immigrants, rural residence, people with limited English proficiency, and sexual minorities. Trust was highest for doctors, followed by government, family/friends, charities, and religious organizations. In adjusted regression models, trusting health information from charitable and religious organizations was higher in ethnoracial minorities and immigrants. Individuals with limited English proficiency also had higher trust in religious organizations compared with those fluent in English. Trusting health information from doctors was lower among individuals with limited English proficiency. There was evidence in support of additive and multiplicative intersectional frameworks for understanding trust in vulnerable and underserved populations; however, the extent to which differences in trust explain disparities in health behaviors and outcomes should be examined.


Anchorage-dependent expression of cyclin A in primary cells requires a negative DNA regulatory element and a functional Rb.
Many cells, when cultured in suspension, fail to express cyclin A, a regulatory component of cell cycle kinases cdc2 and cdk2 and as a consequence, do not enter S phase. However, many cell type-specific differences are disclosed between not only normal and transformed cells, but also between cell lines whose proliferation is strictly anchorage-dependent. These apparent discrepancies are seen in established cell lines most probably because of adaptative events that have occurred during cell culture. We have therefore used primary cells to understand how cyclin A transcription is controlled by cell anchorage properties. To this aim, we have used embryonic fibroblasts from either wild type, Rb(-/-) or p107(-/-)/p130(-/-) mice and tested the effect of an ectopic expression of Rb mutants. In the experiments reported here, we show that anchorage-dependent expression of cyclin A (i) is reflected by the in vivo occupancy of a negative DNA regulatory element previously shown to be instrumental in the down regulation of cyclin A transcription in quiescent cells (Cell Cycle Responsive Element: CCRE) (ii) requires a functional Rb but neither p107 nor p130 (iii) mutation of the CCRE abolishes both adhesion-dependent regulation and response to Rb.


What is important to patients in palliative care? A scoping review of the patient's perspective.
The research conducted in palliative care is often medically oriented. There are few studies clarifying the patient's preferences, priorities and desires in palliative care. The occupational therapy research conducted mostly concerns occupational therapy interventions based on the profession's experiences. Further knowledge is needed regarding what patients in palliative care want to prioritize. The aim was to describe what patients in palliative care describe as important at the end of life. A scoping review was conducted using the inclusion criteria: articles published in 2004-August 2015; written in English; participants >18 years with life-threatening illness without possible cure; focusing on the patient's experience. Seventeen articles were included in the review and they were based on interviews. The theme 'Continuing occupational participation is important for people at the end of life' was identified. This included five sub-themes: maintaining previous occupational patterns; feeling needed; being involved in the social environment; leaving a legacy; and living as long as you live. The results show that continued occupational participation is important for people in palliative care. Occupational therapists can contribute to this by taking a highly person-centered approach and gaining information about what matters most for their clients.


Synthesis and chiroptical properties of Methanocycloocta
The synthesis of chiral methanocyclocta[b]indoles, the fused structures obtained from enantiomeric bicyclo[3.3.1]nonanones via Fisher indolization reaction, is reported. The starting optically active bicyclo[3.3.1]nonane-2,6-dione (1) was obtained by a chiral HPLC enantiomer separation on a swollen microcrystalline triacetylcellulose column and by the enzymatic resolution of the racemic dione. The circular dichroism (CD) spectra of the chiral structures 4, 5, and 7 were recorded, and the absolute configuration for the indole compounds was assigned. The theoretical calculations of the CD spectrum of diindole 4 reproduce the (1)B(b) couplet at 229 nm but predict wrong signs for the (1)L(a) and (1)L(b) bands using standard polarization directions. The CD spectrum of indole ketone 5 is reproduced correctly.


Protocol for validating cardiovascular and cerebrovascular ICD-9-CM codes in healthcare administrative databases: the Umbria Data Value Project.
Administrative healthcare databases can provide a comprehensive assessment of the burden of diseases in terms of major outcomes, such as mortality, hospital readmissions and use of healthcare resources, thus providing answers to a wide spectrum of research questions. However, a crucial issue is the reliability of information gathered. Aim of this protocol is to validate International Classification of Diseases, 9th Revision-Clinical Modification (ICD-9-CM) codes for major cardiovascular diseases, including acute myocardial infarction (AMI), heart failure (HF), atrial fibrillation (AF) and stroke. Data from the centralised administrative database of the entire Umbria Region (910 000 residents, located in Central Italy) will be considered. Patients with a first hospital discharge for AMI, HF, AF or stroke, between 2012 and 2014, will be identified in the administrative database using the following groups of ICD-9-CM codes located in primary position: (1) 410.x for AMI; (2) 427.31 for AF; (3) 428 for HF; (4) 433.x1, 434 (excluding 434.x0), 436 for ischaemic stroke, 430 and 431 for haemorrhagic stroke (subarachnoid haemorrhage and intracerebral haemorrhage). A random sample of cases, and of non-cases, will be selected, and the corresponding medical charts retrieved and reviewed for validation by pairs of trained, independent reviewers. For each condition considered, case adjudication of disease will be based on symptoms, laboratory and diagnostic tests, as available in medical charts. Divergences will be resolved by consensus. Sensitivity and specificity with 95% CIs will be calculated. Research protocol has been granted approval by the Regional Ethics Committee. Study results will be disseminated widely through peer-reviewed publications and presentations at national and international conferences.


