Subcellular location of corticosteroid-induced alkaline phosphatase in canine hepatocytes.
Dogs received either 4 mg/kg of prednisone or sterile saline daily for 32 days. Serum samples were assayed every 4 days for total alkaline phosphatase (ALP) and corticosteroid-induced ALP isoenzyme (CIALP) activity. The initial and major increase of serum ALP was attributed to the liver isoenzyme of ALP (LALP), however, CIALP began to increase by day 8 and was significantly increased by day 24. Prior to treatment and on day 32, sections of liver from control and prednisone-treated dogs were stained for ALP activity after blocking the staining activity of LALP with levamisole. The staining activity of CIALP was compared to the staining activity of LALP in liver sections from control dogs and from dogs in which the bile duct was ligated. It was determined that CIALP was located in that area of the hepatocyte membranes which comprise the bile canaliculi.


Incidence of High-Risk Radiologic Features in Patients Without Local Recurrence After Stereotactic Ablative Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer.
To investigate, in the setting of stereotactic ablative radiation therapy (SABR) for early-stage non-small cell lung cancer, the incidence and patterns of change in high-risk radiologic features (HRFs) in patients known to have no local recurrence. Computed tomography (CT) scans of patients treated using volumetric modulated arc therapy SABR between 2008 and 2013 were eligible if follow-up scans were available for 2 years and no local recurrences were diagnosed. All scans were reviewed at a workstation using an add-on tool for ClearCanvas (Synaptive Medical). Five clinicians who were blinded to clinical outcomes scored the presence of HRFs: enlarging opacity (EO), sequential enlarging opacity, enlarging opacity after 12 months (EO12), bulging margin, loss of linear margins, cranio-caudal growth, and loss of air bronchogram. After each review, clinicians recommended follow-up procedures based on published recommendations. A total of 88 patients (747 CT scans) were evaluated. The HRFs most frequently recorded by ≥3 observers on at least 1 follow-up scan were EO (64.8%), EO12 (50.0%), and sequential enlarging opacity (13.6%). Fifty-six patients developed EO within the first year after SABR, and of these, 46 also developed subsequent EO (EO12). In 76 patients who developed EO after 1 year of follow-up, 30 had not manifested EO previously. Three or more HRFs have been associated with recurrences, and this was observed on CT scan in 22.7% of patients. In their routine care, 6 patients had undergone a positron emission tomography scan because of a suspected local recurrence, and 4 underwent an attempt at biopsy. More than 50% of patients without a local recurrence after SABR develop HRFs. Because ≥3 HRFs were present in nearly 25% of patients, further refinement of follow-up recommendations are necessary.


Production of IL 2 and IFN-gamma by T cells from malaria patients in response to Plasmodium falciparum or erythrocyte antigens in vitro.
T cells from patients acutely infected with malaria exhibit a disease-related stimulation of DNA synthesis in response to Plasmodium falciparum antigen in vitro. This response is weak and short-lived, suggestive of induction of suppressor mechanisms. Exogenous T cell growth factor (IL 2) that was added to antigen-stimulated T cell cultures enhanced proliferation in antigen-responsive cultures, indicating that the lymphocytes expressed IL 2 receptors. In contrast, the addition of IL 2 to cultures that did not respond to antigen had no effect. Antigen-responsive cultures contained endogenous IL 2 as well, and the antigen-induced lymphocyte proliferation was correlated with IL 2 production. However, the results suggested that IL 2 production by the patients' T cells was insufficient or actively shut off, and that this was responsible for the premature cessation of their DNA synthesis. Supernatants from 60% of the T cell cultures treated with malaria antigen and from 30% treated with RBC ghost antigen contained interferon-gamma (IFN-gamma), as determined by a cytopathic effect inhibition assay combined with acid treatment and antibody neutralization or by an IFN-gamma-specific ELISA. There was no obvious correlation between antigen-induced lymphocyte proliferation and the presence of IFN-gamma in the culture supernatants. A high IFN-gamma activity was also seen in antigen-treated cultures from P. falciparum-immune donors living in highly endemic malaria areas. In contrast, no IFN-gamma was found in supernatants of antigen-treated T cells from healthy donors or patients with Plasmodium vivax malaria. Thus, the IFN-gamma activity of these cultures appears to reflect the presence of antigen-reactive T cells and may be useful as a sensitive indicator of cellular immunity in P. falciparum malaria.


[Non-functioning neuroendocrine tumor of the pancreas: report of a clinical case and review of the literature].
The authors report the case of a 26-year-old woman, with a palpable abdominal mass, dyspepsia, pain and weight loss. These symptoms were caused by a non-functioning or biologically inactive neuroendocrine tumour (BINT), weighing 510 g and located in the tail of the pancreas. The treatment opted for was a surgical resection consisting in a distal pancreatectomy. The results of the operation were satisfactory and the woman is now alive and in good health, without recurrence, after 7 years. The authors then go on to analyse the concept of non-functioning neuroendocrine tumours and the problems relating to their symptoms, location and nature. These tumours, which arise, from the pancreatic islet cells, fail to produce a clinical syndrome owing to insufficient peptide production or insufficient release, or concurrent secretion, of inhibitory peptides by the tumour or production of biologically inactive molecular forms of the peptides (without clinical effects). The value of tumour markers and the indications and type of surgery are also discussed according to the different patterns of tumour spread (local, locoregional and metastatic disease). It is stressed that a complete surgical resection is the only curative treatment for these tumours. Encouraging results have been recently obtained by adjuvant treatment with somatostatin analogues, chemotherapeutic agents and/or inteferon.


Investigation of spatial clustering from individually matched case-control studies.
The paper demonstrates how existing theory to assess spatial clustering based on second-moment properties of a labelled point process can be adapted to matched case-control studies. The null hypothesis that cases are a random sample from the superposition of cases and controls is replaced by the hypothesis that each case is a random sample from the set consisting of itself and its k matched controls. We compare the proposed test with other tests of spatial clustering, and describe an application to data on childhood diabetes in Yorkshire, England.


Tobacco litigation as a public health and cancer control strategy.
To provide an overview of the class action and medical cost reimbursement suits of the third wave of tobacco litigation and to analyze their chances for success and their efficacy as a public health and cancer control strategy. The application of standard, predictive legal reasoning to documents from three class action lawsuits, four of the five state medical cost reimbursement lawsuits, documents from the tobacco industry, and appropriate secondary sources. Victory in any of the class actions would result in a transfer of costs, albeit an inefficient one, from injured smokers to the tobacco industry. Victory in any of the medical cost reimbursement suits would result in a transfer of costs from injured states forced to shoulder the economic burden of tobacco-induced illnesses to the tobacco industry. Such a transfer of costs would likely have the immediate impact of significantly lowering cigarette consumption, while the long-term effects would probably be much more devastating. Victory in at least some of the third wave cases is likely, because a number of factors promise to enable plaintiffs to overcome the previously impenetrable defenses of the tobacco industry.


Does multidisciplinary care enhance the management of advanced breast cancer?: evaluation of advanced breast cancer multidisciplinary team meetings.
To assess the contribution of the advanced breast cancer (ABC) multidisciplinary team meetings (MDMs) to patient care and clinical outcomes. Members of ABC MDMs at two health services completed questionnaires in November 2007. The questionnaire asked about the performance of the MDMs and their contribution to improvement in patient care in five domains: medical management, psychosocial care, palliative care, care in the community, and benefits for team members. A final section covered the perceived value and importance of the MDM in patient management. Descriptive statistics (frequencies, mean, and standard deviation) were used to summarize the performance, improvement, and importance scores. A total of 27 multidisciplinary team members (73%) completed the questionnaire. The MDM performed best in medical management (mean performance score out of 5 [M] = 3.78) and palliative care (M = 3.77). These were also the areas that were most improved through the MDM. Benefits to team members and care in the community (both M = 3.05) ranked lowest by both measures. The MDM provided the most benefit for patient management in the areas of "awareness of services available" (M = 4.32), "efficiency of referrals" (M = 4.27) and "supportive care for patients" (M = 4.27). "Awareness of services available," "psychological care for patients," and "continuity of care" were considered the most important (M = 4.64). The study provides evidence that MDMs make an important contribution to the logistical and medical management of patients with advanced breast cancer.


Selective and Tunable Galectin Binding of Glycopolymers Synthesized by a Generalizable Conjugation Method.
Glycopolymers, conjugates of synthetic polymers with pendant carbohydrates, are becoming increasingly important to probe the role of carbohydrates in cellular processes and for applications like biosensors and drug delivery. A library of glycopolymers bearing different sugar moieties was synthesized by grafting amino-functionalized sugars to poly(acrylic acid) via DMTMM coupling. Primary amines were introduced at the anomeric (C-1) position to a number of unprotected mono-, di-, and trisaccharides using ammonium carbamate and conjugated to poly(acrylic acid) of different molecular weights, synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. This approach provides a simple and efficient route for the preparation of glycopolymers that differ only in the identity or degree of substitution of the sugar moiety on the polymer. The binding parameters (ka, kd, and KD) of these new glycopolymers to galectins-1 and -3 were quantified using surface plasmon resonance. The galectins selectively bound only to lactose-containing polymers, and the binding affinity was dependent on the galectin type, degree of sugar substitution and the molecular weight of polymer chains. Binding to both galectin-1 and -3 increased with a higher degree of sugar substitution, and higher molecular weight of the polymer backbone, reaching KD values on the order of 10-11 M.


Coral reef growth in the galapagos: limitation by sea urchins.
The regular echinoid Eucidaris thouarsii is a conspicuous omnivore on coral bottoms in the Galápagos. Unlike Eucidaris in Panama and mainland Ecuador, Galápagos Eucidaris are large and abundant and graze heavily in the open on live corals day and night. These differences are probably due in large part to more intense predation by fishes on mainland compared with island urchin populations. An assessment of coral growth versus coral attrition from grazing shows that Eucidaris interferes with the establishment of pocilloporid reef frame and therefore reduces reef growth in the Galápagos.


