The demographics and economics of long-term oxygen therapy.
Home oxygen therapy represents a scientifically validated and universally accepted therapeutic regimen for the treatment of chronic hypoxemia secondary to COPD. The clinical benefits of home oxygen, including a decrease in morbidity and often a concomitant increase in the quality of life have been repeatedly confirmed through rigorous worldwide trials, studies, and investigations. However, since home oxygen is an expensive treatment modality, important questions continue to be raised about the overall cost-benefit of the intervention. Such scrutiny is expected to continue, especially in the United States, as the entire issue of health care cost-containment remains atop the domestic political agenda. Providers of home oxygen therapy have traditionally realized quite favorable reimbursement for home oxygen equipment, especially for those patient-customers covered under the Medicare program. However, recent Medicare reimbursement reductions of more than 30% have raised serious questions about the ability of home oxygen providers, especially those with annual revenues less than $1 million, to sustain their historical high level of support services to home oxygen patient-customers. Of particular concern is the economic hardship of supplying portable oxygen, especially for those patient-customers with unusually high ambulatory needs. The use of oxygen-conserving devices is viewed by some as one strategy to better control the costs of supplying portable oxygen, although there are those who still question whether or not oxygen-conserving devices can effectively forestall arterial oxygen desaturation across the entire spectrum of ambulation. Given the evidence now being reported that compliance in using home oxygen as prescribed may well be much lower than originally believed, the time is probably right to revisit the role played by home oxygen providers in determining continuing need through the performance of periodic reassessments. Such reassessments, if designed according to prescribed and validated protocols and conducted by home respiratory therapists under orders of the prescribing physician, would be a valuable tool to ensure continued medical need and identifying noncompliance. This would help ensure that those needing and using home oxygen would continue to receive the benefit. At the same time, patient-customers who, for one reason or another, stop using their oxygen equipment despite repeated encouragement, would have the equipment removed. The net result would be that reimbursement dollars currently wasted on home oxygen equipment that is not being used could be reallocated for those patient-customers willing and able to use the equipment as prescribed.


Reinvestigation of carvotanacetone after 100 years along with minor terpenoid constituents of Blumea malcolmii Hook. F. essential oil.
Reinvestigation of essential oil constituents of Blumea malcolmii Hook. F. (Asteraceae) was carried out after 100 years using gas chromatography equipped with flame ionisation detector (GC-FID) and gas chromatography coupled with mass spectrometry (GC/MS). Eighteen constituents, representing 99.2% of the total oil, were identified. The major compound was identified by GC/MS and NMR ((1)H and (13)C) as carvotanacetone (92.1%). The minor compounds of essential oil have also been identified for the first time in B. malcolmii. The oil was found to be rich in oxygenated monoterpene-type constituents (95.0%).


eIF4E phosphorylation promotes tumorigenesis and is associated with prostate cancer progression.
Translational regulation plays a critical role in the control of cell growth and proliferation. A key player in translational control is eIF4E, the mRNA 5' cap-binding protein. Aberrant expression of eIF4E promotes tumorigenesis and has been implicated in cancer development and progression. The activity of eIF4E is dysregulated in cancer. Regulation of eIF4E is partly achieved through phosphorylation. However, the physiological significance of eIF4E phosphorylation in mammals is not clear. Here, we show that knock-in mice expressing a nonphosphorylatable form of eIF4E are resistant to tumorigenesis in a prostate cancer model. By using a genome-wide analysis of translated mRNAs, we show that the phosphorylation of eIF4E is required for translational up-regulation of several proteins implicated in tumorigenesis. Accordingly, increased phospho-eIF4E levels correlate with disease progression in patients with prostate cancer. Our findings establish eIF4E phosphorylation as a critical event in tumorigenesis. These findings raise the possibility that chemical compounds that prevent the phosphorylation of eIF4E could act as anticancer drugs.


Proteomics analysis of Toxoplasma gondii merozoites reveals regulatory proteins involved in sexual reproduction.
Sexual reproduction plays a crucial role in the transmission and life cycle of toxoplasmosis. The merozoites are the only developmental stage capable of differentiation into male and female gametes, thereby initiating sexual reproduction to form oocysts that are excreted into the environment. Hence, our study aimed to perform proteomic analyses of T. gondii Pru strain merozoites, a pre-sexual developmental stage in cat IECs, and tachyzoites, an asexual developmental stage, using the tandem mass tag (TMT) method in order to identify the differentially expressed proteins (DEPs) of merozoites. Proteins functions were subjected to cluster analysis, and DEPs were validated through the qPCR method. The results showed that a total of 106 proteins were identified, out of which 85 proteins had quantitative data. Among these, 15 proteins were differentially expressed within merozoites, with four exhibiting up-regulation and being closely associated with the material and energy metabolism as well as the cell division of T. gondii. Two novel DEPs, namely S8GHL5 and A0A125YP41, were identified, and their homologous family members have been demonstrated to play regulatory roles in oocyte maturation and spermatogenesis in other species. Therefore, they may potentially exhibit regulatory functions during the differentiation of micro- and macro-gametophytes at the initiation stage of sexual reproduction in T. gondii. In conclusion, our results showed that the metabolic and divisional activities in the merozoites surpass those in the tachyzoites, thereby providing structural, material, and energetic support for gametophytes development. The discovery of two novel DEPs associated with sexual reproduction represents a significant advancement in understanding Toxoplasma sexual reproduction initiation and oocyst formation.


[Actual therapeutic options in the treatment of generalized anxiety disorders].
Among a variety of drugs used in the treatment of anxiety disorders, benzodiazepines and antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are at present the most established and prescribed. In fact, recent guidelines recommend the antidepressants SSRI and SNRI as well as pregabaline, a newly developed drug, as the 1st choice treatment in generalized anxiety disorder (GAD). However, antidepressants have several disadvantages (latency of onset of action, adverse effects and drug interactions) that should not be neglected. Pregabaline is a drug with a new mechanism of action. Clinical studies up to now indicate a rather rapid and efficient anxiolytic effect comparable to that of benzodiazepines, with no risk of abuse. Pregabaline has been recently introduced in Switzerland for the treatment of GAD.


Effect of Omega-3 Fatty Acids on Coronary Plaque Morphology - A Serial Computed Tomography Angiography Study.
Omega-3 fatty acids have been proposed to be useful in the prevention of cardiac events. High-risk plaque (HRP) and plaque progression on serial coronary computed tomography angiography (CTA) have been suggested to be the predecessor of acute coronary syndrome (ACS). The purpose of this study was to investigate whether addition of omega-3 fatty acids to statin therapy for secondary prevention would lead to change in plaque characteristics detected by using serial CTA.Methods and Results: This study enrolled 210 patients with ACS: no eicosapentaenoic acid (EPA)/ docosahexaenoic acid (DHA; EPA/DHA), low-dose EPA+DHA, high-dose EPA+DHA, and high-dose EPA alone. HRP was significantly more frequent in patients with plaque progression (P=0.0001). There was a significant interaction between plaque progression and EPA dose regardless of the DHA dose; 20.3% in EPA-none (no EPA/DHA), 15.7% in EPA-low (low-dose EPA+DHA), and 5.6% in EPA-high (high-dose EPA+DHA and high-dose EPA alone). On multivariate logistic regression analysis, HRP (OR 6.44, P<0.0001), EPA-high (OR 0.13, P=0.0004), and Rosvastatin (OR 0.24, P=0.0079) were the independent predictors for plaque progression. In quantitative analyses (n=563 plaques), the interval change of low attenuation plaque (LAP) volume was significantly different based on EPA dose; LAP was significantly increased in the EPA-none group and significantly decreased in the EPA-high group. In patients with ACS, addition of high-dose EPA (EPA-high) to statin therapy, compared to statin therapy without EPA, was associated with a lower rate of plaque progression.


Emergence of a butterfly: the life experiences of type 1 diabetes Taiwanese patients during the 16-25 years old transition period.
Purpose: To explore the life experiences of patients with type 1 diabetes transition from adolescence into adulthood in Taiwan.Methods: Descriptive phenomenological design was used. Fourteen participants were individually interviewed using a semi-structured interview.Results: The life experiences of patients with type 1 diabetes transition from adolescence into adulthood experience a metamorphosis from awareness of responsibility to figuring out a way to care for themselves. Six themes emerged: (1) hibernation: awareness of responsibility; (2) emergence: attempts to take responsibility; (3) perseverance: encountering difficulties; (4) anxiety: multiple worries; (5) hesitation: back-and-forth," and (6) exit: finding a way out."Conclusions: During the transition phase, the participants experienced the trials of various situations. Regardless of whether they are able to independently bear the responsibilities of self-management, they all hope to turn around the challenges of disease control and take ownership of their disease. Like a butterfly that emerges from a cocoon, they hoped to overcome the dangers of taking flight through trial and error and navigating the world. The results of this study can serve as a reference for clinical care and developing localized intervention strategies targeted to the transition period between adolescence and young adulthood.


Correction of moderate to severe hallux valgus with combined proximal opening wedge and distal chevron osteotomies: a reliable technique.
The mainstay of surgical correction of hallux valgus is first metatarsal osteotomy, either proximally or distally. We present a technique of combining a distal chevron osteotomy with a proximal opening wedge osteotomy, for the correction of moderate to severe hallux valgus. We reviewed 45 patients (49 feet) who had undergone double osteotomy. Outcome was assessed using the American Orthopaedic Foot and Ankle Society (AOFAS) and the Short Form (SF) -36 Health Survey scores. Radiological measurements were undertaken to assess the correction. The mean age of the patients was 60.8 years (44.2 to 75.3). The mean follow-up was 35.4 months (24 to 51). The mean AOFAS score improved from 54.7 to 92.3 (p < 0.001) and the mean SF-36 score from 59 to 86 (p < 0.001). The mean hallux valgus and intermetatarsal angles were improved from 41.6(o) to 12.8(o) (p < 0.001) and from 22.1(o) to 7.1(o), respectively (p < 0.001). The mean distal metatarsal articular angle improved from 23(o) to 9.7(o). The mean sesamoid position, as described by Hardy and Clapham, improved from 6.8 to 3.5. The mean length of the first metatarsal was unchanged. The overall rate of complications was 4.1% (two patients). These results suggest that a double osteotomy of the first metatarsal is a reliable, safe technique which, when compared with other metatarsal osteotomies, provides strong angular correction and excellent outcomes with a low rate of complications. Cite this article: Bone Joint J 2016;98-B:1202-7.