Ketone Body Signaling Mediates Intestinal Stem Cell Homeostasis and Adaptation to Diet.
Little is known about how metabolites couple tissue-specific stem cell function with physiology. Here we show that, in the mammalian small intestine, the expression of Hmgcs2 (3-hydroxy-3-methylglutaryl-CoA synthetase 2), the gene encoding the rate-limiting enzyme in the production of ketone bodies, including beta-hydroxybutyrate (βOHB), distinguishes self-renewing Lgr5+ stem cells (ISCs) from differentiated cell types. Hmgcs2 loss depletes βOHB levels in Lgr5+ ISCs and skews their differentiation toward secretory cell fates, which can be rescued by exogenous βOHB and class I histone deacetylase (HDAC) inhibitor treatment. Mechanistically, βOHB acts by inhibiting HDACs to reinforce Notch signaling, instructing ISC self-renewal and lineage decisions. Notably, although a high-fat ketogenic diet elevates ISC function and post-injury regeneration through βOHB-mediated Notch signaling, a glucose-supplemented diet has the opposite effects. These findings reveal how control of βOHB-activated signaling in ISCs by diet helps to fine-tune stem cell adaptation in homeostasis and injury.


Potentially preventable events: an actionable set of measures for linking quality improvement and cost savings.
Rising health care costs will result in reduced payments to providers, but across-the-board provider payment reductions are not the answer. Instead, existing payment systems should be reformed to strengthen value for the dollars spent. This can be accomplished by increasing efficiency, improving quality and outcomes, and lowering costs. Payment system reforms must be practical, transparent, identify opportunities for care improvement, and demonstrate material cost savings. Most importantly, because the current growth in health care costs is unsustainable, these reforms must be able to be implemented today. A set of comprehensive measures is being used by state government and private payers in the United States to adjust payment, based on improved outcomes quality. This article details the use of this set of measures, referred to as potentially preventable events, and demonstrates how they are being applied to achieve health care value.


Induction of cartilage integration by a chondrocyte/collagen-scaffold implant.
The integration of implanted cartilage is a major challenge for the success of tissue engineering protocols. We hypothesize that in order for effective cartilage integration to take place, matrix-free chondrocytes must be induced to migrate between the two tissue surfaces. A chondrocyte/collagen-scaffold implant system was developed as a method of delivering dividing cells at the interface between two cartilage surfaces. Chondrocytes were isolated from bovine nasal septum and seeded onto both surfaces of a collagen membrane to create the chondrocyte/collagen-scaffold implant. A model of two cartilage discs and the chondrocyte/collagen-scaffold sandwiched in between was used to effect integration in vitro. The resulting tissue was analysed histologically and biomechanically. The cartilage-implant-cartilage sandwich appeared macroscopically as one continuous piece of tissue at the end of 40 day cultures. Histological analysis showed tissue continuum across the cartilage-scaffold interface. The integration was dependent on both cells and scaffold. Fluorescent labeling of implanted chondrocytes demonstrated that these cells invade the surrounding mature tissue and drive a remodelling of the extracellular matrix. Using cell-free scaffolds we also demonstrated that some chondrocytes migrated from the natural cartilage into the collagen scaffold. Quantification of integration levels using a histomorphometric repair index showed that the chondrocyte/collagen-scaffold implant achieved the highest repair index compared to controls, reflected functionally through increased tensile strength. In conclusion, cartilage integration can be achieved using a chondrocyte/collagen-scaffold implant that permits controlled delivery of chondrocytes to both host and graft mature cartilage tissues. This approach has the potential to be used therapeutically for implantation of engineered tissue.


