Rate dependence of acute PTH release and association between basal plasma calcium and set point of calcium-PTH curve in dialysis patients.
In vivo, the control of calcium-mediated acute PTH release during induced hypo- or hypercalcaemia is linked not only to plasma calcium concentration per se but also to the rate and direction of calcium change. In fact, during induced hypocalcaemia, the predominant mechanism that causes PTH to be released is the reduction of plasma Ca(2+) irrespective of the absolute starting concentration of ionized calcium. This mechanism, which is rate-dependent and even activated in conditions of hypercalcaemia, may be involved in the association, reported in several papers, between the basal Ca(2+) and the set point of the calcium-PTH curve. The calcium-PTH relationship was studied in 12 dialysis patients under conditions of induced low and high predialysis plasma Ca(2+). At each level of basal Ca(2+), dynamic tests were conducted using two methodological approaches. In method A patients underwent low (0.5 mmol/l) calcium dialysis in the stimulation test and high (2 mmol/l) calcium dialysis in the inhibition test, while the dialysate calcium (CaD) was kept constant during each test. In this way a higher but variable rate of change in plasma Ca(2+) was achieved. In method B, CaD was progressively decreased (stimulation test) and increased (inhibition test) during the tests in order to obtain a lower but more constant rate of change in plasma Ca(2+). Consequently, for each patient, four calcium-PTH curves were produced: low basal Ca(2+) with methods A and B, and high basal Ca(2+) with methods A and B. Basal plasma Ca(2+) was similar in A and B at low (1.16+/-0.02 vs 1.15+/-0.02 mmol/l) and high (1.25+/-0.02 vs 1.26+/-0.02 mmol/l) basal plasma Ca(2+). The set point was higher in A than in B both at low (1.12+/-0.02 vs 1.10+/-0.02 mmol/l, P=0.01) and high (1.20+/-0.02 vs 1.16+/-0.02 mmol/l, P=0.03) basal Ca(2+) as was the slope (542+/-41 vs 426+/-44%/mmol, P=0.02; 615+/-73 vs 389+/-25%/mmol, P=0.01). No significant difference was found between A and B as regards minimal PTH and plasma Ca(2+) at minimal PTH (Camin) in both calcaemic states. Maximal PTH was slightly higher in B at low (510+/-97 vs 548+/-107 pg/ml, P=NS) and high basal plasma Ca(2+) (410+/-97 vs 464+/-108 pg/ml, P=0.02). Plasma calcium at maximal PTH (Camax) was significantly higher in A (1.1+/-0.03 vs 0.99+/-0.02 mmol/l, P=0.001) at high basal plasma Ca(2+). The set point was strictly related to basal plasma Ca(2+) in both methods, but the slope of the linear regression was significantly steeper with method A. The set point was predicted to increase by 0.881 (CI 0.772-0.990) mmol/l for each mmol/l of increase in basal plasma Ca(2+) with method A and by 0.641 (CI 0.546-0.737) mmol/l for each mmol/l of increase in basal plasma Ca(2+) with method B. (i) Higher and variable rates of change in plasma Ca(2+) produce a higher set point value and a steeper slope of the calcium-PTH curve when compared to lower and more constant rates of calcium change. (ii) The different slope of the linear correlations between basal plasma Ca(2+) and set point in the two methods suggests that the rate-dependent mechanism of acute PTH release plays a significant role in the association between set point and basal plasma Ca(2+). (iii) The significance of the set point is questionable when the calcium-PTH curve is carried out in vivo.


Sleep macrostructure is modulated by positive and negative social experience in adult pet dogs.
The effects of emotionally valenced events on sleep physiology are well studied in humans and laboratory rodents. However, little is known about these effects in other species, despite the fact that several sleep characteristics differ across species and thus limit the generalizability of such findings. Here we studied the effect of positive and negative social experiences on sleep macrostructure in dogs, a species proven to be a good model of human social cognition. A non-invasive polysomnography method was used to collect data from pet dogs (n = 16) participating in 3-hour-long sleep occasions. Before sleep, dogs were exposed to emotionally positive or negative social interactions (PSI or NSI) in a within-subject design. PSI consisted of petting and ball play, while NSI was a mixture of separation, threatening approach and still face test. Sleep macrostructure was markedly different between pre-treatment conditions, with a shorter sleep latency after NSI and a redistribution of the time spent in the different sleep stages. Dogs' behaviour during pre-treatments was related to the macrostructural difference between the two occasions, and was further modulated by individual variability in personality. This result provides the first direct evidence that emotional stimuli affect subsequent sleep physiology in dogs.


