The ixCELL-DCM Trial: Rationale and Design.
Ixmyelocel-T is an investigational patient-specific, expanded, multicellular therapy produced from a patient's own bone marrow. It is produced by selectively expanding two key types of bone marrow mononuclear cells (BM-MNCs), CD90+ mesenchymal stem cells (MSCs), and CD45+CD14+ autofluorescent, alternatively activated macrophages. Earlier clinical trials suggested that intramyocardial ixmyelocel-T might improve clinical, functional, symptomatic, and quality of life outcomes in patients with ischemic dilated cardiomyopathy (IDCM). This ongoing randomized, double-blinded, placebo-controlled phase 2b trial (ixCELL-DCM) was designed to assess the efficacy, safety, and tolerability of catheter-based transendocardial injection of ixmyelocel-T in patients with heart failure due to IDCM. Patients (N = 114) with New York Heart Association class III or IV symptomatic heart failure due to IDCM, who have left ventricular ejection fraction ≤35% and an automatic implantable cardioverter defibrillator, but are ineligible for revascularization procedures, were randomly assigned (1:1 ratio) to ixmyelocel-T or placebo (vehicle control). The primary efficacy endpoint is a composite of the total number of deaths, cardiovascular hospitalizations, or unplanned clinic visits to treat acutely decompensated heart failure during the 12 months following treatment administration. Secondary endpoints include the win ratio analysis for hierarchical occurrences of clinical events in the primary endpoint, total numbers of clinical events, left ventricular structure and function, and quality-of-life assessments. ixCELL-DCM is one of the largest cell therapy trials in heart failure patients to date and the first double-blinded, placebo-controlled study of ixmyelocel-T administered via transendocardial catheter-based injections in patients with heart failure secondary to IDCM.


Acute inhibition of inflammation mediated by sympathetic nerves: the inflammatory reflex.
In this review we will try to convince the readers that the immune system is controlled by an endogenous neural reflex, termed inflammatory reflex, that inhibits the acute immune response during the course of a systemic immune challenge. We will analyse here the contribution of different sympathetic nerves as possible efferent arms of the inflammatory reflex. We will discuss the evidence that demonstrates that neither the splenic sympathetic nerves nor the hepatic sympathetic nerves are necessary for the endogenous neural reflex inhibition of inflammation. We will discuss the contribution of the adrenal glands to the reflex control of inflammation, noting that the neurally mediated release of catecholamines in the systemic circulation is responsible for the enhancement of the anti-inflammatory cytokine interleukin 10 (IL10) but not of the inhibition of the pro-inflammatory cytokine tumor necrosis factor α (TNF). We will conclude by reviewing the evidence that demonstrates that the splanchnic anti-inflammatory pathway, composed by preganglionic and postganglionic sympathetic splanchnic fibres with different target organs, including the spleen and the adrenal glands, is the efferent arm of the inflammatory reflex. During the course of a systemic immune challenge, the splanchnic anti-inflammatory pathway is endogenously activated to inhibit the TNF and enhance the IL10 response, independently, presumably acting on separate populations of leukocytes.


Mid-infrared absorption of trapped electrons in titanium(iv) oxide particles using a photoacoustic FTIR technique.
Mid-infrared absorption of titanium(iv) oxide (TiO2) under ultraviolet (UV) irradiation was studied by Fourier transform infrared spectroscopy using a photoacoustic (PA) technique. UV irradiation induced an upward shift of the PA spectra, which is due to the trivalent titanium (Ti3+) species produced by electron accumulation. The PA spectra under UV irradiation mainly depend on the crystal structure, indicating that the energy levels of Ti3+ are largely determined by crystal structures.


Relative validity of a brief dietary survey to assess food intake and adherence to national dietary guidelines among Sri Lankan adults.
Suboptimal diet is the leading cause of global morbidity and mortality. Addressing this problem requires context-specific solutions informed by context-specific data collected by context-specific tools. This study aimed to assess the relative validity of a newly developed brief dietary survey to estimate food intake and adherence to the Food Based Dietary Guidelines for Sri Lankans. Between December 2018 and February 2019, we interviewed 94 Sri Lankan adults living in Colombo (Western Province), Kalutara (Western Province), and Trincomalee (Eastern Province). We assessed the relative validity of the Sri Lankan Brief Dietary Survey (SLBDS) with Wilcoxon rank-sum tests, Spearman's Rho correlation coefficients, Bland-Altman plots, and Cohen's kappa tests using a 24-h Dietary Recall (24DR) as reference. Ninety-four adults (40.7 years ±12.6; 66% female) completed both surveys during the same interview. With the exception of 'Fish, pulses, meat and eggs' food group median intake, which was underestimated by the SLBDS compared to the 24DR, there was no strong evidence of difference between median intakes reported by the two methods. Correlation coefficients were highest for 'Milk and dairy products' (0.84) at the food group level and for 'dosa', 'hoppers', 'milk rice', and 'dried fish' (1.00) among individual food and beverages. Visual exploration of Bland-Altman plots showed acceptable agreement between the SLBDS and 24DR, with the SLBDS tending to overestimate consumption as the number of servings of 'Rice, bread, other cereals and yams' and 'Vegetables' consumed increased and slightly underestimate consumption as the number of servings of 'Fish, pulses, meat and eggs', 'Milk and dairy products', and 'Nuts' increased. Kappa values ranged from from 0.59 (95% CI: 0.32-0.86) for 'Vegetables' to 0.81 (95% CI: 0.66-0.96) for 'Fruit' indicating a moderate to strong level of agreement. Having been developed for and relatively validated with the study population in question, our study shows that the SLBDS can be used as a fit for purpose research tool. Additional research is needed to assess SLBDS test-retest reliability and to validate further the reporting of salt, oil, and coconut intake.


Developmental fluoxetine exposure facilitates sexual behavior in female offspring.
A growing number of infants are being exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. SSRIs target the serotoninergic system and are a popular treatment for maternal mood disorders. Serotonin itself plays a key role in the sexual differentiation through its role in the development of the hypothalamic-pituitary-gonadal axis, and previous research has shown that developmental SSRI exposure has an effect on sexual behavior in male offspring. Our aim was to determine the role of developmental exposure to a popular SSRI medication, fluoxetine, on sexual differentiation of the brain and behavior in female offspring using a rodent model of maternal adversity. Stressed and non-stressed Sprague-Dawley rat dams were chronically treated with either fluoxetine (5 mg/kg/day) or vehicle beginning on postnatal day 1. Four groups of female offspring were used: (1) control + vehicle, (2) control + fluoxetine, (3) prenatal stress + vehicle, and (4) prenatal stress + fluoxetine. Primary results show that in adult female offspring, developmental fluoxetine exposure facilitates proceptive and receptive behaviors with a significant increase in the number of proceptive behaviors, a significant increase in the lordosis quotient, and a significant decrease in the rejection quotient. This research contributes in the understanding of the long-term impact developmental fluoxetine exposure on the hypothalamus-pituitary-gonadal (HPG) system in adult female offspring.


BreastMark: an integrated approach to mining publicly available transcriptomic datasets relating to breast cancer outcome.
Breast cancer is a complex heterogeneous disease for which a substantial resource of transcriptomic data is available. Gene expression data have facilitated the division of breast cancer into, at least, five molecular subtypes, namely luminal A, luminal B, HER2, normal-like and basal. Once identified, breast cancer subtypes can inform clinical decisions surrounding patient treatment and prognosis. Indeed, it is important to identify patients at risk of developing aggressive disease so as to tailor the level of clinical intervention. We have developed a user-friendly, web-based system to allow the evaluation of genes/microRNAs (miRNAs) that are significantly associated with survival in breast cancer and its molecular subtypes. The algorithm combines gene expression data from multiple microarray experiments which frequently also contain miRNA expression information, and detailed clinical data to correlate outcome with gene/miRNA expression levels. This algorithm integrates gene expression and survival data from 26 datasets on 12 different microarray platforms corresponding to approximately 17,000 genes in up to 4,738 samples. In addition, the prognostic potential of 341 miRNAs can be analysed. We demonstrated the robustness of our approach in comparison to two commercially available prognostic tests, oncotype DX and MammaPrint. Our algorithm complements these prognostic tests and is consistent with their findings. In addition, BreastMark can act as a powerful reductionist approach to these more complex gene signatures, eliminating superfluous genes, potentially reducing the cost and complexity of these multi-index assays. Known miRNA prognostic markers, mir-205 and mir-93, were used to confirm the prognostic value of this tool in a miRNA setting. We also applied the algorithm to examine expression of 58 receptor tyrosine kinases in the basal-like subtype, identifying six receptor tyrosine kinases associated with poor disease-free survival and/or overall survival (EPHA5, FGFR1, FGFR3, VEGFR1, PDGFRβ, and TIE1). A web application for using this algorithm is currently available. BreastMark is a powerful tool for examining putative gene/miRNA prognostic markers in breast cancer. The value of this tool will be in the preliminary assessment of putative biomarkers in breast cancer. It will be of particular use to research groups with limited bioinformatics facilities.


Association of Dialysis Duration with Outcomes after Transplantation in a Japanese Cohort.
Evidence regarding the differences in clinical outcomes after preemptive kidney transplantation (PKT) and non-PKT in Japan is lacking. We conducted a retrospective cohort study at a single center in Japan. Consecutive patients ages >18 years old who had received a kidney transplant from a living donor between November of 2001 and December of 2013 at our institution (n=786) were enrolled. The primary study outcome was the occurrence of clinical events before the end of 2014. Clinical events were defined as any of the following: death with functioning graft (DWFG), graft loss, or post-transplant cardiovascular disease (CVD). The median follow-up period was 61.0 (35.3-94.0) months. PKT was performed in 239 patients (30.4%). Clinical events occurred in 78 (9.9%). In the Cox proportional hazard model for univariate analysis, factors found to be associated with higher risk of clinical events included older age, men, ABO incompatibility, longer dialysis duration, diabetes, pretransplant CVD, and large ventricular mass index. PKT was associated with lower risk. Clinical event rate in patients who received a PKT was 3.3% compared with 10.8%, 11.1%, 10.4%, 10.2%, 16.7%, and 16.2% among patients who were on dialysis for <1, 1 to <2, 2 to <3, 3 to <4, 4 to <5, and ≥5 years before transplant, respectively (P=0.002). The multivariate analysis showed that ABO incompatibility (hazard ratio [HR], 2.98; 95% confidence interval [95% CI], 1.89 to 4.71), duration of dialysis per year (HR, 1.07; 95% CI, 1.03 to 1.11), and diabetes (HR, 3.54; 95% CI, 2.05 to 6.12) were only three independent risk factors for the incidence of clinical events. Even in Japan, where the long-term outcomes of patients on hemodialysis are excellent, PKT could be beneficial to reduce DWFG, graft loss, and post-transplant CVD.