Comparative genomic analyses of nickel, cobalt and vitamin B12 utilization.
Nickel (Ni) and cobalt (Co) are trace elements required for a variety of biological processes. Ni is directly coordinated by proteins, whereas Co is mainly used as a component of vitamin B12. Although a number of Ni and Co-dependent enzymes have been characterized, systematic evolutionary analyses of utilization of these metals are limited. We carried out comparative genomic analyses to examine occurrence and evolutionary dynamics of the use of Ni and Co at the level of (i) transport systems, and (ii) metalloproteomes. Our data show that both metals are widely used in bacteria and archaea. Cbi/NikMNQO is the most common prokaryotic Ni/Co transporter, while Ni-dependent urease and Ni-Fe hydrogenase, and B12-dependent methionine synthase (MetH), ribonucleotide reductase and methylmalonyl-CoA mutase are the most widespread metalloproteins for Ni and Co, respectively. Occurrence of other metalloenzymes showed a mosaic distribution and a new B12-dependent protein family was predicted. Deltaproteobacteria and Methanosarcina generally have larger Ni- and Co-dependent proteomes. On the other hand, utilization of these two metals is limited in eukaryotes, and very few of these organisms utilize both of them. The Ni-utilizing eukaryotes are mostly fungi (except saccharomycotina) and plants, whereas most B12-utilizing organisms are animals. The NiCoT transporter family is the most widespread eukaryotic Ni transporter, and eukaryotic urease and MetH are the most common Ni- and B12-dependent enzymes, respectively. Finally, investigation of environmental and other conditions and identity of organisms that show dependence on Ni or Co revealed that host-associated organisms (particularly obligate intracellular parasites and endosymbionts) have a tendency for loss of Ni/Co utilization. Our data provide information on the evolutionary dynamics of Ni and Co utilization and highlight widespread use of these metals in the three domains of life, yet only a limited number of user proteins.


Effects of R- and S-enantiomers of chiral non-steroidal anti-inflammatory drugs in experimental colitis.
Prostaglandins appear to play an important role in down-regulating intestinal inflammation and promoting repair of injury. In experimental colitis, inhibition of prostaglandin synthesis with nonsteroidal anti-inflammatory drugs (NSAID) leads to marked exacerbation of tissue injury. It has been suggested that the ability of chiral NSAID to inhibit prostaglandin synthesis is completely attributable to the s-enantiomer, while the r-enantiomer is a much weaker inhibitor. Thus, it is possible that r-enantiomers of chiral NSAID will have reduced intestinal toxicity and reduced ability to exacerbate colitis. In the present study, we compared r- and s-enantiomers of two chiral NSAID (flurbiprofen and etodolac) in terms of their ability to exacerbate colitis in the rat. We found that r-flurbiprofen and r-etodolac did not exacerbate colitis, in contrast to the s-enantiomers or racemates. The r-enantiomers also had significantly less inhibitory activity on prostaglandin synthase. Reduced biliary excretion of r-etodolac may have also contributed to the lack of detrimental effects in this model. The results support the hypothesis that prostaglandins play an essential role in down-regulating colonic inflammation and promoting repair.


Pilon Fractures: Challenges and Solutions.
Pilon fractures include a wide range of complexity. The timing and type of definitive fixation is dictated by the soft tissue injury and energy imparted to the fracture. One should have a low threshold for staged protocols and delayed definitive fixation to avoid complications. Proper radiographs and advanced imaging should be obtained for an exacting diagnosis and preoperative planning. Diligent management of the soft tissue and anatomic restoration of the articular surface, length, rotation, and axial alignment with stable fixation to the diaphysis should be obtained once feasible. Intramedullary implants with percutaneous articular fixation for simple or extra-articular patterns provide good results with little soft tissue insult in the zone of injury. Minimally invasive plate osteosynthesis techniques can help mitigate some concerns with soft tissue compromise while obtaining good articular alignment. Locking or conventional plating with lag screw fixation is used for complex articular injuries with or without fibular fixation. External fixators are generally used for temporizing measures but can be utilized as definitive fixation when indicated. There is a role for acute fusion in severely comminuted, osteoporotic, or arthritic fractures in patients with poor healing potential. This article outlines the diagnostic workup and treatment of these vexing injuries with solutions to challenges that arise.


Effects of exposure of Clostridium difficile PCR ribotypes 027 and 001 to fluoroquinolones in a human gut model.
The incidence of Clostridium difficile infection is increasing, with reports implicating fluoroquinolone use. A three-stage chemostat gut model was used to study the effects of three fluoroquinolones (ciprofloxacin, levofloxacin, and moxifloxacin) on the gut microbiota and two epidemic C. difficile strains, strains of PCR ribotypes 027 and 001, in separate experiments. C. difficile total viable counts, spore counts, and cytotoxin titers were determined. The emergence of C. difficile isolates with reduced antibiotic susceptibility was monitored with fluoroquinolone-containing medium, and molecular analysis of the quinolone resistance-determining region was performed. C. difficile spores were quiescent in the absence of fluoroquinolones. Instillation of each fluoroquinolone led to C. difficile spore germination and high-level cytotoxin production. High-level toxin production occurred after detectable spore germination in all experiments except those with C. difficile PCR ribotype 027 and moxifloxacin, in which marked cytotoxin production preceded detectable germination, which coincided with isolate recovery on fluoroquinolone-containing medium. Three C. difficile PCR ribotype 027 isolates and one C. difficile PCR ribotype 001 isolate from fluoroquinolone-containing medium exhibited elevated MICs (80 to > or =180 mg/liter) and possessed mutations in gyrA or gyrB. These in vitro results suggest that all fluoroquinolones have the propensity to induce C. difficile infection, regardless of their antianaerobe activities. Resistant mutants were seen only following moxifloxacin exposure.


Meiotic drive, postzygotic isolation, and the Snowball Effect.
As populations diverge, they accumulate incompatibilities which reduce gene flow and facilitate the formation of new species. Simple models suggest that the genes that cause Dobzhansky-Muller incompatibilities should accumulate at least as fast as the square of the number of substitutions between taxa, the so-called snowball effect. We show, however, that in the special- but possibly common- case in which hybrid sterility is due primarily to cryptic meiotic (gametic) drive, the number of genes that cause postzygotic isolation may increase nearly linearly with the number of substitutions between species.


An in silico approach to determine challenges in the bioavailability of ciprofloxacin, a poorly soluble weak base with borderline solubility and permeability characteristics.
Ciprofloxacin is administered as the hydrochloride salt in immediate release formulations for the treatment of various infectious diseases in different patient populations. Due to its weakly basic properties and poor solubility, the in vivo behaviour of this compound could be influenced by both physicochemical and physiological factors. The first aim of this study was to investigate the behaviour of ciprofloxacin (Ciprobay® 500 mg tablets) in the human gastro-intestinal tract with in vitro dissolution, transfer and two-stage experiments. Ciprobay® IR tablets dissolved completely in FaSSGF-V2, but dissolution was incomplete in FaSSIF-V2 and in an achlorhydric medium (FaSSGF-achlorhydric) and slow precipitation was observed in all three media. Ciprofloxacin did not precipitate in the transfer model but in the two-stage test, a simplified version of the transfer model, some precipitation was detected. In the second part of this study the data obtained in the in vitro transfer experiment were integrated into a Physiologically Based Pharmacokinetic (PBPK) Model. Based on the in vitro results, it was concluded that precipitation of ciprofloxacin would be unlikely in vivo. When precipitation was assumed to be negligible in the PBPK model, good predictions of plasma concentration time profiles provided by Bayer Pharma AG and obtained from the open literature were attained. Parameter Sensitivity Analysis (PSA) was conducted on several parameters which may influence the in vivo behaviour of ciprofloxacin. It was shown that precipitation in the gastro-intestinal tract in humans after a dose of 500 mg is not a determinant of the PK profile. PSA further suggested that ciprofloxacin behaves in vivo as a BCS Class I drug according to the Biopharmaceutics Classification System (BCS), even though on the basis of available solubility and permeability data the compound has been categorised as a BCS II/IV drug. These findings illustrate the importance of coupling in vitro results with in silico PBPK models to better understand the in vivo behaviour of weakly basic drugs. The PBPK model of ciprofloxacin, which was set up for healthy volunteers, was also modified to predict the in vivo behaviour of ciprofloxacin in several different patient populations. It was shown on the basis of these simulations that the plasma concentration time profile may be less influenced by disease state than previously expected.


Haematological analyses in rainbow trout Oncorhynchus mykiss affected by viral haemorrhagic septicaemia (VHS).
Rainbow trout Oncorhynchus mykiss weighing 87 +/- 15 g (mean +/- SD) were infected with viral haemorrhagic septicaemia virus (VHSV) and the haematological and biochemical profiles of peripheral blood examined. Depending on the clinical signs and gross pathology, the fish were divided into 2 groups: Group A included fish in the acute stage, Group B comprised fish in the chronic stage. Red blood cells were subjected to 6 haematological tests and blood plasma to 14 biochemical tests, which provided findings on changed substrate concentrations and enzyme activities. Diseased fish, compared to healthy fish, had a significantly lower red blood cell count, and lower haematocrit and haemoglobin levels. As for the biochemical parameters, the fish had less total protein, creatinine, glucose, triacylglycerol, inorganic phosphate, total calcium and sodium, and more blood urea, nitrogen and potassium. Uric acid levels remained unchanged. Increases were recorded in the catalytic concentration of alanine aminotransferase, aspartate aminotransferase and lactate dehydrogenase. A decrease was recorded in the catalytic concentration of alkaline phosphatase. Fish with VHS in the chronic stage, compared with healthy fish, were in worse condition, with a significantly reduced Fulton coefficient and Clark coefficient, and a higher hepatosomatic index and visceral somatic index.


Manifest anxiety and maternal-fetal attachment in pregnant women with previous fetal losses.
To explore associations between manifest anxiety (Taylor's Manifest Anxiety Scale, TMAS), major obstetric and demographic features and maternal-fetal attachment (MFA) (Maternal Antenatal Attachment Scale, MAAS) in women with previous miscarriages. One hundred pregnant women with previous miscarriages, having uncomplicated singleton pregnancy, not receiving any medications, and conceived in a natural manner . Ages ranged between 19 and 47 years, gestational age between 4 and 35 weeks. Hierarchical multiple linear regression, Kruskal-Wallis test, and ANCOVA were used in data analysis. Maternal age, gestational age, previous abortions, parity, maternal education, and marital status in combination contributed significantly to the regression model in prediction of the MAAS quality and intensity scores. Adding the TMAS score accounted for an additional 17% of variation in the MAAS quality score, and the change in R2 was significant. There was a negative relationship between the TMAS and the MAAS quality scores. The TMAS score did not contribute to prediction of the MAAS intensity. The highest TMAS values were in the women having anxious, ambivalent or affectless preoccupation. Prevention of negative consequences of poor quality of MFA in women with previous miscarriages should include early screening for manifest anxiety.