The Clinical Value of N-Terminal Pro B-Type Natriuretic Peptide in Evaluating Obstructive Sleep Apnea in Patients With Coronary Artery Disease.
Natriuretic peptides have been identified as biomarkers of increased myocardial wall stress in the context of obstructive sleep apnea (OSA) in the general population. However, the relationship between N-terminal pro B-type natriuretic peptide (NT-proBNP) and OSA remains unclear in patients with coronary artery disease (CAD). Hence, we aimed to investigate the clinical value of NT-proBNP in evaluating OSA in a large population of patients with CAD. Consecutive patients with CAD were prospectively enrolled between February 2015 and March 2018. Portable respiratory monitoring was applied to facilitate the diagnosis of sleep apnea. Patients were as assigned to the non-OSA (when the respiratory events index [REI] or 3% oxygen desaturation index [ODI] < 15 events/h) and OSA (when the REI or 3% ODI ≥ 15 events/h) groups. Multivariate analyses were used to explore the independent association between NT-proBNP levels and OSA. A total of 1,292 consecutive patients were included with a mean NT-proBNP value of 826.57 μg/L. Patients with high levels of NT-proBNP experienced increasing severity of OSA in those with CAD (P = .0004). Univariate analysis demonstrated that NT-proBNP was a risk factor for OSA (odds ratio [OR] 1.10, 95% confidence interval [CI] 1.03-1.18, P = .005). In addition, multivariate analysis revealed that NT-proBNP was independently associated with the presence of OSA (OR 1.11, 95% CI 1.02-1.20, P = .012) even after adjusting for other cofounding factors. Elevated levels of NT-proBNP were independently associated with a higher likelihood of OSA in patients with CAD. Periodically screening for NT-proBNP levels may provide early identification of OSA.


Filters in autologous blood retransfusion systems affect the amount of blood cells retransfused in total knee arthroplasty: a pilot study.
A pilot study was undertaken to evaluate whether filters integrated in postoperative retransfusion systems affect the amount of blood cells retransfused after total knee arthroplasty. Twenty-two consecutive patients received either the Donor retransfusion system (n=12 patients) or the Bellovac ABT retransfusion system (n=10). Both systems differ with respect to the type of filter, a Pall Lipiguard filter and a Sangopur filter, respectively. At the beginning of the retransfusion, blood samples were taken before and after the filter. The filter of the Donor system significantly decreased the amount of leukocytes and erythrocytes, whereas the filter of the Bellovac system did not. As a result the haemoglobin level of retransfused blood with the Donor system was significantly lower than with the Bellovac system. It can be concluded that the type of filter integrated in two postoperative autologous blood retransfusion systems significantly affected the amount of blood cells retransfused in patients undergoing total knee arthroplasty.


Evidence that adiponectin receptor 1 activation exacerbates ischemic neuronal death.
Adiponectin is a hormone produced in and released from adipose cells, which has been shown to have anti-diabetic and anti-inflammatory actions in peripheral cells. Two cell surface adiponectin receptors (ADRs) mediate the majority of the known biological actions of adiponectin. Thus far, ADR expression in the brain has been demonstrated in the arcuate and the paraventricular nucleus of hypothalamus, where its activation affects food intake. Recent findings suggest that levels of circulating adiponectin increase after an ischemic stroke, but the role of adiponectin receptor activation in stroke pathogenesis and its functional outcome is unclear. Ischemic stroke was induced in C57BL/6 mice by middle cerebral artery occlusion (MCAO) for 1 h, followed by reperfusion. Primary cortical neuronal cultures were established from individual embryonic neocortex. For glucose deprivation (GD), cultured neurons were incubated in glucose-free Locke's medium for 6, 12 or 24 h. For combined oxygen and glucose deprivation (OGD), neurons were incubated in glucose-free Locke's medium in an oxygen-free chamber with 95% N2/5% CO2 atmosphere for either 3, 6, 9, 12 or 24 h. Primary neurons and brain tissues were analysed for Adiponectin and ADRs using reverse transcriptase polymerase chain reaction (RT-PCR), immunoblot and immunochemistry methods. Cortical neurons express ADR1 and ADR2, and that the levels of ADR1 are increased in neurons in response to in vitro or in vivo ischemic conditions. Neurons treated with either globular or trimeric adiponectin exhibited increased vulnerability to oxygen and glucose deprivation which was associated with increased activation of a pro-apoptotic signaling cascade involving p38 mitogen-activated protein kinase (p38MAPK) and AMP-activated protein kinase (AMPK). This study reveals a novel pathogenic role for adiponectin and adiponectin receptor activation in ischemic stroke. We show that cortical neurons express ADRs and reveal a pro-apoptotic role for ADR1 activation in neurons, which may render them vulnerable to ischemic death.


General practitioners' experience of using a questionnaire when assessing cancer patients' needs: a qualitative study.
International guidelines recommend health care professionals to use supportive tools like questionnaires when assessing cancer patients' needs. Little is known about GPs' perspectives and experience in this regard. To examine how GPs experience to involve a short questionnaire, completed by patients' prior to a consultation, when addressing the patients' problems and needs. The aim is to contribute to the knowledge concerning the use of questionnaires as part of clinical cancer care in general practice. Semi-structured individual interviews with 11 GPs in the Region of Southern Denmark purposefully sampled with regard to gender, years working in general practice and practice form. Interviews were analyzed using systematic text condensation. Most GPs found that using the questionnaire provided a supportive structure to the consultation. The questionnaire helped to bring forward issues of importance to the patients, which might otherwise not have been mentioned and enhanced a patient-centered approach. A few GPs found the use of the questionnaire to be restraining, detracting focus from the patient and impede usual practice. This study shows that using questionnaires may have the potential to improve clinical cancer care in general practice in relation to needs assessment of cancer patients and the results support current recommendations.


Efficacy of a workplace osteoporosis prevention intervention: a cluster randomized trial.
Osteoporosis is a debilitating disease. Adequate calcium consumption and physical activity are the two major modifiable risk factors. This paper describes the major outcomes and efficacy of a workplace-based targeted behaviour change intervention to improve the dietary and physical activity behaviours of working women in sedentary occupations in Singapore. A cluster-randomized design was used, comparing the efficacy of a tailored intervention to standard care. Workplaces were the units of randomization and intervention. Sixteen workplaces were recruited from a pool of 97, and randomly assigned to intervention and control arms (eight workplaces in each). Women meeting specified inclusion criteria were then recruited to participate. Workplaces in the intervention arm received three participatory workshops and organization-wide educational activities. Workplaces in the control/standard care arm received print resources. Outcome measures were calcium intake (milligrams/day) and physical activity level (duration: minutes/week), measured at baseline, 4 weeks and 6 months post intervention. Adjusted cluster-level analyses were conducted comparing changes in intervention versus control groups, following intention-to-treat principles and CONSORT guidelines. Workplaces in the intervention group reported a significantly greater increase in calcium intake and duration of load-bearing moderate to vigorous physical activity (MVPA) compared with the standard care control group. Four weeks after intervention, the difference in adjusted mean calcium intake was 343.2 mg/day (95 % CI = 337.4 to 349.0, p < .0005) and the difference in adjusted mean load-bearing MVPA was 55.6 min/week (95 % CI = 54.5 to 56.6, p < .0005). Six months post intervention, the mean differences attenuated slightly to 290.5 mg/day (95 % CI = 285.3 to 295.7, p < .0005) and 50.9 min/week (95 % CI =49.3 to 52.6, p < .0005) respectively. This workplace-based intervention substantially improved calcium intake and load-bearing moderate to vigorous physical activity 6 months after the intervention began. Australia New Zealand Clinical Trial Registry ACTRN12616000079448 . Registered 25 January 2016 (retrospectively registered).


Royal Jelly-Mediated Prolongevity and Stress Resistance in Caenorhabditis elegans Is Possibly Modulated by the Interplays of DAF-16, SIR-2.1, HCF-1, and 14-3-3 Proteins.
Recent studies suggest that royal jelly (RJ) and its related substances may have antiaging properties. However, the molecular mechanisms underlying the beneficial effects remain elusive. We report that the effects of RJ and enzyme-treated RJ (eRJ) on life span and health span in Caenorhabditis elegans (C elegans) are modulated by the sophisticated interplays of DAF-16, SIR-2.1, HCF-1, and 14-3-3 proteins. Dietary supplementation with RJ or eRJ increased C. elegans life span in a dose-dependent manner. The RJ and eRJ consumption increased the tolerance of C elegans to oxidative stress, ultraviolet irradiation, and heat shock stress. Our genetic analyses showed that RJ/eRJ-mediated life-span extension requires insulin/IGF-1 signaling and the activities of DAF-16, SIR-2.1, HCF-1, and FTT-2, a 14-3-3 protein. Earlier studies reported that DAF-16/FOXO, SIR-2.1/SIRT1, FTT-2, and HCF-1 have extensive interplays in worms and mammals. Our present findings suggest that RJ/eRJ-mediated promotion of longevity and stress resistance in C elegans is dependent on these conserved interplays. From an evolutionary point of view, this study not only provides new insights into the molecular mechanisms of RJ's action on health span promotion in C elegans, but also has imperative implications in using RJ/eRJ as nutraceuticals to delay aging and age-related disorders.


Induction of a monocyte/macrophage phenotype switch by mesenchymal stem cells might contribute to improved infarct healing postacute myocardial infarction.
Inadequate healing following acute myocardial infarction (AMI) can lead to the development of heart failure. The ischemic myocardium triggers an inflammatory response that clears cell debris and initiates the onset of scar tissue formation. The duration and intensity of this inflammatory response have been linked to the cardiac functioning post-AMI. In order to diminish scar tissue formation and stimulate regeneration of cardiac tissue, mesenchymal stem cell (MSC) have been applied post-AMI and showed beneficial effects on cardiac function. However, other than the expected regeneration of cardiac tissue, modulation of the inflammatory response post-AMI, especially related to an effect on monocytes/macrophages, was recently found to be an important aspect of MSC therapy. In healing post-AMI, monocytes and macrophages are key players that can either stimulate or repress inflammation using different phenotypes. Increased levels of the proinflammatory phenotype have clinically been associated with poor cardiac functional outcome post-AMI. MSC have been suggested to switch the monocytes/macrophages phenotype into a more anti-inflammatory state and might therefore beneficially influence the duration and intensity of the inflammatory response and subsequent cardiac function post-AMI. To gain more insight into this effect of MSC, this review provides an overview of the most relevant studies regarding this modulatory effect of MSC on monocytes/macrophages including its mechanisms to improve cardiac functioning post-AMI.