Inhibitory effects of tocopherols on expression of the cyclooxygenase-2 gene in RAW264.7 cells stimulated by lipopolysaccharide, tumor necrosis factor-α or Porphyromonas gingivalis fimbriae.
Tocopherols, which include α-, β-, γ-, and δ-tocopherol, protect cells against harmful free radicals and play an important role in preventing many human diseases such as cancer, inflammatory disorders, and ageing itself. However, the causal relationships between periodontal or oral chronic diseases and tocopherols have not been sufficiently studied. The present study investigated the inhibitory effects of these compounds on the expression of cyclooxygenase-2 (COX2) mRNA in RAW264.7 cells stimulated with lipopolysaccharide (LPS), tumor necrosis factor-α (TNFα) or fimbriae of Poryphyromonas gingivalis (Pg), an oral anaerobe. The cytotoxicity (EC₅₀) of tocopherols toward RAW cells was determined using a cell counting kit (CCK-8). The regulatory effect of these compounds on the expression of COX2 mRNA stimulated with LPS, TNFα or Pg fimbriae was investigated using real-time polymerase chain reaction (PCR). Each tocopherol had similarly low cytotoxicity. COX2 gene expression in RAW cells after exposure to the three different macrophage activators was inhibited by the tocopherols (p<0.01). Compared to α-tocopherol, β-, γ- and δ-tocopherol exhibited greater inhibitory effects (p<0.05). Tocopherols exhibit anti-inflammatory activity, and β-, γ- and δ-tocopherol have particularly more potent anti-inflammatory activity than α-tocopherol. Tocopherols may have potential utility for prevention of periodontal and chronic oral diseases.


[Problems of the diagnosis and treatment of compression neuropathy of the median nerve: an analysis of typical medical practice].
An analysis of typical medical errors in the diagnosis and treatment of compression neuropathy of the median nerve at the level of the wrist (carpal tunnel syndrome - CTS). Previous diagnoses and treatment of 85 patients with CTS (14 men and 71 women), aged from 36 to 84 years (middle age 62±10.6 years), who underwent surgery in our clinics were evaluated. The wrong diagnosis was made in most of patients (60%). The osteochondrosis of cervical spine (45.8%) and diabetic polyneuropathy (5.8%) were the most common mistaken diagnoses. Proper neurophysiological measurements using the Phalen's test and Tinel's sign were not performed in the majority of patients. Magnetic resonance imaging (MRI) of the cervical spine was often unreasonably made, the electroneuromyography was not used. Nonsteroidal anti-inflammatory drugs (NSAIDs), vitamin B group were improperly prescribed to the patients diagnosed with CTS. Local corticosteroids injections were not prescribed to most of patients, immobilization of the wrist was not recommended at the early stage of disease and decompressive surgery at the advanced stage of disease. Clinical observation of the patient with long period of misdiagnosing is presented. Despite the long-standing history of CTS, surgical decompression led to regression of symptoms and complete professional rehabilitation. It is necessary to inform physicians about manifestations, diagnostic criteria and effective methods of treatment of CTS.


Analysis of Gender Sensitivity of Turkey's Disaster Legislation to Create a Disaster-Resilient Society.
Disasters frequently occur in Turkey. Although there is comprehensive disaster legislation in Turkey, it has not been well studied in terms of gender sensitivity. This study aimed to evaluate the disaster legislation of Turkey in the context of gender equality. We investigated 17 non-technical disaster legislations to determine in what context and to what level disaster management is gender-sensitive in Turkey. We also carried out a workshop with experts from governmental bodies and nongovernmental organizations (NGOs), and academics to discuss the gender sensitivity of the legislations. We found that only two of the 17 legislations included a gender perspective. One legislation addressed gender equality and equity very well, while one was partially gender-sensitive and the others 5 were gender blind. The workshop was conducted in collaboration with the Disaster and Emergency Management Presidency (AFAD) and 33 participants from 19 organizations. The participants agreed that the disaster legislation did not include a gender perspective and acknowledged the importance of integrating a gender perspective into the disaster policies of Turkey. They recommended that the AFAD and emergency response units should have at least one female president or vice president, gender equality training should be provided to officers and managers of government and non-governmental disaster institutions, and a working group should be established to develop strategies that integrate gender perspectives into disaster and emergency policies. The disaster legislation of Turkey is not gender sensitive. It is important to incorporate language terminologies, understanding, and approaches that are sensitive to gender into disaster-related legislation and regulations.


Quantitative studies on the mixed lymphocyte interaction in rats. I. Conditions and parameters of response.
Some of the conditions and parameters of the proliferative response in the mixed lymphocyte interaction have been studied with the use of culture inocula consisting of lymphoid cells from various immunogenetically diverse, isogenic strains of rats. Procedures are described by which consistent culture responses can be obtained which are measurable in terms of incorporation of radioactive thymidine into a trichloroacetic acid precipitable cell fraction. Results of experiments with this "mixed lymphocyte interaction" show that (a) Incorporation of thymidine into the mixed cultures is detectable only during and after the 4th day of incubation. Use of culture inocula derived from the thoracic duct or partially purified suspensions of lymphocytes from the peripheral blood provides further evidence that it is the small lymphocyte which synthesizes DNA in these cultures. The addition of peritoneal exudate cells, presumably containing some macrophages, to the mixed lymphocyte cultures does not alter the kinetics of the response. (b) Proliferative responses occur in mixed cultures of cells only when the donors differ by alleles at the important Ag-B histocompatibility locus. (c) Proliferative reactivity in mixed cultures of lymphocytes from parental and hybrid donors is unidirectional. With the use of chromosomally marked cells from donors of different sexes, it was established that only parental lymphocytes are dividing in mixed cultures of parental and hybrid cells. The results of these experiments strongly support the premise that the proliferative response in mixed cultures of lymphocytes represents a de novo immunologic reaction on the cellular level against histocompatibility antigens.


Biological Signatures of Alzheimer's Disease.
Alzheimer's disease (AD) is the most prevalent and severe neurodegenerative disease affecting more than 0.024 billion people globally, more common in women as compared to men. Senile plaques and amyloid deposition are among the main causes of AD. Amyloid deposition is considered as a central event which induces the link between the production of β amyloid and vascular changes. Presence of numerous biomarkers such as cerebral amyloid angiopathy, microvascular changes, senile plaques, changes in white matter, granulovascular degeneration specifies the manifestation of AD while an aggregation of tau protein is considered as a primary marker of AD. Likewise, microvascular changes, activation of microglia (immune defense system of CNS), amyloid-beta aggregation, senile plaque and many more biomarkers are nearly found in all Alzheimer's patients. It was seen that 70% of Alzheimer's cases occur due to genetic factors. It has been reported in various studies that apolipoprotein E(APOE) mainly APOE4 is one of the major risk factors for the later onset of AD. Several pathological changes also occur in the white matter which include dilation of the perivascular space, loss of axons, reactive astrocytosis, oligodendrocytes and failure to drain interstitial fluid. In this review, we aim to highlight the various biological signatures associated with the AD which may further help in discovering multitargeting drug therapy.


[Action of acid cathepsins on the myosin and sarcoplasmic proteins of normal and denervated rat muscles].
The activity of acid cathepsins in extracts of the healthy and denervated rat muscles was determined, using the proper and homologous sarcoplasmic proteins and myosin as substrates. Splitting of the sarcoplasmic proteins produces a 50% increase and that of myosin produces a 110% increase in the activity of acid cathepsins of the denervated muscles as compared to that of healthy ones. Substrates isolated from the healthy and denervated muscles are splitted by acid cathepsins with the same intensity.


Nanoarmor: cytoprotection for single living cells.
Single cell modification or hybridization technology has become a popular direction in bioengineering in recent years, with applications in clean energy, environmental stewardship, and sustainable human development. Here, we draw attention to nanoarmor, a representative achievement of cytoprotection and functionalization technology. The fundamental principles of nanoarmor need to be studied with input from multiple disciplines, including biology, chemistry, and material science. In this review, we explain the role of nanoarmor and review progress in its applications. We also discuss three main challenges associated with its development: self-driving ability, heterojunction characteristics, and mineralization formation. Finally, we propose a preliminary classification system for nanoarmor.


Mucociliary transport in trachea of patients with cystic fibrosis.
Mucociliary tracheal transport rates were measured in 20 patients with cystic fibrosis, in whom these rates ranged from 0 to 12.8 mm/min. The patients were divided into 3 roughly equal groups on the basis of their transport rates. (1) Those in whom no abnormality in mucociliary transport was detected in the trachea; (2) those in whom normal transport rates were measured but in whom abnormalities such as cessation, or reversal of bolus movement were observed; (3) those in whom no normal transport rates were observed. In the first group the rates were similar to those observed in a population of healthy adults. These normal rates were observed in some patients who had a productive cough. The mean mucociliary tracheal transport rate increased with increasing maximum midexpiratory flow. Those patients with a low Shwachman score and poor arterial oxygen tension tended to fall into groups 2 and 3. In the ciliary dyskinesia assay in rabbit trachea the serum from the patients with the higher transport rates tended to initiate more rapid discharge of material from the epithelium and ciliary dyskinesia.


Sulfated glycopeptides from middle ear effusions of secretory otitis media.
The middle ear effusion specimens were obtained by myringotomy and aspiration from 4 children of 4-7 years old, who had been diagnosed as patients with secretory otitis media on the basis of conductive hearing loss and tympanogram. In cases 1 and 2, their ear fluids were macroscopically serous, while those of cases 3 and 4 were mucous. These ear fluids were digested with pronase and the digests were analyzed by cellulose acetate membrane electrophoresis with alcian blue and high-iron-diamine stainings. All samples were found to contain glycopeptides possibly derived from sulfated mucin-type glycoproteins with small amounts of glycosaminoglycans. The glycoconjugates from cases 3 and 4 were further examined after hyaluronidase and chondroitinase ABC treatments, followed by heparitinase digestion. The resultant glycopeptide fractions appeared to be electrophoretically homogeneous and their chemical compositions suggested that they were typical mucin-type glycopeptides. Furthermore, they contained sulfates. The data suggest that in secretory otitis media, one of the major components of middle ear effusions is sulfated mucin-type glycoprotein.