Conjugation site heterogeneity causes variable electrostatic properties in Fc conjugates.
Immunoconjugates, including antibody-drug conjugates and Fc-conjugates, represent a rapidly growing class of therapeutics undergoing clinical development. Despite their growing popularity, the high intrinsic heterogeneity of immunoconjugates often complicates the development process and limits their widespread application. In particular, immunoconjugate charge variants exhibit markedly different colloidal stabilities, solubilities, pharmacokinetics, and tissue distributions. Charge variants arise spontaneously due to degradation and, depending on the type of drug, linker, and conjugation site, through drug conjugation. Electrostatic changes in naked antibodies often result in poor performance characteristics, and therefore, charge alterations due to degradation are critical to control. Charge properties are expected to be equally important to producing well-behaved ADCs. Charge-based methods of analysis, such as isoelectric focusing and ion exchange chromatography, are capable of probing the underlying complexities within immunoconjugate drug products. Despite the utility of these methods, there are only a few published reports of charge-based assays applied to immunoconjugates. In the present study, we sought to identify the effects of chemical conjugation on the electrostatic properties of Fc-conjugates. In order to minimize the effects of post-translational modifications (e.g., deamidation), a single Fc charge variant was isolated prior to conjugation of a fluorescent probe, Alexa Fluor 350, to the side chains of lysine residues. The resulting Fc-conjugates were assessed by a variety of analytical techniques, including isoelectric focusing and ion exchange chromatography, to determine their charge properties.


Hands, tables and groups make rehabilitation awesome!
Technology has helped improve rehabilitation programs by providing patients with engaging alternatives to otherwise monotonous and repetitive exercises. In recent years, therapists have looked towards multi-touch technologies to further enhance patient rehabilitation programs. So far, the focus has mainly been on single-user interaction, largely ignoring many of the benefits patients receive from socially interacting with therapists, caregivers and their peers. To make use of these valuable interactions, we have developed a suite of multi-touch activities for motor and cognitive rehabilitation. These applications can easily be adjusted to meet the needs of individual patients and enable therapists to quantitatively measure patient behavior and performance. We also reflect on design-related discussions we had with practicing occupational therapists and provide a set of design considerations to guide future rehabilitation activities.


C. H. McCloy lecture: fifty years of advancements in fitness and activity research.
Over the past 50 years progress in fitness and activity research has been influenced by social events, technical innovations, and changes in the field of physical education and kinesiology. The conventional wisdom of the 1950s yielded to a new wisdom based on research evidence. The author's research, as well as the research of others, from 1960 to the present is discussed. The new wisdom focuses on health-related fitness and physical activity promotion based on health behavior change strategies.


Comparison of Intraperitoneal and Intraepididymal Quercetin for the Prevention of Testicular Torsion/Detorsion-induced Injury.
To compare the effects of intraepididymal quercetin (IE-QE) with those of intraperitoneal quercetin (IP-QE) on testicular torsion/detorsion (TD)-induced ischemia/reperfusion (IR) injury of the testes in an experimental rat model. Twenty-four rats were divided into 4 groups: sham (S), TD, TD treated with IP-QE, and TD treated with IE-QE. The IP-QE group received 20 mg/kg QE intraperitoneally, whereas the IE-QE group received quercetin (QE) epididymally. After surgically induced TD, sera and testicular tissues were obtained for the analysis of biochemical parameters including glutathione peroxidase (GPx), malondialdehyde, total antioxidant status, total oxidant status, oxidative stress index, histologic changes, and evaluation of germ cell apoptosis. The oxidative stress index and oxidants (malondialdehyde and total oxidant status) were increased with a concomitant decrease in the antioxidants (GPx and total antioxidant status) in the TD group. Severe histopathological damage, indicated by low Johnsen scores and high testicular injury grades, and germ cell apoptosis were found in the TD group compared with the other groups. Rats treated with QE showed significantly less IR injury, with moderately altered biochemical parameters, histopathological damage, and germinal cell apoptosis compared with the TD group. Most importantly, we found no significant differences in the biochemical parameters, histopathological changes, and germinal cell apoptosis between the IP-QE and IE-QE groups. IE-QE was comparable to IP-QE in the treatment of testicular TD. Local QE therapy should be considered as a new approach to treating testicular IR injury due to TD.


Assessing the validity of using administrative data to identify patients with epilepsy.
Previous validation studies assessing the use of administrative data to identify patients with epilepsy have used targeted sampling or have used a reference standard of patients in the neurologist, hospital, or emergency room setting. Therefore, the validity of using administrative data to identify patients with epilepsy in the general population has not been previously assessed. The purpose of this study was to determine the validity of using administrative data to identify patients with epilepsy in the general population. A retrospective chart abstraction study was performed using primary care physician records from 83 physicians distributed throughout Ontario and contributing data to the Electronic Medical Record Administrative data Linked Database (EMRALD) A random sample of 7,500 adult patients, from a possible 73,014 eligible, was manually chart abstracted to identify patients who had ever had epilepsy. These patients were used as a reference standard to test a variety of administrative data algorithms. An algorithm of three physician billing codes (separated by at least 30 days) in 2 years or one hospitalization had a sensitivity of 73.7% (95% confidence interval [CI] 64.8-82.5%), specificity of 99.8% (95% CI 99.6-99.9%), positive predictive value (PPV) of 79.5% (95% CI 71.1-88.0%), and negative predictive value (NPV) of 99.7% (95% CI 99.5-99.8%) for identifying patients who had ever had epilepsy. The results of our study showed that administrative data can reasonably accurately identify patients who have ever had epilepsy, allowing for a "lifetime" population prevalence determination of epilepsy in Ontario and the rest of Canada with similar administrative databases. This will facilitate future studies on population level patterns and outcomes of care for patients living with epilepsy.


Variability in Pathologists' Interpretations of Individual Breast Biopsy Slides: A Population Perspective.
The effect of physician diagnostic variability on accuracy at a population level depends on the prevalence of diagnoses. To estimate how diagnostic variability affects accuracy from the perspective of a U.S. woman aged 50 to 59 years having a breast biopsy. Applied probability using Bayes' theorem. B-Path (Breast Pathology) Study comparing pathologists' interpretations of a single biopsy slide versus a reference consensus interpretation from 3 experts. 115 practicing pathologists (6900 total interpretations from 240 distinct cases). A single representative slide from each of the 240 cases was used to estimate the proportion of biopsies with a diagnosis that would be verified if the same slide were interpreted by a reference group of 3 expert pathologists. Probabilities of confirmation (predictive values) were estimated using B-Path Study results and prevalence of biopsy diagnoses for women aged 50 to 59 years in the Breast Cancer Surveillance Consortium. Overall, if 1 representative slide were used per case, 92.3% (95% CI, 91.4% to 93.1%) of breast biopsy diagnoses would be verified by reference consensus diagnoses, with 4.6% (CI, 3.9% to 5.3%) overinterpreted and 3.2% (CI, 2.7% to 3.6%) underinterpreted. Verification of invasive breast cancer and benign without atypia diagnoses is highly probable; estimated predictive values were 97.7% (CI, 96.5% to 98.7%) and 97.1% (CI, 96.7% to 97.4%), respectively. Verification is less probable for atypia (53.6% overinterpreted and 8.6% underinterpreted) and ductal carcinoma in situ (DCIS) (18.5% overinterpreted and 11.8% underinterpreted). Estimates are based on a testing situation with 1 slide used per case and without access to second opinions. Population-adjusted estimates may differ for women from other age groups, unscreened women, or women in different practice settings. This analysis, based on interpretation of a single breast biopsy slide per case, predicts a low likelihood that a diagnosis of atypia or DCIS would be verified by a reference consensus diagnosis. This diagnostic grey zone should be considered in clinical management decisions in patients with these diagnoses. National Cancer Institute.


Preventive Vaccination with Mesenchymal Stem Cells Protects Mice from Lethal Infection Caused by Herpes Simplex Virus 1.
Herpes simplex viruses 1 and 2 (HSV-1 and HSV-2) infect almost all organs and tissues, cause genital herpes-the most common sexually transmitted disease-disorders of the central nervous system (CNS), and lead to severe complications in children. Despite the available drugs, the incidence of HSV-1/2 continues to rise. None of the prophylactic vaccine candidates have shown a protective effect in trials nor approval for use in clinical practice. We have investigated the protective properties of mesenchymal stem cells (MSC) isolated from the bone marrow of mice. A comparative analysis of the protective response to the introduction of primary and modified MSCs (mMSC) was carried out using the plasmid containing gene of the HSV and an inactivated virus in a model of lethal HSV-1 infection in mice. mMSCs were obtained by transfection of the Us6 gene encoding glycoprotein D (gD) of the HSV, the plasmid contained the same gene. After twofold immunization with primary MSCs, the formation of antibodies interacting with the viral antigen (according to enzyme immunoassay data) and neutralizing the infectious activity of HSV-1 in the reaction of biological neutralization was observed in the peripheral blood of mice. In addition, the introduction of primary MSCs induced the production of interferon gamma (INF-γ) which is detected in the peripheral blood of mice. After infection with HSV-1, the immunized mice showed significantly increased titers of virus-specific antibodies, an increased level of IFNγ, and were completely protected from lethal HSV-1 infection. The protective effect of the other three immunogens was lower and did not exceed 50-65%. Considering the wide availability of MSCs, the proven safety of intravenous administration, and the results obtained in this work on the ability to induce innate, adaptive and protective immunity to HSV-1, MSCs can be considered a promising basis for the development of new cellular vaccines for the prevention of herpesvirus and other viral infections.


Effects of oral N-acetylcysteine on cell content and macrophage function in bronchoalveolar lavage from healthy smokers.
Bronchoalveolar lavage (BAL) was performed in fourteen healthy non-smokers and eleven healthy smokers. In smokers BAL was performed before and after eight weeks' treatment with N-acetylcysteine (NAC; 200 mg t.i.d.). Cell number, composition and viability were determined in the BAL fluid. Alveolar macrophages (AMs) were cultured before examination of their phagocytic capacity and their ability to produce leukotriene B4 (LTB4). BAL fluid from smokers contained more cells than that from non-smokers (p less than 0.001). This was mainly attributable to increases in both proportion and absolute number of AMs (p less than 0.001) and to an increase in absolute number of neutrophils (p less than 0.05). However, there was a decrease in proportion of lymphocytes in BAL fluid from smokers (p less than 0.001). Phagocytic capacity of adherent cells and capacity of AMs to generate LTB4 after stimulation with opsonized zymosan (OZy) were decreased in smokers (p less than 0.05 and p less than 0.01 respectively). NAC treatment of smokers did not affect cell number but resulted in an increased proportion of lymphocytes in BAL fluid (p less than 0.05). The phagocytic capacity of AMs was not significantly altered but was improved in five of eleven smokers after NAC treatment. NAC also enhanced the decreased LTB4 secretion by smokers' AMs (p less than 0.05). We conclude that smoking leads to reduced phagocytic capacity and LTB4 secretion of AMs and that oral NAC treatment may improve the function of AMs.