Postnatal arsenic exposure and attention impairment in school children.
Over the last few decades there has been an increased concern about the health risks from exposure to metallic trace elements, including arsenic, because of their potential neurotoxic effects on the developing brain. This study assessed whether urinary arsenic (UA) levels are associated with attention performance and Attention-Deficit/Hyperactivity Disorder (ADHD) in children living in an area with high industrial and mining activities in Southwestern Spain. A cross-sectional study was conducted on 261 children aged 6-9 years. Arsenic levels were determined in urine samples. Attention was measured by using 4 independent tools: a) tests from the Behavioral Assessment and Research System (BARS) designed to measure attention function: Simple Reaction Time Test (RTT), Continuous Performance Test (CPT) and Selective Attention Test (SAT); b) AULA Test, a virtual reality (VR)-based test that evaluates children's response to several stimuli in an environment simulating a classroom; c) Child Behavior Checklist (CBCL), administered to parents; and d) Teacher's Report Form (TRF), administered to teachers. Multivariate linear and logistic regression models, adjusted for potential confounders, were used to estimate the magnitude of the association between UA levels and attention performance scores. Higher UA levels were associated with an increased latency of response in RTT (β = 12.3; 95% confidence interval (CI): 3.5-21.1) and SAT (β = 3.6; 95% CI: .4-6.8) as well as with worse performance on selective and focalized attention in the AULA test (β for impulsivity = .6; 95% CI: .1-1.1; β for inattention = .5; 95% CI: .03-1.0). A dose-response relationship was observed between UA levels and inattention and impulsivity scores. In contrast, results from the CBCL and TRF tests failed to show a significant association with UA levels. In conclusion, UA levels were associated with impaired attention/cognitive function, even at levels considered safe. These results provide additional evidence that postnatal arsenic exposure impairs neurological function in children.


Exploring clinical reasoning in novices: a self-regulated learning microanalytic assessment approach.
The primary objectives of this study were to examine the regulatory processes of medical students as they completed a diagnostic reasoning task and to examine whether the strategic quality of these regulatory processes were related to short-term and longer-term medical education outcomes. A self-regulated learning (SRL) microanalytic assessment was administered to 71 second-year medical students while they read a clinical case and worked to formulate the most probable diagnosis. Verbal responses to open-ended questions targeting forethought and performance phase processes of a cyclical model of SRL were recorded verbatim and subsequently coded using a framework from prior research. Descriptive statistics and hierarchical linear regression models were used to examine the relationships between the SRL processes and several outcomes. Most participants (90%) reported focusing on specific diagnostic reasoning strategies during the task (metacognitive monitoring), but only about one-third of students referenced these strategies (e.g. identifying symptoms, integration) in relation to their task goals and plans for completing the task. After accounting for prior undergraduate achievement and verbal reasoning ability, strategic planning explained significant additional variance in course grade (ΔR(2 ) = 0.15, p < 0.01), second-year grade point average (ΔR(2) = 0.14, p < 0.01), United States Medical Licensing Examination Step 1 score (ΔR(2) = 0.08, p < 0.05) and National Board of Medical Examiner subject examination score in internal medicine (ΔR(2) = 0.10, p < 0.05). These findings suggest that most students in the formative stages of learning diagnostic reasoning skills are aware of and think about at least one key diagnostic reasoning process or strategy while solving a clinical case, but a substantially smaller percentage set goals or develop plans that incorporate such strategies. Given that students who developed more strategic plans achieved better outcomes, the potential importance of forethought regulatory processes is underscored.


Prevalence and Correlates of Medical Financial Hardship in the USA.
High patient out-of-pocket (OOP) spending for medical care is associated with medical debt, distress about household finances, and forgoing medical care because of cost in the USA. To examine the national prevalence of medical financial hardship domains: (1) material conditions from increased OOP expenses (e.g., medical debt), (2) psychological responses (e.g., distress), and (3) coping behaviors (e.g., forgoing care); and factors associated with financial hardship. We identified adults aged 18-64 years (N = 68,828) and ≥ 65 years (N = 24,614) from the 2015-2017 National Health Interview Survey. Multivariable analyses of nationally representative cross-sectional survey data were stratified by age group, 18-64 years and ≥ 65 years. Prevalence of material, psychological, and behavioral hardship and hardship intensity. Approximately 137.1 million (95% CI 132.7-141.5) adults reported any medical financial hardship in the past year. Hardship is more common for material, psychological and behavioral domains in adults aged 18-64 years (28.9%, 46.9%, and 21.2%, respectively) than in adults aged ≥ 65 years (15.3%, 28.4%, and 12.7%, respectively; all p < .001). Lower educational attainment and more health conditions were strongly associated with hardship intensity in multivariable analyses in both age groups (p < .001). In the younger group, the uninsured were more likely to report multiple domains of hardship (52.8%), compared to those with some public (26.5%) or private insurance (23.2%) (p < .001). In the older group, individuals with Medicare only were more likely to report hardship in multiple domains (17.1%) compared to those with Medicare and public (12.1%) or Medicare and private coverage (10.1%) (p < .001). Medical financial hardship is common in the USA, especially in adults aged 18-64 years and those without health insurance coverage. With trends towards higher patient cost-sharing and increasing health care costs, risks of hardship may increase in the future.