Current academic clinical trials in ovarian cancer: Gynecologic Cancer Intergroup and US National Cancer Institute Clinical Trials Planning Meeting, May 2009.
To review the current status of large phase academic clinical trials for women with ovarian cancer, address cross-cutting issues, and identify promising areas for future collaboration. In May 2009, the Gynecologic Cancer Intergroup, which represents 19 Cooperative Groups conducting trials for women with gynecologic cancer, and the US National Cancer Institute convened a Clinical Trials Planning Meeting. The topics covered included the impact of new developments in cancer biology upon molecular targets and novel agents, pharmacogenomics, advances in imaging, the potential benefit of diet and exercise to reduce the risk of recurrence, academic partnership with industry, statistical considerations for phases 2 and 3 trials, trial end points, and symptom benefit and health-related quality-of-life issues. The clinical trials discussed spanned the spectrum of ovarian cancer from initial diagnosis, staging, and cytoreductive surgery to consolidation chemotherapy, and treatment of recurrent disease. Ongoing and effective collaboration with industry, government, and patients aims to ensure that the most important scientific questions can be answered rapidly. We encourage women with ovarian cancer and their oncologists to consider participation in the academic clinical trials conducted by the member groups of the Gynecologic Cancer Intergroup.


Electromyographs of the flexor digitorum profundus muscle are useful for the diagnosis of inclusion body myositis.
The frequent observation of high-amplitude and long-duration motor unit potentials (MUPs) in inclusion body myositis (IBM) is problematic, because it may lead to a misdiagnosis of amyotrophic lateral sclerosis (ALS). To document the diagnostic utility of EMG from the flexor digitorum profundus (FDP) muscle for IBM. Quantitative analyses of MUP parameters were performed in the FDP and biceps brachii (BB) muscles from 7 biopsy-confirmed IBM patients. In the FDP muscle, all MUP parameters were significantly decreased in IBM patients, which indicated the predominance of low-amplitude and short-duration MUPs in this muscle. In the BB muscle, most parameters were increased, suggesting the frequent contamination of high-amplitude and long-duration MUPs. Low-amplitude MUPs in the FDP muscle indicate the presence of an advanced myopathy in this muscle that was extremely weak for all subjects. Examining the FDP muscle would reduce the chance of misdiagnosing IBM as ALS.


Nivolumab Versus Docetaxel in Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer: Two-Year Outcomes From Two Randomized, Open-Label, Phase III Trials (CheckMate 017 and CheckMate 057).
Purpose Nivolumab, a programmed death-1 inhibitor, prolonged overall survival compared with docetaxel in two independent phase III studies in previously treated patients with advanced squamous (CheckMate 017; ClinicalTrials.gov identifier: NCT01642004) or nonsquamous (CheckMate 057; ClinicalTrials.gov identifier: NCT01673867) non-small-cell lung cancer (NSCLC). We report updated results, including a pooled analysis of the two studies. Methods Patients with stage IIIB/IV squamous (N = 272) or nonsquamous (N = 582) NSCLC and disease progression during or after prior platinum-based chemotherapy were randomly assigned 1:1 to nivolumab (3 mg/kg every 2 weeks) or docetaxel (75 mg/m2 every 3 weeks). Minimum follow-up for survival was 24.2 months. Results Two-year overall survival rates with nivolumab versus docetaxel were 23% (95% CI, 16% to 30%) versus 8% (95% CI, 4% to 13%) in squamous NSCLC and 29% (95% CI, 24% to 34%) versus 16% (95% CI, 12% to 20%) in nonsquamous NSCLC; relative reductions in the risk of death with nivolumab versus docetaxel remained similar to those reported in the primary analyses. Durable responses were observed with nivolumab; 10 (37%) of 27 confirmed responders with squamous NSCLC and 19 (34%) of 56 with nonsquamous NSCLC had ongoing responses after 2 years' minimum follow-up. No patient in either docetaxel group had an ongoing response. In the pooled analysis, the relative reduction in the risk of death with nivolumab versus docetaxel was 28% (hazard ratio, 0.72; 95% CI, 0.62 to 0.84), and rates of treatment-related adverse events were lower with nivolumab than with docetaxel (any grade, 68% v 88%; grade 3 to 4, 10% v 55%). Conclusion Nivolumab provides long-term clinical benefit and a favorable tolerability profile compared with docetaxel in previously treated patients with advanced NSCLC.


Lead Level in Umbilical Cord Blood and its Effects on Newborns Anthropometry.
High concentration of blood lead is accompanied by adverse health effects on growth of foetus and the newborn. The aim of this study was to determine umbilical cord blood lead level and its relationship with birth weight, length and head circumference of the newborns in Abadan, Iran. In this cross-sectional study, 3 ml blood was collected from the umbilical cord vein in 147 newborns, immediately after the birth. Blood lead was measured using atomic absorption spectrophotometry. Data collection instruments included demographic questionnaire (age of mother, gestational age, newborn gender, job and education of mother) and also data registration form (umbilical cord blood lead concentration, weight, length, and head circumference of newborn). Data was analyzed with SPSS software version 16.0. The mean of umbilical cord blood lead was determined 0.65±0.32 µg/dl (0.3-1.35 µg/dl). The decrease of birth weight with increased blood lead level was small and was not statistically significant. There was reverse significant correlation between umbilical cord blood lead level and birth length and head circumference. There was no significant correlation between blood lead and other variables such as age, weight, education and job of mother and gestational age. Umbilical blood lead level was determined <5 µg/ dl. Excess of umbilical cord blood lead caused decreasing birth weight, length and head circumference of the newborns.


Lossless watermarking for image authentication: a new framework and an implementation.
We present a novel framework for lossless (invertible) authentication watermarking, which enables zero-distortion reconstruction of the un-watermarked images upon verification. As opposed to earlier lossless authentication methods that required reconstruction of the original image prior to validation, the new framework allows validation of the watermarked images before recovery of the original image. This reduces computational requirements in situations when either the verification step fails or the zero-distortion reconstruction is not needed. For verified images, integrity of the reconstructed image is ensured by the uniqueness of the reconstruction procedure. The framework also enables public(-key) authentication without granting access to the perfect original and allows for efficient tamper localization. Effectiveness of the framework is demonstrated by implementing the framework using hierarchical image authentication along with lossless generalized-least significant bit data embedding.


Topical management and wound care approaches for hidradenitis suppurativa.
Hidradenitis suppurativa (HS) is a chronic inflammatory disease that affects the follicular unit in apocrine glandbearing skin, resulting in deep-seated nodules, sinus tracts, abscesses, and ultimately scarring. HS is a highly distressing condition, and has one of the highest impacts on quality of life compared to other dermatologic diseases. Various topical therapies have been described that may be used alone or in conjunction with systemic or physical modalities for HS. Additionally, proper wound care is essential to the successful management of HS, particularly given the suppurative nature of the disease. However, limited evidence exists regarding the optimal regimen for topical therapy and wound care. On the basis of existing literature, we provide a comprehensive review of topical management and wound care.


Differential Effects of Comorbid Psychiatric Disorders on Treatment Outcome in Posttraumatic Stress Disorder from Childhood Trauma.
Patients with posttraumatic stress disorder (PTSD) frequently have comorbid diagnoses such as major depressive disorder (MDD) and anxiety disorders (AD). Studies into the impact of these comorbidities on the outcome of PTSD treatment have yielded mixed results. The different treatments investigated in these studies might explain the varied outcome. The purpose of this study was to examine the impact of these comorbidities on the outcome of two specific PTSD treatments. MDD and AD were analyzed as predictors and moderators in a trial comparing 12 sessions of either eye movement desensitization and reprocessing (EMDR) or imagery rescripting (IR) in 155 adult patients with PTSD from childhood trauma. The primary outcome was reduction of PTSD symptoms (clinician-administered PTSD Scale for DSM-5, CAPS-5) assessed at eight-week follow-up and a secondary outcome was self-report PTSD symptoms (Impact of Event Scale, IES-R). MDD was not a predictor of treatment outcome but did have a significant moderator effect. Patients with MDD showed a better outcome if they were treated with IR, whereas patients without MDD improved more in the EMDR condition. No impact of AD emerged. It seems essential to consider comorbid MDD when planning PTSD treatment to improve treatment outcomes. More research is needed to replicate our findings and focus on different kinds of PTSD treatments and other comorbidities.


Results of a population screening intervention for tuberculosis in a Nunavik village, Quebec, 2015-2016.
A small village in Nunavik, Quebec experienced a tuberculosis (TB) outbreak in 2012-2013 and then a resurgence in 2015-2016. Cases were still occurring, despite the fact that contact tracing had already been conducted on one quarter of the population. A decision was taken to conduct large-scale screening of the population for TB. To describe the results of a population-based TB screening intervention designed to identify individuals with latent TB infection (LTBI) or active TB requiring treatment. The history of TB infection (either active TB or LTBI, defined as a positive tuberculin skin test result of at least five mm induration) and treatment (considered adequate if at least 80% of prescribed doses were taken) were determined. Those who were two years of age and older and had not been included in contact tracing after June 1, 2015 were included for TB screening (n=1,026 eligible individuals). Screening included a nurse assessment, tuberculin skin test (TST) for those with previous negative TST or of unknown status and chest X-ray for the others. Of the eligible individuals in the affected village, 1,004 (98%) participated in the screening. Of these, 30% had a history of previous TB infection. A TST screening was administered to 71% of the participants, 10% of whom had positive results. Assessments were performed on 425 participants and 385 underwent a chest X-ray. Fifty-two cases of previously diagnosed active TB and three cases of new active TB were documented. In addition, there were 247 individuals with LTBI who had been previously identified (191 were found to have had adequate LTBI treatment, 56 were found to have had inadequate LTBI treatment) and 69 were identified with de novo LTBI. In addition, 633 participants were found to have no TB infection. There were 125 participants who were referred for LTBI treatment. Follow-up information was available for 120 and 85 (71%) of these completed the treatment. Within this northern village, which had persistent TB transmission despite classic control measures, population-based screening had a high degree of coverage and was an effective way to detect additional cases of individuals with active TB and those with LTBI.