[Prospective clinical study on serum immunity in IgG-antibodies positive patients convalescent from severe acute respiratory syndrome].
To investigate the serum immunological characteristics in patients convalescent from severe acute respiratory syndrome (SARS). In the 1 st, 3 rd, 6 th month after their discharge, eg. SARS-IgG, T cell subsets, blood routine, and the blood biochemistry were systemically determined in SARS convalescent patients. The SARS-antibodies could be used as the diagnostic evidence. During the 6 months after discharge, the titers of SARS-antibodies were high, but they lowered along with passage of time. At the first recheck, the CD4(+) lymphocyte count was lower than normal level in 55.9% of patients, the CD3(+) lymphocyte count was lower than normal level in 31.2% of patients, and the CD8(+) lymphocyte count was lower than normal level in 14.0% of patients. At the second recheck, the levels of T cell subsets recovered to normal level in the most patients. T cell subsets, and the number of leukocyte are abnormal in some patients convalescent from SARS. All the indexes examined recover to normal levels half year after discharge. Therefore, it is necessary to follow up the changes in the levels of SARS-antibodies.


WWOX suppresses prostate cancer cell progression through cyclin D1-mediated cell cycle arrest in the G1 phase.
WW domain-containing oxidoreductase (WWOX) has been reported to be a tumor suppressor in multiple cancers, including prostate cancer. WWOX can induce apoptotic responses to inhibit tumor progression, and the other mechanisms of WWOX in tumor suppression have also been reported recently. In this study, we found significant down-regulation of WWOX in prostate cancer specimens and prostate cancer cell lines compared with the normal controls. In addition, an ectopically increased WWOX expression repressed tumor progression both in vitro and in vivo. Interestingly, overexpression of WWOX in 22Rv1 cells led to cell cycle arrest in the G1 phase but did not affect sub-G1 in flow cytometry. GFP-WWOX overexpressed 22Rv1 cells were shown to inhibit cell cycle progression into mitosis under nocodazole treatment in flow cytometry, immunoblotting and GFP fluorescence. Further, cyclin D1 but not apoptosis correlated genes were down-regulated by WWOX both in vitro and in vivo. Restoration of cyclin D1 in the WWOX-overexpressed 22Rv1 cells could abolish the WWOX-mediated tumor repression. In addition, WWOX impair c-Jun-mediated cyclin D1 promoter activity. These results suggest that WWOX inhibits prostate cancer progression through negatively regulating cyclin D1 in cell cycle lead to G1 arrest. In summary, our data reveal a novel mechanism of WWOX in tumor suppression.


[The influence of cooking on radiocaesium contamination of edible mushrooms].
Radiocaesium concentration in some kinds of edible mushrooms collected in October 1990 has been determined to evaluate the radiocaesium activity 5 years after Chernobyl accident. The highest activity was found in Xerocomus subtomentosus (1080.5 Bq/kg of fresh weight), then in Rozites caperata (768.5 Bq/kg) and Xerocomus badius (562.5 Bq/kg); the lowest--in Suillus luteus (52.0 Bq/kg) and Cantharellus cibarius (63.0 Bq/kg). Studies on the influence of cooking on radiocaesium activity revealed that parboiling and boiling of mushrooms led to high, even 85% losses of radiocaesium in the product. Samples of Xerocomus badius collected in various sites of North-East Poland in 1995 averaged to 195.4 +/- 125.5 Bq/kg of fresh weight.


Characterization of AmpC-mediated resistance in clinical Salmonella isolates recovered from humans during the period 1992 to 2003 in England and Wales.
The increase in AmpC-mediated resistance in salmonellae constitutes a serious public health concern, since these enzymes confer resistance to a wide range of beta-lactams. One hundred six isolates were selected from 278,308 Salmonella isolates based on resistance to ampicillin and cephalosporins and were subjected to further characterization. Nine isolates had a cefoxitin inhibition diameter < or = 17 mm and were proven to be AmpC positive by multiplex PCR. Sequence analysis revealed the presence of bla(DHA-1), bla(CMY-2), and bla(CMY-4) genes. All nine isolates presented different pulsed-field gel electrophoresis restriction profiles. The AmpC genetic determinants were present in transferable plasmids of around 11, 42, 70, 98, and 99 MDa. A combination of size and restriction fragment length polymorphism (RFLP) analysis showed that all the bla(CMY) plasmids investigated in our study were different, which suggests that bla(CMY) may be located in different plasmid environments. Some United Kingdom isolates linked to foreign travel showed RFLP plasmid patterns consistent with plasmids previously seen in the United States, which suggests that bla(CMY-2) has also been disseminated through plasmid transfer. The fact that two of the domestically acquired United Kingdom isolates presented previously unseen RFLP plasmid patterns could indicate that these strains have followed routes different from those prevalent in North America or other parts of the world. This study represents the first report of bla(CMY) genes in Salmonella isolates in the United Kingdom and the first report of CMY-4 in Salmonella enterica serotype Senftenberg worldwide.


Risk of stillbirth from medications, illnesses and medical procedures.
Associations between stillbirth and 14 medical exposures during pregnancy were examined using deliveries in 1984 in 10 California counties. Cases (n = 332) were stillbirths and infant deaths within 24 h of birth. Randomly selected live births served as controls (n = 357) and were frequency matched by maternal age and county. Using questionnaire and vital statistics data, logistic regression and proportional hazards modelling were performed with adjustment for potential confounders. The most prevalent exposures were ultrasound (65% of cases, 58% of controls) and acetaminophen (45% of cases, 54% of controls). Prescription pain medication, when taken in the first 2 gestational months, was strongly associated with stillbirths due to congenital anomalies (odds ratio = 7.5, 95% confidence interval [CI] 2.3, 24.1). First and second trimester use of prescription pain or migraine medication was positively associated with all stillbirths (rate ratio [RR] range 1.3-1.6). Fertility drugs were positively associated with stillbirths in total and stillbirths due to complications of the placenta, cord and membranes (RR = 1.8, 95% CI 0.8, 4.1; and RR = 2.5, 95% CI 0.9, 7.2 respectively). No associations were found for aspirin, amniocentesis, diagnostic X-rays or fever, consistent with previous studies. This report is among the few studies of specific causes of stillbirth and medical exposures by gestational time window.


Metabolism of 1,25-dihydroxyvitamin D3.
Synthesis of 1,25(OH)2D3 is controlled by numerous factors. The major ones, however, are the circulating amounts of parathyroid hormone (the secretion of which is stimulated by low serum calcium), serum or extracellular fluid phosphorus concentrations, circulating levels of 1,25(OH)2D3 itself, and perhaps serum calcium directly. Many of the other factors noted have effects in vitro only or effects that are observed inconsistently or in one species only. Thus, in low-calcium states, 1,25(OH)2D3 synthesis increases because of increased parathyroid hormone activity. Parathyroid hormone may stimulate 1,25(OH)2D3 synthesis directly or via alterations (a decrease) in serum phosphorus or both. Low serum phosphorus will stimulate 1,25(OH)2D3 synthesis independent of parathyroid hormone levels. Low serum calcium may directly stimulate 25(OH)D3 1 alpha-hydroxylase activity independently of parathyroid hormone. In general terms the vitamin D-endocrine system tends to correct abnormalities in calcium and phosphorus homeostasis. The further metabolism of 1,25(OH)2D3 to other metabolites appears to be mainly a degradative or excretory process. Currently there is no evidence that 1,25(OH)2D3 must itself be altered to other metabolites prior to inducing intestinal calcium transport or bone mobilization. The processes involved in the excretion of 1,25(OH)2D3, such as side-chain oxidation and biliary excretion, are not regulated by serum calcium, phosphorus, or 1,25(OH)2D3 levels. The biliary excretion pathway is also unsaturable over a very wide range and not regulated by calcium, phosphorus, or vitamin D3. Therefore these processes, which account for a large part of the metabolism of 1,25(OH)2D3, are largely unregulated by factors that control the synthesis of 1,25(OH)2D3 and regulate the formation of other calcium-controlling hormones. Other processes involved in the metabolism of 1,25(OH)2D3, such as 24-hydroxylation and 26-hydroxylation, occur in normocalcemic and normophosphatemic states. 24-Hydroxylation is also induced by 1,25(OH)2D3, which benefits the organism, because excessive 1,25(OH)2D3 in various tissues can be altered to a less active metabolite, 1,24,25(OH)3D3. Although there is still no evidence concerning the regulation of C-24 oxidation by dietary calcium and phosphorus levels, the fact that this process is induced by 1,25(OH)2D3 suggests that the metabolic pathway functions in much the same manner as the 24-hydroxylation pathway. The formation of 1,25(OH)2D3-26,23-lactone occurs in normocalcemic states and in situations in which 1,25(OH)2D3 has been administered.


Early detection of immunization: a study based on an animal model using 1H nuclear magnetic resonance spectroscopy.
Vaccines require a period of at least three months for clinical trials, hence a method that can identify elicitation of immune response a few days after the first dose is a necessity. Evolutionary variable selections are modeling approaches for proper manipulation of available data which were used to set up an animal model for classification of time dependent 1HNMR metabolomic profiles and pattern recognition of fluctuations of metabolites in two groups of male rabbits. One group of rabbits was immunized with human red blood cells and the other used as control. Blood was obtained every 48 h from each rabbit for a period of six weeks and the serum monitored for antibodies and metabolites by 1HNMR spectra. Evaluation of data was carried out using orthogonal signal correction followed by principal component analysis and partial least square. A neural network was also set up to predict immunization profiles. A distinct separation in patterns of significant metabolites was obtained between the two groups, just a few days after the first and the second dose. These metabolites were used as targets of neural networks where each sample was used as test, validation and training and their quantitative influence predicted by regression. This model could be used for prediction of immunization in rabbits a few days after the first dose with 96% accuracy. Similar animals and human vaccine trials would assist greatly in reaching early conclusions in advance of the usual two month immunization schedule; resulting in an appreciable saving of cost and time.