Heterogeneity among violence-exposed women: applying person-oriented research methods.
Variability of experience and outcomes among violence-exposed people pose considerable challenges toward developing effective prevention and treatment protocols. To address these needs, the authors present an approach to research and a class of methodologies referred to as person oriented. Person-oriented tools support assessment of meaningful patterns among people that distinguish one group from another, subgroups for whom different interventions are indicated. The authors review the conceptual base of person-oriented methods, outline their distinction from more familiar variable-oriented methods, present descriptions of selected methods as well as empirical applications of person-oriented methods germane to violence exposure, and conclude with discussion of implications for future research and translation between research and practice. The authors focus on violence against women as a population, drawing on stress and coping theory as a theoretical framework. However, person-oriented methods hold utility for investigating diversity among violence-exposed people's experiences and needs across populations and theoretical foundations.


Surface plasmon resonance study of protein-carbohydrate interactions using biotinylated sialosides.
Lectins are carbohydrate binding proteins found in plants, animals, and microorganisms. They serve as important models for understanding protein-carbohydrate interactions at the molecular level. We report here the fabrication of a novel sensing interface of biotinylated sialosides to probe lectin-carbohydrate interactions using surface plasmon resonance spectroscopy (SPR). The attachment of carbohydrates to the surface using biotin-NeutrAvidin interactions and the implementation of an inert hydrophilic hexaethylene glycol spacer (HEG) between the biotin and the carbohydrate result in a well-defined interface, enabling desired orientational flexibility and enhanced access of binding partners. The specificity and sensitivity of lectin binding were characterized using Sambucus nigra agglutinin (SNA) and other lectins including Maackia amurensis lectin (MAL), concanavalin A (Con A), and wheat germ agglutinin (WGA). The results indicate that alpha2,6-linked sialosides exhibit high binding affinity to SNA, while alteration in sialyl linkage and terminal sialic acid structure compromises the affinity by a varied degree. Quantitative analysis yields an equilibrium dissociation constant (KD) of 777 +/- 93 nM for SNA binding to Neu5Ac alpha2,6-LHEB. Transient SPR kinetics confirms the K D value from the equilibrium binding studies. A linear relationship was obtained in the 10-100 microg/mL range with limit of detection of approximately 50 nM. Weak interactions with MAL, Con A, and WGA were also quantified. The control experiment with bovine serum albumin indicates that nonspecific interaction on this surface is insignificant over the concentration range studied. Multiple experiments can be performed on the same substrate using a glycine stripping buffer, which selectively regenerates the surface without damaging the sialoside or the biotin-NeutrAvidin interface. This surface design retains a high degree of native affinity for the carbohydrate motifs, allowing distinction of sialyl linkages and investigation pertaining to the effect of functional group on binding efficiency. It could be easily modified to identify and quantify binding patterns of any low-affinity biologically relevant systems, opening new avenues for probing carbohydrate-protein interactions in real time.


Editor's Choice- Impact of identifying precipitating factors on 30-day mortality in acute heart failure patients.
The aim of this study was to describe the prevalence and prognostic value of the most common triggering factors in acute heart failure. Patients with acute heart failure from 41 Spanish emergency departments were recruited consecutively in three time periods between 2011 and 2016. Precipitating factors were classified as: (a) unrecognized; (b) infection; (c) atrial fibrillation; (d) anaemia; (e) hypertension; (f) acute coronary syndrome; (g) non-adherence; and (h) two or more precipitant factors. Unadjusted and adjusted logistic regression models were used to assess the association between 30-day mortality and each precipitant factor. The risk of dying was further evaluated by week intervals over the 30-day follow-up to assess the period of higher vulnerability for each precipitant factor. Approximately 69% of our 9999 patients presented with a triggering factor and 1002 died within the first 30 days (10.0%). The most prevalent factors were infection and atrial fibrillation. After adjusting for 11 known predictors, acute coronary syndrome was associated with higher 30-day mortality (odds ratio (OR) 1.87; 95% confidence interval (CI) 1.02-3.42), whereas atrial fibrillation (OR 0.75; 95% CI 0.56-0.94) and hypertension (OR 0.34; 95% CI 0.21-0.55) were significantly associated with better outcomes when compared to patients without precipitant. Patients with infection, anaemia and non-compliance were not at higher risk of dying within 30 days. These findings were consistent across gender and age groups. The 30-day mortality time pattern varied between and within precipitant factors. Precipitant factors in acute heart failure patients are prevalent and have a prognostic value regardless of the patient's gender and age. They can be managed with specific treatments and can sometimes be prevented.


