Increased cancer risk in patients with cutaneous lupus erythematosus and systemic lupus erythematosus compared with the general population: A Danish nationwide cohort study.
To investigate if patients with cutaneous lupus erythematosus (CLE) or systemic lupus erythematosus (SLE) have an increased risk of cancer compared with the general population, and furthermore to identify specific cancer types associated with increased risk. This is an observational cohort study of 5310 patients with CLE or SLE identified in the Danish National Patient Register from 1 January 1995 to 31 December 2014. The cohort was followed up for cancer by linkage to the Danish Cancer Registry. Based on the age, sex, and calendar specific cancer rates of the general population of Denmark, standardised incidence ratios (SIRs) were calculated. The patients with CLE or SLE were followed for 40.724 person-years, each group's average duration of follow-up being 6.9 and 8.1 years. The SIR for overall cancer (except non-melanoma skin cancer (NMSC)) was increased in patients with CLE 1.35 (95%CI 1.15 to 1.58) and patients with SLE 1.45 (95%CI 1.30 to 1.62). Both groups had high risks of hematological - including a 3-4-fold increased risk of non-Hodgkin lymphoma -, pancreatic, and lung cancers. Several cancers associated with oncogenic viruses as liver and tongue/mouth/pharynx were increased in the SLE group, while the risk of ovarian cancer was increased 2-4-fold only in the CLE group. The overall risk of cancer was significantly increased in both patients with CLE and SLE. SIRs for hematological, pancreatic and lung cancers were elevated in both groups. Extra awareness of cancer in patients with SLE and patients with CLE should be considered.


Treatment of postmenopausal osteoporosis, patient perspectives - focus on once yearly zoledronic acid.
Oral bisphosphonates are of proven efficacy in preventing fractures in postmenopausal osteoporosis. However, poor adherence limits their real-world efficacy and clinical utility. Zoledronic acid (ZOL) is a potent bisphosphonate administered by annual intravenous infusion, effectively ensuring adherence to therapy over the following year. According to available data, 66% to 79% of patients have expressed a preference for ZOL over oral bisphosphonates. This is likely to lead to enhanced clinical outcomes, although long-term (repeat annual) adherence is currently unknown. ZOL is of proven efficacy, with hip fracture reduction of 41% and morphometric vertebral fracture reduction of 70% over 3 years in the HORIZON PFT trial. It has demonstrated a good side-effect profile with postinfusion flu-like symptoms being the most common. Additionally, it has been associated with decreased mortality in patients following surgery for hip fracture. There is no clear association between exposure and the rate of serious or nonserious atrial fibrillation. We review adherence to oral bisphosphonates, and the pharmacokinetics, efficacy, safety, and patient preference for ZOL.


Soybean whole-plant ensiled with chitosan and lactic acid bacteria: Microorganism counts, fermentative profile, and total losses.
Chitosan is a biopolymer derived from chitin deacetylation, present in the exoskeleton of crustaceans and insects. Chitosan has been evaluated as rumen modulator and silage additive due to its antimicrobial properties. The objective of this study was to determine the effects of both chitosan and a bacterial additive on microbiological quality, chemical composition, nutrient in vitro degradation, fermentative profile, and total losses of whole-soybean plant silage (SS) harvested at R6 stage. Four treatments in a factorial arrangement were randomly assigned to 40 experimental minisilos as no additives (CON), 8 g/t fresh forage of microbial inoculant (INO; Kera SIL, Kera Nutrição Animal, Bento Gonçalves, Brazil); 5 g/kg of fresh forage chitosan (CHI); and CHI + INO. Microbial inoculant was composed of Lactobacillus plantarum (4.0 × 1010 cfu/g) and Propionibacterium acidipropionici (2.6 × 1010 cfu/g). The CHI and INO alone increased counts of lactic bacteria and anaerobic bacteria and decreased counts of mold and yeast in SS. The CHI or INO alone increased in vitro degradation of dry matter, crude protein, and neutral detergent fiber, and decreased nonfiber carbohydrate content of SS. Chitosan increased NH3-N and lactate concentrations and decreased ethanol concentration in SS. The CHI increased dry matter recovery from SS; INO increased silage aerobic stability. The combination of CHI+INO showed the lowest value of gas losses. In general, the combination of CHI and INO had small positive effects on gas losses of SS; however, both CHI or INO alone improved nutrient in vitro degradation and decreased mold and yeast in SS. Chitosan or INO utilization improves SS quality.


Evolving methodologies and concepts in 4D nucleome research.
The genome requires tight regulation in space and time to maintain viable cell functions. Advances in our understanding of the 3D genome show a complex hierarchical network of structures, involving compartments, membraneless bodies, topologically associating domains, lamina associated domains, protein- or RNA-mediated loops, enhancer-promoter contacts, and accessible chromatin regions, with chromatin state regulation through epigenetic and transcriptional mechanisms. Further technology developments are poised to increase genomic resolution, dissect single-cell behaviors, including in vivo dynamics of genome folding, and provide mechanistic perspectives that identify further 3D genome players by integrating multiomics information. We highlight recent key developments in 4D nucleome methodologies and give a perspective on their future directions.


Grating superposition method: ultrafast electromagnetic numerical analysis for random structures.
A very efficient numerical tool to electromagnetically analyze random structures is proposed. The principle is treating random structure as superposition of diffraction gratings. Then, influence of each component grating can be computed with any electromagnetic grating theory which is well established for its accuracy and computation speed. This article explains how to treat obtained data in detail. Applied to single-tiered scatteres, the proposed method gives comparable results with a standard way based on FDTD method in far shorter time.


Real-time assay for testing components of protein synthesis.
We present a flexible, real-time-coupled transcription-translation assay that involves the continuous monitoring of fluorescent Emerald GFP formation. Along with numerical simulation of a reaction kinetics model, the assay permits quantitative estimation of the effects on full-length protein synthesis of various additions, subtractions or substitutions to the protein synthesis machinery. Since the assay uses continuous fluorescence monitoring, it is much simpler and more rapid than other assays of protein synthesis and is compatible with high-throughput formats. Straightforward alterations of the assay permit determination of (i) the fraction of ribosomes in a cell-free protein synthesis kit that is active in full-length protein synthesis and (ii) the relative activities in supporting protein synthesis of modified (e.g. mutated, fluorescent-labeled) exogenous components (ribosomes, amino acid-specific tRNAs) that replace the corresponding endogenous components. Ribosomes containing fluorescent-labeled L11 and tRNAs labeled with fluorophores in the D-loop retain substantial activity. In the latter case, the extent of activity loss correlates with a combination of steric bulk and hydrophobicity of the fluorophore.


Calcineurin activity is regulated both by redox compounds and by mutant familial amyotrophic lateral sclerosis-superoxide dismutase.
Calcineurin (CN) is a protein phosphatase involved in a wide range of cellular responses to calcium-mobilizing signals, and a role for this enzyme in neuropathology has been postulated. We have investigated the possibility that redox modulation of CN activity is relevant to neuropathological conditions where an imbalance in reactive oxygen species has been described. We have monitored CN activity in cultured human neuroblastoma SH-SY5Y cells and obtained evidence that CN activity is promoted by treatment with ascorbate or dithiothreitol and impaired by oxidative stress. Evidence for the existence of a redox regulation of this enzyme has been also obtained by overexpression of wild-type antioxidant Cu,Zn superoxide dismutase (SOD1) that promotes CN activity and protects it from oxidative inactivation. On the contrary, overexpression of mutant SOD1s associated with familial amyotrophic lateral sclerosis (FALS) impairs CN activity both in transfected human neuroblastoma cell lines and in the motor cortex of brain from FALS-transgenic mice. These data suggest that CN might be a target in the pathogenesis of SOD1-linked FALS.


Clinical profile of delirium in patients treated for femoral neck fractures.
The incidence of delirium, its predisposing factors, clinical profile, associated symptoms and consequences were investigated in 54 consecutive patients, 19 men and 35 women, mean age 77.1 years, admitted to an 'ortho-geriatric unit' with femoral neck fractures. The incidence of postoperative delirium was 15/54 (27.8%) and a logistic regression model found that dementia and a prolonged waiting time for the operation increased the risk of postoperative delirium. Delirium during the night was most common but in 5 patients the delirium was worst in the morning. Patients with delirium suffered more anxiety, depressed mood, emotionalism, delusions and hallucinations. A larger proportion of patients with delirium could not return to their previous dwelling, and a larger proportion of delirious patients were either dead, wheelchair-bound or bedridden at the 6-month follow-up (p < 0.005). The conclusion is that delirium is common and has a serious impact on the outcome after hip fracture surgery.


Seroprevalence of Bovine Brucellosis and Associated Risk Factors in Western Ethiopia.
Brucellosis is a contagious bacterial disease, which affects domestic animals, humans, and wildlife in Ethiopia and other countries. A cross-sectional study design using a simple random sampling technique was conducted in Diga, Guto, Gida, and Sibu Sire districts of East Wollega Zone, Western Oromia, from November 2019 to July 2020 to determine the prevalence of bovine brucellosis and identify associated risk factors. A lottery method was used during serum collection and risk factors identified during interview. A total of 1152 serum samples were collected from cattle of 6 months age and above. Serum samples were tested by enzyme linked immunosorbent assay (I-ELISA). An overall seroprevalence of brucellosis was 1.82% (21/1152). Statically significant variation (P<0.05) in seroprevalence of bovine brucellosis was recorded among potential risk factors such as breed [P≤0.05; OR:8.905; CI:1.568-50.573], parity [P≤0.05; OR:0.017; CI:0.042-5.195], retained fetal membrane [P≤0.001; OR:0.018; CI:0.00-2.169], and abortion history [P≤0.001; OR:0.030; CI:0.004-0.212]. Conversely, seroprevalence variations in sex, district, villages, body condition score, and age were statistically insignificant (P>0.05). The current study revealed bovine brucellosis is posing a threat to livestock with no strict control and prevention scheme in place. Therefore, public awareness creation about the zoonotic importance of the disease is crucial and the Government should establish legislation, support, control, and prevention of the disease recommended.