Mechanisms of nocturnal gastroesophageal reflux events in obstructive sleep apnea.
Obstructive sleep apnea (OSA) is associated with increased nocturnal gastroesophageal reflux (nocturnal GER) events and symptoms. Treatment of OSA with continuous positive airway pressure (CPAP) reduces nocturnal GER in patients with OSA. This study sought to determine the: (1) relationship of nocturnal GER events with apnea/hypopnea and arousal, (2) effect of upper airway obstruction on the barrier function of the lower esophageal sphincter (LES), (3) mechanism of LES failure for each nocturnal GER event and (4) effect of CPAP on LES function during sleep. Eight patients with OSA and nocturnal GER underwent polysomnography with esophageal manometry and pH monitoring. The first half of the night was spent without CPAP and the second half with 10 cmH(2)O CPAP. Baseline LES barrier pressure (P (b)) was low in these patients. When patients were off CPAP, there were 2.7 ± 1.8 nocturnal GER events per hour and 70 ± 39 obstructive respiratory events per hour. There was no direct relationship between the occurrence of GER and obstructive events. While upper airway obstruction did not alter P (b), CPAP tended to increase the nadir P (b) during LES relaxation (LESR) and decreased the duration of LESR. Upper airway obstructive and nocturnal GER events are not directly related. The relatively low P (b) in these OSA patients raises the possibility of weakening of the gastroesophageal junction from repetitive strain associated with obstructed breathing events. The favourable effect of CPAP on nocturnal GER is possibly due to an increase in nadir P (b) and decrease in the duration for which the LES relaxes during swallow-induced and transient LESR.


Standardised Exercise Prescription for Patients with Chronic Coronary Syndrome and/or Heart Failure: A Consensus Statement from the EXPERT Working Group.
Whereas exercise training, as part of multidisciplinary rehabilitation, is a key component in the management of patients with chronic coronary syndrome (CCS) and/or congestive heart failure (CHF), physicians and exercise professionals disagree among themselves on the type and characteristics of the exercise to be prescribed to these patients, and the exercise prescriptions are not consistent with the international guidelines. This impacts the efficacy and quality of the intervention of rehabilitation. To overcome these barriers, a digital training and decision support system [i.e. EXercise Prescription in Everyday practice & Rehabilitative Training (EXPERT) tool], i.e. a stepwise aid to exercise prescription in patients with CCS and/or CHF, affected by concomitant risk factors and comorbidities, in the setting of multidisciplinary rehabilitation, was developed. The EXPERT working group members reviewed the literature and formulated exercise recommendations (exercise training intensity, frequency, volume, type, session and programme duration) and safety precautions for CCS and/or CHF (including heart transplantation). Also, highly prevalent comorbidities (e.g. peripheral arterial disease) or cardiac devices (e.g. pacemaker, implanted cardioverter defibrillator, left-ventricular assist device) were considered, as well as indications for the in-hospital phase (e.g. after coronary revascularisation or hospitalisation for CHF). The contributions of physical fitness, medications and adverse events during exercise testing were also considered. The EXPERT tool was developed on the basis of this evidence. In this paper, the exercise prescriptions for patients with CCS and/or CHF formulated for the EXPERT tool are presented. Finally, to demonstrate how the EXPERT tool proposes exercise prescriptions in patients with CCS and/or CHF with different combinations of CVD risk factors, three patient cases with solutions are presented.


Photoacoustic microscopy of tyrosinase reporter gene in vivo.
Photoacoustic tomography is a hybrid modality based on optical absorption excitation and ultrasonic detection. It is sensitive to melanin, one of the primary absorbers in skin. For cells that do not naturally contain melanin, melanin production can be induced by introducing the gene for tyrosinase, the primary enzyme responsible for expression of melanin in melanogenic cells. Optical resolution photoacoustic microscopy was used in the ex vivo study reported here, where the signal from transfected cells increased by more than 10 times over wild-type cells. A subsequent in vivo experiment was conducted to demonstrate the capability of photoacoustic microscopy to spectrally differentiate between tyrosinase-catalyzed melanin and various other absorbers in tissue.