The role of phospholipase C and phosphatidylinositol 3-kinase in vascular smooth muscle cell migration and proliferation.
Vascular smooth muscle cell (SMC) proliferation and migration both contribute to the formation of intimal hyperplasia. Phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3-K) are ubiquitous signaling proteins that mediate multiple cellular events. In this study, we investigate the role of PLC and PI3-K in platelet-derived growth factor (PDGF) and extracellular matrix protein (ECM) induced SMC proliferation and migration. Proliferation of human saphenous vein SMC was assessed by (3)H-thymidine incorporation. SMC migration was evaluated using a microchemotaxis chamber. U-73122 was used as a general inhibitor for PLC, and D609 and ET-18-OCH3, respectively, were used to block the isotypes of PLC, phosphatidylcholine- (PC-), and phosphatidylinositol- (PI-) specific PLC. PI3-K activity was inhibited using two selective inhibitors, LY-294002 and wortmannin. PDGF and Type 1 collagen (CN-I) stimulated SMC proliferation, whereas PDGF and four distinct extracellular matrix proteins CN-I, Type 4 collagen (CN-IV), fibronectin (FN), and laminin (LN) stimulated SMC migration. Both isotypes of PLC as well as PI3-K were necessary for PDGF- and CN-I-induced proliferation. Signaling for migration, however, was more specific. Of the various signaling proteins studied, only PI-PLC was necessary for PDGF-induced SMC migration. Conversely, PI3-K was the only signaling protein necessary for SMC migration in response to ECM proteins. The signaling pathways necessary for PDGF- and CN-I-induced SMC proliferation involve both isotypes of PLC as well as PI3-K. The signaling pathways used by growth factors and ECM to stimulate SMC migration are more selective. Understanding the intracellular signaling pathways required for SMC proliferation and migration may allow the development of tools to selectively block intimal hyperplasia.


[Evaluating children health conditions in a small community: the study of Itapirapuã, Ribeira Valley, SP].
A household survey for evaluating the mortality, morbidity, nutritional status and health services utilization of children aged under five years was carried out in a rural village in Ribeira, São Paulo State. Most children belonged to families of rural laborers earning less than 80 US dollars per month and living under inadequate environmental conditions. The infant mortality rate was equal to 83 per thousand and 35% of the children were affected by moderate or severe stunting, rates which are well above those for the State. The main reasons for clinic attendances and hospital admissions were acute respiratory infections and diarrhea. The median duration of breastfeeding was 14.4 months, the highest reported for Brazil. Only 40% of the mothers had received antenatal care, and 56% delivered in a hospital - of whom 35% had a caesarean section. Vaccine coverage reached 65% of children aged 12 months or more. This survey revealed an enclave of high morbidity and mortality within Brazil's richest state. It also showed that with a limited budget and within a short time it is possible to obtain valuable information for planning child survival strategies.


Importance of open access to atypical antipsychotics for the treatment of schizophrenia and bipolar disorder: a European perspective.
To assess European psychiatrists' prescribing behaviour and their perceived need for access to a wide range of atypical antipsychotics for patients with schizophrenia and bipolar disorder. A blinded, internet survey of psychiatrists from the UK, Germany, Italy and the Netherlands occurred in 2007. Key inclusion criteria for psychiatrists: practising full time; practising for 5-35 years; prescribed atypical antipsychotics in prior 6 months to > or =20 patients with schizophrenia or bipolar disorder. Eligible psychiatrists selected records for four patients with schizophrenia or bipolar disorder for whom they prescribed > or =1 atypical antipsychotic since January 2004. Survey response rates were: UK, 14.8% (n = 107); Germany, 9.6% (n = 104); Italy, 8.9% (n = 101) and the Netherlands, 3.7% (n = 51); 363 psychiatrists reported on 1442 patients. Psychiatrists perceived a greater difference among atypical antipsychotics as a class (mean, 5.1 on a 7-point scale [7 = 'highly differentiated']) but not selective serotonin reuptake inhibitors (mean, 3.6). On average, psychiatrists used 6.8 different atypical antipsychotics across their patients with schizophrenia and 4.4 across their patients with bipolar disorder, with 2.5 and 2.4 changes required following first-line treatment to stabilise therapy, respectively. The most common reason for switching medication was lack of efficacy. Psychiatrists reported that expected consequences for patients should access to atypical antipsychotics be restricted would include illness deterioration, non-adherence and hospitalisation. Although this study is limited by potential selection biases, these data suggest that European psychiatrists tailor antipsychotic medications for patients with schizophrenia or bipolar disorder according to patients' needs and specific drug attributes.