Are (the log-odds of) hospital mortality rates normally distributed? Implications for studying variations in outcomes of medical care.
Hierarchical regression models are increasingly being used to examine variations in outcomes following the provision of medical care across providers. These models frequently assume a normal distribution for the provider-specific random effects. The appropriateness of this assumption for examining variations in health care outcomes has never been explicitly tested. To compare hierarchical logistic regression models in which the provider-specific random effects were either a normal distribution or a mixture of three normal distributions. We used data on 18,825 patients admitted to 109 hospitals in Ontario with a diagnosis of acute myocardial infarction. We used the Deviance Information Criterion, Bayes factors and predictive distributions to compare the evidence between the two competing models. There was strong evidence that the distribution of hospital-specific log-odds of mortality was a mixture of three normal distributions compared to the evidence that it was normal. In some scenarios, the hospital-specific posterior tail probabilities of unacceptably high mortality were lower when a logistic-normal model was fit compared to when a logistic-mixture of normal distributions model was fit. Additionally, in these same scenarios, fewer hospitals were classified as having higher than acceptable mortality when the logistic-mixture of three normal distributions was used. These findings have important consequences for those who use hierarchical models to examine variations in outcomes of medical care across providers since the mixture of three normal distributions model indicated that variations in outcomes across providers was greater than indicated by the logistic-normal model.


Immediate and midterm follow-up results of using an electrodetachable, fully retrievable SOLO stent system in the endovascular coil occlusion of wide-necked cerebral aneurysms.
Stent-assisted embolization is an alternative endovascular treatment method for wide-necked intracranial aneurysms. Currently available stents have the limitations of poor radial force, difficult delivery systems, and lack of full retrievability. The authors report on their preliminary experience with the use of a new, fully retrievable, self-expanding neurovascular stent, which has a high radial force and easy delivery system, combined with coil or Onyx embolization for the treatment of wide-necked aneurysms, including 6-month follow-up data. Fifteen patients with 18 wide-necked intracranial aneurysms were treated using the SOLO stent system and detachable platinum coils. Aneurysms were located at the posterior communicating artery (seven lesions), midbasilar artery (one lesion), internal carotid artery (ICA) bifurcation (one lesion), ICA-ophthalmic artery segment (eight lesions), and posterior cerebral artery (one lesion). Eleven aneurysms were small, six were large, and one was giant. Only one of these aneurysms was in the acute stage of subarachnoid hemorrhage; balloon remodeling alone failed to keep the coils in the aneurysm sac. Only one stent required retrieving and repositioning after it had been fully deployed, and retrieval was easy and successful. No thromboembolic complication, dissection/rupture, or vasospasm occured during stent placement. Follow-up angiograms obtained at 6 months posttreatment in the 18 aneurysms demonstrated that all stents were patent with no evidence of intimal hyperplasia or stenosis. In all cases but one, 100% lesion occlusion was observed at the 6-month control angiography examination. Only one aneurysm had recanalized. The fully retrievable self-expandible SOLO stent is a feasible, secure, and effective system with a high radial force and ease of delivery in treating wide-necked intracranial aneurysms in combination with coil embolization.


Management strategy of solitary pulmonary nodules.
Solitary pulmonary nodules (SPNs) are increasingly detected with the widespread use of chest computed tomography (CT) scans. The management of patients with SPN should begin with estimating the probability of cancer from the patient's clinical risk factors and CT characteristics. The decision-making process need to incorporate the probability of cancer, the potential benefits and harms of surgery, the accuracy of the available diagnostic tests and patient preferences. For patients with a very low probability of cancer, careful observation with serial CT is warranted. For patients in the intermediate range of probabilities, either CT-guided fine-needle aspiration biopsy (FNAB) or positron emission tomography (PET), is recommended. For those with a high probability of cancer, surgical diagnosis is warranted.


Arterial Thrombosis in Patients with Antiphospholipid Syndrome: A Review and Meta-Analysis.
There is a scarcity of high-quality randomized controlled trials (RCTs) comparing antithrombotic regimens for secondary prevention of arterial thrombosis (AT) in antiphospholipid syndrome (APS). We reviewed different antithrombotic regimens used for this purpose. We searched for studies on management of AT in APS on PubMed and Web of Science. Eleven studies (5 RCTs, 3 prospective, and 3 retrospective cohort studies) comparing different regimens and reporting outcomes specifically for patients with index AT events were identified. Treatments were vitamin K antagonists (VKA; 9 studies), non-VKA oral anticoagulant (NOAC; 3 studies), single antiplatelet therapy (SAPT; 7 studies), dual antiplatelet therapy (DAPT; 2 studies), and VKA combined with SAPT (4 studies). We performed a meta-analysis for the outcomes: recurrent AT, any (arterial or venous) recurrent thromboembolism, and major bleeding. Recurrent AT was reduced with VKA plus SAPT versus VKA (risk ratio [RR]: 0.43; 95% confidence interval [CI]: 0.22-0.85) and with DAPT versus SAPT (RR: 0.29; 95% CI: 0.09-0.99). Any recurrent thromboembolism was reduced with VKA plus SAPT versus VKA alone (RR: 0.41; 95% CI: 0.24-0.69) and versus SAPT alone (RR: 0.36; 95% CI: 0.13-0.96). There were no significant differences between other treatments for thromboembolism and for none of the comparisons regarding major bleeding. In a sensitivity analysis, excluding low-quality studies, VKA was more effective than NOAC to prevent recurrent AT (RR: 0.25; 95% CI: 0.07-0.93). Combined antithrombotic therapy might be more effective than single agents as secondary prophylaxis in APS with AT, and does not seem to compromise with safety, but the quality of evidence is generally low. NOACs should be avoided for patients with APS and AT.


#ThisIsBrachytherapy: Increasing awareness of brachytherapy.
The use of brachytherapy continues to be a vital application of radiation oncology for various cancers. Despite this, there has been a decrease in the utilization of brachytherapy in many cancers. Social media in medicine facilitates engagement and advocacy. We launched a social media campaign to bring awareness of brachytherapy throughout the world with #ThisIsBrachytherapy hashtag on July 17, 2019. #ThisIsBrachytherapy hashtag was registered with Symplur Healthcare Hashtag Project. We collected total tweet counts, retweet counts, impression counts, geolocation, top 10 influencers, associated hashtags, associated words, and word sentiment score. The campaign launched on July 17, 2019, had a total of 145 tweets on that day with 213,416 impressions. Twenty-seven accounts (45%) were identified as physicians. Top countries which tweeted, among those with information available, included the United States, United Kingdom, and Australia. Since July 17, 2019, there has been an increase in tweets using #ThisIsBrachytherapy, with 1990 total tweets with 1,999,248 impressions. Fifty-four percent (1030) of the tweets contained photos and 319 contained links. This was from 462 unique users. Word sentiment was overwhelmingly positive. Associated hashtags with #ThisIsBrachytherapy included most commonly #radonc, #brachytherapy, #brachy, #prostatecancer, and #pcsm. The #ThisIsBrachytherapy inaugural campaign was successful and has continued to grow throughout the months after the initiation. By continuing to advocate for brachytherapy through the social media campaign #ThisIsBrachytherapy, we can empower radiation oncologists, especially trainees, and patients to address underutilization.


Fractionation and ecotoxicological implication of potentially toxic metals in sediments of three urban rivers and the Lagos Lagoon, Nigeria, West Africa.
The potential environmental impact of sediment-bound Cd, Cr, Cu, Pb and Zn in three trans-urban rivers in Lagos state and in the Lagos Lagoon was assessed by use of the modified Community Bureau of Reference (BCR) sequential extraction. The quality of the data was checked using BCR CRM 143R and BCR CRM 701. Good agreement was obtained between found and certified/indicative values. Of the rivers, the Odo-Iyaalaro, was generally the most contaminated and the Ibeshe the least. Higher concentrations of metals were generally found in the dry season compared to the wet season. Cadmium and Zn were released mostly in the acid exchangeable step of the sequential extraction, indicating that they have the greatest potential mobility and bioavailability of the analytes studied. Chromium and Cu were associated mainly with the reducible and oxidisable fractions, and Pb predominantly with the reducible and residual fractions. Sediments with the highest pseudototal analyte concentrations also released higher proportions of analytes earlier in the sequential extraction procedure. The study suggests that, during the dry season, potentially toxic metals (PTM) may accumulate in sediments in relatively labile forms that are released and can potentially be transported or bioaccumulate in the rainy season. Application of risk assessment codes and Hankanson potential risk indices indicated that Cd was the element of greatest concern in the Lagos Lagoon system. The study indicated that there is a need to strengthen environmental management and pollution control measures to reduce risk from PTM, but that even relatively simple strategies, such as seasonal restrictions on dredging and fishing, could be beneficial.


Quantitative analyses of messenger RNA of human endogenous retrovirus in patients with systemic lupus erythematosus.
Human endogenous retrovirus (HERV) has emerged as a possible causative agent of systemic lupus erythematosus (SLE). To investigate the role of HERV in the etiology of SLE, we performed quantitative analyses of messenger RNA (mRNA) of the HERV clone 4-1 in patients with SLE. Reverse transcriptase (RT)-polymerase chain reaction (PCR) and real-time quantitative PCR (RQ-PCR; TaqMan methodology) were used in this experiment. The quantities of mRNA of the HERV clone 4-1 gag region in patients with SLE were significantly higher than in healthy controls, and the amounts of such mRNA in the patients were decreased by steroid treatment. These phenomena may be related to the production of viral components derived from HERV clone 4-1 and contribute to the pathogenesis of SLE; studies using a larger number of patients are required to confirm these points.


Amygdala-prefrontal cortex functional connectivity during threat-induced anxiety and goal distraction.
Anxiety produced by environmental threats can impair goal-directed processing and is associated with a range of psychiatric disorders, particularly when aversive events occur unpredictably. The prefrontal cortex (PFC) is thought to implement controls that minimize performance disruptions from threat-induced anxiety and goal distraction by modulating activity in regions involved in threat detection, such as the amygdala. The inferior frontal gyrus (IFG), orbitofrontal cortex (OFC), and ventromedial PFC (vmPFC) have been linked to the regulation of anxiety during threat exposure. We developed a paradigm to determine if threat-induced anxiety would enhance functional connectivity between the amygdala and IFG, OFC, and vmPFC. Healthy adults performed a computer-gaming style task involving capturing prey and evading predators to optimize monetary rewards while exposed to the threat of unpredictable shock. Psychophysiological recording (n = 26) and functional magnetic resonance imaging scanning (n = 17) were collected during the task in separate cohorts. Task-specific changes in functional connectivity with the amygdala were examined using psychophysiological interaction analysis. Threat exposure resulted in greater arousal measured by increased skin conductance but did not influence performance (i.e., monetary losses or rewards). Greater functional connectivity between the right amygdala and bilateral IFG, OFC, vmPFC, anterior cingulate cortex, and frontopolar cortex was associated with threat exposure. Exposure to unpredictable threat modulates amygdala-PFC functional connectivity that may help maintain performance when experiencing anxiety induced by threat. Our paradigm is well-suited to explore the neural underpinnings of the anxiety response to unpredictable threat in patients with various anxiety disorders.