Incidence, significance, and kinetic mechanism responsible for leukemoid reactions in patients in the neonatal intensive care unit: a prospective evaluation.
To prospectively investigate the incidence, significance, and kinetic mechanism responsible for leukemoid reactions in patients in the neonatal intensive care unit (NICU). We prospectively studied all infants admitted to the NICU at the University of Florida who, during a period of 12 consecutive months, had a leukemoid reaction. All those identified had a standardized evaluation consisting of (1) karyotype analysis, (2) bacterial cultures, (3) evaluations for toxoplasmosis, other (congenital syphilis and viruses), rubella, cytomegalovirus, and herpes simplex virus) (TORCH), (4) determination of blood viscosity, (5) use of marrow aspirates for morphology, clonogenic progenitor cell assays, and cell-cycle analysis of progenitors, (6) determination of serum concentrations of granulocyte and granulocyte-macrophage colony-stimulating factors, and (7) serial complete blood cell counts until the leukemoid reaction remitted. During 12 months, 707 patients were admitted to the NICU and 4262 complete blood cell counts were performed on samples from these patients. A leukemoid reaction was identified in nine patients, all of whom were preterm (born at 24 to 38 weeks' gestation). Peak blood leukocyte concentrations were 51.7 +/- 15.6 x 10(3)/microl (mean +/- SD). The leukemoid reactions were detected during the first 4 days of life in seven patients, on day 9 in one, and on day 25 in one. An abnormal karyotype (47, XY, +21) was present in one infant. Mothers of four infants had received betamethasone antenatally. None had elevated whole blood viscosity or positive findings on bacterial or TORCH evaluations. None of the bone marrow findings were consistent with steroid-induced leukocytosis; all studies indicated accelerated neutrophil production. Serum concentrations of granulocyte-macrophage colony-stimulating factor were either negligible or nondetectable. Serum granulocyte colony-stimulating factor was elevated in three patients, low in two, and nondetectable in four. The leukemoid reactions persisted for 5 to 32 days, the longest being in the patient with trisomy 21. Leukemoid reactions were not particularly rare in our NICU (1.3% of patients). The reactions were not associated with hyperviscosity and, except in one patient with a karyotype abnormality, were transient. The responsible kinetic mechanism was increased neutrophil production, not steroid-induced leukocytosis.


Clinical prediction of pathological complete response after preoperative chemoradiotherapy for rectal cancer.
The clinical pretreatment factors that accurately predict response to chemoradiation in rectal cancer are not currently known. The aim of this study is to evaluate the clinical factors associated with a pathological complete response after preoperative chemoradiotherapy for rectal cancer. This study is a retrospective review of prospectively collected data. This study was conducted at a tertiary care hospital/referral center in South Korea. From December 2000 to September 2011, a total of 391 consecutive patients with rectal cancer who underwent neoadjuvant chemoradiotherapy followed by radical surgery were identified. The treatment consisted of concurrent chemoradiation, which included preoperative 5-fluorouracil-based chemotherapy and pelvic radiation (median, 5040 cGy); this was followed 8 weeks later (median, 57 days) by surgery with curative intent. The primary outcome measured was the clinicopathological comparison between pathological complete response (n = 57, 14.6%) and non-pathological complete response (n = 334, 85.4%) groups. The pathological complete response groups had a higher percentage of noncircumferential tumors, nonmacroscopic ulceration, well differentiation, small tumor diameter, early clinical T stage, early clinical N stage, or low levels of pretreatment CEA than the non-pathological complete response group. In multivariate regression analysis, independent predictors of a higher pathological complete response rate were noncircumferentiality (p = 0.007; OR, 3.214), nonmacroscopic ulceration (p = 0.002; OR, 6.702), and low pretreatment CEA level (p = 0.004; OR, 2.656). Significant differences in the pathological complete response rate existed among the 4 risk stratification groups (p < 0.001). For the prediction of pathological complete response by the clinical risk score model, the sensitivity was 64.1% and the specificity was 73.7% (area under the curve, 0.706; p < 0.001). This study was limited because it was a single-institution study with a small sample size. Pretreatment clinical variables, including tumor circumferentiality, macroscopic ulceration, and CEA level, may be important determinants in achieving a pathological complete response.