The ethanol extracts of sporoderm-broken spores of Ganoderma lucidum inhibit colorectal cancer in vitro and in vivo.
The medicinal mushroom Ganoderma lucidum (G. lucidum) has been reported to possess a variety of pharmacological activities including anticancer effects. However, the anti-colorectal cancer effects and the potential molecular mechanisms of the ethanol extracts of sporoderm-broken spores of G. lucidum (BSGLEE), which mainly contains triterpenoids, have not been reported. The aim of the present study was to investigate the anticancer effects and molecular mechanisms exerted by BSGLEE on colorectal cancer in vitro and in vivo. MTT assay revealed that BSGLEE at 1.6 to 10 mg/ml significantly inhibited HCT116 cell proliferation in a dose- and time-dependent manner. Flow cytometric analysis demonstrated that BSGLEE induces apoptosis and cell cycle arrest at G0/G1 phase, which are associated with deregulation of the expression of key genes and proteins (p21, p16, cyclin D1, Bcl-2, bax, NAG-1, PARP and caspase-3) that regulate apoptosis and cell cycle cascades. Moreover, BSGLEE significantly inhibited HCT116 cell migration via downregulating MMP-1, MMP-2 and upregulating E-cadherin expression at mRNA levels. Oral gavage of 75 and 150 mg/kg BSGLEE significantly inhibited HCT116 xenograft tumor growth in nude mice, which was accompanied by suppressed Ki-67 staining as determined by immunochemistry. Collectively, we found that BSGLEE effectively inhibits colorectal cancer carcinogenesis through induction of apoptosis, inhibition of migration and promotion of cell cycle arrest. Our results suggest that triterpenoids of sporoderm-broken spores of G. lucidum ethanol extracts may serve as a promising anticancer agent for colorectal cancer chemoprevention and therapy.


Diagnostic approach to acute diarrheal illness in a military population on training exercises in Thailand, a region of campylobacter hyperendemicity.
High rates of Campylobacter fluoroquinolone resistance highlight the need to evaluate diagnostic strategies that can be used to assist with clinical management. Diagnostic tests were evaluated with U.S. soldiers presenting with acute diarrhea during deployment in Thailand. The results of bedside and field laboratory diagnostic tests were compared to stool microbiology findings for 182 enrolled patients. Campylobacter jejuni was isolated from 62% of the cases. Clinical and laboratory findings at the time of presentation were evaluated to determine their impact on the posttest probability, defined as the likelihood of a diagnosis of Campylobacter infection. Clinical findings, the results of tests for inflammation (stool occult blood testing [Hemoccult], fecal leukocytes, fecal lactoferrin, plasma C-reactive protein), and the numbers of Campylobacter-specific antibody-secreting cells in peripheral blood failed to increase the posttest probability above 90% in this setting of Campylobacter hyperendemicity when these findings were present. Positive results by a Campylobacter-specific commercial enzyme immunoassay (EIA) and, less so, a research PCR were strong positive predictors. The negative predictive value for ruling out Campylobacter infection, defined as a posttest probability of less than 10%, was similarly observed with these Campylobacter-specific stool-based tests as well the fecal leukocyte test. Compared to the other tests evaluated, the Campylobacter EIA is a sensitive and specific rapid diagnostic test that may assist with diagnostic evaluation, with consideration of the epidemiological setting, logistics, and cost.


Proton-associated sucrose transport of mammalian solute carrier family 45: an analysis in Saccharomyces cerevisiae.
The members of the solute carrier 45 (SLC45) family have been implicated in the regulation of glucose homoeostasis in the brain (SLC45A1), with skin and hair pigmentation (SLC45A2), and with prostate cancer and myelination (SLC45A3). However, apart from SLC45A1, a proton-associated glucose transporter, the function of these proteins is still largely unknown, although sequence similarities to plant sucrose transporters mark them as a putative sucrose transporter family. Heterologous expression of the three members SLC45A2, SLC45A3 and SLC45A4 in Saccharomyces cerevisiae confirmed that they are indeed sucrose transporters. [(14)C]Sucrose-uptake measurements revealed intermediate transport affinities with Km values of approximately 5 mM. Transport activities were best under slightly acidic conditions and were inhibited by the protonophore carbonyl cyanide m-chlorophenylhydrazone, demonstrating an H(+)-coupled transport mechanism. Na(+), on the other hand, had no effect on sucrose transport. Competitive inhibition assays indicated a possible transport also of glucose and fructose. Real-time PCR of mouse tissues confirmed mRNA expression of SLC45A2 in eyes and skin and of SLC45A3 primarily in the prostate, but also in other tissues, whereas SLC45A4 showed a predominantly ubiquitous expression. Altogether the results provide new insights into the physiological significance of SLC45 family members and challenge existing concepts of mammalian sugar transport, as they (i) transport a disaccharide, and (ii) perform secondary active transport in a proton-dependent manner.


Fluorescence and solution NMR study of the active site of a 160-kDa group II intron ribozyme.
We have reconstructed the group II intron from Pylaiella littoralis (PL) into a hydrolytic ribozyme, comprising domains 1-3 (D123) connected in cis plus domain 5 (D5) supplied in trans that efficiently cleaves spliced exon substrates. Using a novel gel-based fluorescence assay and nuclear magnetic resonance (NMR) spectroscopy, we monitored the direct binding of D5 to D123, characterized the kinetics of the spliced exon hydrolysis reaction (which is mechanistically analogous to the reverse of the second catalytic step of splicing), and identified the binding surface of D123 on D5. This PL ribozyme acts as an RNA endonuclease even at low monovalent (100 mM KCl) and divalent ion concentrations (1-10 mM MgCl(2)). This is in contrast to other group II intron ribozyme systems that require high levels of salt, making NMR analysis problematic. D5 binds tightly to D123 with a K(d) of 650 +/- 250 nM, a K(m) of approximately 300 nM, and a K(cat) of 0.02 min(-1) under single turnover conditions. Within the approximately 160-kDa D123-D5 binary complex, site-specific binding to D123 leads to dramatic chemical shift perturbation of residues localized to the tetraloop and internal bulge within D5, suggesting a structural switch model for D5-assisted splicing. This minimal ribozyme thus recapitulates the essential features of the reverse of the second catalytic step and represents a well-behaved system for ongoing high-resolution structural work to complement folding and catalytic functional studies.


A Qualitative Exploration of ACPE Standard 4 Key Elements From the Perspective of Student Pharmacists.
Attitudes and skills reflecting the Accreditation Council for Pharmacy Education Standard 4 (ACPE-S4) remain an important component of pharmacy education. The objectives of this study were (1) explore student perspectives on the importance of ACPE-S4 key elements, and (2) identify experiences that students described as supporting ACPE-S4 attitude and skill development. This was a qualitative study using focus groups and dyadic interviews with student pharmacists to collect data on ACPE-S4 key element importance and skill acquisition. A general inductive qualitative approach was used to analyze data, with 2 study authors independently reviewing all transcripts and assigning codes to text segments. Authors then met to discuss coding, iteratively organize coded segments into categories and subcategories, and select representative quotes. Overall, 3 focus groups and 3 dyadic interviews were conducted with a total of 20 students. Students ranked professionalism and self-awareness as the 2 most important key elements. From qualitative analysis, 4 categories and 10 subcategories of educational activities, programs, and experiences were identified as follows: Mentorship (Identifying a Mentor, Formal Mentorship Programs), Curriculum (Practice Lab, Professional Development Course, Interprofessional Education, Experiential Education), Cocurriculum (Organizational Involvement, Volunteer Hours), and Opportunities Outside Academic Setting (Work, Conferences, and Innovative Pharmacy Practices). Participants articulated several opportunities for developing the skills and attitudes reflecting ACPE-S4 key elements. Incorporating student input into ACPE-S4 attitude and skill development may help pharmacy programs consider how to design, refine, and implement initiatives and experiences to help students develop skills across ACPE-S4 focus areas.


Implementing the donor-acceptor approach in electronically conducting copolymers via electropolymerization.
Electropolymerization has become a convenient method for synthesizing and characterizing complex organic copolymers having intrinsic electronic conductivity, including the donor (D)-acceptor (A) class of electronically conducting polymers (ECPs). This review begins with an introduction to the electrosynthesis of common second-generation ECPs. The information obtainable from electroanalytical studies, charge carriers such as polarons (positive and negative) and bipolarons (positive and negative) and doping will be discussed. The evolutionary chain of ECPs is then presented. ECPs comprising electron-rich D and electron-deficient A moieties have been shown to possess intrinsic electronic conductivity and unique optical and electronic properties. They are third generation ECPs and electropolymerization of mixtures of D and A leads to stoichiometrically controlled block copolymers. These D-A type ECPs are discussed on the basis of selected representative materials. Since the discovery of electropolymerization as a powerful tool to synthesize copolymers of conjugated monomers with a pre-determined ratio of D and A repeat units present in the polymer, the field of D-A type ECPs has grown considerably and the literature available since 2004 to 2021 is summarized and tabulated. Electronic and optical properties of the materials determined by computational chemistry are presented. The data obtained from electrochemical and optical methods are compared with those obtained from computational methods and reasons for discrepancies are given. The literature on the concept of electropolymerization extended to synthesizing triblock and many-block copolymers is reviewed. Finally, applications of D-A polymers in optoelectronic devices (organic solar cells and field-effect transistors) and in bio-imaging are explained quoting appropriate examples.


Approach for Non-Intrusive Detection of the Fit of Orthopaedic Devices Based on Vibrational Data.
The soft tissues of residual limb amputees are subject to large volume fluctuations over the course of a day. Volume fluctuations in residual limbs can lead to local pressure marks, causing discomfort, pain and rejection of prostheses. Existing methods for measuring interface stress encounter several limitations. A major problem is that the measurement instrumentation is applied in the sensitive interface between the prosthesis and residual limb. This paper presents the principle investigation of a non-intrusive technique to evaluate the fit of orthopaedic prosthesis sockets in transfemoral amputees based on experimentally obtained vibrational data. The proposed approach is based on changes in the dynamical behaviour detectable at the outer surface of prostheses; thus, the described interface is not affected. Based on the experimental investigations shown and the derived results, it can be concluded that structural dynamic measurements are a promising non-intrusive technique to evaluate the fit of orthopaedic prosthesis sockets in transfemoral amputee patients. The obtained resonance frequency changes of 2% are a good indicator of successful applicabilityas these changes can be detected without the need for complex measurement devices.


Plasma cell myeloma diagnosed in pregnancy.
Plasma cell myeloma (PCM) is an essentially incurable neoplastic disorder of terminally differentiated B cells. The neoplastic clone usually secretes a monoclonal protein in the serum or urine (the 'M band'). About 20% of PCM secrete light chains only, which are detectable in the urine as Bence Jones protein. The clinical picture is one of bone marrow failure, due to infiltration of the marrow by malignant plasma cells; renal failure due to damage to renal tubules by the excess light chains and pain due to lytic lesions of the bones. The outcome remains poor with median survival of 5 years.