Combining ReaxFF Simulations and Experiments to Evaluate the Structure-Property Characteristics of Polymeric Binders in Si-Based Li-Ion Batteries.
High energy capacity silicon (Si) anodes in Li-ion batteries incorporate polymeric binders to improve cycle life, which is otherwise limited by large volume and stress fluctuations during charging/discharging cycles. Several properties of the polymeric binder play a role in achieving optimal battery performance, including interfacial adhesion strength, mechanical elasticity, and lithium-ion conduction rate. In this work, we utilize atomistic simulations with the ReaxFF force field and complementary experiments to investigate how these properties dictate the performance of Si/binder anodes. We study three C/N/H-based polymer binders with varying structures (pyrolyzed polyacrylonitrile (PPAN), polyacrylonitrile (PAN), and polyaniline (PANI)) to determine how the structure-property characteristics of the binder affect performance. The Si/binder adhesion analysis reveals some counter-intuitive results: although an individual PANI chain has a stronger affinity to Si compared to PPAN, the PANI bulk binds weaker to the Si surface. Interfacial structural analyses from simulations of the bulk phase show that PANI chains have poor stacking at the interface, while PPAN chains exhibit dense and highly ordered stacking behavior, leading to stronger adhesion. PPAN also has a lower Young's modulus compared to PANI and PAN owing to its ordered and less entangled bulk structure. This added elasticity better accommodates volume changes associated with cycling, making it a more suitable candidate for Si anodes. Finally, both simulations and experimental measurements of Li-ion diffusion rates show higher Li mobility through PPAN than PAN and PANI because the ordered stacking of PPAN chains creates channels that are favorable for Li diffusion to the Si surface. Galvanostatic charge-discharge cycling experiments show that PPAN is indeed a highly promising binder for Si anodes in Li-ion batteries, retaining a capacity of ∼1400 mAh g-1 for 150 cycles. This work demonstrates that the orientation and structure of the polymer at and near the interface are essential for optimizing binder performance as well as showcases the initial steps for binder evaluation, selection, and application for electrodes in Li-ion batteries.


Cardiac myxoma: an unusual cause of sudden death in childhood.
Primary tumors of the heart and pericardium are rare in autopsy series. Considering all age groups, the most common cardiac tumor is the myxoma. They may arise in any of the four chambers or, rarely, on the heart valves. About 90% are located in the atria, with the left-to-right ratio of 4:1. The majority of patients are usually in the age group of 30-60 years. Female predominance has been reported. In this report, we describe a six-year-old boy with right atrial myxoma. A 5x4x3 cm, polypoid, smooth-surfaced, brown-colored tumor was found in the right atrium. It was attached by the stalk to the atrial septum. Microscopically, the tumor had the typical appearance of a myxoma with spindle cells widely spaced by abundant myxoid matrix. The diagnosis was based on histopathological and immunohistochemical findings. Sudden death may occur in patients with atrial myxoma. Death is caused by coronary or systemic embolization or by obstruction of blood flow at the mitral or tricuspid valve.


Rapid immune activation by CpG motifs in bacterial DNA. Systemic induction of IL-6 transcription through an antioxidant-sensitive pathway.
Unmethylated CpG dinucleotides (CpG motif) in bacterial DNA or synthetic oligodeoxynucleotides (CpG DNA) rapidly activate murine B cells to secrete IL-6 and IgM, as well as to proliferate. Within 30 min after CpG DNA stimulation in vivo, IL-6 mRNA levels were increased in liver, spleen, and thymus cells. Serum IL-6 protein was markedly increased within 1 h of stimulation. Treatment of a B cell line with CpG DNA led to an increase in the transcriptional activity of the IL-6 promoter. This CpG DNA-induced IL-6 production was not mediated via either a protein kinase C (PKC)-, protein kinase A (PKA)-, or nitric oxide (NO.)-dependent pathway but was inhibited by an antioxidant. In addition, the level of intracellular reactive oxygen species was increased within 20 min after CpG DNA, but not control non-CpG DNA, treatment. These results suggest that CpG DNA-induced IL-6 production is mediated through a reactive oxygen intermediate-dependent pathway. CpG DNA-mediated IL-6 production was enhanced by simultaneous signals delivered through the Ag receptor. The addition of neutralizing Abs against IL-6 to B cell cultures along with CpG oligodeoxynucleotides essentially abolished the CpG DNA-induced increased IgM secretion but had no significant effect on the B cell proliferation induced by the CpG motif. Our results suggest that the induction of IL-6 expression in response to CpG motifs in bacterial DNA may be an important immune defense mechanism that facilitates a rapid response to microbial infection.


Obesity, glucose intolerance and diabetes and their links to cardiovascular disease. Implications for laboratory medicine.
This article provides an overview of the role of metabolite toxicity, low-grade inflammation and disturbed cellular signaling in obesity, glucose intolerance and diabetes. It also highlights links between this continuum of deteriorating glucose tolerance and atherosclerosis. Obesity, diabetes mellitus, and cardiovascular disease are all related to diet and to the level of physical activity. They have reached epidemic proportions worldwide. Glucose intolerance and diabetes increase the risk of atherosclerotic events. Moreover, obesity, and glucose intolerance or diabetes, are components of the metabolic syndrome, which also imparts an increased cardiovascular risk. There is increasing recognition that common mechanisms contribute to diabetes and cardiovascular disease. Following increased calorie intake and/or decreased physical activity, fuel metabolism generates excess of 'toxic' metabolites, particularly glucose and fatty acids. Homeostasis is affected by the endocrine output from the adipose tissue. Reactive oxygen species are generated, creating oxidative stress, which exerts major effects on signaling pathways, further affecting cellular metabolism and triggering low-grade inflammatory reaction. This perspective on the diabetic syndrome has been reflected in the approach to its treatment, which integrates maintenance of glycemic control with primary and secondary cardiovascular prevention. Laboratory medicine should support diabetes care with an integrated package of tests which, in addition to glycemic control, enable assessment and monitoring of the risk of microvascular complications as well as cardiovascular disease.


EGF promotes in vivo tumorigenic growth of primary chicken embryo fibroblasts expressing v-myc and enhances in vitro transformation by the v-erbA oncogene.
We report that the activation of the endogenous chicken EGF receptor leads to the tumorigenic growth in vivo of early passage chicken embryo fibroblasts (CEFs) that express a nonsarcomagenic oncogene, v-myc. To provide a continuous paracrine source of this growth factor in vivo, we employed irradiated Rat-1 cells which had been stably transfected with a synthetic cDNA to human EGF. Expression of another non-sarcomagenic nuclear oncogene, v-erbA, prones the CEFs to in vitro transformation by EGF, but does not cause EGF dependent tumorigenicity in vivo. The short period of incubation in the in vivo assay employed by our study (10 days), together with the genetic stability of primary chicken embryo fibroblasts, make it very likely that the reported alterations in cellular behaviour are a direct and primary effect of the expression of the relevant oncogenes and their cooperation with the EGF induced response. Dose response and ligand binding assays suggest that the EGF response is transmitted via the chicken c-erbB molecule, which by virtue of its preference for TGF-alfa is distinct from the mammalian EGF receptors studied so far. The level of expression of the endogenous chicken EGF receptor is within the same range as that reported for primary human fibroblasts (5-7 x 10(3) per cell). The cooperative effect of v-myc with chicken c-erbB probably takes place at a post receptor level, as its expression did not affect the steady state level or affinity for ligand of the chicken EGF receptor.


Body Mass Index Influence on the Clinical Outcomes for Nonvalvular Atrial Fibrillation Patients Admitted to a Hospital Treated with Direct Oral Anticoagulants: A Retrospective Cohort Study.
Considering that the current fixed dose of direct oral anticoagulants (DOACs) might have insufficient anticoagulation effect for overweight patients, the aim of this study was to compare the effectiveness and safety of anticoagulation between dabigatran and rivaroxaban in different body mass index (BMI) population. We conducted a retrospective cohort study of 2402 DOAC anticoagulated patients with atrial fibrillation who underwent catheter ablation (1290 dabigatran, 53.7% and 1112 rivaroxaban, 46.3%) between January 2017 and December 2018. Patients were distributed based on the BMI into nonobese (1362, BMI <25 kg/m2), preobese (521, BMI 25.0-29.9 kg/m2), class I obese (344, BMI 30.0-34.9 kg/m2) and class II+ obese (175, BMI ≥35.0 kg/m2). We collected information regarding clinical features, laboratory data, bleeding complications and systemic embolic events from the electrical medical records system during 12 months. The incidence of systemic embolism and stroke complications was higher in the class II+ obese group (P=0.001 and P=0.003). The incidence of bleeding complications and the levels of anticoagulation parameters under the bleeding threshold were similar among the four groups (P>0.05). Cumulative Kaplan-Meier analysis illustrated that rivaroxaban-treated patients who belonged to higher BMI subgroups were more likely to experience shorter time to thrombosis (TTT) (12-month TTT rates of 0.5% for nonobese vs 1.7% for class I obese patients, HR=3.716, P=0.005; 12-month TTT rates of 0.5%, for nonobese vs 4.0% for class II+ obese patients, HR=6.843, P=0.001). However, no statistical significant difference in terms of the time to bleeding complications and the time to cumulative events among the four groups was observed. By multivariate analysis, a higher BMI value (BMI ≥25 kg/m2) (P=0.019; OR=2.094, 95%CI: 1.129-3.883) was an independent predictor for thrombosis in patients treated with dabigatran or rivaroxaban. Positive linear relationship was observed between BMI levels and occurrence rate of thrombosis and bleeding in under anticoagulation patients with NVAF (R2=0.451 and R2=0.383, respectively). The fixed dose of 15 mg rivaroxaban might carry a risk of under exposure, which would lead to an increase of thromboembolic complications in patients with high BMI. Therefore, rivaroxaban dose increase was suggested for obese patients. Use of DOACs appears to have considerable safety in obese patients.