Exogenous Delivery of Link N mRNA into Chondrocytes and MSCs-The Potential Role in Increasing Anabolic Response.
Musculoskeletal disorders, such as osteoarthritis and intervertebral disc degeneration are causes of morbidity, which concomitantly burdens the health and social care systems worldwide, with massive costs. Link N peptide has recently been described as a novel anabolic stimulator for intervertebral disc repair. In this study, we analyzed the influence on anabolic response, by delivering synthetic Link N encoding mRNA into primary human chondrocytes and mesenchymal stromal cells (SCP1 cells), Furthermore, both cell types were seeded on knitted titanium scaffolds, and the influence of Link N peptide mRNA for possible tissue engineering applications was investigated. Synthetic modified Link N mRNA was efficiently delivered into both cell types and cell transfection resulted in an enhanced expression of aggrecan, Sox 9, and type II collagen with a decreased expression of type X collagen. Interestingly, despite increased expression of BMP2 and BMP7, BMP signaling was repressed and TGFβ signaling was boosted by Link N transfection in mesenchymal stromal cells, suggesting possible regulatory mechanisms. Thus, the exogenous delivery of Link N peptide mRNA into cells augmented an anabolic response and thereby increased extracellular matrix synthesis. Considering these findings, we suppose that the cultivation of cells on knitted titanium scaffolds and the exogenous delivery of Link N peptide mRNA into cells could mechanically support the stability of tissue-engineered constructs and improve the synthesis of extracellular matrix by seeded cells. This method can provide a potent strategy for articular cartilage and intervertebral disc regeneration.


Automated mapping of explosives particles in composition C-4 fingerprints.
A method is described to perform automated mapping of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) particles in C-4 fingerprints. The method employs polarized light microscopy and image analysis to map the entire fingerprint and the distribution of RDX particles. This method can be used to evaluate a large number of fingerprints to aid in the development of threat libraries that can be used to determine performance requirements of explosive trace detectors. A series of 50 C-4 fingerprints were characterized, and results show that the number of particles varies significantly from print to print, and within a print. The particle size distributions can be used to estimate the mass of RDX in the fingerprint. These estimates were found to be within +/-26% relative of the results obtained from dissolution gas chromatography/micro-electron capture detection for four of six prints, which is quite encouraging for a particle counting approach. By evaluating the average mass and frequency of particles with respect to size for this series of fingerprints, we conclude that particles 10-20 microm in diameter could be targeted to improve detection of traces of C-4 explosives.


Monolayered multipolymeric buccal films with drug and polymers of opposing solubilities for ARV therapy: physico-mechanical evaluation and molecular mechanics modelling.
Although buccal permeation investigations with antiretroviral drug solutions have confirmed their transbuccal delivery potential, studies on their formulation into delivery systems are lacking. Multipolymeric monolayered films (MMFs) with drugs and polymers of opposing solubilities will offer several advantages for the controlled release delivery of didanosine (DDI) via the buccal route. The aim of this study was to employ a co-blending-co-plasticization technique for preparation of MMFs containing Eudragit(®) RS 100 (EUD) and Hydroxypropyl methylcellulose (HPMC) and to undertake molecular modelling and in vitro characterizations. Uniform drug content (91-105%) with low variability was obtained for all films. Co-blending of DDI:HPMC:EUD (1:1:10) was required to achieve controlled drug release. The buccal permeability potential of DDI from the MMFs was successfully demonstrated with a permeability coefficient of 0.72±0.14×10(-2) cm/h and a steady state flux of 71.63±13.54 μg/cm(2) h. Films had acceptable mucoadhesivity (2184 mN), mechanical strength (0.698 N/mm(2)) and surface pH (6.63). The mechanism inherent to the mucoadhesive and drug release profile performance of the MMFs was elucidated via static lattice molecular mechanics simulations wherein a close corroboration among the in vitro-in silico (IVIS) data was observed. These extensive physico-mechanical and molecular atomistic studies have confirmed the use of MMFs containing DDI, HPMC and EUD as a buccal delivery system.