Consensus report on the future of animal-free systemic toxicity testing.
Since March 2013, animal use for cosmetics testing for the European market has been banned. This requires a renewed view on risk assessment in this field. However, in other fields as well, traditional animal experimentation does not always satisfy requirements in safety testing, as the need for human-relevant information is ever increasing. A general strategy for animal-free test approaches was outlined by the US National Research Council`s vision document for Toxicity Testing in the 21st Century in 2007. It is now possible to provide a more defined roadmap on how to implement this vision for the four principal areas of systemic toxicity evaluation: repeat dose organ toxicity, carcinogenicity, reproductive toxicity and allergy induction (skin sensitization), as well as for the evaluation of toxicant metabolism (toxicokinetics) (Fig. 1). CAAT-Europe assembled experts from Europe, America and Asia to design a scientific roadmap for future risk assessment approaches and the outcome was then further discussed and refined in two consensus meetings with over 200 stakeholders. The key recommendations include: focusing on improving existing methods rather than favoring de novo design; combining hazard testing with toxicokinetics predictions; developing integrated test strategies; incorporating new high content endpoints to classical assays; evolving test validation procedures; promoting collaboration and data-sharing of different industrial sectors; integrating new disciplines, such as systems biology and high throughput screening; and involving regulators early on in the test development process. A focus on data quality, combined with increased attention to the scientific background of a test method, will be important drivers. Information from each test system should be mapped along adverse outcome pathways. Finally, quantitative information on all factors and key events will be fed into systems biology models that allow a probabilistic risk assessment with flexible adaptation to exposure scenarios and individual risk factors.


[Comparative study of two methods for laryngeal mask insertion].
To compare two ways of inserting laryngeal airway masks: uninflated and partially inflated to 75% of the volume, as recommended by manufacturers. We studied 60 ASA I-II patients scheduled for outpatient surgery under general anesthesia with numbers 3 or 4 laryngeal masks, after having obtained informed consent from the patients (or parents in the case of minors). The patients were randomly assigned to two groups. In group A the masks were inserted inflated to 75% of volume as recommended by manufacturers, whereas in group B deflated masks were inserted as described by Brain. Anesthesia was standardized for all patients. One patient was withdrawn from the study when a technical error was detected. We recorded the presence of criteria predictive of difficult airway management, systolic and diastolic blood pressures, heart rate at four times (baseline, before and after induction and after insertion of the mask), number of insertion tries, final mask volume needed for adequate ventilation, need for an additional dose of the hypnotic drug and complications. No statistically significant differences between the two insertion methods were found. Difficult airway management criteria were unrelated to difficulty of mask insertion. Correct insertion of an uninflated mask proved impossible in one patient, in whom we were then able to insert an inflated mask. No differences were found between inflated insertion and Brain's uninflated insertion technique. We believe that inflated mask insertion might be useful when uninflated insertion proves impossible.


Chest Imaging in Patients Hospitalized With COVID-19 Infection - A Case Series.
COVID-19 (Corona Virus Disease-19) is a zoonotic illness first reported in the city of Wuhan, China in December 2019, and is now officially a global pandemic as declared by the World Health Organization. The infection is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 infected patients can be asymptomatic carriers or present with mild-to-severe respiratory symptoms. Imaging, including computed tomography is not recommended to screen/diagnose COVID-19 infections, but plays an important role in management of these patients, and to rule out alternative diagnoses or coexistent diseases. In our multicenter case series, we outline the clinical presentations and illustrate the most common imaging manifestations in patients hospitalized with COVID-19.


Peer Counseling: Method, Metaphor, or Mindset?
Peer Counseling and Peer-to-Peer-Counseling are two common counseling formats worldwide where people meet each other at eye level. Rooted in the Independent Living and Self-Help Movement, "classic" Peer Counseling can be considered a professional counseling service offered by and for people with disabilities. In this article, the question is explored whether Peer Counseling is far more reaching than just being labeled as a counseling method. In many countries, it has now found a permanent place in the counseling landscape among others. Furthermore, the question arises whether it does not also serve as a metaphor for a self-determined way of life. In addition, in this study it will be determined whether and why the mindset and attitude are also important in professional Peer Counseling. Since 2018, Peer Counseling has been offered at over 500 counseling centers in Germany as part of the "Ergänzende unabhängige Teilhabeberatung-EUTB®" (Additional Independent Participation Consulting). At a low-threshold and accessible level, advice seekers can find competent individual-centered professional counseling here-often from experts by experience: peers. For many people seeking advice, this is the first and last point of contact for all matters relating to rehabilitation, inclusion and social participation. As part of my PhD-project, I am doing research on Peer Counseling and parallel to this, I train EUTB- and Peer Counselors. Peer Counseling actually is (much more than) a counseling approach which represents a true enrichment for everyone.


Cellular localization of guidance cues in the establishment of retinotectal topography.
Topographic projections of the nervous system are essential to numerous brain functions. They arise during development as a result of encounters between projecting growth cones and particular target cells. Cellular localization of guidance cues can indicate the sequential processes involved in establishment of such topography. The map formed by retinal ganglion cells on their target nuclei has served widely as a model system to investigate mechanisms underlying the highly precise and stereotypic connectivity of the nervous system. To investigate cellular localization of guidance cues in the developing retinotectal system, a three-compartment chamber was created to delimit areas where cultured embryonic chick retinal ganglion axons and tectal cells encounter one another and guidance behavior could be readily assessed. Whereas explants from nasal retinae extended fibers across their natural target population, fibers from temporal regions of retinae failed to invade areas of growing posterior tectal cells. This preservation of relevant guidance information on living cell populations enabled an evaluation of retinal ganglion cell growth cone behavior after encounter with individual tectal cells. Posterior tectal neurons appeared selectively repulsive for temporal retinal ganglion cell growth cones, causing growth cone collapse and retraction. On the contrary, neuroepithelial cells from all regions of the tectum attenuated retinal ganglion axon extension, without inducing sudden retraction. Nasal growth cones traversed or tracked more often along neuroepithelial cells from their natural target area, potentially indicating a second set of guidance cues possibly localized to posterior glia. Together, these differential interactions suggest that development of retinotectal topography critically depends on cell-specific cues, which are distributed selectively on particular populations of target cells.


Two-Aperture Microfluidic Probes as Flow Dipole: Theory and Applications.
A microfluidic probe (MFP) is a mobile channel-less microfluidic system under which a fluid is injected from an aperture into an open space, hydrodynamically confined by a surrounding fluid, and entirely re-aspirated into a second aperture. Various MFPs have been developed, and have been used for applications ranging from surface patterning of photoresists to local perfusion of organotypic tissue slices. However, the hydrodynamic and mass transfer properties of the flow under the MFP have not been analyzed, and the flow parameters are adjusted empirically. Here, we present an analytical model describing the key transport properties in MFP operation, including the dimensions of the hydrodynamic flow confinement (HFC) area, diffusion broadening, and shear stress as a function of: (i) probe geometry (ii) aspiration-to-injection flow rate ratio (iii) gap between MFP and substrate and (iv) reagent diffusivity. Analytical results and scaling laws were validated against numerical simulations and experimental results from published data. These results will be useful to guide future MFP design and operation, notably to control the MFP "brush stroke" while preserving shear-sensitive cells and tissues.


Resorbable osteosynthetic devices in pediatric traumatology: a prospective series of 24 cases.
Bioresorbable devices are commonly used in traumatology. The biomechanical stability of these materials has improved in the past decade, and they have proven to be biologically non-hazardous, while their main advantage is that their use avoids reintervention for removal of the device. A prospective monocentric study was conducted: 24 patients presenting with a fracture that was amenable to osteosynthesis by small-diameter screws were included. These comprised ten tibial spine fractures, four osteochondritis dissecans of the distal femur, eight fractures of the medial epicondyle of the distal humerus, and two distal tibial apophyseal fractures. One or more screws were used that were made of a copolymer of poly-L-lactide-poly-D-lactide acid and trimethylene carbonate with a diameter of 2.8 mm. All patients were immobilized with a cast. Clinical and radiographic monitoring was conducted every month. The entire follow-up protocol had a duration of 24 months. One patient with osteochondritis dissecans presented with joint effusion. Joint stiffness at the time of cast removal resolved completely after 4 months, except for with three children (one epicondyle fracture, two tibial spine fractures). No subjective or objective instability could be detected by clinical examination. Radiographic follow-up revealed no secondary displacement, and all of the fractures had healed. No osteolysis was seen around the screws. No growth disturbances were noticed. Bioresorbable materials thus appear to be a suitable alternative approach for certain pediatric fractures. Their use resulted in outcomes similar to traditional techniques in terms of functional properties and bone healing. Although initial costs are presumably slightly higher, by avoiding a removal operation the total financial burden is most likely reduced. III.


Subcellular localization of the retinoblastoma protein.
The subcellular localization of the retinoblastoma (RB) protein has been studied in primate cell lines by immunofluorescence staining using different monoclonal and polyclonal antibodies. The protein appeared as granules of heterogeneous size over the interphase nuclei. Computer assisted digital overlap analysis indicated that it was predominantly localized in euchromatic areas with low DNA density. The largest RB positive grains lined up on the heterochromatin/euchromatin boundary. During mitosis, the RB protein dissociated from the condensing chromosomes. It was dispersed throughout the cytoplasm during metaphase and anaphase, and it reassociated with the decondensing chromatin during telophase. A new monoclonal antibody, designated aRB1C1, was raised against a bacterial TrpE/human retinoblastoma protein. It specifically recognized the nonphosphorylated and differentially phosphorylated forms of the RB protein in immunoprecipitation experiments. A collection of RB expressing cell lines gave a positive staining reaction with the antibody, whereas the RB negative Weri-RB-27 retinoblastoma and OHS osteosarcoma cells failed to react. Wild-type RB complementary DNA was introduced into Weri-RB-27 by retrovirus mediated gene transfer. Similar experiments were performed with the DU145 prostatic carcinoma cell line that expresses a mutant RB protein. Reconstituted cells of both lines expressed the normal size RB protein and gave a positive immunofluorescence reaction with the aRB1C1 and other anti-RB antibodies. The new monoclonal antibody, however, showed cell type dependent differences of the staining pattern compared to other anti-RB antibodies, suggesting differentiation dependent accessibility to its epitope.