R-B enteric differential system for identification of Enterobacteriaceae.
The R/B Enteric Differential System for identifying enteric bacteria has been evaluated with 451 "unknown" cultures from the stock culture collection of the Center for Disease Control. An average of 89.6% of these cultures were correctly identified by the R/B system, when used as recommended by the manufacturer but without the assistance of serology. This percentage ranged, however, from 47% for Klebsiella to 100% for Serratia and Providencia. Of 11 groups or genera of Enterobacteriaceae tested, only three (Enterobacter, Serratia, and Providencia) were identified with 95% or better accuracy. Four groups (Arizona, Citrobacter, Escherichia, and Salmonella) attained 90 to 95% accuracy of identification, and three groups (Edwardsiella, Proteus, and Shigella) scored between 85 and 90% accuracy. We recommend the R/B system as a screening device which is reasonably successful in grouping bacteria but not as a substitute for more exacting conventional procedures.


Microtubules regulate migratory polarity through Rho/ROCK signaling in T cells.
Migrating leukocytes normally have a polarized morphology with an actin-rich lamellipodium at the front and a uropod at the rear. Microtubules (MTs) are required for persistent migration and chemotaxis, but how they affect cell polarity is not known. Here we report that T cells treated with nocodazole to disrupt MTs are unable to form a stable uropod or lamellipodium, and instead often move by membrane blebbing with reduced migratory persistence. However, uropod-localized receptors and ezrin/radixin/moesin proteins still cluster in nocodazole-treated cells, indicating that MTs are required specifically for uropod stability. Nocodazole stimulates RhoA activity, and inhibition of the RhoA target ROCK allows nocodazole-treated cells to re-establish lamellipodia and uropods and persistent migratory polarity. ROCK inhibition decreases nocodazole-induced membrane blebbing and stabilizes MTs. The myosin inhibitor blebbistatin also stabilizes MTs, indicating that RhoA/ROCK act through myosin II to destabilize MTs. Our results indicate that RhoA/ROCK signaling normally contributes to migration by affecting both actomyosin contractility and MT stability. We propose that regulation of MT stability and RhoA/ROCK activity is a mechanism to alter T-cell migratory behavior from lamellipodium-based persistent migration to bleb-based migration with frequent turning.


Standardization in clinical enzymology: a challenge for the theory of metrological traceability.
The goal of standardization for measurement of the catalytic concentration of enzymes is to achieve comparable results in human samples, independent of the reagent kits, instruments, and laboratory where the assay is performed. To pursue this objective, the IFCC has established reference systems for the most important clinical enzymes. These systems are based on the following requirements: a) reference methods, well described and evaluated extensively; b) suitable reference materials; and c) reference laboratories operating in a highly controlled manner. When these reference systems are used appropriately, the diagnostic industry can assign traceable values to commercial calibrators. Clinical laboratories that use procedures with validated calibrators to measure human specimens can now obtain values that are traceable to higher-order reference procedures. These reference systems constitute the structure of the traceability chain to which the routine methods can be linked via an appropriate calibration process, provided that they have a comparable specificity (i.e., they are measuring the same catalytic quantity).


The Impact of Clinical Factors, Vitamin B12 and Total Cholesterol on Severity of Anorexia Nervosa: A Multicentric Cross-Sectional Study.
Severe forms of Anorexia Nervosa (AN) are characterized by medical complications, psychiatric comorbidity, and high mortality. This study investigated potential associations between clinical/biological factors and the severity of AN, measured by the Body Mass Index (BMI). Red and white blood cells, hemoglobin, platelets, iron, vitamins D and B12, folate, and total cholesterol were measured in a mixed sample of 78 inpatients and outpatients. Linear regressions and one-way analyses of variance (ANOVAs) were carried out to evaluate the relationship between BMI and clinical/biochemical variables. BMI was significantly lower in hospitalized patients (F = 4.662; p = 0.034) and in those under pharmacological treatment (F = 5.733; p = 0.019) or poly-therapy (F = 5.635; p = 0.021). Higher vitamin B12 (β = -0.556, p < 0.001), total cholesterol (β = -0.320, p = 0.027), and later age at onset (with a trend towards significance) (β = -0.376, p = 0.058) were associated with a lower BMI. Increased total cholesterol and vitamin B12, later age at onset, current pharmacological treatment, and poly-therapy might be distinctive in patients with a lower BMI. In clinical practice, these findings may contribute to the early identification of AN patients at higher risk of developing complicated or chronic forms of the disorder. Further studies on larger samples are needed to identify potential predictive factors of AN severity in the framework of precision medicine.


Steroid therapy in obstructive airway diseases.
Asthma and chronic obstructive pulmonary disease (COPD) are two common illnesses that cause significant morbidity and mortality. Steroids are widely used in both conditions. They act through steroid or glucocorticoid receptors (GR) causing up or down regulation of protein synthesis resulting in an increase in lipocortin 1 and beta 2 adrenergic receptors, and decreased levels and activities of cytokines or cytokine receptors, which reduces the inflammatory process in the airways and decreases bronchial hyperreactivity. Consequently symptoms of airway obstruction are alleviated and lung function is improved. In asthma, steroids have been convincingly shown to be effective in the treatment of both acute exacerbations and chronic condition. In COPD, however, only a subset of patients seem to respond favourably to steroid therapy. Therapeutic trials are therefore recommended before committing to a long-term treatment in order to determine this subset of patients, as no markers of steroid responsiveness can be identified. The inhaled steroids currently available have a good safety profile with significant side effects occurring only occasionally. Such side effects are usually confined to the oropharynx, causing local irritation, candidiasis and dysphonia, which can be easily overcome. Biochemical abnormalities involving bone, adrenal, carbohydrate and lipid profiles have been noted with high doses of inhaled steroids; however, these have no significant clinical effects.


Methodological aspects of a GIS-based environmental health inspection program used in the Athens 2004 Olympic and Para Olympic Games.
The use of geographical information system (GIS) technologies in public health surveillance is gradually gaining momentum around the world and many applications have already been reported in the literature. In this study, GIS technology was used to help county departments of Public Health to implement environmental health surveillance for the Athens 2004 Olympic and Para Olympic Games. In order to assess the workload in each Olympic county, 19 registry forms and 17 standardized inspection forms were developed to register and inspect environmental health items requiring inspection (Hotels, restaurants, swimming pools, water supply system etc), respectively. Furthermore, related databases were created using Epi Info 2002 and a geographical information system (GIS) were used to implement an integrated Environmental Health inspection program. The project was conducted in Athens by the Olympic Planning Unit (OPU) of the National School of Public Health, in close cooperation with the Ministry of Health and Social Solidarity and the corresponding departments of Public Health in all municipalities that were scheduled to host events during the Athens 2004 Olympic and Para Olympic games. A total of 44,741 premises of environmental health interest were geocoded into GIS databases and several electronic maps were developed. Using such maps in association with specific criteria, we first identified the maximum workload required to execute environmental health inspections in all premises within the eleven Olympic County Departments of Public Health. Six different scenarios were created for each county, based on devised algorithms in order to design the most effective and realistic inspection program using the available inspectors from each municipality. Furthermore, GIS applications were used to organize the daily inspection program for the Olympic games, provide coloured displays of the inspection results and link those results with the public health surveillance of specific cases or outbreak investigation. Our computerised program exhibited significant efficiency in facilitating the prudent use of public health resources in implementing environmental health inspections in densely populated urban areas as well as in rural counties. Furthermore, the application of simple algorithms in integrating human and other resources provided tailored and cost-effective applications to different public health agencies.


Cumin scented leaf essential oil of Cinnamomum chemungianum: compositions and their in vitro antioxidant, α-amylase, α-glucosidase and lipase inhibitory activities.
As part of our work on prospecting of Cinnamomum of the Western Ghats, chemical compositions, antioxidant, α-amylase, α-glucosidase and lipase inhibitory activities of leaf essential oil (EO) of Cinnamomum chemungianum were evaluated. Chemical characterisation of the cumin scented leaf EO from five locations in the southern Western Ghats revealed that they were highly varied. EO from Kannikatti (CC2) exhibited good α-amylase inhibitory activity with IC50 value of 5.97 μg/mL, whereas the EOs from Chemungi (CC1) and Athirumala (CC5) showed better α-glucosidase inhibition with IC50 of 56.65 and 62.12 μg/mL, respectively. The EOs from Chemungi, Kannikatti and Athirumala were found to inhibit lipase with IC50 of 919.75, 923.17 and 838.46 μg/mL, respectively. The EO of C. chemungianum may be used in food products as it has cumin scent and mild inhibitory activities.


Transcriptional and translational expression kinetics of the early gene encoding the BICP27 protein of bovine herpesvirus type 1.
The expression kinetics of an essential trans-regulatory protein, ICP27, from herpes simplex virus type 1 correspond to that of an immediate-early gene whose expression increases rapidly upon infection and then decreases as of 7 hr postinfection. In contrast, here we report that the bovine herpesvirus type 1 (BHV-1) homolog BICP27, a 50-kDa protein, is expressed as an early gene. Both the transcript and protein accumulated gradually reaching peak levels at approximately 12 hr postinfection, after which point steady state levels were maintained up to 24 hr. Thus the expression profiles of ICP27 and BICP27 are significantly different, suggesting that they may possess different functions.


Beliefs of chronically ill Japanese patients that lead to intentional non-adherence to medication.
To identify factors, associated with personal beliefs, involved in intentional non-adherence to prescribed medication of Japanese patients with chronic diseases. A cross-sectional study of Japanese subjects with chronic, primarily liver, gastrointestinal, or nervous system diseases who had been prescribed oral medicines for regular use, was performed. The subjects were admitted to a university hospital and were interviewed face-to-face on admission. Intentional non-adherence was defined as experience of deliberate adjustment of self-managed prescription medicines during the few months prior to hospital admission. Patients' beliefs about taking medicines were assessed from the perspective of what the patient valued in order to take medicines without anxiety; whether the patient valued information about the medication such as its function and side-effects and/or mutual reliance on doctors. Using logistic multivariate regression analyses, factors associated with intentional non-adherence were identified. Among 154 subjects, 51 showed intentional non-adherence. Intentional non-adherence was associated with the following three factors: (a) the patients' beliefs with respect to taking medicines without anxiety, especially putting no value on mutual reliance on the patient-doctor relationship (P < 0.001) and putting great value on knowing the drug's side-effects (P < 0.001), (b) poor comprehension of general aspects of medication (P for trend < 0.001), and (c) being in the prime of life (40-59 years) (P = 0.011). Comprehension of the function of each medicine, experience of side-effects, anxiety about taking medicines, and the number of types of medicines taken, were not associated with non-adherence. Beliefs on which individual Japanese patients with chronic diseases attach value in order to take medicines without anxiety were potential factors for intentional non-adherence. This emphasizes the necessity of a patient-oriented approach to take account of patients' personal beliefs about medicines to increase adherence rate in Japan.