Critical appraisal. 2015 Update: Approaches to Caries Removal.
Every day in the United States and around the world, complete caries removal in vital, asymptomatic teeth with deep caries lesions ends in unavoidable exposure of the pulp. As a result, the complexity and cost of treatment increase dramatically, and many patients are left with extraction as their only viable option. This Critical Appraisal updates a previous appraisal (2013). Since that review three, systematic reviews of the literature and one large, randomized controlled clinical trial (RCT) have been published. Thus, newer, higher quality evidence is available that supports alternative treatments designed to preserve the vitality of the tooth and thus avoid extraction.


Nutritional Management in Bariatric Surgery Patients.
The obesity epidemic, mainly due to lifestyle changes in recent decades, leads to serious comorbidities that reduce life expectancy. This situation is affecting the health policies of many nations around the world. Traditional measures such as diet, physical activity, and drugs are often not enough to achieve weight loss goals and to maintain the results over time. Bariatric surgery (BS) includes various techniques, which favor rapid and sustained weight loss. BS is a useful and, in most cases, the best treatment in severe and complicated obesity. In addition, it has a greater benefit/risk ratio than non-surgical traditional therapies. BS can allow the obese patient to lose weight quickly compared with traditional lifestyle changes, and with a greater probability of maintaining the results. Moreover, BS promotes improvements in metabolic parameters, even diabetes remission, and in the quality of life. These changes can lead to an increase of life expectancy by over 6 years on average. The nutrition of people before and after BS must be the subject of indications from a trained staff, and patients must be followed in the subsequent years to reduce the risk of malnutrition and the associated problems. In particular, it is still debated whether it is necessary to lose weight prior to surgery, a procedure that can facilitate the surgeon's work reducing the surgical risk, but at the same time, lengthens preparation times increasing the risks associated with concomitant pathologies. Furthermore, preventing nutritional deficiencies prior to the intervention can improve the results and reduce short- and long-term mortality.


Crystal structure of the inclusion complex of the antibacterial agent triclosan with cyclomaltoheptaose and NMR study of its molecular encapsulation in positively and negatively charged cyclomaltoheptaose derivatives.
The inclusion complexes of triclosan with native cyclomaltoheptaose (beta-cyclodextrin, betaCD) as well as with negatively and positively charged derivatives are studied. The structure of the inclusion complex betaCD/triclosan in the crystalline state [P1, a=15.189(5), b=15.230(6), c=16.293(6), alpha=91.07(4), beta=91.05(3) gamma=100.71(3)] comprises two crystallographically independent host macrocycles A and B. The packing results in betaCD dimers that align head-to-head and form infinite channels along the c-axis. Only one guest molecule statistically disordered over two positions, (the dichlorophenyl ring in the cavities of either A or B) corresponds to each dimer (a 2:1 host/guest complex). The enclosed dichlorophenyl ring enters the dimer through the primary side, whereas the hydrophilic chlorophenol ring extends in the space between dimers. Water molecules in five positions are also enclosed in the intradimer region, arranged on a plane perpendicular to the sevenfold axis of betaCD. The NMR spectroscopic studies in aqueous solution show the presence of both 1:1 and 2:1 betaCD/triclosan complexes. In the first case, two different 1:1 complexes are simultaneously present, each with either ring entering the narrow primary side of one betaCD molecule. In the 2:1 complex both rings of triclosan are included in two independent betaCD hosts, a precursor to the supramolecular arrangement found in the crystalline form. In the case of the negatively charged sodium heptakis[6-deoxy-6-(3-thiopropionate)]-betaCD, the NMR studies at pH 7.9 show a complete inclusion of triclosan inside the host in two orientations, one for the non-ionized (phenol) and reverse for the ionized (phenolate) form. Finally, for the positively charged heptakis(6-aminoethylamino-6-deoxy)-betaCD, inclusion of triclosan is possible only when the pH is raised to 10 and it is concluded that both aromatic rings are alternatively inside the cavity. However in that case also, inclusion of the entire guest in the elongated cavity is suggested.


Genetic networks in osseointegration.
Osseointegration-based dental implants have become a well-accepted treatment modality for complete and partial edentulism. The success of this treatment largely depends on the stable integration and maintenance of implant fixtures in alveolar bone; however, the molecular and cellular mechanisms regulating this unique tissue reaction have not yet been fully uncovered. Radiographic and histologic observations suggest the sustained retention of peri-implant bone without an apparent susceptibility to catabolic bone remodeling; therefore, implant-induced bone formation continues to be intensively investigated. Increasing numbers of whole-genome transcriptome studies suggest complex molecular pathways that may play putative roles in osseointegration. This review highlights genetic networks related to bone quality, the transient chondrogenic phase, the vitamin D axis, and the peripheral circadian rhythm to elute the regulatory mechanisms underlying the establishment and maintenance of osseointegration.