Metabolic Syndrome and Risk of Ischemic Stroke in Atrial Fibrillation: ARIC Study.
Background and Purpose- Metabolic syndrome (MetS), a prothrombotic state, is associated with an increased risk of atrial fibrillation (AF) and stroke. The CHA2DS2-VASc score does not account for the MetS components of prehypertension, prediabetes mellitus, abdominal obesity, elevated triglycerides, and low HDL (high-density lipoprotein). Data are limited on the association of MetS with stroke in AF, independent of CHA2DS2-VASc variables. Our aim was to identify MetS components associated with ischemic stroke in participants with AF in the ARIC study (Atherosclerosis Risk in Communities). Methods- We included 1172 participants with incident AF within 5 years of measurement of MetS components. MetS was defined by ATP criteria and International Diabetes Federation criteria. Incident ischemic stroke was physician adjudicated. Multivariable Cox proportional hazards regression was used to assess the association of MetS components with stroke. Results- After a median follow-up of 14.8 years, there were 113 ischemic stroke cases. Of the individual MetS components, low HDL was borderline associated with increased stroke risk (hazard ratio, 1.48 [95% CI, 0.99-2.21]) after adjustment for CHA2DS2-VASc variables while the remaining MetS variables were not associated with stroke risk. The presence of ≥3 components of MetS was not significantly associated with ischemic stroke after adjustment for CHA2DS2-VASc variables (hazard ratio, 1.38 [95% CI, 0.91-2.11]). The risk of stroke increased by 13% for each additional component of MetS; however, this association was borderline significant (hazard ratio, 1.13 [95% CI, 0.99-1.28]). Conclusions- The presence of MetS was not significantly associated with ischemic stroke after adjustment for CHA2DS2-VASc variables. Consideration of MetS is unlikely to improve stroke prediction in AF.


Impact of loss of NF-κB1, NF-κB2 or c-REL on SLE-like autoimmune disease and lymphadenopathy in Fas(lpr/lpr) mutant mice.
Defects in apoptosis can cause autoimmune disease. Loss-of-function mutations in the 'death receptor' FAS impair the deletion of autoreactive lymphocytes in the periphery, leading to progressive lymphadenopathy and systemic lupus erythematosus-like autoimmune disease in mice (Fas(lpr/lpr) (mice homozygous for the lymphoproliferation inducing spontaneous mutation)) and humans. The REL/nuclear factor-κB (NF-κB) transcription factors regulate a broad range of immune effector functions and are also implicated in various autoimmune diseases. We generated compound mutant mice to investigate the individual functions of the NF-κB family members NF-κB1, NF-κB2 and c-REL in the various autoimmune pathologies of Fas(lpr/lpr) mutant mice. We show that loss of each of these transcription factors resulted in amelioration of many classical features of autoimmune disease, including hypergammaglobulinaemia, anti-nuclear autoantibodies and autoantibodies against tissue-specific antigens. Remarkably, only c-REL deficiency substantially reduced immune complex-mediated glomerulonephritis and extended the lifespan of Fas(lpr/lpr) mice. Interestingly, compared with the Fas(lpr/lpr) animals, Fas(lpr/lpr)nfkb2(-/-) mice presented with a dramatic acceleration and augmentation of lymphadenopathy that was accompanied by severe lung pathology due to extensive lymphocytic infiltration. The Fas(lpr/lpr)nfkb1(-/-) mice exhibited the combined pathologies caused by defects in FAS-mediated apoptosis and premature ageing due to loss of NF-κB1. These findings demonstrate that different NF-κB family members exert distinct roles in the development of the diverse autoimmune and lymphoproliferative pathologies that arise in Fas(lpr/lpr) mice, and suggest that pharmacological targeting of c-REL should be considered as a strategy for therapeutic intervention in autoimmune diseases.


Pathogenesis of Chandler's syndrome, essential iris atrophy and the Cogan-Reese syndrome. I. Alterations of the corneal endothelium.
Eight keratoplasty and 14 trabeculectomy specimens from Chandler's syndrome, Essential Iris Atrophy, and the Cogan-Reese syndrome were studied by electron microscopic and morphometric methods. The corneal endothelium in these conditions undergoes the most varied and complex alterations of any of the endotheliopathies so far studied. The size, shape, and density are altered, and the apical surface shows a myriad of abnormalities including alterations of the intercellular borders and junctions, and formation of numerous microvilli, filopodia, and "blebs." Whereas many cells have features indicative of metabolic activity, and others may have undergone division, still others appear to have been injured as they are disrupted and necrotic. There is also evidence for the presence of a low-grade, long-standing chronic inflammation and an associated loss of contact inhibition with formation of multiple endothelial layers. These changes do not encompass the entire endothelium, as some regions remain relatively unaffected, and each specimen presents a unique morphology. The endothelium is most affected in cases of Essential Iris Atrophy. Some changes may be related to such processes as cell migration and reparative activities. However, the presence of cell necrosis (apoptosis) and chronic inflammation (endotheliitis) may be more specifically related to the ICE syndrome endotheliopathy. The slit lamp and specular microscopy findings characteristic of this disease are correlated with the described histologic abnormalities.


Initial Phase NT-proBNP, but Not Copeptin and High-Sensitivity Cardiac Troponin-T Yielded Diagnostic and Prognostic Information in Addition to Clinical Assessment of Out-of-Hospital Cardiac Arrest Patients With Documented Ventricular Fibrillation.
Sudden cardiac arrest (SCA) secondary to ventricular fibrillation (VF) may be due to different cardiac conditions. We investigated whether copeptin, hs-cTnT and NT-proBNP in addition to clinical assessment may help to identify the etiology of SCA and yield prognostic information. EDTA-blood was collected prior to or at hospital admission from patients with SCA of assumed cardiac origin. Clinical data were obtained from hospital records. VF was the primary heart rhythm in 77 patients who initially were divided into 2 groups based on whether they had an ischemic or non-ischemic mechanism as the most likely cause of SCA. They were further divided into 4 groups according to whether or not they had a history of previous heart disease. The patients were categorized by baseline clinical information, ECG, echocardiography and coronary angiography; Group 1 (n = 43): SCA with first AMI, Group 2 (n = 10): SCA with AMI and previous MI, Group 3 (n = 3): SCA without AMI and without former heart disease, Group 4 (n = 18): SCA without AMI and with known heart disease. Copeptin and hs-cTNT did not differ between patient groups, whereas NT-proBNP was significantly higher in patients with established heart disease without AMI and differed between non-AMI and AMI. Furthermore, NT-proBNP was significantly elevated in non-survivors as compared to survivors. NT-proBNP provided both diagnostic and prognostic information in blood samples collected close to out-of-hospital resuscitation of VF patients, whereas copeptin and hs-cTnT failed to do so. ClinicalTrials.gov, NCT02886273.


Damages for pain and suffering in tort law.
Legislation enacted between 2002 and 2005 by each Australian State and Territory reformed and partially codified the common law of personal injuries. This column examines the nature and history of damages for pain and suffering and analyses the approach taken by different Australian jurisdictions to compensation for non-economic loss. Non-economic loss is generally composed of pain and suffering, loss of amenities of life, and loss of enjoyment of life (some jurisdictions, eg New South Wales, also include disfigurement, and loss of expectation of life). Several jurisdictions have imposed thresholds that a claimant must meet as a prerequisite to suing for damages at common law.


The Effect of Polyphenols on Hypercholesterolemia through Inhibiting the Transport and Expression of Niemann-Pick C1-Like 1.
The Niemann-Pick C1-like 1 (NPC1L1) protein is a cholesterol transporter that is expressed in the small intestine. This report describes the discovery of NPC1L1, its transport properties, and the inhibitory effects of polyphenols on NPC1L1. NPC1L1 was identified in 2004 while searching for ezetimibe molecular targets. Excessive synthesis of cholesterol results in hyperlipidemia, which increases the amount of bile cholesterol excreted into the duodenum. The inhibition of NPC1L1 decreases blood cholesterol because food and bile cholesterol are also absorbed from NPC1L1 in the intestine. Some polyphenols, particularly luteolin, have been reported as NPC1L1-mediated anti-dyslipidemia constituents. Luteolin affects NPC1L1 through two mechanisms. Luteolin directly inhibits NPC1L1 by binding to it, which occurs in a short timeframe similar to that for ezetimibe. The other mechanism is the inhibition of NPC1L1 expression. Luteolin reduced the binding of Sterol-regulatory element-binding protein 2 (SREBP2) in the promoter region of the NPC1L1 gene and decreased mRNA levels of SREBP2 and hepatocyte nuclear factor 4α. These data suggest that luteolin decreases the expression of NPC1L1 through regulation of transcription factors. This review also explores the effect of other polyphenols on NPC1L1 and hypercholesterolemia.


[Sex differences in angina pectoris; a literature study].
To gain insight into differences in frequency, presentation and course of angina pectoris between males and females. Literature study. Department of General Practice, Social Medicine and Nursing Home Medicine, University of Nijmegen, the Netherlands. Articles were selected by automatized search systems (Nederlands Tijdschrift voor Geneeskunde, Huisarts en Wetenschap, Medline, FAMLI), with use of search terms, following which the relevance of the articles was assessed on the basis of title and abstract. Use was also made of publications on four major Dutch registration systems of general practices. The four articles on incidence and prevalence showed that angina pectoris occurs as often in males as in females. However, females on average were 10 years older at onset. In females, angina pectoris was more frequently the first manifestation of cardiovascular disease, as against myocardial infarction in males. No articles on research into the sex differences in presentation of angina pectoris were found. The course of angina pectoris (five articles) were more favourable in females: they less often developed myocardial infarction and the mortality rates after 5 and after 9 years were lower. There were no differences between males and females in the frequency of angina pectoris, but in females the prognosis is better.


The role of hepatic lipid composition in obesity-related metabolic disease.
Obesity is a primary antecedent to non-alcoholic fatty liver disease whose cardinal feature is excessive hepatic lipid accumulation. Although total hepatic lipid content closely associates with hepatic and systemic metabolic dysfunction, accumulating evidence suggests that the composition of hepatic lipids may be more discriminatory. This review summarises cross-sectional human studies using liver biopsy/lipidomics and proton magnetic resonance spectroscopy to characterise hepatic lipid composition in people with obesity and related metabolic disease. A comprehensive literature search identified 26 relevant studies published up to 31st March 2021 which were included in the review. The available evidence provides a consistent picture showing that people with hepatic steatosis possess elevated saturated and/or monounsaturated hepatic lipids and a reduced proportion of polyunsaturated hepatic lipids. This altered hepatic lipid profile associates more directly with metabolic derangements, such as insulin resistance, and may be exacerbated in non-alcoholic steatohepatitis. Further evidence from lipidomic studies suggests that these deleterious changes may be related to defects in lipid desaturation and elongation, and an augmentation of the de novo lipogenic pathway. These observations are consistent with mechanistic studies implicating saturated fatty acids and associated bioactive lipid intermediates (ceramides, lysophosphatidylcholines and diacylglycerol) in the development of hepatic lipotoxicity and wider metabolic dysfunction, whilst monounsaturated fatty acids and polyunsaturated fatty acids may exhibit a protective role. Future studies are needed to prospectively determine the relevance of hepatic lipid composition for hepatic and non-hepatic morbidity and mortality; and to further evaluate the impact of therapeutic interventions such as pharmacotherapy and lifestyle interventions.