Deconvoluting effects of vine and soil properties on grape berry composition.
Grape berry composition is influenced by several factors including grapevine and soil properties and their interactions. Understanding how these factors interact to determine berry composition is integral to producing berries with desired composition. Here we used extensive spatio-temporal data to identify significant vine and soil features that influence Shiraz berry composition. The concentrations of berry flavonoids (anthocyanins, tannin and total phenolics), total soluble solids and pH were typically negatively associated with canopy, crop and berry size factors whereas titratable acidity was positively associated. The strengths of the associations, however, were generally greater with the crop and berry size factors than with the canopy size factor. The analyses also resolved separate influences of berry and crop size on berry composition. Soil properties had significant influences on berry composition; however, when influences of soil factors on vine-attributes were accounted for, the apparent effects of soil factors on berry composition were largely non-existent. At each site, variations in berry composition were more strongly associated with crop and berry size than with canopy size factors. Apparent influences of soil properties on berry composition are indirect, being mediated via their effects on vine attributes (canopy, crop and berry sizes).


[Clinical features of the initial manifestations of slowly-progressing schizophrenia].
On examining 200 patients with slowly progressing schizophrenia it was found that the initial psychopathological disturbances appeared in most cases (in 122 patients) at an age under 20 years, while the distinct progress of the disease was noted much later, in the third or the fourth decade of the life. In 31.5% of the observations, the initial disorders were autochthonous, while in 68.5% they were provoked mainly by psychogenic and environmental factors. A comparison of the autochthonous and provoked initial disturbances showed that both types were presented by affective and obsessive-phobic disorders which could be detected long before the appearance of the clinical manifestation of the process. Clinical aspects of the initial disorders, their time course and interconnections with the symptoms of the subsequent, more advanced stages of the disease are analyzed. The author concludes that the disorders discussed belong to the latent stage of slowly progressing schizophrenia.


Enhancing service delivery through title x funding: findings from California.
The federal Title X grant program provides funding for family planning services for low-income women and men. In California, all clinics receiving Title X funds participate in the state's family planning program, Family PACT, along with other public and private providers. The relative extent to which Title X-funded clinics and other Family PACT providers have incorporated enhancements beyond their core medical services has never been studied. In 2010, a survey was sent to public- and private-sector Family PACT clinicians to assess whether funding streams were associated with the availability of special services: extended clinic hours, outreach to vulnerable populations, services for clients not proficient in English and use of advanced clinic-based technologies. Bivariate and logistic regression analyses controlling for potentially confounding factors were conducted. Greater proportions of Title X-funded clinics than of other public and private providers had Spanish-speaking unlicensed clinical staff (89% vs. 71% and 58%, respectively) and Spanish-language signs (95% vs. 85% and 82%). Title X-funded providers were more likely than other public providers to offer extended clinic hours, provide outreach to at least three vulnerable or hard-to-reach populations, and use three or more advanced technologies (odds ratios, 2.0-2.9). Compared with other Family PACT providers, clinics that receive Title X funding have implemented greater infrastructure enhancements to promote access and improve the quality of service for underserved populations. This may be because Title X-funded providers have more financial opportunities to provide the array of services that best respond to their clients' needs.


Primary Auditory Cortex is Required for Anticipatory Motor Response.
The ability of the brain to predict future events based on the pattern of recent sensory experience is critical for guiding animal's behavior. Neocortical circuits for ongoing processing of sensory stimuli are extensively studied, but their contributions to the anticipation of upcoming sensory stimuli remain less understood. We, therefore, used in vivo cellular imaging and fiber photometry to record mouse primary auditory cortex to elucidate its role in processing anticipated stimulation. We found neuronal ensembles in layers 2/3, 4, and 5 which were activated in relationship to anticipated sound events following rhythmic stimulation. These neuronal activities correlated with the occurrence of anticipatory motor responses in an auditory learning task. Optogenetic manipulation experiments revealed an essential role of such neuronal activities in producing the anticipatory behavior. These results strongly suggest that the neural circuits of primary sensory cortex are critical for coding predictive information and transforming it into anticipatory motor behavior.


Toxoplasmosis I. Studies by the Fluorescein-labelled Antibody Technique.
The fluorescein-labelled antibody technique was investigated for the diagnosis of toxoplasmosis. The direct method, the inhibition and indirect modifications are suitable for the demonstration of Toxoplasma gondii in fluid and tissue-impression slides from animals in the acute phase of infection. The method was not applicable with the frozen tissue sections. The fluorescein-labelled antibody inhibition technique detected antibodies in immune sera from various species of animal. However the titres obtained were lower than with the complement-fixation test.


Gatifloxacin-induced severe hypoglycemia in a patient with type 2 diabetes mellitus.
A case of Gatifloxacin-induced severe and recurrent hypoglycemia in 62-year-old type 2 diabetic patient is presented. Possible mechanisms responsible for hypoglycemia are discussed and the literature on the subject is reviewed.


Regional delivery of an adenovirus vector containing the Escherichia coli cytosine deaminase gene to provide local activation of 5-fluorocytosine to suppress the growth of colon carcinoma metastatic to liver.
To evaluate the hypothesis that regional delivery of an adenovirus vector containing the Escherichia coli cytosine deaminase gene (AdCMV.CD) together with systemic 5-FC could suppress the growth of metastatic colon cancer in the liver, the AdCMV.CD vector was injected 0.8-1 cm from the site of a human colon cancer tumor in the livers of nude mice. The growth of the human colon cancer cells was quantified by dot blot analysis of genomic DNA extracted from tumor-bearing liver, hybridized with a human-specific Alu probe. The combination of regional AdCMV.CD plus systemic 5-fluorocytosine (5-FC) suppressed the growth of the metastatic tumors over the 21 days of evaluation following vector administration. Histologic evaluation showed necrosis at the site of the tumor in the livers of mice treated with AdCMV.CD/5-FC, but not in control groups. Evaluation of the potential toxicity of AdCMV.CD plus 5-FC on the normal liver showed only mild, self-limited dose-related inflammation, with no deaths. These data suggest that the regional administration of AdCMV.CD together with systemic 5-FC may be a safe and effective strategy to suppress the growth of metastases of colorectal carcinoma in the liver.


Helping Children Hurt Themselves: Why Pediatricians Ought to Support Adolescent Football Players in Their Athletic Goals.
Participation in sports such as football puts youth-athletes at high risk of injury. Helmets cannot protect players from the possibility of traumatic brain injury, and repeated concussive injuries can lead to chronic traumatic encephalopathy later in life. In light of such facts, the morally appropriate role of physicians who treat patient-athletes comes into question. I argue that pediatricians ought to be committed to a high level of shared decision making, whereby their goal, rather than being to provide the medically best advice (which, let's be honest, would be to not play football at all), would be to provide the medically best advice in light of patients' honestly professed plans and goals. If patient-athletes see their doctor as an ally, who wants them on the field as much as they want to be there, they will be more likely to trust their pediatrician to help in the realization of those goals, even if they report an injury. While this approach could feel like a medical betrayal, in that the physician could feel complicit in helping a patient to continue engaging in high-risk behavior, I argue that medical outcomes will be better than if patient-athletes see physicians as an obstruction to their athletic goals.


A lysosome-locating and acidic pH-activatable fluorescent probe for visualizing endogenous H2O2 in lysosomes.
There is increasing evidence indicating that lysosomal H2O2 is closely related to autophagy and apoptotic pathways under both physiological and pathological conditions. Therefore, fluorescent probes that can be exploited to visualize H2O2 in lysosomes are potential tools for exploring diverse roles of H2O2 in cells. However, functional exploration of lysosomal H2O2 is limited by the lack of fluorescent probes capable of compatibly sensing H2O2 under weak acidic conditions (pH = 4.5) of lysosomes. Lower spatial resolution of the fluorescent visualization of lysosomal H2O2 might be caused by the interference of signals from cytosolic and mitochondrial H2O2, as well as the non-specific distribution of the probes in cells. In this work, we developed a lysosome-locating and acidic-pH-activatable fluorescent probe for the detection and visualization of H2O2 in lysosomes, which consists of a H2O2-responsive boronate unit, a lysosome-locating morpholine group, and a pH-activatable benzorhodol fluorophore. The response of the fluorescent probe to H2O2 is significantly more pronounced under acidic pH conditions than that under neutral pH conditions. Notably, the present probe enables the fluorescence sensing of endogenous lysosomal H2O2 in living cells without external stimulations, with signal interference from the cytoplasm and other intracellular organelles being negligible.


Fluid mechanics and rheology of the jumping spider body fluid.
Spiders use their inner body fluid ("blood" or hemolymph) to drive hydraulic extension of their legs. In hydraulic systems, performance is highly dependent on the working fluid, which needs to be chosen according to the required operating speed and pressure. Here, we provide new insights into the fluid mechanics of spider locomotion. We present the three-dimensional structure of one of the crucial joints in spider hydraulic actuation, elucidate the fluid flow inside the spider leg, and quantify the rheological properties of hemolymph under physiological conditions. We observe that hemolymph behaves as a shear-thinning non-Newtonian fluid with a fluid behavior index n = 0.5, unlike water (n = 1.0).


Brain and skull metastases of hepatic or pancreatic cancer--report of six cases.
Brain and skull metastases from primary hepatic or pancreatic cancer are very rare. The authors describe six cases of metastatic tumors. These are skull (three cases) and brain (one) metastasis of hepatic cancer and brain metastasis (two) of pancreatic cancer. In three hepatic cancer patients, the metastatic lesions were diagnosed before the diagnosis of primary cancer. In these patients, plain skull x-ray showed osteolytic lesions and vascular enlargement. A postcontrast computed tomographic (CT) scan showed an enhanced high-density epidural mass. Angiograms showed a tumor stain fed by abnormal vessels from the external carotid artery. In one patient with a metastatic brain tumor from hepatic cancer, a CT scan showed a high-density mass with hematoma. In one of the brain metastases from pancreatic cancer, a CT scan revealed a cystic, ring-like enhanced lesion in the thalamus. In the other case, a CT scan showed an isodensity mass in the vermis and hydrocephalus. Metastatic tumors from primary hepatic cancer were soft and hemorrhagic, but they were clearly demarcated from the surrounding tissue. In the case of thalamic metastasis, the cyst content was aspirated and an anticancer agent was administered into the cystic cavity. In the other cases, the tumors were totally removed. The outcome was very poor in all cases.