An assessment of encapsulated versus hand-mixed glass ionomer restoratives.
Capsulation should enable uniform proportioning and mixing of dental restoratives so that functional properties of the cementitious mass will not be susceptible to clinically induced variability. Mechanical mixing induces a definite pore distribution determined by the viscosity of the system. This study evaluated the mixing process on the performance of a range of glass ionomer dental restoratives. Mean compressive fracture strengths and standard deviations and the associated Weibull Moduli (m) were determined for six glass ionomer restoratives that were either encapsulated or mixed by hand. Working characteristics were assessed using an oscillating rheometer. Scanning electron microscopy and image analysis was used to investigate the influence of the mixing method on pore distribution. The fracture strength data for some encapsulated restoratives resulted in significant differences compared with hand-mixing. Rotomix (compared with the Capmix mechanical agitator) resulted in increased Weibull moduli and 10% failure stress for the two restoratives that were investigated. Encapsulated restoratives that were prepared utilizing Rotomix or Capmix resulted in no significant differences for working characteristics; however, the setting time for the ChemFlex in Caps was extended compared with the hand-mixed ChemFlex. Not all restoratives had reduced porosity and improved performance following mixing with a Rotomix. This suggested that optimization of the initial viscosity of the system by manipulating the individual proportions of the constituents may not have been appropriate for all the restoratives investigated. The increased viscosity for hand-mixed ChemFlex prepared to a consistency of 3.8 g/ml compared with encapsulated ChemFlex in Caps prepared to a consistency of 3.5 g/ml was responsible for the reduced setting time.


Chickpea supplementation prior to colitis onset reduces inflammation in dextran sodium sulfate-treated C57Bl/6 male mice.
The potential for a chickpea-supplemented diet (rich in fermentable nondigestible carbohydrates and phenolic compounds) to modify the colonic microenvironment and attenuate the severity of acute colonic inflammation was investigated. C57Bl/6 male mice were fed a control basal diet or basal diet supplemented with 20% cooked chickpea flour for 3 weeks prior to acute colitis onset induced by 7-day exposure to dextran sodium sulfate (DSS; 2% w/v in drinking water) and colon and serum levels of inflammatory mediators were assessed. Despite an equal degree of DSS-induced epithelial barrier histological damage and clinical symptoms between dietary groups, biomarkers of the ensuing inflammatory response were attenuated by chickpea pre-feeding, including reduced colon tissue activation of nuclear factor kappa B and inflammatory cytokine production (tumor necrosis factor alpha and interleukin (IL)-18). Additionally, colon protein expression of anti-inflammatory (IL-10) and epithelial repair (IL-22 and IL-27) cytokines were increased by chickpea pre-feeding. Furthermore, during acute colitis, chickpea pre-feeding increased markers of enhanced colonic function, including Relmβ and IgA gene expression. Collectively, chickpea pre-feeding modulated the baseline function of the colonic microenvironment, whereby upon induction of acute colitis, the severity of the inflammatory response was attenuated.


Interaction of the N terminus of ADP-ribosylation factor with the PH domain of the GTPase-activating protein ASAP1 requires phosphatidylinositol 4,5-bisphosphate.
Arf GAP with Src homology 3 domain, ankyrin repeat, and pleckstrin homology (PH) domain 1 (ASAP1) is a multidomain GTPase-activating protein (GAP) for ADP-ribosylation factor (ARF)-type GTPases. ASAP1 affects integrin adhesions, the actin cytoskeleton, and invasion and metastasis of cancer cells. ASAP1's cellular function depends on its highly-regulated and robust ARF GAP activity, requiring both the PH and the ARF GAP domains of ASAP1, and is modulated by phosphatidylinositol 4,5-bisphosphate (PIP2). The mechanistic basis of PIP2-stimulated GAP activity is incompletely understood. Here, we investigated whether PIP2 controls binding of the N-terminal extension of ARF1 to ASAP1's PH domain and thereby regulates its GAP activity. Using [Δ17]ARF1, lacking the N terminus, we found that PIP2 has little effect on ASAP1's activity. A soluble PIP2 analog, dioctanoyl-PIP2 (diC8PIP2), stimulated GAP activity on an N terminus-containing variant, [L8K]ARF1, but only marginally affected activity on [Δ17]ARF1. A peptide comprising residues 2-17 of ARF1 ([2-17]ARF1) inhibited GAP activity, and PIP2-dependently bound to a protein containing the PH domain and a 17-amino acid-long interdomain linker immediately N-terminal to the first β-strand of the PH domain. Point mutations in either the linker or the C-terminal α-helix of the PH domain decreased [2-17]ARF1 binding and GAP activity. Mutations that reduced ARF1 N-terminal binding to the PH domain also reduced the effect of ASAP1 on cellular actin remodeling. Mutations in the ARF N terminus that reduced binding also reduced GAP activity. We conclude that PIP2 regulates binding of ASAP1's PH domain to the ARF1 N terminus, which may partially regulate GAP activity.


Knowledge, Attitude and Implementation of Evidence-Based Practice among Physiotherapists Working in the Kingdom of Saudi Arabia: A Cross-Sectional Survey.
The current study aimed to investigate knowledge, attitudes, and implementation of evidence-based practice among physiotherapists working in Saudi Arabia. A sample of physiotherapists working in various outpatient settings in Saudi Arabia participated in this survey. Sixty-four therapists (30 females, 34 males) completed a 28-item survey questionnaire. Approximately half of the participants indicated that evidence-based practice was useful and important for clinical practice. About 60% of the participants reported that they have adopted the evidence-based practice on a regular basis. Participants who had a membership in a physiotherapy organization and had advanced degrees showed more positive attitudes (t = -2.31, p = 0.02 and t = -2.15, p = 0.04, respectively) and greater levels of knowledge (t = -2.32, p = 0.02 and t = -3.86, p = 0.001, respectively) regarding evidence-based practice terminology. Furthermore, place of training (trained overseas) was associated with a positive attitude towards literature findings (t = 2.26, p = 0.03). The results of this study demonstrated that participants reported that evidence-based practice had not been extensively implemented, despite positive attitudes regarding its implementation among physiotherapists practicing in Saudi Arabia.


The two-component system RstAB regulates production of a polysaccharide capsule with a role in virulence in the marine pathogen Photobacterium damselae subsp. damselae.
The marine bacterium Photobacterium damselae subsp. damselae (Pdd) causes disease in marine animals and humans. Previous studies demonstrated that mutation of the two-component system RstAB strongly impacts virulence of this pathogen, but the RstAB regulon has not been thoroughly elucidated. We here compared the transcriptomes of Pdd RM-71 and ΔrstA and ΔrstB derivatives using RNA-seq. In accordance with previous studies, RstAB positively regulated cytotoxins Dly, PhlyP and PhlyC. This analysis also demonstrated a positive regulation of outer membrane proteins, resistance against antimicrobials and potential virulence factors by this system. Remarkably, RstAB positively regulated two hitherto uncharacterised gene clusters involved in the synthesis of a polysaccharide capsule. Presence of a capsular layer in wild-type cells was confirmed by transmission electron microscopy, whereas rstA and rstB mutants were non-capsulated. Mutants for capsule synthesis genes, wza and wzc exhibited acapsular phenotypes, were impaired in resistance against the bactericidal action of fish serum and mucus, and were strongly impaired in virulence for fish, indicating a major role of capsule in virulence. Collectively, this study demonstrates that RstAB is a major positive regulator of key virulence factors including a polysaccharide capsule essential for full virulence in a pathogenic Photobacterium.


Are Fassier-Duval rods at risk of migration in patients undergoing spine magnetic resonance imaging?
The Fassier-Duval (FD) rod is a stainless-steel device widely used to correct bone deformities and reduce the risk of fractures in patients with osteogenesis imperfecta (OI). Since these are telescopic expandable rods, there has been a reluctance to perform magnetic resonance imaging (MRI) in patients with OI secondary to a theoretical risk of migration during the MRI scans. The primary aim of this study was to assess the risk of migration of FD rods in patients who underwent MRI of the spine. The secondary aims are to assess the heating effects and artifact of these implants. We retrospectively reviewed our database for all patients with OI who had undergone FD rodding and subsequent MRI evaluation for craniofacial and spinal disorders. Ten patients were eligible to be included in the study. The MRI examination was performed in all patients using a1.5 T magnet. The radiographic images pre-MRI and post-MRI were evaluated and compared to assess whether or not migration of implants had occurred. Patients' charts and MRI logbooks were reviewed to assess the heating effects based on patient-reported events during or immediately after the MRI. In addition, the scans were reviewed to evaluate peri-implant soft tissues to assess for changes that might indicate such effect. Artifact was judged to be present if it interfered with the evaluation of any portion of spinal anatomy of clinical interest. Ten patients underwent 19 FD roddings. The indications for MRI in these patients were basilar invagination, basilar impression, platybasia, and complex scoliosis. None of the implants have shown any migration, heating effect, or artifact. FD rods are safe and pose no risk of migration, heating effects, or artifact when undergoing an MRI of the spine using a 1.5 T magnet. With the introduction of magnet strengths higher than 1.5 T, further testing should be performed. Level IV.


Clear Aligner Therapy: Up to date review article.
The advantages of Clear Aligners Therapy (CAT) include the braces being virtually invisible, comfortable to wear, and removable for eating and brushing; that way, CAT can be used to treat a wide range of orthodontic issues. In 1999, the company Align Technology introduced the frst commercial clear aligner system called Invisalign. The Invisalign system was initially only available to orthodontists, but later became available to general dentists as well. The system quickly gained popularity among patients who were looking for a more discreet and comfortable alternative to traditional braces. In 2000, Align Technology received FDA clearance for the Invisalign system, which further increased its popularity. The biomechanics of clear aligners involve the use of custom-made tooth aligners that are specifcally shaped to guide teeth into desired positions. These aligners are typically made from flexible materials such as polyurethane or ethylene vinyl acetate and are adjusted to apply the necessary forces for tooth movement. Attachment devices, such as power ridges or buttons, are often used to enhance or assist in specifc tooth movements and for retention of the aligner. The use of attachments allows for the exertion of desired force on the teeth, which is crucial for the success of Clear Aligner Therapy. CAT should be used if patients are concerned about the esthetic appearances of their teeth-for example, actors and other individuals that rely on their appearances in public in a professional context-and if the misalignment is not severe, so that clear aligners can still work. One should not use CAT in cases of severe crowding or spacing issues that require extractions. If the patient has complex jaw discrepancies or skeletal issues or if teeth need to be moved extensively in multiple directions, CAT is likely not going to be strong enough. In conclusion, Clear Aligner Therapy is a safe, effective, and convenient orthodontic treatment option that offers patients a virtually invisible way to achieve a straighter, more beautiful smile. With continued advancements in technology and a growing body of research supporting its effectiveness, the future of Clear Aligner Therapy looks bright.