Dentine hypersensitivity - Australian dentists' perspective.
Dentine hypersensitivity is a frequent clinical presentation though inadequately comprehended by dentists. The objective of this study was to describe Australian dentists' perception on the occurrence, predisposing factors, triggers, diagnosis and management of dentine hypersensitivity. Eight hundred dentists were randomly selected using the Australian Dental Association membership list and invited to participate in a questionnaire-based survey. Out of 295 responding dentists, 284 private practitioners were included in the final analysis. Most dentists perceived that the occurrence of dentine hypersensitivity was <20% and commonest among 30-49 year olds. According to them, abrasion and gingival recession were the main predisposing factors whilst cold stimuli were the commonest trigger. A differential diagnosis-based approach was adopted by a majority to diagnose dentine hypersensitivity although routine screening was resorted to by a few. Most dentists were aware of the current mechanisms underlying dentine hypersensitivity whereas the majority perceived that ongoing predisposing factors was the main reason for dentine tubules to remain exposed. The commonest management strategy employed by most dentists was to prescribe desensitizing agents for home use. Australian dentists' perception of dentine hypersensitivity is generally consistent with the current scientific consensus on this subject.


A clinical trial of injectable testosterone undecanoate as a potential male contraceptive in normal Chinese men.
This is a pilot dose-finding study of spermatogenic suppression using testosterone undecanoate (TU) injections alone in normal Chinese men. Thirty-two healthy men were recruited. Volunteers underwent pretreatment evaluation, then a treatment period in which group I (n = 13) received 500 mg TU, group II (n = 12) received 1000 mg TU, and group III (n = 7) received placebo, respectively, at monthly intervals during the treatment period (or until azoospermia was achieved). Thereafter, they underwent a recovery period until all parameters returned to pretreatment levels. Eleven of 12 volunteers in the 500-mg TU group, and all volunteers in the 1000-mg TU group became azoospermic. Faster suppression of spermatogenesis was achieved in the 1000-mg TU group. Serum testosterone increased significantly in the higher dose group at weeks 8 and 12, but remained within the normal range. Mean serum LH and FSH were profoundly suppressed by both doses to undetectable levels at week 16. TU injections did not cause a significant change in high density lipoprotein cholesterol levels. No serious side-effects were found. We conclude that both dosages of TU can effectively, safely, and reversibly suppress spermatogenesis in normal Chinese men.


Use of Optimal Medical Therapy in Patients With Cardiovascular Disease Undergoing Cardiac Rehabilitation.
Optimal medical therapy (OMT) in patients with coronary artery disease (CAD) and/or heart failure (HF) is underused despite the established benefits of these medications. Cardiac rehabilitation (CR) may be one place where OMT could be promoted. We sought to describe the prevalence and characteristics of OMT use in patients with CAD or HF undergoing CR. We included patients with CAD (myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, angina) and HF enrolled in our CR program. For patients with CAD, we defined OMT to consist of aspirin or other antiplatelets, statins, and beta-blockers (BB). For patients with HF or EF ≤ 40%, OMT included BB, spironolactone, and either Angiotensin Converting Enzyme inhibitors (ACEi)/angiotensin receptor blockers or angiotensin receptor neprilysin inhibitor (ARNI). For CAD patients with normal EF, OMT also included ACEi/ARB/ARNI if they also had diabetes type 2. From January 2015 to December 2019, 828 patients were referred to CR and 743 attended. Among 612 patients (mean age: 65, 23% female) with CAD, 483 (79%) patients were on OMT. Of the 131 HF patients (mean age: 64, 21% female) enrolled in CR, only 23 (18%) met all 3 OMT criteria, whereas most patients were on only 1 (93 %) or 2 (76%) HF specific medications. Spironolactone was the least prescribed (22%) medication. Over the study period, we observed a steady increase in the use of ARNI (2015: 0% vs 2019: 27%, p < 0.01). Among the individuals, 69 patients experienced both CAD and HF, while only 7 patients were under OMT for both CAD and HF. Most patients attending CR with CAD are receiving OMT, but most patients with HF are not. Although OMT has improved over time, there remains room for improvement, particularly among patients with HF.