Hypocholesterolaemic effect of rat-administered oral doses of the isolated 7S globulins from cowpeas and adzuki beans.
The role of seed proteins, especially soyabean 7S globulins, in controlling dyslipidaemia is widely acknowledged. Amino acid sequence homology among the proteins of this family could reflect similar biological functions in other species. The aim of the present study was to unveil a hypolipidaemic effect of the 7S globulins from cowpeas (7S-C) and adzuki beans (7S-A), administered orally to rats fed a hypercholesterolaemic (HC; high cholesterol and TAG) diet for 28 d. A total of forty-five rats were divided into five groups (nine rats per group): (1) standard (STD) diet; (2) HC diet; (3) HC diet + 7S-C (300 mg/kg per d); (4) HC diet + 7S-A (300 mg/kg per d); and (5) HC diet + simvastatin (SVT; 50 mg/kg per d), as a control. Significant decreases in food intake and final body weight of rats receiving HC + 7S-C and HC + 7S-A diets compared with groups fed the HC and STD diets were observed. Significant decreases in serum total and non-HDL-cholesterol of 7S-C, 7S-A and SVT groups were also observed. HDL-cholesterol levels increased in the 7S-C, 7S-A and SVT groups, while hepatic cholesterol and TAG concentrations were significantly lower than in the HC diet group for the 7S-C-supplemented group only. Faecal excretions of fat and cholesterol in HC diet groups were considerably higher in animals consuming the 7S globulins. The results show that cowpea and adzuki bean 7S globulins promote cholesterol-decreasing effects in hypercholesterolaemic rats even at low dosages, as already observed for other legume seed storage proteins of this family. This main effect is discussed in relation to the possible mechanisms of action.


ADHD Prescription Medications and Their Effect on Athletic Performance: A Systematic Review and Meta-analysis.
Stimulant medications used for the treatment of Attention Deficit-Hyperactivity Disorder (ADHD) are believed to provide a physical advantage in athletics, but several of these medications are not regulated by the World Anti-Doping Association. Given the prevalence of ADHD among the athlete population and concern for abuse of ADHD medications, this review and meta-analysis aimed to evaluate effects of ADHD medications on athletic performance, thereby appraising the validity of claims of performance enhancement. A search of MEDLINE, Embase, CINAHL, and Cochrane Review databases was performed for all randomized controlled trials evaluating athletic performance after ingestion of placebo or ADHD treatment medications from August 2020 through November 2020. All RCTs identified from these search criteria were included for screening, with exclusion of any animal studies. Two reviewers (JB, CK) assessed methodological quality and risk of bias using CONSORT 2010 and Cochrane Collaboration tools. Study results were compiled with corresponding p values for each finding. Effect sizes (Cohen's D) for athletic performance and physiological changes were aggregated for each study. Studies were further screened for homogeneity that would allow for meta-analysis. Heterogeneity was calculated using I2. A total of 13,033 abstracts evaluating amphetamine, methamphetamine, methylphenidate, and bupropion were screened. The final analysis included nine studies, six of which found significant improvement in athletic performance with use of stimulant medications (p < 0.05). Methylphenidate and amphetamine were consistently identified to have a performance effect. Secondary effects identified included significant increase in heart rate, core temperature, and elevation of various serum hormone levels (p < 0.05). Effect size evaluation found seven studies demonstrating small to large effects on physical performance, as well as in categories of cardiometabolic, temperature, hormone, and ratings of perceived exertion, to varying degrees. A meta-analysis was performed on two studies, demonstrating conflicting results. Dopaminergic/noradrenergic agonist medications appear to have a positive effect on athletic performance, as well as effects on physiological parameters. Further consideration of medications currently not regulated, i.e. bupropion, is warranted given evidence of athletic performance enhancement. PROSPERO trial registration number: CRD42020211062; 10/29/2020 retrospectively registered.


Independent associations between weight status and disability in adults: results from the Health Survey for England.
While direct links between obesity and some illnesses are well-established, there is a relative paucity of research on associations between obesity and disabilities. The aim of this study was to test for significant associations between overweight and obesity and the presence of a wide range of disabling conditions in adults, controlling for sex, age, education, social class, income, cigarette smoking status and alcohol consumption. Data were extracted from the Health Survey for England (2001); a cross-sectional survey of the community-dwelling population. In total, 8613 adult participants were included in the analysis. Multivariate logistic regression was employed to test whether the odds of having a range of disabling conditions are higher in the overweight and obese populations compared with those in the ideal weight range. The risk of nearly all disabling conditions tested was elevated in the obese and morbidly obese groups. Of great importance for public health, the risks of musculoskeletal illness, arthritis and rheumatism, and personal care disability were significantly elevated, even in those in the overweight category (currently about half of the adult population living in the UK). Obesity is independently associated with a range of disabling conditions in adults. The present study highlights the need for further research into the mechanisms by which these associations occur.


Insights into the Serum Metabolic Adaptations in Response to Inspiratory Muscle Training: A Metabolomic Approach Based on 1H NMR and UHPLC-HRMS/MS.
Inspiratory muscle training (IMT) is known to promote physiological benefits and improve physical performance in endurance sports activities. However, the metabolic adaptations promoted by different IMT prescribing strategies remain unclear. In this work, a longitudinal, randomized, double-blind, sham-controlled, parallel trial was performed to investigate the effects of 11 weeks (3 days·week-1) of IMT at different exercise intensities on the serum metabolomics profile and its main regulated metabolic pathways. Twenty-eight healthy male recreational cyclists (30.4 ± 6.5 years) were randomized into three groups: sham (6 cm·H2O of inspiratory pressure, n = 7), moderate-intensity (MI group, 60% maximal inspiratory pressure (MIP), n = 11) and high-intensity (HI group, 85-90% MIP, n = 10). Blood serum samples were collected before and after 11 weeks of IMT and analyzed by 1H NMR and UHPLC-HRMS/MS. Data were analyzed using linear mixed models and metabolite set enrichment analysis. The 1H NMR and UHPLC-HRMS/MS techniques resulted in 46 and 200 compounds, respectively. These results showed that ketone body metabolism, fatty acid biosynthesis, and aminoacyl-tRNA biosynthesis were upregulated after IMT, while alpha linolenic acid and linoleic acid metabolism as well as biosynthesis of unsaturated fatty acids were downregulated. The MI group presented higher MIP, Tryptophan, and Valine levels but decreased 2-Hydroxybutyrate levels when compared to the other two studied groups. These results suggest an increase in the oxidative metabolic processes after IMT at different intensities with additional evidence for the upregulation of essential amino acid metabolism in the MI group accompanied by greater improvement in respiratory muscle strength.


An update on HDV: virology, pathogenesis and treatment.
Hepatitis delta is an inflammatory liver disease caused by infection with HDV. HDV is a single-stranded circular RNA pathogen with a diameter of 36 nm. HDV is classified in the genus Deltavirus and is still awaiting a final taxonomic classification up to the family level. HDV shares similarities with satellite RNA and viroids including a small circular single-stranded RNA with secondary structure that replicates through the 'double rolling circle' mechanism. The HDV RNA genome is capable of self-cleavage through a ribozyme and encodes only one structural protein, the hepatitis delta antigen (HDAg), from the antigenomic RNA. There are two forms of HDAg, a shorter (S; 22 kDa) and a longer (L; 24 kDa) form, the latter generated from an RNA editing mechanism. The S form is essential for viral genomic replication. The L form participates in the assembly and formation of HDV. For complete replication and transmission, HDV requires the hepatitis B surface antigen (HBsAg). Thus, HDV infection only occurs in HBsAg-positive individuals, either as acute coinfection in treatment-naive HBV-infected persons, or as superinfection in patients with pre-existing chronic hepatitis B (CHB). HDV is found throughout the world, but its prevalence, incidence, clinical features and epidemiological characteristics vary by geographic region. There are eight genotypes (1 to 8) distributed over different geographic areas: HDV-1 is distributed worldwide, whereas HDV-2 to 8 are seen more regionally. Levels of HDV viraemia change over the course of HDV infection, being significantly higher in patients with early chronic hepatitis than in cirrhosis. Chronic HDV infection leads to more severe liver disease than chronic HBV monoinfection with an accelerated course of fibrosis progression, an increased risk of hepatocellular carcinoma and early decompensation in the setting of established cirrhosis. Current treatments include pegylated interferon-α and liver transplantation; the latter of which can be curative. Further studies are needed to develop better treatment strategies for this challenging disease.


Longitudinal Hemodynamics of Transcatheter and Surgical Aortic Valves in the PARTNER Trial.
Use of transcatheter aortic valve replacement (TAVR) for severe aortic stenosis is growing rapidly. However, to our knowledge, the durability of these prostheses is incompletely defined. To determine the midterm hemodynamic performance of balloon-expandable transcatheter heart valves. In this study, we analyzed core laboratory-generated data from echocardiograms of all patients enrolled in the Placement of Aortic Transcatheter Valves (PARTNER) 1 Trial with successful TAVR or surgical AVR (SAVR) obtained preimplantation and at 7 days, 1 and 6 months, and 1, 2, 3, 4, and 5 years postimplantation. Patients from continued access observational studies were included for comparison. Successful implantation after randomization to TAVR vs SAVR (PARTNER 1A; TAVR, n = 321; SAVR, n = 313), TAVR vs medical treatment (PARTNER 1B; TAVR, n = 165), and continued access (TAVR, n = 1996). Five-year echocardiogram data were available for 424 patients after TAVR and 49 after SAVR. Death or reintervention for aortic valve structural indications, measured using aortic valve mean gradient, effective orifice area, Doppler velocity index, and evidence of hemodynamic deterioration by reintervention, adverse hemodynamics, or transvalvular regurgitation. Of 2795 included patients, the mean (SD) age was 84.5 (7.1) years, and 1313 (47.0%) were female. Population hemodynamic trends derived from nonlinear mixed-effects models showed small early favorable changes in the first few months post-TAVR, with a decrease of -2.9 mm Hg in aortic valve mean gradient, an increase of 0.028 in Doppler velocity index, and an increase of 0.09 cm2 in effective orifice area. There was relative stability at a median follow-up of 3.1 (maximum, 5) years. Moderate/severe transvalvular regurgitation was noted in 89 patients (3.7%) after TAVR and increased over time. Patients with SAVR showed no significant changes. In TAVR, death/reintervention was associated with lower ejection fraction, stroke volume index, and aortic valve mean gradient up to 3 years, with no association with Doppler velocity index or valve area. Reintervention occurred in 20 patients (0.8%) after TAVR and in 1 (0.3%) after SAVR and became less frequent over time. Reintervention was caused by structural deterioration of transcatheter heart valves in only 5 patients. Severely abnormal hemodynamics on echocardiograms were also infrequent and not associated with excess death or reintervention for either TAVR or SAVR. This large, core laboratory-based study of transcatheter heart valves revealed excellent durability of the transcatheter heart valves and SAVR. Abnormal findings in individual patients, suggestive of valve thrombosis or structural deterioration, were rare in this protocol-driven database and require further investigation. clinicaltrials.gov Identifier: NCT00530894.


Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation.
Immunotherapies targeting pathological tau have recently emerged as a promising approach for treatment of neurodegenerative disorders. We have previously showed that the mouse antibody DC8E8 discriminates between healthy and pathological tau, reduces tau pathology in murine tauopathy models and inhibits neuronal internalization of AD tau species in vitro.Here we show, that DC8E8 and antibodies elicited against the first-in-man tau vaccine, AADvac1, which is based on the DC8E8 epitope peptide, both promote uptake of pathological tau by mouse primary microglia. IgG1 and IgG4 isotypes of AX004, the humanized versions of DC8E8, accelerate tau uptake by human primary microglia isolated from post-mortem aged and diseased brains. This promoting activity requires the presence of the Fc-domain of the antibodies.The IgG1 isotype of AX004 showed greater ability to promote tau uptake compared to the IgG4 isotype, while none of the antibody-tau complexes provoked increased pro-inflammatory activity of microglia. Our data suggest that IgG1 has better suitability for therapeutic development.


Faith Community Nursing: Faith Element Enhances Cardiovascular Risk Reduction Program Outcomes.
The high prevalence of hypertension among African Americans makes faith-based education programs culturally appropriate. Faith-enhanced health education is a way to reach these often healthcare-disenfranchised populations. With Every Heartbeat is Life (WEHL), a community-based heart health program, was enhanced with Scripture and prayer for this project. The program took place in an African American nondenominational church. The Scripture-enhanced WEHL program emphasized biblical teachings of self-care with standard lessons on nutrition, exercise, smoking cessation, and disease management interventions that increased knowledge of hypertension and associated cardiovascular risks.


Clinical and functional evaluation of the efficacy of otilonium bromide: a multicenter study in Italy.
Seventy-two patients complaining of abdominal pain were studied in a double blind trial with otilonium bromide (OB) (40 mg tid or placebo). In our patients we performed, before and after the treatment, a clinical evaluation (symptom variations) and functional studies (sigmoid manometry during bowel distension). As regards clinical parameters, otilonium bromide significantly reduced abdominal pain and bloating and significantly increased (p less than 0.02) the pain threshold. However the comparison with the placebo group did not show any difference between the two groups. Sigmoid motility during distension was significantly reduced (p less than 0.05) in OB group, whereas it did not change in the placebo group. We can conclude that, in irritable bowel syndrome (IBS) patients, OB is able to improve symptoms and to reduce stimulated motor activity of the sigmoid.


Understanding the interactive influence of hydrolytic conditions on biocatalytic production of fructooligosaccharides from inulin.
Statistical optimization of hydrolytic conditions for the production of fructooligosaccharides (FOSs) from pure inulin using Aspergillus tritici endoinulinase was carried out in a batch system. FOSs yield 99.19% was obtained under the optimized hydrolytic conditions i.e. inulin concentration (7.3%), enzyme load (65 IU), hydrolysis time (13 h) and agitation (100 rpm). The closeness of value of co-efficient of determination (R2) to 1, good agreement between model's predicted and experimental values, low percentage error (<5%), high adequate precision (>4%) and F value (11,634.32), and low Lack of fit (0.60) of the designed model authenticates its fitness. High substrate concentration, low enzyme load and short hydrolysis span justifies efficiency of developed process for the preparation of FOSs from inulin using fungal endoinulinase. TLC chromatographic and densitometry studies confirmed the synthesis of short-chain length FOSs. FOSs preparation contained 33.85% GF2 (ketose), 24.50% GF3 (nystose), 7.26% GF4 (fructofuranosylnystose) and 33.58% FOSs of DP5-9.


Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy.
Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in individuals below the age of 40. We recently reported that IL-17A is required for the development of DCMi. We show a novel pathway connecting IL-17A, cardiac fibroblasts (CFs), GM-CSF, and heart-infiltrating myeloid cells with the pathogenesis of DCMi. Il17ra(-/-) mice were protected from DCMi, and this was associated with significantly diminished neutrophil and Ly6Chi monocyte/macrophage (MO/MΦ) cardiac infiltrates. Depletion of Ly6Chi MO/MΦ also protected mice from DCMi. Mechanistically, IL-17A stimulated CFs to produce key chemokines and cytokines that are critical downstream effectors in the recruitment and differentiation of myeloid cells. Moreover, IL-17A directs Ly6Chi MO/MΦ in trans toward a more proinflammatory phenotype via CF-derived GM-CSF. Collectively, this IL-17A-fibroblast-GM-CSF-MO/MΦ axis could provide a novel target for the treatment of DCMi and related inflammatory cardiac diseases.


The future of emergency medicine: an evolutionary perspective.
Emergency medicine (EM) has grown rapidly over the past 50 years, evolving from a specialty defined by its locational identity--a hospital receiving room--to the specialty picked fourth-most-frequently by graduating U.S. medical students and to being the focal point of clinical care and of research on time-sensitive medical conditions. The authors review the forces that led to the growth of EM and those that will shape its future--in particular, cost, quality, and technology. A balancing of cost and quality considerations will likely drive EM education and research endeavors. The future of the field will be determined in part by resolution of the tension between the current inefficient conditions of emergency departments (EDs), which are crowded because of the temporary boarding of admitted patients for whom a bed is not yet ready, and the desired provision of quality care under emergent conditions. That is, patients with stroke, myocardial infarction, sepsis, or severe injuries from trauma require a working diagnosis and interventions that are initiated shortly after presentation, but ED personnel distracted by the demands of caring for boarded patients are unable to deliver optimal ED care. The reduction or elimination of boarding will enhance education and research within EDs and will contribute to an efficient system of high-quality EM services.


Molecular area effects in Cepaea.
Enzyme polymorphisms in the land snail Cepaea nemoralis in the central Pyrenees show concordant geographic patterns of strong differentiation that are not correlated with the distributions of characters of shell color and banding or with the major pattern of variation in climate and vegetation type. Three regions of relative genetic uniformity separated by steep clines in allele frequencies are designated as "molecular area effects." A model of allopatric differentiation of populations in temporary geographic isolation during the last period of Pleistocene glaciation, followed by invasion of the Pyrenees and hybridization in secondary contact, is proposed to account for the present-day pattern of genetic differentiation. The genetic structure of the Pyrenean populations of C. nemoralis is not interpretable in terms of stasipatric or parapatric models of speciation.


Effect of nicotine chewing gum as an adjunct to general practitioner's advice against smoking.
This study was designed to see whether the offer and prescription of nicotine chewing gum would enhance the efficacy of general practitioners' advice to stop smoking. A sample of 1938 cigarette smokers who attended the surgeries of 34 general practitioners in six group practices were assigned by week of attendance (in a balanced design) to one of three groups: (a) non-intervention controls, (b) advice plus booklet, and (c) advice plus booklet plus the offer of nicotine gum. Follow up was done after four months and one year. The results show a clear advantage for those offered the nicotine gum (p less than 0.001). After correction for those who refused or failed chemical validation and those who switched from cigarettes to a pipe or cigars, the proportions who were abstinent at four months and still abstinent at one year were 3.9%, 4.1%, and 8.8% in the three groups, respectively. These percentages are based on all cigarette smokers who attended the surgeries including those who did not wish to stop and those in the gum group who did not try the gum (47%). The effect of the offer and prescription of gum was to motivate more smokers to try to stop, to increase the success rate among those who tried, and to reduce the relapse rate of those who stopped. The self selected subgroup of 8% who used more than one box of 105 pieces of gum achieved a success rate of 24%. It would be feasible and effective for general practitioners to include the offer of nicotine gum and brief instructions on its use as part of a minimal intervention routine with all cigarette smokers. A general practitioner who adopts such a routine with similar success could expect to achieve about 35-40 long term ex-smokers a year and so save the lives of about 10 of them. If replicated by all general practitioners throughout the country the yield of ex-smokers would be about one million a year.


Clinical features and [11C]-CFT PET analysis of PARK2, PARK6, PARK7-linked autosomal recessive early onset Parkinsonism.
Mutations in the Parkin, PINK1, and DJ-1 genes can cause autosomal recessive early onset Parkinsonism. We studied three families with the mutations of the Parkin, PINK1 and DJ-1 genes, respectively, with a dopamine transporter ligand [(11)C]-CFT positron emission tomography. A marked bilaterally and dissymmetrically decrement of [(11)C]-CFT uptake was found in all these patients, and putamen as well as caudate nucleus was affected. We also found asymptomatic Parkin and PINK1 heterozygotes showed a mild but significant decrement in [(11)C]-CFT uptake, but this phenomenon was not found in the DJ-1-heterozygotes. Our results suggested the three autosomal recessive forms of early onset are similar to each other on pathophysiological grounds, a sub-clinical disease process in Parkin and PINK1-heterozygotes, but not in DJ-1-heterozygotes.


Ultra-high permeable phenine nanotube membranes for water desalination.
Nanopore desalination technology hinges on high water-permeable membranes which, at the same time, block ions efficiently. In this study, we consider a recently synthesized [Science363, 151-155 (2019)] phenine nanotube (PNT) for water desalination applications. Using both equilibrium and non-equilibrium molecular dynamics simulations, we show that the PNT membrane completely rejects salts, but permeates water at a rate which is an order-of-magnitude higher than that of all the membranes used for water filtration. We provide the microscopic mechanisms of salt rejection and fast water-transport by calculating the free-energy landscapes and electrostatic potential profiles. A collective diffusion model accurately predicts the water permeability obtained from the simulations over a wide range of pressure gradients. We propose a method to calculate the osmotic water permeability from the equilibrium simulation data and find that it is very high for the PNT membrane. These remarkable properties of PNT can be applied in various nanofluidic applications, such as ion-selective channels, ionic transistors, sensing, molecular sieving, and blue energy harvesting.