Peanut (Arachis hypogaea L.) S-adenosylmethionine decarboxylase confers transgenic tobacco with elevated tolerance to salt stress.
Polyamines play an important role in stress response. In the pathway of polyamines synthesis, S-adenosylmethionine decarboxylase (SAMDC) is one of the key enzymes. In this study, a full length cDNA of SAMDC (AhSAMDC) was isolated from peanut (Arachis hypogaea L.). Phylogenetic analysis revealed high sequence similarity between AhSAMDC and SAMDC from other plants. In peanut seedlings exposed to sodium chloride (NaCl), the transcript level of AhSAMDC in roots was the highest at 24 h that decreased sharply at 72 and 96 h after 150 mM NaCl treatment. However, the expression of AhSAMDC in peanut leaves was significantly inhibited, and the transcript levels in leaves were not different compared with control These results implied the tissue-specific and time-specific expression of AhSAMDC. The physiological effects and functional mechanism of AhSAMDC were further evaluated by overexpressing AhSAMDC in tobaccos. The transgenic tobacco lines exhibited higher germination rate and longer root length under salt stress. Reduced membrane damage, higher antioxidant enzyme activity, and higher proline content were also observed in the transgenic tobacco seedlings. What's more, AhSAMDC also led to higher contents of spermidine and spermine, which can help to scavenge reactive oxygen species. Together, this study suggests that AhSAMDC enhances plant resistance to salt stress by improving polyamine content and alleviating membrane damage.


Evaluation of a breastmilk hand expression toolkit: the M.I.L.K survey study.
Breastmilk hand expression (BMHE) is recommended to promote lactation, relieve breast engorgement, and collect milk for future infant feedings. Resources to teach this skill are limited and infrequently developed in partnership with the obstetrical population. In collaboration with maternity care experts and individuals with recent breastfeeding experience, we designed a one-page toolkit that describes the process of BMHE and includes step-by-step instructions and images to illustrate the technique. This study aimed to evaluate the readability, clarity of content, layout, and informational value of this BMHE toolkit. Individuals who intended to breastfeed, were currently breastfeeding, or had recently breastfed were electronically surveyed and completed a two-part survey that consisted of radio, multi-select, Likert scale, and open-ended questions. Part one captured sociodemographic factors, obstetrical history, and breastfeeding practices. Part two collected feedback on the BMHE toolkit. Participants were recruited electronically through social media and posters were circulated in antenatal and postnatal care settings in Ottawa, Canada between November 2020 and February 2021. Of the 123 participants, 117 (95.1%) had heard of hand expression prior to reviewing the toolkit and 99 (80.5%) had hand expressed before. Among the 48 participants who were no longer exclusively breastfeeding at the time of the survey, 22 (45.8%) had exclusively breastfed their infant for at least six months and 7 (14.6%) had discontinued exclusive breastfeeding within the first month. When asked about the BMHE toolkit, 118 (95.9%) participants said it was informative, 115 (93.5%) said it was easy to understand, and 114 (92.7%) said it was well laid-out. When asked about information seeking behaviours, participants indicated a preference for online resources (58.5%) and video resources (22.0%). The BMHE toolkit was well received by participants and the feedback was favourable overall. The survey feedback will be used to create a revised version of the toolkit that has been validated by the obstetrical patient population. Future research should focus on identifying implementation strategies to optimize the use of the toolkit and increase its effectiveness as an educational resource to teach participants correctly BMHE.


A Fully Actuated Robotic Assistant for MRI-Guided Prostate Biopsy and Brachytherapy.
Intra-operative medical imaging enables incorporation of human experience and intelligence in a controlled, closed-loop fashion. Magnetic resonance imaging (MRI) is an ideal modality for surgical guidance of diagnostic and therapeutic procedures, with its ability to perform high resolution, real-time, high soft tissue contrast imaging without ionizing radiation. However, for most current image-guided approaches only static pre-operative images are accessible for guidance, which are unable to provide updated information during a surgical procedure. The high magnetic field, electrical interference, and limited access of closed-bore MRI render great challenges to developing robotic systems that can perform inside a diagnostic high-field MRI while obtaining interactively updated MR images. To overcome these limitations, we are developing a piezoelectrically actuated robotic assistant for actuated percutaneous prostate interventions under real-time MRI guidance. Utilizing a modular design, the system enables coherent and straight forward workflow for various percutaneous interventions, including prostate biopsy sampling and brachytherapy seed placement, using various needle driver configurations. The unified workflow compromises: 1) system hardware and software initialization, 2) fiducial frame registration, 3) target selection and motion planning, 4) moving to the target and performing the intervention (e.g. taking a biopsy sample) under live imaging, and 5) visualization and verification. Phantom experiments of prostate biopsy and brachytherapy were executed under MRI-guidance to evaluate the feasibility of the workflow. The robot successfully performed fully actuated biopsy sampling and delivery of simulated brachytherapy seeds under live MR imaging, as well as precise delivery of a prostate brachytherapy seed distribution with an RMS accuracy of 0.98mm.


RMediation: an R package for mediation analysis confidence intervals.
This article describes the RMediation package,which offers various methods for building confidence intervals (CIs) for mediated effects. The mediated effect is the product of two regression coefficients. The distribution-of-the-product method has the best statistical performance of existing methods for building CIs for the mediated effect. RMediation produces CIs using methods based on the distribution of product, Monte Carlo simulations, and an asymptotic normal distribution. Furthermore, RMediation generates percentiles, quantiles, and the plot of the distribution and CI for the mediated effect. An existing program, called PRODCLIN, published in Behavior Research Methods, has been widely cited and used by researchers to build accurate CIs. PRODCLIN has several limitations: The program is somewhat cumbersome to access and yields no result for several cases. RMediation described herein is based on the widely available R software, includes several capabilities not available in PRODCLIN, and provides accurate results that PRODCLIN could not.


mRNA-1273 protects against SARS-CoV-2 beta infection in nonhuman primates.
B.1.351 is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant most resistant to antibody neutralization. We demonstrate how the dose and number of immunizations influence protection. Nonhuman primates received two doses of 30 or 100 µg of Moderna's mRNA-1273 vaccine, a single immunization of 30 µg, or no vaccine. Two doses of 100 µg of mRNA-1273 induced 50% inhibitory reciprocal serum dilution neutralizing antibody titers against live SARS-CoV-2 p.Asp614Gly and B.1.351 of 3,300 and 240, respectively. Higher neutralizing responses against B.1.617.2 were also observed after two doses compared to a single dose. After challenge with B.1.351, there was ~4- to 5-log10 reduction of viral subgenomic RNA and low to undetectable replication in bronchoalveolar lavages in the two-dose vaccine groups, with a 1-log10 reduction in nasal swabs in the 100-µg group. These data establish that a two-dose regimen of mRNA-1273 will be critical for providing upper and lower airway protection against major variants of concern.


Grafting with hydroxyapatite granules for defects of acetabular bone at revision total hip replacement: a minimum ten-year follow-up.
The long-term results of grafting with hydroxyapatite granules for acetabular deficiency in revision total hip replacement are not well known. We have evaluated the results of revision using a modular cup with hydroxyapatite grafting for Paprosky type 2 and 3 acetabular defects at a minimum of ten years' follow-up. We retrospectively reviewed 49 acetabular revisions at a mean of 135 months (120 to 178). There was one type 2B, ten 2C, 28 3A and ten 3B hips. With loosening as the endpoint, the survival rate was 74.2% (95% confidence interval 58.3 to 90.1). Radiologically, four of the type 3A hips (14%) and six of the type 3B hips (60%) showed aseptic loosening with collapse of the hydroxyapatite layer, whereas no loosening occurred in type 2 hips. There was consolidation of the hydroxyapatite layer in 33 hips (66%). Loosening was detected in nine of 29 hips (31%) without cement and in one of 20 hips (5%) with cement (p = 0.03, Fisher's exact probability test). The linear wear and annual wear rate did not correlate with loosening. These results suggest that the long-term results of hydroxyapatite grafting with cement for type 2 and 3A hips are encouraging.


Morphological abnormalities during early-life development of the estuarine mummichog, Fundulus heteroclitus, as an indicator of androgenic and anti-androgenic endocrine disruption.
We tested the hypothesis that gross morphological abnormalities are a sensitive indicator of exposure to waterborne androgenic and anti-androgenic compounds during embryonic, larval and juvenile stages of development in the common estuarine killifish, the mummichog (Fundulus heteroclitus; Pisces: Cyprinodontidae). Static exposures with daily renewal were carried out with 10-100,000 ng/L of the androgen agonist, 17alpha-methyltestosterone (MT), or the androgen antagonist, cyproterone acetate (CA), for 60 days post-fertilization (PF) in duplicate exposures. Measured concentrations were 78.4-155.8% of nominal concentrations for MT and 13.5-168.1% for CA. No dose-related or consistent effects of MT or CA were observed before hatch. In 60 days PF juveniles, incidence of skeletal abnormalities (scoliosis, lordosis, head, facial and fin), soft tissue abnormality (anal swelling) and hemorrhaging were significantly increased by MT but only at high concentrations (> or =1000 ng/L). The 10,000 and 100,000 ng/L concentrations of MT produced a wider range of abnormalities than 1000ng/L. Over 90% of fish exposed to 10,000 or 100,000 ng/L were abnormal with an average of over 3.5 abnormalities per fish. CA did not increase the incidence of any type of abnormality. Survival of juveniles to the end of the exposure was reduced by MT at concentrations of 1000 ng/L and greater in the first experiment and at concentrations of 10,000 ng/L and greater in the second experiment. Juvenile length was reduced by high concentrations of MT (> or =10,000 ng/L) in the first experiment and by most concentrations in the second experiment. We conclude that morphological abnormalities in early-life stages of mummichogs are not a sensitive indicator of exposure to androgenic or anti-androgenic waterborne EDSs at environmentally relevant concentrations.


Size Control of On-Surface Self-Assembled Nanochains Using Soft Building Blocks.
Owing to their conformational flexibility, soft molecules with side chains play a crucial role in molecular self-assembly or self-organization processes toward bottom-up building of supramolecular nanostructures. However, the influence of the rotating side chains in the confined space and subsequent surface-confined supramolecular self-assembly remains rarely explored. Herein, using the spatial confinement effect between soft building blocks, we realized size control on surface-confined supramolecular coordination self-assembly through the synergy between the repulsive steric hindrance and the attractive chemical interactions. Combining scanning tunneling microscopy with density functional theory calculations and Monte Carlo simulations, we elucidated the effective repulsive force generated by the thermal wiggling motions of the soft building blocks, allowing length tuning of the self-assembled chain structures. Through a delicate balance between the repulsive interaction induced by the spatial confinement effect and the coordinate chemical interaction, we provide a new strategy for controlling the geometry of the on-surface supramolecular nanostructures.