Acupuncture for treatment of secondary osteoporosis in patients with spinal cord injury: a controlled study.
We explored the effect of adjunctive acupuncture on secondary osteoporosis in patients with spinal cord injury (SCI). Patients with subacute SCI were recruited and divided into two groups by patient choice: group 1 patients received standard combination therapy and group 2 patients received combination therapy plus acupuncture for 3 months. The concentrations of IgG, IgM and tumour necrosis factor α (TNFα) in serum and the bone mineral density were measured before and after treatment. The decrease in the concentration of TNFα and IgM in patients in group 2 compared with those in group 1 was statistically significant. The IgG level showed no significant change in either group. Bone mineral density increased more after adjunctive acupuncture, but the difference was not significant. Further research is needed to determine whether acupuncture as an adjunct to combination therapy can reduce osteoporosis in patients with subacute SCI. P153-2008-36.


Effects of stocking density and dietary vitamin C on performance, meat quality, intestinal permeability, and stress indicators in broiler chickens.
The objective of the current study was to investigate the effects of stocking density (SD) and dietary supplementation of vitamin C on growth performance, meat quality, intestinal permeability, and stress indicators in broiler chickens. The study was conducted using a completely randomized design with a 2 × 2 factorial arrangement consisting of 2 different SD and 2 supplemental levels of dietary vitamin C. A total of 1,368 Ross 308 broiler chickens of 21 days of age with similar body weights (BW) were randomly allotted to 1 of 4 treatments with 6 replicates each. Different numbers of birds per identical floor pen (2.0 m × 2.4 m) were used to create 2 different SD levels of low SD (9 birds/m2) and high SD (18 birds/m2). The basal diet was formulated with no supplemental vitamin C to meet or exceed nutrient recommendations of the Ross 308 manual. The other diet was prepared by supplementing 200 mg/kg vitamin C in the basal diet. The study lasted for 14 days. At the end of the study, 3 male birds per replicate were selected to analyze meat quality, intestinal permeability, and stress indicators such as blood heterophil:lymphocyte (H:L) and feather corticosterone (CORT) concentrations. Results indicated that there were no interactions between different SD and dietary supplementation of vitamin C for all measurements. For the main effects of SD, birds raised at high SD had less (p < 0.01) BW, BW gain, and feed intake with increasing stress responses including greater blood H:L and feather CORT concentrations (p < 0.01) than those raised at low SD. Transepithelial electrical resistance in the jejunal mucosa was decreased (p < 0.05) at high SD, indicating an increase in intestinal permeability. However, the main effects of dietary supplementation of 200 mg/kg vitamin C were insignificant for all measurements. In conclusion, high SD of broiler chickens impairs growth performance and intestinal barrier function with increasing stress responses. However, dietary supplementation of vitamin C may have little beneficial effects on broiler chickens raised at the high SD condition used in the present study.


Frequency, hematopathology, and detection of a new isodicentric variant of deletion 20q.
The ider(20)(p11.21)del(20)(q11q13) anomaly was recognized only recently. Thus, its frequency and clinical significance has not been extensively studied. Due to small size and ambiguous G-band pattern, ider(20q) is usually missed in cytogenetic studies. Furthermore, the commercial FISH probe D20S108 does not distinguish among del(20q), ider(20q), and monosomy 20. Thus, we determined the frequency and hematopathology of patients with ider(20q), and the best cytogenetic methods to detect chromosome 20 anomalies. To do this, we performed FISH on interphase and metaphase cells for 12 patients with -20,+mar and 12 patients with only del(20q) in their karyotype. The marker chromosome in patients with -20,+mar proved to be ider(20q). FISH with D20S108 and 20qter distinguished ider(20q) from del(20q) and monosomy 20. Review of blood and bone marrow slides for nine patients with ider(20q) showed that one had acute myeloid leukemia and eight had myelodysplastic syndromes. Patients with ider(20q) had a more consistent presentation of multilineage dysplasia with additional involvement of the granulocytic series than patients with del(20q). This study shows ider(20q) is common in clinical practice--1/10th the incidence of del(20q)--and is strongly associated with myelodysplasia and acute myeloid leukemia.