Effects of crude extracts of a saxitoxin-producer strain of the cyanobacterium Cylindrospermopsis raciborskii on the swimming behavior of wild and laboratory reared guppy Poecilia vivipara.
The cyanobacterium Cylindrospermopsis raciborskii is an invasive species in water supply reservoirs worldwide, which can produces cylindrospermopsins and saxitoxins. In the wild, guppy (Poecilia vivipara) can be exposed to cyanotoxins, but those born and reared in laboratory are free of this contact. The aim of this paper was to comparatively measure the locomotor activity of 'wild' and 'lab' P. vivipara before and after exposure to crude extracts of two different cultures of C. raciborskii (CYRF-01), a saxitoxin-procucer strain. The movement of each fish was recorded using an image monitoring system (Videomex V®) before and after 48 h exposure to cyanobacterial extracts. Each experiment was performed during 4 h, with 1 h acclimation and 3 h recording period of the parameters Distance performed (DP), Swimming time (SwT), Stereotypic time (StT), Resting time (RT) and Average speed (AS). The quantification of saxitoxin in the solutions was performed by the enzyme-linked immunosorbent assay (ELISA). The weight or the total length did not influence the locomotor activity of fish in any of the experiments. The saxitoxin value was similar for both cultures (Culture 1: 7.3 μg L-1 and Culture 2: 8.6 μg L-1). However, in experiments with Culture 1 an increased activity in most parameters was observed, while in Culture 2, a decreased activity was observed only in 'lab' fish. Wild fish was less affected, showing higher resistance to both cyanobacterial crude extracts. This study showed that different cultures of the same strain of C. raciborskii and with similar contents of saxitoxin are able to change the locomotor activity of P. vivipara, contributing to the validation of the use of behavioral parameters to the evaluation of sublethal effects of toxic cyanobacteria on fish.


Laser-Based People Detection and Obstacle Avoidance for a Hospital Transport Robot.
This paper describes the development of a laser-based people detection and obstacle avoidance algorithm for a differential-drive robot, which is used for transporting materials along a reference path in hospital domains. Detecting humans from laser data is an important functionality for the safety of navigation in the shared workspace with people. Nevertheless, traditional methods normally utilize machine learning techniques on hand-crafted geometrical features extracted from individual clusters. Moreover, the datasets used to train the models are usually small and need to manually label every laser scan, increasing the difficulty and cost of deploying people detection algorithms in new environments. To tackle these problems, (1) we propose a novel deep learning-based method, which uses the deep neural network in a sliding window fashion to effectively classify every single point of a laser scan. (2) To increase the speed of inference without losing performance, we use a jump distance clustering method to decrease the number of points needed to be evaluated. (3) To reduce the workload of labeling data, we also propose an approach to automatically annotate datasets collected in real scenarios. In general, the proposed approach runs in real-time and performs much better than traditional methods. Secondly, conventional pure reactive obstacle avoidance algorithms can produce inefficient and oscillatory behaviors in dynamic environments, making pedestrians confused and possibly leading to dangerous reactions. To improve the legibility and naturalness of obstacle avoidance in human crowded environments, we introduce a sampling-based local path planner, similar to the method used in autonomous driving cars. The key idea is to avoid obstacles by switching lanes. We also adopt a simple rule to decrease the number of unnecessary deviations from the reference path. Experiments carried out in real-world environments confirmed the effectiveness of the proposed algorithms.