External and internal fixation for comminuted intra-articular fractures of distal radius.
Distal radius fractures are a common injury and without proper treatment leads to high functional impairment and frequent complications. The aim of this study was to see the functional outcome in patients with comminuted distal radius fractures treated with combined external fixation and open reduction and volar plating. All comminuted distal radius fractures classified as type C in AO/OTA classification were enrolled for the study from 2005 till 2008. The clinical scoring chart modified by Cooney was used to evaluate the functional outcome. There were twenty-two patients with the average age of 42.18 years (range 19-60) with 15 male and 7 females. The follow-up period was from 14 to 46 months. Accordingly, there were 11 (50%) excellent, 7 (31%) good, 2 (9%) fair and 2 (9%) poor results. There were very few complications in our series. In three patients additional K-wire supplementation was necessary along with external and open internal fixation. Comminuted intra-articular fractures of distal radius should be treated by open reduction and combined internal and external fixation to achieve a high rate of patient satisfaction and satisfactory functional outcome.


Influence of dietary lipids on hepatic mRNA levels of proteins regulating plasma lipoproteins in baboons with high and low levels of large high density lipoproteins.
Selective breeding of baboons has produced families with increased plasma levels of large high density lipoproteins (HDL1) and very low (VLDL) and low (LDL) density lipoproteins when the animals consume a diet enriched in cholesterol and saturated fat. High HDL1 baboons have a slower cholesteryl ester transfer, which may account for the accumulation of HDL1, but not of VLDL and LDL. To investigate the mechanism of accumulation of VLDL + LDL in plasma of the high HDL1 phenotype, we selected eight half-sib pairs of baboons, one member of each pair with high HDL1, the other member with little or no HDL1 on the same high cholesterol, saturated fat diet. Baboons were fed a chow diet and four experimental diets consisting of high and low cholesterol with corn oil, and high and low cholesterol with lard, each for 6 weeks, in a crossover design. Plasma lipids and lipoproteins and hepatic mRNA levels were measured on each diet. HDL1 phenotype, type of dietary fat, and dietary cholesterol affected plasma cholesterol and apolipoprotein (apo) B concentrations, whereas dietary fat alone affected plasma triglyceride and apoA-I concentrations. HDL1 phenotype and dietary cholesterol alone did not influence hepatic mRNA levels, whereas dietary lard, compared to corn oil, significantly increased hepatic apoE mRNA levels and decreased hepatic LDL receptor and HMG-CoA synthase mRNA levels. Hepatic apoA-I message was associated with cholesterol concentration in HDL fractions as well as with apoA-I concentrations in the plasma or HDL. However, hepatic apoB message level was not associated with plasma or LDL apoB levels. Total plasma cholesterol, including HDL, was negatively associated with hepatic LDL receptor and HMG-CoA synthase mRNA levels. However, compared with low HDL1 baboons, high HDL1 baboons had higher concentrations of LDL and HDL cholesterol at the same hepatic mRNA levels. These studies suggest that neither overproduction of apoB from the liver nor decreased hepatic LDL receptor levels cause the accumulation of VLDL and LDL in the plasma of high HDL1 baboons. These studies also show that, in spite of high levels of VLDL + LDL and HDL1, the high HDL1 baboons had higher levels of mRNA for LDL receptor and HMG-CoA synthase. This paradoxical relationship needs further study to understand the pathophysiology of VLDL and LDL accumulation in the plasma of animals with the high HDL1 phenotype.


Enhanced morphine-induced ethanol drinking in alcohol-preferring alko alcohol rats sensitized to morphine.
Alcohol-preferring alko alcohol (AA) rats are more susceptible to morphine-induced behavioral and neurochemical sensitization than alcohol nonpreferring alko nonalcohol (ANA) rats. Alko alcohol rats sensitized to morphine, however, do not show enhanced acquisition of ethanol drinking. The purpose of the present study was to clarify further interactions between morphine-induced behavioral sensitization and voluntary ethanol drinking in the AA rats. Alko alcohol rats drinking ethanol in a limited 6-hour access paradigm were sensitized to morphine with repeated injections of morphine (5-15 mg/kg). Injection days alternated with days of ethanol access. Controls had access only to water and/or were given injections of saline. After a 5-day washout period from ethanol and morphine, the rats were challenged with morphine or saline and subsequent ethanol drinking or locomotor activity was recorded. Ethanol intake was suppressed during the repeated treatment with morphine, and the morphine-treated rats did not differ in ethanol intake from the controls when given access to ethanol after the washout. Intake of ethanol was, however, increased when the rats were challenged with morphine [1 or 10 mg/kg, subcutaneously (s.c.)], while in the controls an increase in ethanol intake was seen only after 1 mg/kg morphine. Sensitization to the locomotor stimulating effects of morphine was revealed in the morphine-treated rats after a challenge with morphine (3 or 10 mg/kg, s.c.). The controls that had been drinking ethanol also showed a sensitized response after morphine (3 mg/kg). Ethanol did not interfere with the development of sensitization to morphine. Furthermore, the neuroadaptations induced by repeated exposure to ethanol were sufficient to cause behavioral cross-sensitization to morphine. Sensitization to the behavioral effects of morphine alone, however, neither enhances the reinforcing properties of voluntarily consumed ethanol nor contributes to increase in its intake. The increase in ethanol intake found after an acute dose of morphine was augmented in rats withdrawn from repeated treatment with morphine. The data suggest that the neuronal mechanisms underlying behavioral sensitization to morphine probably are distinct from those mediating reinforcement from ethanol and that the morphine-induced neuroadaptations contribute to the enhancement of increase in ethanol intake by morphine.


¹⁸F-FDG PET-CT during chemo-radiotherapy in patients with non-small cell lung cancer: the early metabolic response correlates with the delivered radiation dose.
To evaluate the metabolic changes on ¹⁸F-fluoro-2-deoxyglucose positron emission tomography integrated with computed tomography (¹⁸ F-FDG PET-CT) performed before, during and after concurrent chemo-radiotherapy in patients with locally advanced non-small cell lung cancer (NSCLC); to correlate the metabolic response with the delivered radiation dose and with the clinical outcome. Twenty-five NSCLC patients candidates for concurrent chemo-radiotherapy underwent ¹⁸F-FDG PET-CT before treatment (pre-RT PET-CT), during the third week (during-RT PET-CT) of chemo-radiotherapy, and 4 weeks from the end of chemo-radiotherapy (post-RT PET-CT). The parameters evaluated were: the maximum standardized uptake value (SUVmax) of the primary tumor, the SUVmax of the lymph nodes, and the Metabolic Tumor Volume (MTV). SUVmax of the tumor and MTV significantly (p=0.0001, p=0.002, respectively) decreased earlier during the third week of chemo-radiotherapy, with a further reduction 4 weeks from the end of treatment (p<0.0000, p<0.0002, respectively). SUVmax of lymph nodes showed a trend towards a reduction during chemo-radiotherapy (p=0.06) and decreased significantly (p=0.0006) at the end of treatment. There was a significant correlation (r=0.53, p=0.001) between SUVmax of the tumor measured at during-RT PET-CT and the total dose of radiotherapy reached at the moment of the scan. Disease progression free survival was significantly (p=0.01) longer in patients with complete metabolic response measured at post-RT PET-CT. In patients with locally advanced NSCLC, ¹⁸F-FDG PET-CT performed during and after treatment allows early metabolic modifications to be detected, and for this SUVmax is the more sensitive parameter. Further studies are needed to investigate the correlation between the metabolic modifications during therapy and the clinical outcome in order to optimize the therapeutic strategy. Since the metabolic activity during chemo-radiotherapy correlates with the cumulative dose of fractionated radiotherapy delivered at the moment of the scan, special attention should be paid to methodological aspects, such as the radiation dose reached at the time of PET.


Social class differences in secular trends in established coronary risk factors over 20 years: a cohort study of British men from 1978-80 to 1998-2000.
Coronary heart disease (CHD) mortality in the UK since the late 1970s has declined more markedly among higher socioeconomic groups. However, little is known about changes in coronary risk factors in different socioeconomic groups. This study examined whether changes in established coronary risk factors in Britain over 20 years between 1978-80 and 1998-2000 differed between socioeconomic groups. A socioeconomically representative cohort of 7735 British men aged 40-59 years was followed-up from 1978-80 to 1998-2000; data on blood pressure (BP), cholesterol, body mass index (BMI) and cigarette smoking were collected at both points in 4252 survivors. Social class was based on longest-held occupation in middle-age. Compared with men in non-manual occupations, men in manual occupations experienced a greater increase in BMI (mean difference = 0.33 kg/m(2); 95%CI 0.14-0.53; p for interaction = 0.001), a smaller decline in non-HDL cholesterol (difference in mean change = 0.18 mmol/l; 95%CI 0.11-0.25, p for interaction≤0.0001) and a smaller increase in HDL cholesterol (difference in mean change = 0.04 mmol/l; 95%CI 0.02-0.06, p for interaction≤0.0001). However, mean systolic BP declined more in manual than non-manual groups (difference in mean change = 3.6; 95%CI 2.1-5.1, p for interaction≤0.0001). The odds of being a current smoker in 1978-80 and 1998-2000 did not differ between non-manual and manual social classes (p for interaction = 0.51). Several key risk factors for CHD and type 2 diabetes showed less favourable changes in men in manual occupations. Continuing priority is needed to improve adverse cardiovascular risk profiles in socially disadvantaged groups in the UK.