Decoding HMMs using the k best paths: algorithms and applications.
Traditional algorithms for hidden Markov model decoding seek to maximize either the probability of a state path or the number of positions of a sequence assigned to the correct state. These algorithms provide only a single answer and in practice do not produce good results. We explore an alternative approach, where we efficiently compute the k paths of highest probability to explain a sequence and then either use those paths to explore alternative explanations for a sequence or to combine them into a single explanation. Our procedure uses an online pruning technique to reduce usage of primary memory. Out algorithm uses much less memory than naive approach. For membrane proteins, even simple path combination algorithms give good explanations, and if we look at the paths we are combining, we can give a sense of confidence in the explanation as well. For proteins with two topologies, the k best paths can give insight into both correct explanations of a sequence, a feature lacking from traditional algorithms in this domain.


Three-dimensional imaging of DNA fragments during electrophoresis using a confocal detector.
We have measured the three-dimensional distribution of DNA fragments within an electrophoretic band confined by a glass microchannel. The measurements were made using a confocal microscope and a photon-counting photomultiplier detector. A DNA sequencing standard was loaded into glass microchannel plates containing polyacrylamide gel. The measurements were made by scanning the plates in three dimensions using a mechanical stage under computer control, while electrophoresis was taking place. We found that the distribution of DNA was the same for all the bands measured in the sequencing ladder with an approximate Gaussian distribution along all three axes. These measurements are important to understand what physical forces shape electrophoretic bands confined by a channel and they also aid in the design of high throughput DNA sequencers.


Variables affecting compliance with treatment of post-hospitalized patients with chronic mental illness.
The subjects in this study were 33 patients aged 18 to 60 years who were first admitted to an outpatient mental health department in a 1-year period and were known to have had two or more hospitalizations in State or private psychiatric institutions in the 2 years before intake. The relationships between four patient variables and compliance with recommended treatment were studied. The four variables were (a) severity of psychopathology at intake, (b) evidence of negative communication in a patient's family concerning mental illness and its treatment, (c) degree of social isolation, and (d) use of the health center for treatment of nonpsychiatric medical problems.Using the z test, a significant positive relationship was found between compliance with recommended treatment and the usage of the health center for other medical problems. Presence of negative communication from family and nonadherence to recommended treatment were correlated positively. Living with others significant to the patient did not affect compliance with treatment. Compliance was measured by dividing the patients into those keeping or not keeping 50 percent of appointments with therapists.


Obstructive sleep apnea and related disorders.
OSAS, a common cause of disrupted sleep and EDS, result from repetitive closure of the upper airway during sleep. It probably represents the most severe syndrome related to obstruction of the upper airway; less severe forms include UARS, a syndrome characterized by the need for increased effort to breath but no prominent apneas or hypopneas, and primary snoring. Initial clues to the presence of OSAS and related disorders are derived from the history and include loud snoring, EDS or insomnia, and witnessed apneas. Some patients, especially women, may complain mostly of tiredness or fatigue, and children may present with behavioral abnormalities. Obesity, a large neck circumference, and a crowded oropharynx are common on physical examination. Nonobese patients, in particular, often have retrognathia, a high-arched narrow palate, macroglossia, enlarged tonsils, temporomandibular joint abnormalities, or chronic nasal obstruction. The clinical suspicion of obstructed nocturnal breathing is confirmed by overnight polysomnography, and an MSLT may be used to assess sleepiness. Esophageal manometry during polysomnography facilitates diagnosis of UARS. Treatment most commonly consists of nasal CPAP or BPAP, although problems with compliance make surgical treatment preferable in some cases. Although UPPP eliminates sleep apnea only in a minority of patients, combining UPPP with maxillofacial procedures appears to improve outcomes. Other treatments such as the use of dental appliances or medications, weight loss, and positional therapy may be useful as adjunctive therapy for moderate to severe OSAS or as primary treatments for UARS or mild OSAS.


[Structuro-kinetic organization of the tricarboxylic acid cycle in the active functioning of mitochondria].
Taking into account structural and functional organization of mitochondrial processes it has been shown that at active work there functions in mitochondria an accelerated mechanism of succinic acid formation via coupling of glutamate-oxalacetate transaminase and alpha-ketoglutaratdehydrogenase. This way is closed up into a cycle with the participation of cytosol transaminases which support influx of glutamate, pyruvate and malic acid into mitochondria. When provision of the mitochondria with the substrate proceeds along the transaminase pathway the initial slow region of the tricarboxylic acid cycle is omitted. Thus at active work a faster course is selected. It permits realization of the advantages of succinate dehydrogenase high activity and of oxidation efficiency of succinic acid generated in mitochondria which is essentially higher than that under oxidation of succinic acid and even more of other substrates of the tricarboxylic acid cycle.


Fisher information and Shannon entropy for on-line detection of transient signal high-values in laser Doppler flowmetry signals of healthy subjects.
Laser Doppler flowmetry (LDF) is an easy-to-use method for the assessment of microcirculatory blood flow in tissues. However, LDF recordings very often present TRAnsient Signal High-values (TRASH), generally of a few seconds. These TRASH can come from tissue motions, optical fibre movements, movements of the probe head relative to the tissue, etc. They often lead to difficulties in signal global interpretations. In order to test the possibility of detecting automatically these TRASH for their removal, we process noisy and noiseless LDF signals with two indices from information theory, namely Fisher information and Shannon entropy. For this purpose, LDF signals from 13 healthy subjects are recorded at rest, during vascular occlusion of 3 min, and during post-occlusive hyperaemia. Computation of Fisher information and Shannon entropy values shows that, when calibrated, these two indices can be complementary to detect TRASH and be insensitive to the rapid increases of blood flow induced by post-occlusive hyperaemia. Moreover, the real-time algorithm has the advantage of being easy to implement and does not require any frequency analysis. This study opens new fields of application for Fisher information and Shannon entropy: LDF 'denoising'.


A comparison of unamplified and massively multiplexed PCR amplification for murine antibody repertoire sequencing.
Sequencing antibody repertoires has steadily become cheaper and easier. Sequencing methods usually rely on some form of amplification, often a massively multiplexed PCR prior to sequencing. To eliminate potential biases and create a data set that could be used for other studies, our laboratory compared unamplified sequencing results from the splenic heavy-chain repertoire in the mouse to those processed through two commercial applications. We also compared the use of mRNA vs total RNA, reverse transcriptase, and primer usage for cDNA synthesis and submission. The use of mRNA for cDNA synthesis resulted in higher read counts but reverse transcriptase and primer usage had no statistical effects on read count. Although most of the amplified data sets contained more antibody reads than the unamplified data set, we detected more unique variable (V)-gene segments in the unamplified data set. Although unique CDR3 detection was much lower in the unamplified data set, RNASeq detected 98% of the high-frequency CDR3s. We have shown that unamplified profiling of the antibody repertoire is possible, detects more V-gene segments, and detects high-frequency clones in the repertoire.


[Perinatal hospital mortality: its relationship with prenatal care quality].
Our aim was to analyze infant mortality at the Mexican Institute of Social Security (IMSS) North Veracruz, Mexico, Delegation from the perspective of prenatal care quality. We performed a retrospective case-control study and included all cases of perinatal mortality at the IMSS at North Veracruz from July 1 to December 31, 2003. There were two controls per case matched by gender and date of birth. Prenatal care quality was evaluated by a specifically developed questionnaire. A total of 53 cases were used for the final analysis. Maternal age was similar between cases and controls (p = 0.814). There were fewer prenatal appointments (p = 0.0001), fewer test performed [blood test (p = 0.0001) and urine test (p = 0.004)], higher obstetric risk (p = 0.004), and fewer obstetric ultrasound imaging studies developed (p = 0.022) in cases of perinatal mortality vs. controls. Main variables related with perinatal mortality were the following: absent of blood test (odds ratio [OR] 4.7, 95% confidence interval [Cl 95%] 2.2-9.9, p = 0.0001); urine test (OR 4.4, CI 95% 1.5-12.6, p = 0.004), and obstetric ultrasound studies (OR 2.3, Cl 95%, 1.1-4.8, p = 0.022), and having fewer than five prenatal appointments (OR 2.2, Cl 95% 1.1-4.4, p = 0.018). There is evidence of inadequate prenatal care quality in cases of hospital perinatal mortality in Veracruz. Absence of obstetric ultrasound imaging studies and blood tests during prenatal care increases the risk of perinatal mortality 2-4 times.


Klebsiella pneumoniae MrkD-mediated biofilm formation on extracellular matrix- and collagen-coated surfaces.
The type 3 fimbriae of Klebsiella pneumoniae are comprised of the major fimbrial subunit (MrkA) and the adhesin (MrkD) that has previously been shown to mediate binding to collagen. The ability of adhesive and non-adhesive derivatives of K. pneumoniae to form biofilms on collagen-coated surfaces in continuous-flow chambers was investigated. Unlike biofilm formation on abiotic plastic surfaces, the presence of the MrkD adhesin was necessary for growth on collagen-coated surfaces. Fimbriate strains lacking the MrkD adhesin did not efficiently adhere to and grow on these surfaces. Similarly, purified human extracellular matrix and the extracellular matrix formed by human bronchial epithelial cells grown in vitro provided a suitable substrate for MrkD-mediated biofilm formation, whereas direct binding to the respiratory cells was not observed. Type 3 fimbriae may therefore have two roles in the early stages of adherence and growth on in-dwelling devices such as endotracheal tubes. The MrkA polypeptide could facilitate adsorption to abiotic polymers of recently implanted devices and the MrkD adhesin could enable bacteria to adhere to and grow on polymers coated with host-derived proteins.


[Treatment of obesity in patients with changes of carbohydrate metabolism].
The combination of dextroamphetamines, biguanides and choleretics seems to be a good therapy for obese patients with carbohydrate intolerance, since the ponderary curve and carbohydrate tolerance improve. Results obtained are statistically significant.