Absence of Toll-like receptor 4 explains endotoxin hyporesponsiveness in human intestinal epithelium.
The Toll protein in Drosophila regulates dorsal ventral patterning during embryogenesis, and participates in antibacterial and antifungal host defense. Mammalian homologues are termed Toll-like receptors and, to date, nine have been cloned (TLRI-9) in humans. They are characterized by extracellular leucine-rich repeats and a cytoplasmic domain similar to the interleukin 1 receptor. Both TLR2 and TLR4 recognize various bacterial cell wall components including lipopolysaccharide (LPS). This results in the activation of the NFkappaB pathway. Peripheral blood mononuclear cells (PBMCs) express both TLR2 and TLR4. The authors hypothesized that the expression of TLR 2 and TLR4 in human intestinal epithelial cells differs from PBMCs because of the abundance of LPS in the intestinal lumen. Epithelial cells were isolated from Caco-2 cells, fetal gut explants, and small bowel resection specimens using Hanks/ethylenediamine tetraacetic acid solution. PBMCs were used as positive controls. Ribonucleic acid (RNA) was isolated using the TRIzol method. Standard reverse transcription-polymerase chain reaction examined TLR2 and TLR4 messenger RNA (mRNA) expression. NFkappaB expression was determined using a luciferase reporter assay. TLR2 mRNA was highly expressed in PBMCs and was present in all human intestinal epithelial cells. TLR4 mRNA was detected only in PBMCs. TLR4 is not present in epithelium from children with inflammatory bowel disease. In Caco-2 cells, significant NFkappaB activation in response to LPS occurred only in the presence of TLR4 introduced by complementary deoxyribonucleic acid transfection. Absence of TLR4 is associated with endotoxin hyporesponsiveness of intestinal epithelial cells. TLR4 is not directly involved in inflammation of the intestinal epithelium. Although TLR2 is normally present in the epithelial cell, it plays a limited role in inflammation. It may be activated during conditions in which bacterial cell wall concentrations within the intestine are pathologically high.


Competing ideologies in health care: a personal perspective.
With the introduction of general management and then of planned markets into the National Health Service (NHS), health care in the UK has gone through a massive amount of change. The effect on those working for the NHS has been 'challenging' and often confusing. This paper aims to clarify what is happening by taking an ideological perspective: what ideologies exist, how they are changing and the strategies being used to ensure their survival. Ideologies are basically about power. The relationship between market, managerial and professional ideologies is analysed using charters, codes of conduct and other associated documents. A tentative conclusion is reached that professional ideologies are able to adjust to the overriding market/consumerist ideology. However, the managerial ideology is having difficulty in gaining any real ground against the professional ideology and is having to move strategically by using audit, not just of finance, but also of clinical judgement, to gain power.


Accurate identification of neutralizing antibodies to adenovirus Ad36, -a putative contributor of obesity in humans.
In children and adults, human adenovirus serotype 36 (Ad36) is linked with increased adiposity, and important metabolic alterations. Since this property is not shared by many other human adenovirus serotypes, it is imperative to specifically identify exposure to Ad36. Although serum neutralization assay (SNA) is the gold standard to specifically detect neutralizing antibodies (NA) to Ad36, it requires 2-weeks to complete and considerable training to interpret the results. Whereas, an enzyme-immuno assay (EIA) may provide a quicker and objective determination. Evaluate the accuracy of commercially available EIA kits to detect NA to Ad36. Modify SNA to reduce time and increase objectivity. Sera of 15 seropositive or 16 seronegative subjects confirmed by SNA were used to test: 1) reproducibility of SNA to detect Ad36 exposure, by repeating assays twice; 2) an EIA that detects antibodies to all human adenovirus serotypes (NS-EIA) (Abcam-108705); 3) an EIA supposedly specific for Ad36 antibody (Ad36-EIA) (MyBioSource,#MBS705802), and 4) the concordance of SNA with a novel combination of SNA and immune-staining (SN-IS) kit (Cell BioLabs,#VPK-111). The SNA showed exact reproducibility. NS-EIA detected adenovirus antibodies in 94% samples, confirming the non-specificity of the assay for Ad36 serotype. All seronegative samples (as determined by SNA) were false positive by Ad36-EIA. In 97% samples, SN-IS showed fidelity with Ad36-antibody status as determined by SNA. The available EIA kits are not specific for detecting NA to Ad36. The modified SNA with immune-staining reduces assay time and increases accuracy of detecting by reducing subjectivity.