Glycemic Control Status After Percutaneous Coronary Intervention and Long-Term Clinical Outcomes in Patients With Type 2 Diabetes Mellitus.
Data on the association between glycemic control after percutaneous coronary intervention and clinical outcomes are limited and controversial in diabetic patients. We studied 980 patients with type 2 diabetes mellitus undergoing percutaneous coronary intervention using drug-eluting stents. Based on 2-year glycosylated hemoglobin A (HbA1c) levels, we divided patients into 2 groups of HbA1c<7.0 (n=489) and HbA1c≥7.0 (n=491). Propensity score-matched analysis was performed in 322 pairs. The primary outcome was major adverse cardiac and cerebrovascular events (MACCE), defined as a composite of cardiac death, myocardial infarction, repeat revascularization, or stroke. Median follow-up duration was 5.4 years. The 7-year incidence of MACCE was lower in the HbA1c<7.0 group than in the HbA1c≥7.0 group (26.9% versus 40.3%; adjusted hazard ratio, 0.75; 95% confidence interval, 0.57-0.98; P=0.03). After propensity score matching, the 7-year incidence of MACCE was still lower in the HbA1c<7.0 group than in the HbA1c≥7.0 group (27.5% versus 37.4%; hazard ratio, 0.71; 95% confidence interval, 0.52-0.97; P=0.03), mainly because of a reduction in repeat revascularization (19.9% versus 29.5%; hazard ratio, 0.66; 95% confidence interval, 0.47-0.93; P=0.02). In subgroup analyses, the benefit of glycemic control for MACCE was more prominent in patients with residual SYNTAX score (Synergy Between PCI With Taxus and Cardiac Surgery) >4 than in those with the residual SYNTAX score ≤4 (Pinteraction=0.004). HbA1c<7.0 measured 2 years after percutaneous coronary intervention was associated with a reduced rate of MACCE. Our data suggest that high HbA1c levels 2 years after percutaneous coronary intervention may identify a population at increased risk of adverse events, especially repeat revascularization.


Functional clustering of dendritic activity during decision-making.
The active properties of dendrites can support local nonlinear operations, but previous imaging and electrophysiological measurements have produced conflicting views regarding the prevalence and selectivity of local nonlinearities in vivo. We imaged calcium signals in pyramidal cell dendrites in the motor cortex of mice performing a tactile decision task. A custom microscope allowed us to image the soma and up to 300 μm of contiguous dendrite at 15 Hz, while resolving individual spines. New analysis methods were used to estimate the frequency and spatial scales of activity in dendritic branches and spines. The majority of dendritic calcium transients were coincident with global events. However, task-associated calcium signals in dendrites and spines were compartmentalized by dendritic branching and clustered within branches over approximately 10 μm. Diverse behavior-related signals were intermingled and distributed throughout the dendritic arbor, potentially supporting a large learning capacity in individual neurons.


Validity of same-side reoperation after total hip and knee arthroplasty using administrative databases.
Many arthroplasty outcome studies use administrative data to evaluate complications and mortality. Most databases use International Classification of Diseases, Ninth Revision or Current Procedural Terminology codes, which lack laterality information. This study determined the frequency with which a second operation occurs on the same side after total hip arthroplasty (THA) and total knee arthroplasty (TKA) and identified variables associated with ipsilateral reoperation. In a hospital-based sample of patients undergoing multiple THA or TKA, the side of the index operation was compared with the side of the subsequent operation. Concordance was defined as the percentage of same-side reoperations. Overall concordance was 23% for THA and 22% for TKA, suggesting most reoperations were on the contralateral hip or knee. This study provides estimates of misclassification of reoperation after lower extremity arthroplasty when conducting orthopedic research with administrative data. Studies using these data should be aware of this limitation, and efforts should be made to limit reoperation to revision THA and TKA.


COVID-19-associated liver injury: Adding fuel to the flame.
COVID-19 is mainly characterized by respiratory disorders and progresses to multiple organ involvement in severe cases. With expansion of COVID-19 and SARS-CoV-2 research, correlative liver injury has been revealed. It is speculated that COVID-19 patients exhibited abnormal liver function, as previously observed in the SARS and MERS pandemics. Furthermore, patients with underlying diseases such as chronic liver disease are more susceptible to SARS-CoV-2 and indicate a poor prognosis accompanied by respiratory symptoms, systemic inflammation, or metabolic diseases. Therefore, COVID-19 has the potential to impair liver function, while individuals with preexisting liver disease suffer from much worse infected conditions. COVID-19 related liver injury may be owing to direct cytopathic effect, immune dysfunction, gut-liver axis interaction, and inappropriate medication use. However, discussions on these issues are infancy. Expanding research have revealed that angiotensin converting enzyme 2 (ACE2) expression mediated the combination of virus and target cells, iron metabolism participated in the virus life cycle and the fate of target cells, and amino acid metabolism regulated immune response in the host cells, which are all closely related to liver health. Further exploration holds great significance in elucidating the pathogenesis, facilitating drug development, and advancing clinical treatment of COVID-19-related liver injury. This article provides a review of the clinical and laboratory hepatic characteristics in COVID-19 patients, describes the etiology and impact of liver injury, and discusses potential pathophysiological mechanisms.


Can Cold Water Immersion Enhance Recovery in Elite Olympic Weightlifters? An Individualized Perspective.
We investigated whether cold water immersion (CWI) after intensive training sessions can enhance recovery in elite Olympic weightlifters, taking into account each athlete's individual response pattern. The entire German male Olympic weightlifting national team participated in the study (n = 7), ensuring collection of data from elite athletes only. Using a randomized cross-over design, the athletes went through 2 high-intensity training microcycles consisting of 5 training sessions that were either followed by a CWI or passive recovery. Barbell speed in a snatch pull movement, blood parameters, and subjective ratings of general fatigue and recovery were assessed throughout the study. Physical performance at 2 snatch pull intensities (85% one repetition maximum [1RM]: -0.15% vs. -0.22%, p = 0.94; 90% 1RM: -0.7% vs. +1.23%, p = 0.25) did not differ significantly (condition × time). Although questionnaires revealed a significant decline in the ratings of overall recovery (p < 0.001) and a significantly higher rating of overall stress (p = 0.03) over time, no significant differences between conditions (p = 0.14; p = 0.98) could be revealed. Similarly, neither of the analyzed blood parameters changed significantly between conditions over time (creatine kinase: p = 0.53; urea: p = 0.43; cortisol: p = 0.59; testosterone: p = 0.53; testosterone:cortisol ratio: p = 0.69). In general, CWI did not prove to be an effective tool to enhance recovery in elite Olympic weightlifters over a 3-day intensive training period. However, even though the group was rather homogeneous with regard to performance, there were considerable intersubject differences in their response to CWI. It seems that athletes are best advised on a case-by-case basis.


The accuracy of sex identification in European skeletal remains using the phenice characters.
Three documented European skeletal series were examined to assess the accuracy and reliability of the pubic variables described by Phenice for correctly identifying the sex of adult human skeletal remains. The accuracy and objectivity of these variables, as reported by Phenice, Kelley, Sutherland and Suchey, and Lovell, could not be confirmed on this European material. In general, the subpubic concavity feature, when used alone, proved to be the most reliable variable for sex identification. In this study, the level of correct sex identification that could be achieved using the Phenice variables was shown to be significantly affected by the previous experience of the observer.


Human papillomavirus in cyclophosphamide and diverticulum-associated squamous cell carcinoma of urinary bladder: a case report.
The association of cyclophosphamide therapy with the development of urothelial malignancy has been documented. Bladder diverticula associated with squamous cell carcinoma were also identified. In addition, incorporation of human papillomavirus (HPV) deoxyribonucleic acid (DNA) has been previously shown in urothelial carcinoma by in situ hybridization technique. Here a case is reported of bladder squamous cell carcinoma occurring four years after intravenous pulse therapy with cyclophosphamide in a patient with bladder diverticula where HPV was identified in the lesion. To present knowledge, this is the first case report of bladder squamous cell carcinoma with simultaneous occurrence of three risk factors for urothelial malignancy: cyclophosphamide therapy, diverticulum, and HPV infection.


Journal writing as a complementary therapy for reactive depression: a rehabilitation teaching program.
Brief, recurrent, reactive, or situational depression is a common and costly comorbidity that affects chronically ill patients and their family members. This article describes a program that teaches those individuals how to monitor and cope with symptoms of depression by writing daily in a journal. Twenty patients and family members attended teaching sessions at which videotaped scenes of other patients managing symptoms of depression were shown. After viewing the six scenes, participants wrote about their reactions to each scene and listed the emotions they had experienced that were similar to those shown in the tape. They were then asked to record daily for 4 months their emotions and reactions to situations and to also daily self-rate their levels of energy. They were also provided with a list of recommended activities in which to engage when they were depressed. Two psychiatric nurses evaluated the writings and concluded that the program was influential in helping patients and families overcome many emotionally draining reactions to adverse circumstances.


Morphological and molecular differences in two strains of Ustilago esculenta.
Ustilago esculenta is a fungal endophyte of Zizania latifolia that plays an important agricultural role in this vegetable crop. The purpose of this study was to characterize sporidial (T) and mycelial (M-T) strains of U. esculenta isolated from sporulating and non-sporulating galls on plants growing in Zhejiang province, China. Morphological comparisons of the T strain and M-T strain were made by optical and scanning electron microscope observation. Genetic differences were examined by sequencing the ITS region of the fungus and examining differential protein expression by two-dimensional gel electrophoresis and MALDI-TOF-MS/MS. The sporidial (T) and mycelial (M-T) strains differed in morphological characteristics of their in vitro single colony formations and in cell shape. Alignment of ITS sequences of the T strain and M-T strain revealed a single mutation between the T strain and M-T strain, but the sequences were the same within strains. A total of 146 proteins were only expressed in the M-T strain, and 242 proteins were only expressed in the T strain isolated from infected plants. A total of 222 proteins were up-regulated or down-regulated in the T strain when compared with the M-T strain. Of these, 18 proteins were identified and eight were associated with processes involving energy metabolism and the cytoskeleton. Two morphology-related proteins, MAP kinase kinase and actin, were differentially expressed. The differences noted in the T strain and M-T strain may lead to a better understanding of the life cycle and morphogenesis in U. esculenta.


Liquid biopsy in the setting of leptomeningeal metastases: a systematic review and meta-analysis.
The blood-brain barrier can prevent circulating tumor DNA (ctDNA) derived from the central nervous system from entering the blood making it challenging to evaluate molecular features of leptomeningeal metastasis (LM). Accordingly, we sought to systematically compare the diagnostic power or significance of ctDNA derived from cerebrospinal fluid (CSF) compared to plasma ctDNA in patients with LM. A systematic review and meta-analysis was performed under the PRISMA guideline. We used PubMed, EMBASE, and the EuroPMC to search the literature using combinations of the following terms: circulating tumor DNA, ctDNA, circulating tumor cell, brain metastasis, leptomeningeal metastasis, outcome(s), and prognosis. We included all available English language studies that compared the diagnostic significance of CSF derived and serum ctDNA. All eligible studies level of bias was assessed using the New Castle Ottawa Scale (NOS). Our meta-analysis from 6 included studies (n = 226) that confirmed the diagnostic power of liquid biopsies in detecting genomic alteration is better when taking a CSF-derived samples than from the plasma (RR 1.46 [0.93; 2.29]; I2 = 92%; p-value < 0.01). CSF ctDNA is better at describing molecular landscape for LM; such an understanding may ultimately help inform patient treatment and responses to therapy.