Impact of previous coronary artery bypass surgery on clinical outcome after percutaneous interventions with second generation drug-eluting stents in TWENTE trial and non-enrolled TWENTE registry.
Patients with previous coronary artery bypass grafting (CABG) who underwent percutaneous coronary intervention (PCI) have an increased repeat revascularization rate, but data on contemporary second-generation drug-eluting stents (DES) are scarce. We evaluated 1-year clinical outcome following secondary revascularization by PCI in patients of the TWENTE trial and non-enrolled TWENTE registry, and compared patients with previous CABG versus patients without previous CABG. Of all 1709 consecutive patients, 202 (11.8%) had previously undergone CABG (on average 11.2±8.5 years ago). CABG patients were older (68.5±9.4 years vs. 64.1±10.7 years, P<0.001) and more often had diabetes (28.7% vs. 20.9%, P=0.01) and previous PCI (40.1% vs. 19.8%, P<0.001) compared to patients without previous CABG. Nevertheless, a higher target vessel revascularization (TVR) rate following PCI in the CABG patients (9.4% vs. 2.3%, P<0.001) was the only significant difference in clinical outcome at 1-year follow-up (available for 99.6%). Among CABG patients, the TVR rate was significantly higher in patients treated for graft lesions (n=65; 95.4% in vein grafts) than in patients treated for native coronary lesions only (n=137) (18.5% vs. 5.1%, P=0.002). Among 1638 patients with PCI of native coronary lesions only, there was only a non-significant difference in TVR between patients with previous CABG versus patients without previous CABG (5.1% vs. 2.3%, P=0.08). Patients with previous CABG showed a favorable safety profile after PCI with second-generation DES. Nevertheless, their TVR rate was still much higher, driven by more repeat revascularizations after PCI of degenerated vein grafts. In native coronary lesions, there was no such difference.


Studying the Role of C5-Inhibition Therapy in Scleroderma Renal Crisis-Induced Thrombotic Microangiopathy - A Review of Literature.
The pathogenesis of scleroderma renal crisis (SRC) remains poorly understood but a growing body of evidence suggests that activation of the complement system may be involved in the disease. Recent studies have shown that Eculizumab (monoclonal antibody directed against the complement component C5) is effective in treating patients with SRC who present with symptoms of thrombotic microangiopathy (SRC-TMA). In this study, we conducted a systematic review to characterize the published experience of the presentation and outcome of patients with SRC who were treated with C5 inhibitor, Eculizumab. A literature search was conducted from inception to December 2022 using Medical Subject Headings (MeSH) terms for 'scleroderma', 'scleroderma renal crisis, and 'Eculizumab'. We included case reports, case series, and observational studies which reported the use of Eculizumab with or without Angiotensin-converting enzyme inhibitors (ACE-I) for the treatment of scleroderma renal crisis (SRC) in patients with systemic sclerosis. The study included 17 patients, all of whom were treated with Eculizumab. Additionally, the use of ACE-I was reported in 11/17 (64.7%) patients. Further, plasmapheresis was used in 9/17 (52.9%), steroids in 5/17 (29.4%), cyclophosphamide in 3/17 (17.6%), calcium channel blockers in 3/17 (17.6%), and Rituximab in 3/17 (17.6%) patients. Renal replacement therapy was required in 11/17 (64.7%) patients. 14/17 patients (82.3%) were reported to have clinical (renal or hematologic) improvement with Eculizumab therapy (Table 1). These findings should prompt testing on a larger cohort of SRC-TMA patients. This would help us determine whether aggressive treatment combining ACE-I and Eculizumab can target the various underlying endothelial, inflammatory, and immunologic mechanisms involved in SRC-TMA, and improve patient outcomes.


Antigen persistence is required for somatic mutation and affinity maturation of immunoglobulin.
Whether germinal centers (GC) with follicular dendritic cell (FDC) clusters are the essential sites for affinity maturation of immunoglobulin is still controversial. To re-evaluate the role of GC / FDC in affinity maturation and somatic mutation in a defined antigen system, lymphotoxin-alpha(- / -) and TNF receptor I(- / -) mice, lacking GC / FDC, were immunized with (4-hydroxy-3-nitrophenyl) acetyl-sheep RBC (NP-SRBC). In contrast to soluble hapten-carrier systems, NP-SRBC allows us to compare affinity maturation in the presence or absence of adjuvant. These mice showed a dramatically impaired ability to generate high-affinity IgG to NP, but retained the ability to produce low-affinity anti-NP IgG when NP-SRBC was used in the absence of adjuvant. In contrast to wild-type mice, somatic mutation of the expressed IgG heavy chain gene was rarely detected in these GC / FDC-deficient mice. This suggests that GC / FDC are essential for affinity maturation. Trapping antigen-specific B cells inside the T cell zone of TNFRI(- / -) mice may prolong the interaction between T and B cells, which allows class switching but no further affinity maturation of IgG. Interestingly, GC / FDC-deficient mice could be induced to generate high-affinity, somatically mutated IgG antibodies by immunization with the same amount of NP-SRBC antigen emulsified in incomplete Freund's adjuvant or repeated immunization with the antigen alone. Thus, these data support a model in which prolonged availability of antigen is required for somatic mutation and affinity maturation, and FDC or adjuvants facilitate such processes by slowly releasing antigens.


Ultra-high drug loading improves nanoparticle efficacy against peritoneal mesothelioma.
Peritoneal mesothelioma is an aggressive disease with a median survival of under three years, due to a lack of effective treatment options. Mesothelioma is traditionally considered a "chemoresistant" tumor; however, low intratumoral drug levels coupled with the inability to administer high systemic doses suggests that therapeutic resistance may be due to poor drug delivery rather than inherent biology. While patient survival may improve with repetitive local intraperitoneal infusions of chemotherapy throughout the perioperative period, these regimens carry associated toxicities and significant peri-operative morbidity. To circumvent these issues, we describe ultra-high drug loaded nanoparticles (NPs) composed of a unique poly(1,2-glycerol carbonate)-graft-succinate-paclitaxel (PGC-PTX + PTX) conjugate. PGC-PTX + PTX NPs are cytotoxic, localize to tumor in vivo, and improve survival in a murine model of human peritoneal mesothelioma after a single intraperitoneal (IP) injection compared to multiple weekly doses of the clinically utilized formulation PTX-C/E. Given their unique pharmacokinetics, a second intraperitoneal dose of PGC-PTX + PTX NPs one month later more than doubles the overall survival compared to the clinical control (122 versus 58 days). These results validate the clinical potential of prolonged local paclitaxel to treat intracavitary malignancies such as mesothelioma using a tailored polymer-mediated nanoparticle formulation.


Phantom Restless Legs Syndrome.
Amputees often experience a phantom limb consisting in the vivid impression that the limb is not only still present, but in many cases, painful. These patients may also become restless legs syndrome (RLS) sufferers; conversely, a preexisting RLS may persist after limb amputation. In this brief essay, papers on phantom RLS (pRLS) are reviewed in order to provide clinical elements for the diagnosis and treatment of this peculiar condition. It is relevant that dopamine receptor agonists yielded a marked reduction of the RLS symptoms in all cases reported. Key Messages: pRLS indirectly confirms the innate capacity of the central nervous system to retain a primordial internal body image responsible of phantom sensations. Moreover, it has been hypothesized that pRLS may provide clues for a better comprehension of some mechanisms underlying phantom pain and for the development of new treatment strategies.


Conformational plasticity of RAS Q61 family of neoepitopes results in distinct features for targeted recognition.
The conformational landscapes of peptide/human leucocyte antigen (pHLA) protein complexes encompassing tumor neoantigens provide a rationale for target selection towards autologous T cell, vaccine, and antibody-based therapeutic modalities. Here, using complementary biophysical and computational methods, we characterize recurrent RAS55-64 Q61 neoepitopes presented by the common HLA-A*01:01 allotype. We integrate sparse NMR restraints with Rosetta docking to determine the solution structure of NRASQ61K/HLA-A*01:01, which enables modeling of other common RAS55-64 neoepitopes. Hydrogen/deuterium exchange mass spectrometry experiments alongside molecular dynamics simulations reveal differences in solvent accessibility and conformational plasticity across a panel of common Q61 neoepitopes that are relevant for recognition by immunoreceptors. Finally, we predict binding and provide structural models of NRASQ61K antigens spanning the entire HLA allelic landscape, together with in vitro validation for HLA-A*01:191, HLA-B*15:01, and HLA-C*08:02. Our work provides a basis to delineate the solution surface features and immunogenicity of clinically relevant neoepitope/HLA targets for cancer therapy.


Accuracy of coronary CT angiography using a submillisievert fraction of radiation exposure: comparison with invasive coronary angiography.
Coronary computed tomography angiography (CTA) is increasingly being used for evaluation of coronary artery disease (CAD). As a result of the widely reported potential of carcinogenic risk from x-ray based examinations, many strategies have been developed for dose reduction with CTA. The purpose of this study was to assess the diagnostic accuracy of CTA acquired with a submillisievert fraction of effective radiation dose reconstructed with a model-based iterative reconstruction (MBIR) using invasive coronary angiography (ICA) as a standard of reference. In 36 patients (body mass index range 17 to 39 kg/m(2)) undergoing ICA for CAD evaluation, a CTA was acquired using very low tube voltage (80 to 100 kV) and current (150 to 210 mA) and was reconstructed with MBIR. CAD (defined as ≥50% luminal narrowing) was assessed on CTA and on ICA. CTA resulted in an estimated radiation dose exposure of 0.29 ± 0.12 mSv (range 0.16 to 0.53 mSv), yielding 96.9% (436 of 450) interpretable segments. On an intention-to-diagnose basis, no segment was excluded, and vessels with at least 1 nonevaluable segment and no further finding were classified as false positive. This resulted in a sensitivity, specificity, positive, and negative predictive value and accuracy of 100%, 74%, 77%, 100%, and 86% per patient and 85%, 86%, 56%, 96%, and 85% per vessel, respectively. The use of MBIR reconstruction allows accurate noninvasive diagnosis of CAD with CTA at a submillisievert fraction of effective radiation dose comparable with a chest x-ray in 2 views.


The S-nitrosylation of glyceraldehyde-3-phosphate dehydrogenase 2 is reduced by interaction with glutathione peroxidase 3 in Saccharomyces cerevisiae.
Glutathione peroxidases (Gpxs) are the key anti-oxidant enzymes found in Saccharomyces cerevisiae. Among the three Gpx isoforms, glutathione peroxidase 3 (Gpx3) is ubiquitously expressed and modulates the activities of redox-sensitive thiol proteins involved in various biological reactions. By using a proteomic approach, glyceraldehyde-3-phosphate dehydrogenase 2 (GAPDH2; EC 126.96.36.199) was found as a candidate protein for interaction with Gpx3. GAPDH, a key enzyme in glycolysis, is a multi-functional protein with multiple intracellular localizations and diverse activities. To validate the interaction between Gpx3 and GAPDH2, immunoprecipitation and a pull-down assay were carried out. The results clearly showed that GAPDH2 interacts with Gpx3 through its carboxyl-terminal domain both in vitro and in vivo. Additionally, Gpx3 helps to reduce the S-nitrosylation of GAPDH upon nitric oxide (NO) stress; this subsequently increases cellular viability. On the basis of our findings, we suggest that Gpx3 protects GAPDH from NO stress and thereby contributes to the maintenance of homeostasis during exposure to NO stress.