Antifungal and Anti-Virulent Activity of Origanum majorana L. Essential Oil on Candida albicans and In Vivo Toxicity in the Galleria mellonella Larval Model.
The aim of this study was to investigate and compare in detail both the antifungal activity in vitro (with planktonic and biofilm-forming cells) and the essential oil composition (EOs) of naturally growing (OMN) and cultivated (OMC) samples of Origanum majorana L. (marjoram). The essential oil composition was analyzed using GC-MS. The major constituent of both EOs was carvacrol: 75.3% and 84%, respectively. Both essential oils showed high antifungal activity against clinically relevant Candida spp. with IC50 and IC90 less than or equal to 0.5 µg mL-1 and inhibition of biofilm with a concentration of 3.5 µg mL-1 or less. Cultivated marjoram oil showed higher anti-biofilm activity against C. albicans. In addition, OMC showed greater inhibition of germ-tube formation (inhibition by 83% in Spider media), the major virulence factor of C. albicans at a concentration of 0.125 µg mL-1. Both EOs modulated cell surface hydrophobicity (CSH), but OMN proved to be more active with a CSH% up to 58.41%. The efficacy of O. majorana EOs was also investigated using Galleria mellonella larvae as a model. It was observed that while the larvae of the control group infected with C. albicans (6.0 × 108 cells) and not receiving treatment died in the controls carried out after 24 h, all larvae in the infected treatment group survived at the end of the 96th hour. When the treatment group and the infected group were evaluated in terms of vital activities, it was found that the difference was statistically significant (p < 0.001). The infection of larvae with C. albicans and the effects of O. majorana EOs on the hemocytes of the model organism and the blastospores of C. albicans were evaluated by light microscopy on slides stained with Giemsa. Cytological examination in the treatment group revealed that C. albicans blastospores were phagocytosed and morphological changes occurred in hemocytes. Our results indicated that the essential oil of both samples showed strong antifungal activities against planktonic and biofilm-forming C. albicans cells and also had an influence on putative virulence factors (germ-tube formation and its length and on CSH).


Reappraisal of the role of radiation therapy in lymphoma treatment.
Radiation therapy (RT) for lymphomas has improved dramatically with modern imaging and treatment techniques, encompassing only the necessary volume with minimal doses to normal structures. Prescribed radiation doses are reduced, and fractionation schedules are under revision. With effective systemic treatment only initial macroscopic disease is irradiated. With no or less effective systemic treatment, possible microscopic disease is also included. Risks of long-term side effects of RT have diminished dramatically and should be weighed against risks from more systemic treatment or increased risk of relapse. Lymphoma patients are often elderly, they tolerate modern limited RT very well. Lymphomas refractory to systemic treatments often remain radioresponsive, and brief, mild RT may offer effective palliation. New roles for RT are emerging with immune therapies. RT for "bridging," keeping the lymphoma under control while waiting for immune therapy, is well established. Enhancement of the immune response to lymphomas, so-called "priming," is being intensively researched.


A calculation method for semi automatic follow up of multiple sclerosis by magnetic resonance eco planar perfusion imaging.
Multiple sclerosis (MS) is one of the most common chronic and disabling inflammatory and demyelinating disorders of the central nervous system (CNS). Magnetic Resonance Imaging (MRI) allows the observation of pathological changes in vivo. It has provided a number of important insights into the spatial-temporal evolution of MS pathology in vivo. Conventional MRI with T2-weighted images is useful in the assessment of oedema early in the inflammatory stage, tissue destruction with demyelination and axonal loss, and gliosis later in the chronic stage. Examination by conventional MRI usually requires more than one hour and it does not completely reveal rapid dynamic changes in blood flow. Recently introduced rapid MRI techniques, MR perfusion imaging and MR diffusion imaging, allow measurement of pathophysiological changes at the cellular level with a good temporal resolution. Nevertheless, until now there were no adequate analytical methods available within the clinical routine to differentiate between types of MS lesions using fast perfusion MRI. We present an analytical method capable of recognizing, and distinguishing, the status of MS lesions by calculating some numerical parameters from the MR perfusion images. The method has been tested on 14 patients affected by MS with different lesions and the results have been compared with those obtained with more expensive conventional MRI examinations. The proposed method made it possible to recognize the nature of the MS lesions in 100% of the examined cases without the need to perform long conventional MRI examinations, using instead perfusion MRI eco planar imaging which takes no more than two minutes. Moreover, the reduced time also allowed reduction of the quantity of contrast medium administered to the patient. Further studies may lead to the use of this technique for differential diagnoses in other white matter diseases.