A pattern of early radiation-induced inflammatory cytokine expression is associated with lung toxicity in patients with non-small cell lung cancer.
Lung inflammation leading to pulmonary toxicity after radiotherapy (RT) can occur in patients with non-small cell lung cancer (NSCLC). We investigated the kinetics of RT induced plasma inflammatory cytokines in these patients in order to identify clinical predictors of toxicity. In 12 NSCLC patients, RT to 60 Gy (30 fractions over 6 weeks) was delivered; 6 received concurrent chemoradiation (chemoRT) and 6 received RT alone. Blood samples were taken before therapy, at 1 and 24 hours after delivery of the 1st fraction, 4 weeks into RT, and 12 weeks after completion of treatment, for analysis of a panel of 22 plasma cytokines. The severity of respiratory toxicities were recorded using common terminology criteria for adverse events (CTCAE) v4.0. Twelve cytokines were detected in response to RT, of which ten demonstrated significant temporal changes in plasma concentration. For Eotaxin, IL-33, IL-6, MDC, MIP-1α and VEGF, plasma concentrations were dependent upon treatment group (chemoRT vs RT alone, all p-values <0.05), whilst concentrations of MCP-1, IP-10, MCP-3, MIP-1β, TIMP-1 and TNF-α were not. Mean lung radiation dose correlated with a reduction at 1 hour in plasma levels of IP-10 (r2 = 0.858, p<0.01), MCP-1 (r2 = 0.653, p<0.01), MCP-3 (r2 = 0.721, p<0.01), and IL-6 (r2 = 0.531, p = 0.02). Patients who sustained pulmonary toxicity demonstrated significantly different levels of IP-10 and MCP-1 at 1 hour, and Eotaxin, IL-6 and TIMP-1 concentration at 24 hours (all p-values <0.05) when compared to patients without respiratory toxicity. Inflammatory cytokines were induced in NSCLC patients during and after RT. Early changes in levels of IP-10, MCP-1, Eotaxin, IL-6 and TIMP-1 were associated with higher grade toxicity. Measurement of cytokine concentrations during RT could help predict lung toxicity and lead to new therapeutic strategies.


Preterm birth by vacuum extraction and neonatal outcome: a population-based cohort study.
Very few studies have investigated the neonatal outcomes after vacuum extraction delivery (VE) in the preterm period and the results of these studies are inconclusive. The objective of this study was to describe the use of VE for preterm delivery in Sweden and to compare rates of neonatal complications after preterm delivery by VE to those found after cesarean section during labor (CS) or unassisted vaginal delivery (VD). Data was obtained from Swedish national registers. In a population-based cohort from 1999 to 2010, all live-born, singleton preterm infants in a non-breech presentation at birth, born after onset of labor (either spontaneously, by induction, or by rupture of membranes) by VD, CS, or VE were included, leaving a study population of 40,764 infants. Logistic regression analyses were used to calculate adjusted odds ratios (AOR), using unassisted vaginal delivery as reference group. VE was used in 5.7% of the preterm deliveries, with lower rates in earlier gestations. Overall, intracranial hemorrhage (ICH) occurred in 1.51%, extracranial hemorrhage (ECH) in 0.64%, and brachial plexus injury in 0.13% of infants. Infants delivered by VE had higher risks for ICH (AOR = 1.84 (95% CI: 1.09-3.12)), ECH (AOR = 4.48 (95% CI: 2.84-7.07)) and brachial plexus injury (AOR = 6.21 (95% CI: 2.22-17.4)), while infants delivered by CS during labor had no increased risk for these complications, as compared to VD. While rates of neonatal complications after VE are generally low, higher odds ratios for intra- and extracranial hemorrhages and brachial plexus injuries after VE, compared with other modes of delivery, support a continued cautious use of VE for preterm delivery.


Cloning and characterization of the gene encoding 1-cyclohexenylcarbonyl coenzyme A reductase from Streptomyces collinus.
We report the cloning of the gene encoding the 1-cyclohexenylcarbonyl coenzyme A reductase (ChcA) of Streptomyces collinus, an enzyme putatively involved in the final reduction step in the formation of the cyclohexyl moiety of ansatrienin from shikimic acid. The cloned gene, with a proposed designation of chcA, encodes an 843-bp open reading frame which predicts a primary translation product of 280 amino acids and a calculated molecular mass of 29.7 kDa. Highly significant sequence similiarity extending along almost the entire length of the protein was observed with members of the short-chain alcohol dehydrogenase superfamily. The S. collinus chcA gene was overexpressed in Escherichia coli by using a bacteriophage T7 transient expression system, and a protein with a specific ChcA activity was detected. The E. coli-produced ChcA protein was purified and shown to have similar steady-state kinetics and electrophoretic mobility on sodium dodecyl sulfate-polyacrylamide gels as the enoyl-coenzyme A reductase protein prepared from S. collinus. The enzyme demonstrated the ability to catalyze, in vitro, three of the reductive steps involved in the formation of cyclohexanecarboxylic acid. An S. collinus chcA mutant, constructed by deletion of a genomic region comprising the 5' end of chcA, lost the ChcA activity and the ability to synthesize either cyclohexanecarboxylic acid or ansatrienin. These results suggest that chcA encodes the ChcA that is involved in catalyzing multiple reductive steps in the pathway that provides the cyclohexanecarboxylic acid from shikimic acid.


Bidirectional immune tolerance in nonmyeloablative MHC-mismatched BMT for murine β-thalassemia.
Nonmyeloablative conditioning using total lymphoid irradiation (TLI) and rabbit antithymocyte serum (ATS) (the murine preclinical equivalent of antithymocyte globulin [ATG]) facilitates immune tolerance after bone marrow transplantation (BMT) across major histocompatibility complex (MHC) disparities and may be a useful strategy for nonmalignant disorders. We previously reported that donor effector T-cell function and graft-versus-host disease (GVHD) are regulated via recipient invariant natural killer T-cell (iNKT) interleukin-4-driven expansion of donor Foxp3+ naturally occurring regulatory T cells (Tregs). This occurs via recipient iNKT- and STAT6-dependent expansion of recipient myeloid dendritic cells (MDCs) that induce contact-dependent expansion of donor Treg through PD-1/PD ligand signaling. After TLI/ATS + BMT, Gr-1lowCD11c+ MDCs and Gr-1highCD11cneg myeloid-derived suppressor cells (MDSCs) were enriched in GVHD target organs. We now report that the recovery of both recipient MDSCs (P < .01) and MDCs (P < .01) is significantly increased when the alkylator cyclophosphamide (CTX) is added to TLI/ATS conditioning. In a BALB/c → B6 lethal GVHD model, adoptive transfer of MDSCs from TLI/ATS/CTX-conditioned recipients is associated with significantly improved GVHD colitis and survival (P < .001), conversion of MDSCs to PD ligand-expressing MDCs, and increased donor naturally occurring Treg recovery (P < .01) compared with control treatment. Using BALB/c donors and β-thalassemic HW-80 recipients, we found significantly improved rates of engraftment and GVHD following TLI/ATS/CTX compared with TLI/ATS, lethal or sublethal total body irradiation/ATS/CTX, or CTX/ATS conditioning. These data provide preclinical support for trials of TLI/ATG/alkylator regimens for MHC-mismatched BMT for hemoglobinopathies. The data also delineate innate immune mechanisms by which TLI/ATS/CTX conditioning may augment transplantation tolerance.


Affected Aspects Regarding Literacy and Numeracy in Children Treated for Brain Tumors.
The aim of this study was to investigate the test results of reading speed, reading comprehension, word comprehension, spelling, basic arithmetic skills, and number sense (intuitive understanding of numbers) by children treated for brain tumors. This is a retrospective study based on medical records, including standardized academic tests. In the years of 2010 to 2014, all children in the area of Stockholm between 7 and 18 years (IQ <70) who had no major linguistic or motor difficulties after they had undergone treatment for brain tumors were offered a special education assessment one year after treatment, at school start, or the year before a transition from one stage to another. Our results indicate that children treated for a brain tumor are at risk of having difficulties in spelling, reading speed, and arithmetic and that the test performance may decline over years in arithmetic and spelling. Children diagnosed at age 0 to 6 years may need extra tutoring at school start, especially in basic arithmetic skills. In both reading and mathematics, many children perform better on tests focused on understanding than on tests focused on speed. Continuous special needs assessments including different aspects of literacy and numeracy, are important for understanding each child's specific needs.


Brevundimonas aveniformis sp. nov., a stalked species isolated from activated sludge.
A Gram-negative, rod-like, stalk-producing bacterium, designated strain EMB102(T), was isolated from activated sludge that performed enhanced biological phosphorus removal in a sequencing batch reactor. Cells without stalks were motile with single polar flagella, but cells that did produce stalks were non-motile and lacked polar flagella. Growth of strain EMB102(T) was observed at temperatures between 15 and 35 degrees C (optimum, 30 degrees C) and between pH 6.0 and 9.0 (optimum, pH 7.5-8.5). The predominant fatty acids of strain EMB102(T) were C(18 : 1) omega 7c, C(16 : 0) and C(15 : 0). The predominant polar lipid was phosphatidylglycerol. The G+C content of the genomic DNA was 64.1 mol% and the major quinone was Q-10. Comparative 16S rRNA gene sequence analyses showed that strain EMB102(T) formed a distinct phyletic lineage within the genus Brevundimonas. The levels of 16S rRNA gene sequence similarity between the type strains of Brevundimonas species ranged from 95.8 to 97.5 %. DNA-DNA relatedness levels between the EMB102(T) and closely related Brevundimonas species were below 15.0 %. On the basis of chemotaxonomic data and molecular properties, strain EMB102(T) represents a novel species within the genus Brevundimonas, for which the name Brevundimonas aveniformis sp. nov. is proposed. The type strain is EMB102(T) (=KCTC 12609(T)=DSM 17977(T)).


Click-to-Chelate: development of technetium and rhenium-tricarbonyl labeled radiopharmaceuticals.
The Click-to-Chelate approach is a highly efficient strategy for the radiolabeling of molecules of medicinal interest with technetium and rhenium-tricarbonyl cores. Reaction of azide-functionalized molecules with alkyne prochelators by the Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC; click reaction) enables the simultaneous synthesis and conjugation of tridentate chelating systems for the stable complexation of the radiometals. In many cases, the functionalization of (bio)molecules with the ligand system and radiolabeling can be achieved by convenient one-pot procedures. Since its first report in 2006, Click-to-Chelate has been applied to the development of numerous novel radiotracers with promising potential for translation into the clinic. This review summarizes the use of the Click-to-Chelate approach in radiopharmaceutical sciences and provides a perspective for future applications.