Establishment of a new human pneumococcal standard reference serum, 007sp.
Lot 89SF has been the reference standard serum pool used in pneumococcal enzyme-linked immunosorbent assays (ELISAs) since 1990. In 2005, it was estimated that there remained between 2 and 5 years' supply of lot 89SF. Since lot 89SF was the reference standard used in the evaluation of the seven-valent pneumococcal conjugate vaccine Prevnar (PCV7), the link to clinical efficacy would be severed if stocks became completely depleted. Furthermore, demonstration of immune responses comparable to those elicited by PCV7 is a licensure approach used for new pneumococcal conjugate vaccines, so a replacement reference standard was required. A total of 278 volunteers were immunized with the 23-valent unconjugated polysaccharide vaccine Pneumovax II, and a unit of blood was obtained twice within 120 days following immunization. Plasma was prepared, pooled, and confirmed to be free from hepatitis B virus (HBV), hepatitis C virus (HCV), and HIV. The pooled serum was poured at 6 ml per vial into 15,333 vials and lyophilized. Immunological bridging of 007sp to 89SF was used to establish equivalent reference values for 13 pneumococcal capsular serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F) by five independent laboratories. Antibody concentrations in 007sp were established relative to the lot 89SF reference preparation using the WHO reference ELISA. Subsequently, 12 existing WHO calibration sera had concentrations reassigned for 13 pneumococcal serotypes using new serum 007sp as the reference, and these were compared to concentrations relative to the original reference serum. Agreement was excellent for the 12 WHO calibration sera. The 007sp preparation has replaced 89SF as the pneumococcal reference standard. Sufficient quantity of this new preparation is available such that, with judicious use, it should be available for at least 25 years.


Small-molecule biomarkers for clinical PET imaging of apoptosis.
Apoptosis is a fundamental biologic process. Molecular imaging of apoptosis in vivo may have important implications for clinical practice, assisting in early detection of disease, monitoring of disease course, assessment of treatment efficacy, or development of new therapies. Although a PET probe for clinical imaging of apoptosis would be highly desirable, this is yet an unachieved goal, mainly because of the required challenging integration of various features, including sensitive and selective detection of the apoptotic cells, clinical aspects such as favorable biodistribution and safety profiles, and compatibility with the radiochemistry and imaging routines of clinical PET centers. Several approaches are being developed to address this challenge, all based on novel small-molecule structures targeting various steps of the apoptotic cascade. This novel concept of small-molecule PET probes for apoptosis is the focus of this review.


The case of HNF-1beta mutation with medullary cysts.
We describe one case of long-term post-natal follow-up of hyperechoic fetal kidneys related to HNF-1beta mutation with cystic changes over a 9-year period in a female patient. This diagnosis was suspected on the basis of the renal US findings and was confirmed by complementary genetic examination. After birth, cortical cysts were detected and at the age of 4, medullary cysts were found, that disappeared with time. Currently our patient displays hyperechoic kidneys with only cortical cysts. This case report highlights the variability of US appearances in relation with HNF-1beta genetic mutation.


Learning dynamic models for open loop predictive control of soft robotic manipulators.
The soft capabilities of biological appendages like the arms of Octopus vulgaris and elephants' trunks have inspired roboticists to develop their robotic equivalents. Although there have been considerable efforts to replicate their morphology and behavior patterns, we are still lagging behind in replicating the dexterity and efficiency of these biological systems. This is mostly due to the lack of development and application of dynamic controllers on these robots which could exploit the morphological properties that a soft-bodied manipulator possesses. The complexity of these high-dimensional nonlinear systems has deterred the application of traditional model-based approaches. This paper provides a machine learning-based approach for the development of dynamic models for a soft robotic manipulator and a trajectory optimization method for predictive control of the manipulator in task space. To the best of our knowledge this is the first demonstration of a learned dynamic model and a derived task space controller for a soft robotic manipulator. The validation of the controller is carried out on an octopus-inspired soft manipulator simulation derived from a piecewise constant strain approximation and then experimentally on a pneumatically actuated soft manipulator. The results indicate that such an approach is promising for developing fast and accurate dynamic models for soft robotic manipulators while being applicable on a wide range of soft manipulators.


Activation of the Liver X Receptor by Agonist TO901317 Improves Hepatic Insulin Resistance via Suppressing Reactive Oxygen Species and JNK Pathway.
Activation of Liver X receptors (LXRs), key transcriptional regulators of glucose metabolism, normalizes glycemia and improves insulin sensitivity in rodent models with insulin resistance. However, the molecular mechanism is unclear. This study is aimed to elucidate the mechanism of LXRs-mediated liver glucose metabolic regulation in vitro and in vivo. Db/db mice were used as an in vivo model of diabetes; palmitate (PA)-stimulated HepG2 cells were used as an in vitro cell model with impairment of insulin signaling. TO901317 (TO) was chosen as the LXRs agonist. We demonstrated that TO treatment for 14 days potently improved the hepatic glucose metabolism in db/db mice, including fasting blood glucose, fasting insulin level, and HOMA-IR. TO had no effect on the glucose metabolism in normal WT mice. TO-mediated activation of hepatic LXRs led to strong inhibition of ROS production accompanied by inactivation of JNK pathway and re-activation of Akt pathway. TO also suppressed the expression of gluconeogenic genes such as PEPCK and G-6-pase in db/db mice, but not in WT mice. In HepG2 cells, TO almost completely restored PA-induced Akt inactivation, and suppressed PA-stimulated ROS production and JNK activation. Interestingly, basal level of ROS was also inhibited by TO in HepG2 cells. TO significantly inhibited PA-stimulated expressions of gluconeogenic genes. Finally, we found that anti-oxidative genes, such as Nrf2, were up-regulated after LXRs activation by TO. These results strongly support the notion that activation of LXRs is critical in suppression of liver gluconeogenesis and improvement of insulin sensitivity in diabetic individuals. At molecular levels, the mode of action appears to be as fellows: under diabetic condition, ROS production is increased, JNK is activated, and Akt activity is inhibited; TO-mediated LXR activation potently inhibits ROS production, increases anti-oxidative gene expressions, suppresses JNK activation, and restores Akt activity. Our data provide new evidence to support LXRs as promising therapeutic targets for anti-diabetic drug development.


Instantons re-examined: dynamical tunneling and resonant tunneling.
Starting from trace formulas for the tunneling splittings (or decay rates) analytically continued in the complex time domain, we obtain explicit semiclassical expansions in terms of complex trajectories that are selected with appropriate complex-time paths. We show how this instantonlike approach, which takes advantage of an incomplete Wick rotation, accurately reproduces tunneling effects not only in the usual double-well potential but also in situations where a pure Wick rotation is insufficient, for instance dynamical tunneling or resonant tunneling. Even though only one-dimensional autonomous Hamiltonian systems are quantitatively studied, we discuss the relevance of our method for multidimensional and/or chaotic tunneling.


Development of three multiplex PCR assays targeting the 21 most clinically relevant serogroups associated with Shiga toxin-producing E. coli infection in humans.
Escherichia coli serogroups O5, O15, O26, O45, O55, O76, O91, O103, O104, O111, O113, O118, O121, O123, O128, O145, O146, O157, O165, O172, and O177 are the O-antigen forms of the most clinically relevant Shiga toxin-producing E. coli (STEC) serotypes. In this study, three multiplex PCR assays able to specifically detect these 21 serogroups were developed and validated. For this purpose, the O-antigen gene clusters of E. coli O5 and O76 were fully sequenced, their associated genes were identified on the basis of homology, and serogroup-specific primers were designed. After preliminary evaluation, these two primer pairs were proven to be highly specific and suitable for the development of PCR assays for O5 and O76 serogroup identification. Specific primers were also designed for serogroups O15, O45, O55, O91, O104, O113, O118, O123, O128, O146, O157, O165, O172, and O177 based on previously published sequences, and previously published specific primers for serogroups O26, O103, O111, O121, and O145 were also included. These 21 primer pairs were shown to be specific for their target serogroup when tested against E. coli type strains representing 169 known O-antigen forms of E. coli and Shigella and therefore suitable for being used in PCR assays for serogroup identification. In order to validate the three multiplex PCR assays, 22 E. coli strains belonging to the 21 covered serogroups and 18 E. coli strains belonging to other serogroups were screened in a double-blind test and their sensitivity was determined as 1 ng chromosomal DNA. The PCR assays developed in this study could be a faster, simpler, and less expensive strategy for serotyping of the most clinically relevant STEC strains in both clinical microbiology and public health laboratories, and so their development could benefit for clinical diagnosis, epidemiological investigations, surveillance, and control of STEC infections.


Microelectrophoresis of PGE1 onto single units in the rabbit hypothalamus.
Prostaglandin E1 (PGE1) when micro-injected into the preoptic anterior hypothalamus (PO/AH) of conscious rabbits is a potent pyrogenic agent. We have investigated the action of PGE1 on the activity of single units of the PO/AH area using the microelectrophoretic technique. One hundred and thirty-eight PO/AH units were tested both for their response to changes in local PO/AH temperature and for their response to PGE1 application. Less than 9.0% of the total population of units tested showed any response to PGE1 application. When present, the response was invariably one of mild facilitation. No specific unit type (thermally sensitive or insensitive) appeared to be selectively affected by PGE1. Thus, the proportion of units affected by PGE1 was constant at 8-10% for warm-sensitive, cold-sensitive, or thermally insensitive units. There was no evidence to support an antagonistic role for PGE1 on the effects on norepinephrine on PO/AH units. On the basis of these results, we cannot predicate any simple neuronal basis for the action of PGE1 in producing fever in conscious rabbits. However, it is suggested that the action of PGE1 might be the modulation of presynaptic release of neurotransmitter onto the units of the PO/AH area.