Using the Internet to find offline sex partners.
We aimed to expand upon the demographic characteristics and gender differences among those who have met someone on the Internet who they later met offline and had sex with as well as any relationship with cybersex, sexually transmitted infections, and online sexual problems. We analyzed data collected through an online questionnaire in 2002 in Sweden including a total population of 1836 respondents of which 1458 used the Internet for sexual purposes. Of those, 35% men and 40% women reported to have met offline sex partners online. The majority reported an occurrence of one to two times, whereas 10% reported six or more times. The analysis suggested women aged 34-49 and 50-65 years, homo- and bisexual men, and singles more likely to have this experience. They were also more likely to have engaged in cybersex. No relationships were found with sexually transmitted infections or online sexual problems. The results suggest that using the Internet to find sex partners may be less hazardous for the general Internet users than pointed out by prior research about this behavior often focusing on specific sub groups of Internet users.


Plasma hepcidin is associated with future risk of venous thromboembolism.
Red cell distribution width (RDW) is associated with venous thromboembolism (VTE), but the underlying mechanism(s) is unclear. Iron deficiency is associated with high RDW, and studies suggest an association between iron deficiency and VTE. To assess whether iron deficiency is a risk factor for VTE that explains the association between RDW and VTE, we conducted a nested case-control study of 390 patients with VTE and 802 age- and sex-matched controls selected from the population-based cohort of the Tromsø Study. Physical measurements and blood samples were collected from 1994 to 1995. Logistic regression models were used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) for VTE by RDW, hepcidin, and ferritin light chain (FtL). RDW was inversely associated with hepcidin, FtL, and hemoglobin. The risk of VTE increased linearly across categories of higher plasma hepcidin levels. Participants with hepcidin in the highest quartile had an OR for VTE of 1.32 (95% CI, 1.00-2.42), and those in the >90% percentile had an OR for VTE of 1.66 (95% CI, 1.14-2.42) compared with the reference group (quartiles 2 and 3). The risk estimates remained similar after adjustment for C-reactive protein. The risk of VTE increased by categories of higher RDW and was strengthened after inclusion of hepcidin and FtL in the multivariable model. Our findings reject the hypothesis that iron deficiency explains the association between RDW and VTE and suggest, in contrast, that high body iron levels might increase the risk of VTE.


Sex differences, hormones, and fMRI stress response circuitry deficits in psychoses.
Response to stress is dysregulated in psychosis (PSY). fMRI studies showed hyperactivity in hypothalamus (HYPO), hippocampus (HIPP), amygdala (AMYG), anterior cingulate (ACC), orbital and medial prefrontal (OFC; mPFC) cortices, with some studies reporting sex differences. We predicted abnormal steroid hormone levels in PSY would be associated with sex differences in hyperactivity in HYPO, AMYG, and HIPP, and hypoactivity in PFC and ACC, with more severe deficits in men. We studied 32 PSY cases (50.0% women) and 39 controls (43.6% women) using a novel visual stress challenge while collecting blood. PSY males showed BOLD hyperactivity across all hypothesized regions, including HYPO and ACC by FWE-correction. Females showed hyperactivity in HIPP and AMYG and hypoactivity in OFC and mPFC, the latter FWE-corrected. Interaction of group by sex was significant in mPFC (F = 7.00, p = 0.01), with PSY females exhibiting the lowest activity. Male hyperactivity in HYPO and ACC was significantly associated with hypercortisolemia post-stress challenge, and mPFC with low androgens. Steroid hormones and neural activity were dissociated in PSY women. Findings suggest disruptions in neural circuitry-hormone associations in response to stress are sex-dependent in psychosis, particularly in prefrontal cortex.


Comparison of the Long-Term Outcomes of Mechanical and Bioprosthetic Aortic Valves - A Propensity Score Analysis.
The aim of this study was to assess the long-term outcomes of aortic valve replacement (AVR) with either mechanical or bioprosthetic valves according to age at operation.Methods and Results:A total of 1,002 patients (527 mechanical valves and 475 bioprosthetic valves) undergoing first-time AVR were categorized according to age at operation: group Y, age <60 years; group M, age 60-69 years; and group O, age ≥70 years). Outcomes were compared on propensity score analysis (adjusted for 28 variables). Hazard ratio (HR) was calculated using the Cox regression model with adjustment for propensity score with bioprosthetic valve as a reference (HR=1). There were no significant differences in overall mortality between mechanical and bioprosthetic valves for all age groups. Valve-related mortality was significantly higher for mechanical valves in group O (HR, 2.53; P=0.02). Reoperation rate was significantly lower for mechanical valves in group Y (HR, 0.16; P<0.01) and group M (no events for mechanical valves). Although the rate of thromboembolic events was higher in mechanical valves in group Y (no events for tissue valves) and group M (HR, 9.05; P=0.03), there were no significant differences in bleeding events between all age groups. The type of prosthetic valve used in AVR does not significantly influence overall mortality.


Defunctioning stoma and anastomotic leak rate after total mesorectal excision with coloanal anastomosis in the context of PROCARE.
Anastomotic leakage (AL) after total mesorectal excision is a major adverse event. Construction of a defunctioning stoma (DS) reduces the morbidity of AL. This study aims to illustrate the AL rate and its related morbidity with and without primary stoma formation in the context of a Belgian project, PROCARE. Between January 2006 and March 2011, 1912 patients who underwent elective TME with colo-anal anastomosis for invasive rectal adenocarcinoma up to 15 cm above the anal verge were registered. A primary DS was constructed in 1183 patients (62%). Early clinical AL rate, AL-related re-operation rate, length of stay (LoS), in-hospital mortality were analysed. In patients without leak, mortality was 1.1% and the mean LoS was 14.7 days. AL occurred in 6.5%, varying from 0%-25% between participating centres. In patients with AL, mortality was 4.8% (p < 0.001). In the presence of a primary DS, AL rate was 4.3%, requiring re-operation under narcosis in 78% with no mortality, resulting in a mean LoS of 30.4 days. In the absence of a primary DS, AL rate was 10.2%, requiring re-operation under narcosis in 93% with a mortality of 8.1% and a mean LoS of 33.4 days. Analysis per centre showed a weak relation between percentage of DS construction and AL rate. Construction of a primary DS significantly reduced the incidence of early AL, re-operation rate, and mortality. Although technical aspects of colo-anal anastomosis are of paramount importance, construction of a DS at primary surgery has to be considered by those teams with high early AL rate and/or high AL related mortality.


Current evidence for robotic surgery in radical cystectomy.
Robotic-assisted radical cystectomy (RARC) has been gaining momentum as an alternative to its conventional open radical cystectomy (ORC) for the management of invasive bladder cancer. Although RARC, in general, demonstrated less blood loss and shorter hospital stay than ORC, whether there is any significant difference in the overall complication rate still requires further investigation. Thus, both RARC and ORC share a similar oncology outcome, with comparable positive surgical margin rates, disease-free survival, and overall survival. Techniques of intracorporeal urinary diversion (ICUD) have not yet been standardized. ICUD may result in a lower risk of ureteroileal anastomotic stricture than extracorporeal urinary diversion (ECUD). However, ECUD is still a valid and commonly practiced option according to the available data. In general, RARC has been demonstrated to provide promising results. Long-term data and functional outcome after RARC and ICUD are needed to further validate the role of RARC in the management of bladder cancer.


Survival inequity in vulnerable populations with early-stage hepatocellular carcinoma: a United States safety-net collaborative analysis.
Access to health insurance and curative interventions [surgery/liver-directed-therapy (LDT)] affects survival for early-stage hepatocellular carcinoma (HCC). The aim of this multi-institutional study of high-volume safety-net hospitals (SNHs) and their tertiary-academic-centers (AC) was to identify the impact of type/lack of insurance on survival disparities across hospitals, particularly SNHs whose mission is to minimize insurance related access-to-care barriers for vulnerable populations. Early-stage HCC patients (2012-2014) from the US Safety-Net Collaborative were propensity-score matched by treatment at SNH/AC. Overall survival (OS) was the primary outcome. Multivariable Cox proportional-hazard analysis was performed accounting for sociodemographic/clinical parameters. Among 925 patients, those with no insurance (NI) had decreased curative surgery, compared to those with government insurance (GI) and private insurance [PI, (PI-SNH:60.5% vs. GI-SNH:33.1% vs. NI-SNH:13.6%, p < 0.001)], and decreased median OS (PI-SNH:32.1 vs. GI-SNH:22.8 vs. NI-SNH:9.4 months, p = 0.002). On multivariable regression controlling for sociodemographic/clinical parameters, NI-SNH (HR:2.5, 95% CI:1.3-4.9, p = 0.007) was the only insurance type/hospital system combination with significantly worse OS. NI-SNH patients received less curative treatment than other insurance/hospitals types suggesting that treatment barriers, beyond access-to-care, need to be identified and addressed to achieve survival equity in early-stage HCC for vulnerable populations (NI-SNH).


[Influence of serum IGF-I and testosterone on lipid and glycemic profile in acromegalic men].
To evaluate the influence of IGF-I and testosterone on the lipid profile and glycemia in acromegalic men. Fifteen acromegalic men were studied. The hypogonadic patients presented lower HDL-c and higher tryglicerides, LDL-c, glycemia, GH and IGF-I. Serum IGF-I was inversely correlated with HDL-c (r = - 0.57, p = 0.04) and directly with TG (r = 0.62, p = 0.01) and glycemia (r = 0.66, p = 0.008), whereas serum testosterone correlated directly with HDL-c (r = 0.52, p = 0.05) and inversely with TG (r = - 0.57, p = 0.02), LDL-c (r = - 0.53, p = 0.04) and fasting blood glucose (r = - 0.54, p = 0.03). IGF-I and testosterone were inversely correlated (r = - 0.585, p = 0.028). These results suggest that the most important intervention in reducing cardiovascular risk in these patients is to control the activity of the disease.