Temporal and regional variation in the use of breast-conserving surgery and radiotherapy for older women with early-stage breast cancer from 1983 to 1995.
Authorities recommend radiation therapy after breast-conserving surgery for breast cancer. Numerous studies have reported that older women diagnosed with breast cancer are less likely to receive radiation after breast-conserving surgery. It is unclear how care of older women with breast cancer has changed over time. Women with local or regional stage breast cancer diagnosed between 1983-1995 were identified from the Surveillance, Epidemiology, and End Results (SEER) Cancer Registries. The treatment information in SEER includes type of surgical procedures and receipt of radiation therapy. There were small increases in the percentage of women receiving breast-conserving surgery during the 1980s followed by substantial increases in the 1990s. Age was a major factor in determining receipt of radiation therapy after breast-conserving surgery. A large increase in use of radiotherapy after surgery was observed in women aged > or = 75, from below 30% in 1983 to over 50% in 1995. Women aged > or = 75 diagnosed in 1992-1995 were 1.76 and 2.34 times more likely to receive radiation for local and regional stage respectively, as compared to those in 1983-1987. There was no increase in use of radiation for women aged < 65. There has been a substantial increase in use of breast-conserving surgery and in receipt of radiation therapy after breast-conserving surgery in older women. However, there was a net increase in the percentage of all women with breast cancer who received this surgery without radiotherapy, due to the large increase in the overall percentage of women receiving this surgery.


Analyses of CD20 monoclonal antibody-mediated tumor cell killing mechanisms: rational design of dosing strategies.
Since approval of rituximab for treatment of B cell non-Hodgkin lymphoma, development of monoclonal antibodies (mAbs) for cancer treatment and elucidation of their cytotoxic mechanisms have been subject to intense investigations. Compelling evidence indicates that rituximab and another CD20 mAb, ofatumumab, must use the body's cellular and humoral immune effector functions to kill malignant cells. Other U.S. Food and Drug Administration-approved mAbs, including obinutuzumab, cetuximab, and trastuzumab, require, in part, these effector mechanisms to eliminate tumor cells. Although gram quantities of mAbs can be administered to patients, our investigations of CD20 mAb-based therapies for chronic lymphocytic leukemia (CLL), including correlative measurements in clinical trials and studies with primary cells and cell lines, indicate that effector mechanisms necessary for mAb activity can be saturated or exhausted if tumor burdens are high, thus substantially compromising the efficacy of high-dose mAb therapy. Under these conditions, another reaction (trogocytosis) predominates in which bound CD20 mAb and CD20 are removed from targeted cells by effector cells that express Fcγ receptors, thereby allowing malignant cells to escape unharmed and continue to promote disease pathology. To address this problem, we propose that a low-dose strategy, based on administering 30-50 mg of CD20 mAb three times per week, may be far more effective for CLL than standard dosing because it will minimize effector function saturation and reduce trogocytosis. This approach may have general applicability to other mAbs that use immune effector functions, and could be formulated into a subcutaneous treatment strategy that would be more accessible and possibly more efficacious for patients.


Polyladderane Constructed from a Gemini Monomer through Photoreaction.
Polyladderane, the first polymer to contain the ladderane functional group, was synthesized from a gemini monomer through photoreaction in the solid state. The modular design of the gemini monomers used to create polyladderane allowed specific structural modification, resulting in the formation of two distinct polymer products. Monomers were synthesized by connecting two photoreactive units, either sorbic acids (monomer I) or 2-furanacrylic acids (monomer II), with a 1,4-butanediol linker. Single-crystal X-ray diffraction analysis of the monomers confirmed that they packed in the desired head-to-tail orientation and within a viable distance for photoreaction by electronically complementary interaction. Pre-organized gemini monomers were irradiated with UV light and monitored by FT-IR. Two polyladderanes with cis,anti,cis-[3]-ladderane as a characteristic functional group were constructed stereospecifically in 24-36 hours.


Cost-effectiveness of recombinant versus urinary follicle-stimulating hormone in assisted reproduction techniques in the Spanish public health care system.
To evaluate the relative cost-effectiveness of recombinant and urinary follicle-stimulating hormone (FSH) in assisted reproduction techniques in the Spanish National Health Service. Markov modelling was used to compare costs and outcomes of three complete treatment cycles using recombinant or urinary FSH for controlled ovarian stimulation. Cost and effectiveness estimates were obtained from the literature and from Spanish clinicians. A Monte Carlo technique was used to randomise the distribution of outcomes at each stage. The analysis was performed by passing a virtual population of 100,000 patients through the computer simulation in each of 5000 Monte Carlo simulations. The cost per pregnancy was Euro12,791+/-1202 ($11,346+/-1066) with recombinant and Euro13,007+/-1319 ($11,537+/-1170) with urinary FSH (p < 0.0001). The mean number of cycles per pregnancy was 4.69 and 5.21, respectively. Recombinant FSH is more cost-effective than urinary FSH in the Spanish public health care system.


Serum 25-hydroxyvitamin D concentrations and risk for hip fractures.
The relationship between serum 25-hydroxyvitamin D [25(OH) vitamin D] concentration and hip fractures is unclear. To see whether low serum 25(OH) vitamin D concentrations are associated with hip fractures in community-dwelling women. Nested case-control study. 40 clinical centers in the United States. 400 case-patients with incident hip fracture and 400 control participants matched on the basis of age, race or ethnicity, and date of blood draw. Both groups were selected from 39 795 postmenopausal women who were not using estrogens or other bone-active therapies and who had not had a previous hip fracture. Serum 25(OH) vitamin D was measured and patients were followed for a median of 7.1 years (range, 0.7 to 9.3 years) to assess fractures. Mean serum 25(OH) vitamin D concentrations were lower in case-patients than in control participants (55.95 nmol/L [SD, 20.28] vs. 59.60 nmol/L [SD, 18.05]; P = 0.007), and lower serum 25(OH) vitamin D concentrations increased hip fracture risk (adjusted odds ratio for each 25-nmol/L decrease, 1.33 [95% CI, 1.06 to 1.68]). Women with the lowest 25(OH) vitamin D concentrations (< or =47.5 nmol/L) had a higher fracture risk than did those with the highest concentrations (> or =70.7 nmol/L) (adjusted odds ratio, 1.71 [CI, 1.05 to 2.79]), and the risk increased statistically significantly across quartiles of serum 25(OH) vitamin D concentration (P for trend = 0.016). This association was independent of number of falls, physical function, frailty, renal function, and sex-steroid hormone levels and seemed to be partially mediated by bone resorption. Few case-patients were nonwhite women. Bone mineral density and parathyroid hormone levels were not accounted for in the analysis. Low serum 25(OH) vitamin D concentrations are associated with a higher risk for hip fracture.


Bevacizumab therapy in patients with recurrent uterine neoplasms.
Angiogenesis plays an important role in endometrial carcinogenesis. We reviewed our experience with the anti-VEGF monoclonal antibody bevacizumab for the treatment of recurrent uterine neoplasms. A retrospective analysis of women with recurrent uterine neoplasms treated with bevacizumab was performed. A total of 11 patients were identified, 9 with epithelial endometrial carcinomas and 2 with leiomyosarcomas. All patients had multi-site disease and were heavily pretreated with a median of 3 prior chemotherapy regimens. All received bevacizumab combination therapy which was well-tolerated. Two patients had partial responses, 3 had stable disease, while 5 patients progressed. One subject was not assessable for response. The median progression-free interval was 5.4 months for the entire cohort and 8.7 months for those who achieved clinical benefit (PR or SD). Bevacizumab was well-tolerated and displayed promising anti-neoplastic activity in patients with endometrial cancer and uterine leiomyosarcoma.


[Analysis of the genome compartmentalization phenomenon in normal and neoplastic cells].
Intact cell nuclei (or whole cell lysates) were immobilized on Celite and extracted gradually with gradients of NaCl, LiCl-urea and temperature. Contrary to the notion of DNA integrity and continuity within chromosomes, a heterogeneous spectrum of DNA fragments of large size was obtained, adhesion of which to the nuclear interior widely varied. Similar chromatographic patterns of DNA were observed in analysis of various origin cells both in normal animal tissues and in malignant cells (Djungarian hamster fibroblasts transformed by SV40). Possible artefacts of apparent genome fragmentation caused by radioactive precursors or hydrodynamic shearing were checked up and ruled out as well as endogenous nucleases appear not to be involved in the phenomenon observed. DNA end-labelling in situ enabled to reveal pre-existence of DNA fragments in isolated nuclei.


Catheter-Directed Thrombolysis in the Treatment of Acute Ischemia in Lower Extremities Is Safe and Effective, Especially with Concomitant Endovascular Treatment.
Objective: To evaluate the influence of pre-procedural characteristics on immediate and late results as well as the safety of catheter-directed thrombolysis (CDT) in acute ischemia of the lower extremity. Materials and Methods: A retrospective study comprising 249 patients treated by CDT from January 2006 to December 2012. Outcomes were primary patency, haemorrhagic complications, amputation and mortality. Results: Primary patency for CDT alone was 68%, for CDT plus endovascular treatment 87% and for successful CDT with supplementary surgery 62% giving an overall primary patency of 76%. Two (0.8%) patients suffered from cerebral haemorrhage during CDT. We found a significant correlation between 30 day amputation rate and no visual distal run-off at CDT start (OR 2.31; CI95% 1.09-4.91; p-value=0.02) and onset of symptoms to CDT start of 8-14 days (OR 4.09; CI95% 1.42-11.81; p-value=0.01). Lack of visualized distal run-off was also associated with a significant risk of 30 day mortality (OR 5.84; CI95% 1.26-27.00; p-value=0.02). Conclusion: Our results show that CDT is a feasible and safe treatment option especially when combined with angioplasty +/- stent. However, no distal run-off at primary angiography is associated with higher rates of amputation during follow-up and 30 day mortality.


Zinc and copper plasma concentrations in rheumatoid arthritis patients from a selected population in Iran.
The importance of trace elements in chronic inflammatory diseases is related to their cofactor role in immune system functions and in different metabolic processes in articular tissues. The aim of this study was to compare serum levels of Cu, Zn and Zn/Cu ratio in Rheumatoid Arthritis (RA) patients with healthy volunteers in Sari Rheumatology clinic, 2007. Zn and Cu plasma concentrations were assayed using atomic absorption spectrophotometery in 40 selected RA patients sera based on sex and age compared with healthy volunteers. Statistical analysis was performed by SPSS 10 software using independent sample t-test. Zn plasma content in patient group was significantly lower (p = 0.02) than that in healthy group. Also, Cu plasma content showed no differences in comparison with healthy group (p = 0.15). Results showed no correlation between Cu and Zn plasma concentrations in patient group (p = 0.946). In contrast, significant positive correlation was found between Zn and Zn/Cu ratio (p = 0.000); but decreased Zn/Cu ratio was more influenced by diminished Zn concentration. The study showed that spreading of RA in Iranian Society is related to age, sex, career and nutrition of the patients. However, consumption of Zn and Cu supplements in RA patients may be suggested by future investigations.