A simple lattice model that captures protein folding, aggregation and amyloid formation.
The ability of many proteins to convert from their functional soluble state to amyloid fibrils can be attributed to inter-molecular beta strand formation. Such amyloid formation is associated with neurodegenerative disorders like Alzheimer's and Parkinson's. Molecular modelling can play a key role in providing insight into the factors that make proteins prone to fibril formation. However, fully atomistic models are computationally too expensive to capture the length and time scales associated with fibril formation. As the ability to form fibrils is the rule rather than the exception, much insight can be gained from the study of coarse-grained models that capture the key generic features associated with amyloid formation. Here we present a simple lattice model that can capture both protein folding and beta strand formation. Unlike standard lattice models, this model explicitly incorporates the formation of hydrogen bonds and the directionality of side chains. The simplicity of our model makes it computationally feasible to investigate the interplay between folding, amorphous aggregation and fibril formation, and maintains the capability of classic lattice models to simulate protein folding with high specificity. In our model, the folded proteins contain structures that resemble naturally occurring beta-sheets, with alternating polar and hydrophobic amino acids. Moreover, fibrils with intermolecular cross-beta strand conformations can be formed spontaneously out of multiple short hydrophobic peptide sequences. Both the formation of hydrogen bonds in folded structures and in fibrils is strongly dependent on the amino acid sequence, indicating that hydrogen-bonding interactions alone are not strong enough to initiate the formation of beta sheets. This result agrees with experimental observations that beta sheet and amyloid formation is strongly sequence dependent, with hydrophobic sequences being more prone to form such structures. Our model should open the way to a systematic study of the interplay between the factors that lead to amyloid formation.


Cardiac papillary fibroelastoma of a bicuspid aortic valve in an adolescent: A case report.
Cardiac papillary fibroelastomas (CPFE) are exceptional primary benign cardiac tumours affecting the heart valves. We report here the case of a 15-year-old boy in whom echocardiography performed for non-specific chest pain during follow-up for bicuspid aortic valve showed as accidental finding the presence of a round mobile mass without stalk attached on the inferior side of the aortic valve. The mass did not cause any outflow tract obstruction or aortic insufficiency. Electrocardiogram-gated cardiac computed tomography and magnetic resonance imaging allowed to suspect CPFE. Although the patient was asymptomatic, open cardiac surgery with elective surgical resection of the tumour was performed to avoid systematic emboli. Histology confirmed the diagnosis of CPFE. This is an exceptional case of acquired CPFE in a young patient with bicuspid aortic valve. Due to the risk of systemic embolization, aortic or coronary ostium obstruction, elective excision of such lesions is recommended.


Plasma ferritin concentrations: their clinical significance and relevance to patient care.
In healthy persons the plasma ferritin concentration is a sensitive index of the size of body iron stores. It has been successfully applied to large-scale surveys of the iron status of populations. It has also proved useful in the assessment of clinical disorders of iron metabolism. A low plasma ferritin level has a high predictive value for the diagnosis of uncomplicated iron deficiency anemia. It is of less value, however, in anemia associated with infection, chronic inflammatory disorders, liver disease and malignant hematologic diseases, for which a low level indicates iron deficiency and a high level excludes it, but intermediate levels are not diagnostic. Measuring the plasma ferritin concentration is also useful for the detection of excess body iron, particularly in idiopathic hemochromatosis, but again it lacks specificity in the presence of active hepatocellular disease. If iron overload is suspected in these circumstances determination of the iron content of a percutaneous liver biopsy specimen is required. In families with idiopathic hemochromatosis the combined determination of the plasma ferritin concentration and the transferrin saturation is a sufficient screen to identify affected relatives; however, estimation of the hepatic iron concentration is required to establish the diagnosis.


A Questionnaire of Parental Perceptions of Conscious Sedation in Pediatric Dentistry.
The purpose of this study was to determine the opinions of parents about oral sedation in pediatric dentistry. A 21-question questionnaire, administered to parents of children presenting for care in four pediatric dental practices, collected demographic information, media exposure to sedation, and parental knowledge/opinions regarding sedation procedures, such as NPO (nothing by mouth) guidelines, need for restraint, parental presence, and parental acceptance of treatment scenarios. Among 256 questionnaires completed, 235 were usable. Fifty-eight percent of respondents reported using public insurance. Parents agreed/strongly agreed (75 percent) that protective stabilization should not be necessary during sedation, and 87 percent preferred to stay with their child during the appointment. No parents perceived sedation as unsafe. Seventy-three percent of parents were unaware of media coverage of sedation; 82 percent reported it was acceptable for their child to sleep through a sedation appointment, while only 18 percent found it acceptable for the child to be highly reactive. Parents prefer to remain with their child, believe that sedation is safe and restraint should not be necessary, and are more accepting of the child sleeping during treatment. Most parents are unaware of media coverage of dental sedation for children.


Clinical impact of pre-existing acute exacerbation in patients with interstitial lung disease who underwent lung transplantation.
Acute exacerbation of interstitial lung disease (AE-ILD) significantly impacts prognosis, leading to high mortality rates. Although lung transplantation is a life-saving treatment for selected patients with ILD, its outcomes in those presenting with AE-ILD have yielded conflicting results compared with those with stable ILD. This study aims to investigate the impact of pre-existing AE on the prognosis of ILD patients who underwent lung transplantation. We conducted a single-center retrospective study by reviewing the medical records of 108 patients who underwent lung transplantation for predisposing ILD at Asan Medical Center, Seoul, South Korea, between 2008 and 2022. The primary objective was to compare the survival of patients with AE-ILD at the time of transplantation with those without AE-ILD. Among the 108 patients, 52 (48.1%) experienced AE-ILD at the time of lung transplantation, and 81 (75.0%) required pre-transplant mechanical ventilation. Although the type of ILD (IPF vs. non-IPF ILD) did not affect clinical outcomes after transplantation, AE-ILD was associated with worse survival outcomes. The survival probabilities at 90 days, 1 year, and 3 years post-transplant for patients with AE-ILD were 86.5%, 73.1%, and 60.1%, respectively, while those for patients without AE-ILD were higher, at 92.9%, 83.9%, and 79.6% (p = 0.032). In the multivariable analysis, pre-existing AE was an independent prognostic factor for mortality in ILD patients who underwent lung transplantation. Although lung transplantation remains an effective treatment option for ILD patients with pre-existing AE, careful consideration is needed, especially in patients requiring pre-transplant mechanical respiratory support.


Antigenic probes locate a serum-gelsolin-interaction site on the C-terminal part of actin.
The implication of part of the C-terminal of actin (within the 285-375 sequence) in the interaction of serum gelsolin was investigated by the use of specific antibodies. These antibodies were directed against two or three discrete epitopes, one of which was specific for skeletal-muscle actin. Some of these epitopes were found to be near the serum gelsolin-actin interface. Thus it can be assumed that part of the C-terminal of actin is exposed at the barbed end of the actin filament. The interaction between tropomyosin and actin was also studied.


Antigen challenge inhibits thymic emigration.
T cell development in the thymus involves a series of TCR-mediated control points including TCR-beta selection and positive and negative selection. Approximately half of the thymic sojourn is spent in the medulla, where thymocytes undergo final maturation before emigrating to the periphery. Although it is acknowledged that thymic emigration is an active process, relatively little is known about how this is regulated, why it takes so long, and whether TCR-mediated signaling can influence this step. Using wild-type and TCR transgenic mice, we found that Ag injected i.v. or intrathymically led to a striking reduction in the number of recent thymic emigrants (RTE) in the periphery. This was caused by inhibition of T cell export rather than peripheral deletion, because a cohort of RTE that was already released before in vivo Ag challenge was not depleted, and similar results were observed in Bim-deficient mice, which have impaired T cell deletion. Within the thymus, the loss of RTE was associated with retention of medullary thymocytes rather than increased negative selection. In addition to Ag-specific inhibition of export, some TCR-independent suppression of emigration was also observed that appeared to be partly the result of the inflammatory cytokine TNF. Thus, in addition to its accepted role in intrathymic selection events, TCR signaling can also play an important role in the regulation of thymic emigration.


TREATMENT OF MIGRAINE-Results with Dihydroergocornine Methanesulfonate (DHO-180) and Other Ergot Derivatives.
A comparison of nicotinic acid, a non-narcotic analgesic and a series of injectable and oral ergot preparations tested by various methods in treating 40 patients with typical migraine indicate that ergot alkaloids are far superior in producing symptomatic relief.A comparison of ergotamine tartrate, dihydroergotamine (DHE-45) and dihydroergocornine (DHO-180) indicated that ergotamine tartrate is the most effective and perhaps the most toxic, DHE-45 is slightly less effective and considerably less toxic, and that DHO-180 is the least effective but also the least toxic. When given orally, these alkaloids were about half as effective as when given by injection. EC-110 (ergotamine nitrate with caffeine) was the most effective.DHO-180 in liquid form, given daily for one month, had a marked preventive effect on migraine attacks.


[The analysis of Aconitum by FTIR].
Aconitum is one of an important officinal and noxious plant. Two different Aconitum have been analysed qualitatively by means of FTIR spectrum. The results showed that each component of different Aconitum has the characteristic frequency. The toxicity of processed Aconitum was lower than the toxicity of fresh Aconitum, and can be discriminated from others by FTIR spectrum. This is useful for the further on-line quantitative Aconitum and quality control of processed Aconitum and fresh Aconitum. This method is relatively more precise and quicker, and not damaging of the sample.


IL-17 enhances tumor development in carcinogen-induced skin cancer.
Inflammatory conditions elicited by extrinsic environmental factors promote malignant cell transformation, tumor growth, and metastasis. Although most attention has been focused on innate immune mechanisms of inflammatory carcinogenesis, more recently the role of T cells in cancer promotion has been examined. Although IFN-dependent Th1 responses that promote Stat1 signaling inhibit tumor growth, the role of T helper type 17 responses, and interleukin-17 (IL-17) in particular, has been controversial. Indeed, IL-17 has been reported to either enhance or inhibit the growth of transplantable tumors, depending on the system. Little is known about the role of IL-17 in de novo carcinogenesis. Using IL-17 knockout mice, we examined the role of IL-17 in the classic DMBA/TPA-induced skin carcinogenesis model. Disruption of IL-17 dramatically reduced tumorigenesis in this model in a manner correlated with diminished Stat3 activation in the tumor microenvironment. IL-17 loss reduced Stat3-associated proliferative and antiapoptotic gene expression along with epidermal cell proliferation and hyperplasia. In addition, IL-17 loss was associated with reduced expression of Stat3-regulated chemokines that attract myeloid cells and a decreased infiltration of myeloid cells into the local tumor microenvironment. Together, our findings point to a critical role of the IL-17-Stat3 pathway in supporting cancer-associated inflammation in the tumor microenvironment. Therapeutic approaches that target this pathway may therefore be effective to inhibit carcinogenesis.


Vasovagal syncope treated as epilepsy for 16 years.
The differentiation of vasovagal syncope and epileptic seizure is sometimes problematic, since vasovagal syncope may mimic epileptic seizures in many ways. The present report describes a patient who had been diagnosed and treated as having epilepsy with medically-refractory seizures for 16 years. Often, unlike epileptic seizures, tonic-clonic convulsions and postictal confusion are uncommon features of vasovagal syncope, but these may occur. Our patient was subjected to subcutaneous injection of one ml normal saline, which caused asystole leading to hypoxia and consequently a typical tonic-clonic convulsion. This patient was proved to have vasovagal syncope. The findings in the present case suggest that the possibility of vasovagal syncope should always be taken into consideration when evaluating patients with medically-refractory or unusual pattern of seizures. In such a circumstance, simultaneous video-electroencephalogram/electocardiogram monitoring may help achieve the correct diagnosis.