Structural features and electrostatic energy storage of electric double layers in confined polyelectrolyte solutions under low-salt conditions.
An electric double layer (EDL) in a polyelectrolyte solution plays a crucial role in diverse fields ranging from physical and life sciences to modern technologies. Due to the nonnegligible excluded volume effects, chain connectivity and complex intermolecular interactions, the EDLs in (confined) polyelectrolyte solutions display distinct features compared to those in simple electrolyte solutions. Here, we conducted a systematic study on the characteristics of EDLs in confined polyelectrolyte solutions for salt-free and low salt concentration systems using self-consistent field theory. Results suggest that the characteristic length scales measuring the EDL structures are different for positively and negatively charged surfaces. The former is the same as in the electrolyte solutions, while the latter is smaller due to the accumulation of oppositely charged polyelectrolytes near the surface. Furthermore, for low surface charge densities, a scaling law for the electrostatic energy stored in polyelectrolyte EDLs (in units of mJ m-2) was found to be U ∝ |σ|ν with ν ∼ 2-2.7, which differs from the electrolyte EDLs with ν ∼ 2; however, such a scaling law breaks down for high surface charge densities.


Modification of endotoxin-induced haemodynamic and haematological changes in the rabbit by methylprednisolone, F(ab')2 fragments and rosmarinic acid.
The effects of methylprednisolone, F(ab')2 fragments of human gamma globulins and rosmarinic acid, an inhibitor of complement activation, were tested on endotoxin-induced haemodynamic and haematological changes in the rabbit. Their effects were compared with complement depletion by cobra venom factor (CVF) pretreatment. The results provide further evidence for the role of complement activation and the concomitant triggering of the arachidonic acid cascade in the early phase of shock. The formation of vasoactive prostanoids (prostacyclin and thromboxane A2), the arterial hypotension and the thrombocytopenia were largely dependent on the presence of the intact complement system. F(ab')2 fragments (150 mg kg-1, i.v.) diminished the second fall in blood pressure to some extent but failed to alter any of the other endotoxin-induced changes. Methylprednisolone (40 mg kg-1, i.v.) given 10 min before endotoxin significantly reduced the activation of complement, the second rise of prostacyclin and the secondary hypotension, but was without effect on the early thromboxane peak of the haematological features of endotoxin shock. Rosmarinic acid (20 mg kg-1, i.v.) may be of potential interest for treatment of septic shock, since the drug suppressed the endotoxin-induced activation of complement, the formation of prostacyclin, both hypotensive phases, the thrombocytopenia and the concomitant release of thromboxane A2. The role of leukocytes and their arachidonic acid metabolites in plasma exudation deserves further investigation, because leukopenia and pulmonary oedema were not complement-dependent and were not affected by any of the treatments. Our results indicate that drugs, interfering with complement activation and/or prostaglandin biosynthesis, may be beneficial in endotoxin shock, provided that they are administered at an early stage.


Auditory brainstem responses in patients under treatment of hemodialysis.
This study evaluated the effects of end stage chronic renal failure (CRF) on auditory function and changes in auditory function following a single session of hemodialysis. The experimental group included 31 patients with end-stage renal failure on chronic hemodialysis. The control group consisted of 31 healthy volunteers. The patients were examined prior to and following a session of hemodialysis. Measurements included pure tone audiometry, tympanometry and acoustic reflex measurements, auditory brainstem responses (ABR), and blood now chemistry parameters. Controls underwent the same test battery, with the exception of biochemical and hematological assessment. Prior to hemodialysis sessions, all ABR latencies except interpeak latency I-III were significantly prolonged in the experimental group. A comparison between controls and the experimental group following hemodialysis indicated that wave V absolute latency and interpeak latencies III-V and I-V were significantly prolonged in the slow repetition rate paradigm. In the fast repetition rate, absolute latencies of waves I and V and III-V interpeak latencies were prolonged in the experimental group. Comparison of ABR recordings prior to and following hemodialysis showed overall significant difference between the measures. Post hoc analysis showed a significant improvement in wave I and V latencies in the slow repetition rate and wave V latency in the fast repetition rate. This study showed that neural conduction along the auditory pathway is delayed in patients with end stage CRF as compared to healthy subjects. Dialysis sessions improve overall neural auditory function. However, patients with end stage CRF show delayed conduction even after a session of hemodialysis.


Systemic lupus erythematosus observations of travel burden: A qualitative inquiry.
Explorations of travel impediments among patients suffering from rheumatic diseases have been very limited. Research has consistently indicated a shortage of rheumatologists, resulting in patients potentially having to travel long distances for care. The purpose of our study was to explore how systemic lupus erythematosus (SLE) patients experience travel issues differentially by race and socio-economic status. We conducted semi-structured interviews and a brief demographic survey with 10 patients diagnosed with SLE. Interview transcripts were coded and analyzed using NVivo Analysis Software to facilitate the reporting of recurrent themes and supporting quotations, and an initial codebook was independently developed by two researchers on the study team and then verified together. Patients described three major areas of concern with respect to travel burden in accessing their rheumatologists: reliance on caregivers; meeting financial priorities; and pain and physical limitations. Our data suggest general traveling challenges interfering with medical appointment compliance for several participants and the importance of socio-economic issues when considering travel issues. This study highlights an important area with implications for adherence to medical appointments and participation in research among patients with SLE.


Effect of CpG oligonucleotides on vaccine-induced B cell memory.
Adding synthetic oligodeoxynucleotides containing unmethylated CpG motifs to Anthrax vaccine adsorbed (AVA, the licensed human vaccine) increases the speed and magnitude of the resultant Ab response. Ab titers persist in the protective range for >1 year, significantly longer than in animals vaccinated with AVA alone. Unexpectedly, a majority of mice immunized with CpG-adjuvanted AVA maintained resistance to anthrax infection even after their Ab titers had declined into the subprotective range. The survival of these animals was mediated by the de novo production of protective Abs by high affinity memory B cells re-stimulated immediately after challenge. Thus, a previously unrecognized benefit of CpG oligodeoxynucleotides adjuvants is their ability to expand the long-lived memory B cell population. Current findings demonstrate that CpG-adjuvanted AVA mediates protection both by stimulating a strong/persistent serum Ab response and by generating a high-affinity long-lived pool of memory B cells.


Estimation of urea production rate with [(15)n(2)]urea and [(13)c]urea to measure catabolic rates in diabetes mellitus.
Abstract For verifying catabolic states in insulin-dependent patients and dogs the method estimating urea production rates with (13)C and with doubly (15)N labeled urea, respectively, has been established. For a fast steady state of urea tracer dilution, a prime of 600 times the continuous infusion rate had to be injected. Urea was isolated from plasma samples by protein precipitation and cation exchange chromatography with a consecutive derivatization of the dried urea fraction (trimethylsilyl derivatives). The masses of the fragment ions m/z 189 ((14)N(14)N), 190 ((14)N(15)N) and 191 ((15)N(15)N) urea are monitored to estimate the [(15)N(2)]urea frequency in the overall body urea pool in mol percent excess (MPE). 1 to 15 ng of derivatized urea were measured efficiently. An excellent correlation between expected standard and measured MPE (r = 0.9977) was achieved from solutions containing 1 to 7% [(15)N(2)]urea. The interassay coefficient of variation amounted to < 10% for a [(15)N(2)]urea portion of ≥ 3%. Normoglycemic diabetic patients who were treated with insulin overnight showed significantly higher urea production compared to healthy controls (9.22 ± 2.07 vs. 5.4 ± 0.32 μmol·kg(-1) · min(-1); p < 0.05). Measurements in chronic diabetic dogs proved an increased rate of amino acid catabolism (+ 20% urea production) in systemic versus portal application of insulin in paired studies. This increased nitrogen load in diabetics may accelerate progression of diabetic nephropathy. - Thus, the established stable isotope technique may serve as a sensitive and useful indicator of amino acid catabolism in clinical and experimental research.


Investigation of the in-plane and out-of-plane electrical properties of metallic nanoparticles in dielectric matrix thin films elaborated by atomic layer deposition.
Pt nanoparticles in a Al2O3 dielectric matrix thin films are elaborated by means of atomic layer deposition. These nanostructured thin films are integrated in vertical and planar test structures in order to assess both their in-plane and out-of-plane electrical properties. A shadow edge evaporation process is used to develop planar devices with electrode separation distances in the range of 30 nm. Both vertical and planar test structures show a Poole-Frenkel conduction mechanism. Low trap energy levels (<0.1 eV) are identified for the two test structures which indicates that the Pt islands themselves are not acting as traps in the PF mechanism. Furthermore, a more than three order of magnitude current density difference is observed between the two geometries. This electrical anisotropy is attributed to a large electron mobility difference in the in-plane and out-of-plane directions which can be related to different trap distributions in both directions.


Crystallization and preliminary X-ray analysis of polyamine oxidase from Zea mays L.
Polyamine oxidase catalyses the oxidation of the secondary amino group of spermine, spermidine and their acetyl derivatives. The enzyme plays an important role in the regulation of polyamine intracellular concentration and is a member of the family of flavin-containing amine oxidases. Crystals of maize polyamine oxidase have been grown by the hanging-drop vapour-diffusion technique. The crystals are in hexagonal space group P6122 (or P6522) with cell dimensions a = b = 184.6, c = 280.9 A. A native data set has been collected to 2.7 A resolution at a synchrotron radiation source.


A comparison of parameters used to assess liver damage in sheep treated with carbon tetrachloride.
Changes in serum enzyme levels, liver histology and liver function tests have been correlated to determine the usefulness of these tests in assessing liver status. The effects of carbon tetrachloride administration on these parameters has been determined in a group of 20 sheep. Normal levels, elevated levels after injury and the effect of elapsed time after injury are reported for serum glutamic dehydrogenase, sorbitol dehydrogenase, glutamic-oxaloacetic transaminase, glutamic-pyruvic transaminase, lactate dehydrogenase, fructose-1-phosphate adlolase, alkaline phosphatase, cholesterol and proteins. Variation in the time of elevation of enzyme activities may be useful in determining the elapsed time between acute injury and serum sampling. In comparison to sheep fed an adequate diet, a diet with a restricted protein intake was associated with increased severity of histological lesions and decreased liver function.