The binding of benzoarylsulfonamide ligands to human carbonic anhydrase is insensitive to formal fluorination of the ligand.
It's the water that matters. Pairs of benzo- and perfluorobenzoarylsulfonamide ligands bind to human carbonic anhydrase with a conserved binding geometry, an enthalpy-driven binding, and indistinguishable binding affinities (see picture). These data support the pervasive theory that the lock-and-key model disregards an important component of binding: the water, which fills the binding pocket of the protein and surrounds the ligand.


Incidence and diagnosis of active toxoplasma infection among liver transplant recipients in Western Turkey.
Toxoplasmosis is a serious and potentially life-threatening disease in liver transplant recipients while they are immunosuppressed. We report the clinical and laboratory findings related to active toxoplasma infection associated with 40 immunosuppressed liver transplant procedures that took place over a 12-month period at a major transplant unit in Izmir, Turkey. Twenty-seven (67.5%) of the 40 transplant recipients were found to be seropositive for toxoplasma infection and therefore at risk of reactivated infection. From the serological status of the donors, which was ascertained in 38 of 40 cases, we identified 3 (7.9%) of 38 transplants to be from a seropositive donor to a seronegative recipient. In 10 (26.3%) of 38 transplants, both the donor and recipient were seronegative, and this excluded toxoplasma as a risk. A comparison of real-time polymerase chain reaction (PCR) and nested PCR was undertaken in combination with a range of serological assays (the Sabin-Feldman dye test, enzyme immunoassay immunoglobulin M, and immunosorbent agglutination assay immunoglobulin M). Ethylene diamine tetraacetic acid blood samples from 3 of the 30 recipients at risk from toxoplasma were found positive by PCR, but only 1 of these was found positive in both assays. Among the 3 PCR-positive patients, immunoglobulin M and immunoglobulin G antibody levels increased in only 1 patient. Correlations between symptoms, laboratory findings, and clinical management (use of anti-toxoplasma therapy) are presented. Our findings suggest that toxoplasma presents a significant risk to our liver transplant population and that PCR is a helpful addition in identifying active infections and hence in informing clinical management decisions.


Warning Symptoms Are Associated With Survival From Sudden Cardiac Arrest.
Survival after sudden cardiac arrest (SCA) remains low, and tools for improved prediction of patients at long-term risk for SCA are lacking. Alternative short-term approaches aimed at preemptive risk stratification and prevention are needed. To assess characteristics of symptoms in the 4 weeks before SCA and whether response to these symptoms is associated with better outcomes. Ongoing prospective population-based study. Northwestern United States (2002 to 2012). Residents aged 35 to 65 years with SCA. Assessment of symptoms in the 4 weeks preceding SCA and association with survival to hospital discharge. Of 839 patients with SCA and comprehensive assessment of symptoms (mean age, 52.6 years [SD, 8]; 75% men), 430 (51%) had warning symptoms (50% of men vs. 53% of women; P = 0.59), mainly chest pain and dyspnea. In most symptomatic patients (93%), symptoms recurred within the 24 hours preceding SCA. Only 81 patients (19%) called emergency medical services (911) to report symptoms before SCA; these persons were more likely to be patients with a history of heart disease (P < 0.001) or continuous chest pain (P < 0.001). Survival when 911 was called in response to symptoms was 32.1% (95% CI, 21.8% to 42.4%) compared with 6.0% (CI, 3.5% to 8.5%) in those who did not call (P < 0.001). Potential for recall and response bias, symptom assessment not available in 24% of patients, and missing data for some patients and SCA characteristics. Warning symptoms frequently occur before SCA, but most are ignored. Emergent medical care was associated with survival in patients with symptoms, so new approaches are needed for short-term prevention of SCA. National Heart, Lung, and Blood Institute.


[Fibronectin content in wound secretions as a criterion of the course of wound healing].
The content of soluble immunoreactive fibronectin in wound exudate in 104 patients after appendectomy, laparotomy and thermal injuries was studied both in non-complicated and purulent postoperative wounds. It was shown that in the case of non-complicated wound healing fibronectin reached maximum level at the 2nd and 3rd postoperative days. At the following days the fibronectin content decreased and returned at the 4th-5th days to the first day level. In the purulent wound the amount of fibronectin in the exudate remains low in the hydratation phase rising significantly in the phase of dehydration. The described changes correlate well with the clinical signs of wound healing. The data suggest that the fibronectin content in wound exudate can be used in evaluation of wound healing, prediction of possible complications as well as in control of treatment efficiency.


General subspace learning with corrupted training data via graph embedding.
We address the following subspace learning problem: supposing we are given a set of labeled, corrupted training data points, how to learn the underlying subspace, which contains three components: an intrinsic subspace that captures certain desired properties of a data set, a penalty subspace that fits the undesired properties of the data, and an error container that models the gross corruptions possibly existing in the data. Given a set of data points, these three components can be learned by solving a nuclear norm regularized optimization problem, which is convex and can be efficiently solved in polynomial time. Using the method as a tool, we propose a new discriminant analysis (i.e., supervised subspace learning) algorithm called Corruptions Tolerant Discriminant Analysis (CTDA), in which the intrinsic subspace is used to capture the features with high within-class similarity, the penalty subspace takes the role of modeling the undesired features with high between-class similarity, and the error container takes charge of fitting the possible corruptions in the data. We show that CTDA can well handle the gross corruptions possibly existing in the training data, whereas previous linear discriminant analysis algorithms arguably fail in such a setting. Extensive experiments conducted on two benchmark human face data sets and one object recognition data set show that CTDA outperforms the related algorithms.


Taxonomic study of the genus Brachybacterium: Brachybacterium nesterenkovii sp. nov.
A new species, Brachybacterium nesterenkovii, is proposed for a group of coryneform bacteria that were isolated from milk products. These organisms have morphological, biochemical, and chemotaxonomic characteristics that are peculiar to the genus Brachybacterium. In contrast to strains of the only previously described species of the genus, Brachybacterium faecium, the representatives of the new species lack glycine in their peptidoglycan, although the peptidoglycan is of the same general type, and have large amounts of rhamnose in their cells. The strains of B. nesterenkovii exhibit no serological relationship with strains of B. faecium; in a numerical phenotypic analysis the two species were easily separated and formed clear-cut clusters. DNA-DNA hybridization between the type strains of B. faecium and B. nesterenkovii showed a level of homology of 22%. Strain 35 (= IMV Ac-752) is the type strain of B. nesterenkovii.


Thiohalospira halophila gen. nov., sp. nov. and Thiohalospira alkaliphila sp. nov., novel obligately chemolithoautotrophic, halophilic, sulfur-oxidizing gammaproteobacteria from hypersaline habitats.
A previously unknown ecotype of obligately chemolithoautotrophic, sulfur-oxidizing bacteria was discovered in sediments of various inland hypersaline lakes and a solar saltern. The salt requirements for these bacteria were similar to those of haloarchaea, representing the first example of extreme halophiles occurring among the chemolithoautotrophs. They were enriched and isolated at 4 M NaCl under aerobic conditions with thiosulfate or tetrathionate as the electron donor or under micro-oxic conditions with sulfide. In total, 20 strains were obtained from hypersaline inland lakes in central Asia, central Russia and Crimea and a sea saltern of the Adriatic Sea. The isolates were thin, motile spirilla, some of which possessed a yellow, membrane-bound pigment. They were obligately aerobic, chemolithoautotrophic, sulfur-oxidizing bacteria that used thiosulfate, sulfide, sulfur and tetrathionate as electron donors. The characteristic feature of the group was the production of large amounts of tetrathionate as an intermediate during the oxidation of thiosulfate to sulfate. All but one of the strains grew within the pH range 6.5-8.2 (optimally at pH 7.3-7.8) and at NaCl concentrations from 2.0 to 5 M (optimally at 3.0 M). A single strain, designated ALgr 6sp(T), obtained (by enrichment) from the hypersaline alkaline lakes of the Wadi Natrun valley, was found to be moderately halophilic and facultatively alkaliphilic (capable of growth at pH 10). The predominant cellular fatty acids were quite unusual, with 10-methyl C(16 : 0) and C(16 : 0) predominating. Cells grown at 4 M NaCl accumulated extremely high concentrations of glycine betaine as a compatible solute. The 20 neutrophilic isolates contained three genospecies (on the basis of DNA-DNA relatedness data) but could not be discriminated phenotypically. On the basis of the phenotypic and genotypic analyses, the isolates constitute a novel genus and species, for which the name Thiohalospira halophila gen. nov., sp. nov. is proposed. The type strain of Thiohalospira halophila is HL 3(T) (=DSM 15071(T)=UNIQEM U219(T)). The haloalkaliphilic strain ALgr 6sp(T) represents a second species of the new genus, for which the name Thiohalospira alkaliphila sp. nov. is proposed. The type strain of Thiohalospira alkaliphila is ALgr 6sp(T) (=DSM 17116(T)=UNIQEM U372(T)).


Characterization of immune cells and cytokine localization in the rat utero-placental unit mid- to late gestation.
The success of pregnancy is dependent on the precise regulation of the immune response within the utero-placental environment. Rats are beginning to be widely used as a model for human immune-related pregnancy complications. However, our knowledge of immune cells and cytokine localization in the rat utero-placental tissue is limited. The current study aimed to localize the immune cell populations, including uterine natural killer (uNK) cells, neutrophils, and macrophages within the rat utero-placental unit at two crucial gestational ages, gestational days 15.5 and 18.5. In addition, we characterized the distribution of the cytokines TNFα, IFNγ, and IL-10 in the utero-placental regions at both the above-mentioned gestational ages. Our study has demonstrated co-localization TNFα and IFNγ with uNK cells in perivascular regions of the rat mesometrial triangle at both gestational ages. Neutrophils and IL-10-positive cells were localized at the maternal-fetal interface and in the spiral artery lumen of the rat mesometrial triangle at both gestational ages. TNFα and IL-10 demonstrated a temporal change in the localization from GD15.5 to GD18.5, which coincides with the leading edge of trophoblast invasion into the mesometrial triangle. The current study furthers our knowledge of the localization of uterine immune cells and relevant cytokines, and provides a base from which to research the function of these immune cells and cytokines during rat pregnancy as a model to study human immune-related pregnancy complications.