A Role for Estrogen Receptor alpha36 in Cancer Progression.
Estrogen receptor α (ERα) functions as a ligand dependent transcription factor that directly binds specific estrogen responsive elements, thus regulating the transcription of estrogen sensitive genes. ERα has also been shown to be associated with the plasma membrane (membrane associated ERα, mERα), concentrated in lipid rafts, plasma membrane microdomains with a distinct lipid composition, where it transduces membrane-initiated estrogen-dependent activation of the mitogen-activated protein (MAP) kinase signaling pathway. Two isoforms of ERα have been described: the "traditional" ERα66 (66 kDa) and a lower molecular weight variant: the ERα46 (46 kDa). More recently, a novel ERα variant with a molecular mass of 36 kDa (ERα36) has been discovered. Notably, ERα36 has been found expressed in different human tumor cells, including both ER- positive and ER- negative breast cancer cells. Estrogen signaling at the cell membrane via ERα36 appears as capable of activating multiple pathways of importance for cancer aggressiveness and metastatic potential. The presence of serum autoantibodies reacting with mERα (anti-ERα Abs) in a large percentage of patients with breast cancer has recently been reported by our group. These anti-ERα Abs seem to act as estrogen agonists rapidly triggering MAP kinase pathway activation thus inducing tumor cell proliferation and overcoming cell resistance to anti-estrogen drug tamoxifen. In this review, we describe the involvement of ERα36 in different tumors. We also report the potential pathogenetic activity of anti-ERα Abs and their implication in drug resistance.


Combined 18F-FDG PET/CT and 99mTc 3PRGD2 SPECT/CT imaging in a case of pituitary metastases.
We compare F-FDG PET/CT and 99mTc 3PRGD2 SPECT/CT scans in a case of histologically proved pituitary metastases. The ratio of tumor to cerebellum (T/C) of 99mTc 3PRGD2 SPECT is much higher than that for 18F-FDG PET. We then conduct the same scans for a pituitary adenoma patient for better comparison. The T/C of 18F-FDG is not able to differentiate pituitary metastases from pituitary adenoma. However, The T/C of 99mTc 3PRGD2 observed in pituitary metastases was higher than that in pituitary adenoma.


Cyclist safety on bicycle boulevards and parallel arterial routes in Berkeley, California.
This study compares the safety of bicyclists riding on bicycle boulevards to those riding on parallel arterial routes in Berkeley, California. Literature on the impact of motor vehicle traffic characteristics on cyclist safety shows that high motor vehicle speeds and volumes and the presence of heavy vehicles are all detrimental to cyclist safety. This suggests that cyclists may be safer on side streets than on busy arterials. Bicycle boulevards-traffic-calmed side streets signed and improved for cyclist use-purport to offer cyclists a safer alternative to riding on arterials. Police-reported bicycle collision data and manually collected cyclist count data from bicycle boulevards and parallel arterial routes in Berkeley, California from 2003 to 2010 are used to test the hypothesis that Berkeley's bicycle boulevards have lower cyclist collision rates and a lower proportion of bicycle collisions resulting in severe injury. While no significant difference is found in the proportion of collisions that are severe, results show that collision rates on Berkeley's bicycle boulevards are two to eight times lower than those on parallel, adjacent arterial routes. The difference in collision rate is highly statistically significant, unlikely to be caused by any bias in the collision and count data, and cannot be easily explained away by self-selection or safety in numbers. Though the used dataset is limited and the study design is correlational, this study provides some evidence that Berkeley's bicycle boulevards are safer for cyclists than its parallel arterial routes. The results may be suggestive that, more generally, properly implemented bicycle boulevards can provide cyclists with a safer alternative to riding on arterials.


Stereoselectivity of idarubicin reduction in various animal species and humans.
1. The (13S)-dihydro derivative of idarubicin, (13S)-idarubicinol, is the major urinary metabolite of idarubicin in humans. Idarubicinol epimers were quantified by h.p.l.c. in urine from rats, mice, rabbits, dogs and man after i.v. administration of idarubicin, and in man after oral dosing. The (13R)- and (13S)-epimers of idarubicinol were determined in rat bile. 2. After i.v. injection of idarubicin. (13R)-idarubicinol was not detectable in mice and rabbit urine and no more than 0.5% of the dose was present in the urine of other species. In man, the proportion of (13R)-idarubicinol in total idarubicinol was similar after i.v. (4.1%) and oral (3.8-5.0%) administration of idarubicin; the same applies to rat bile and urine. 3. Reduction of idarubicin in vivo is dependent upon ketone reductases, and proceeds more stereoselectively than that of most ketones giving rise to the (13S)-epimer almost exclusively. The high stereospecificity in idarubicin reduction might result from chiral induction due to the presence of asymmetric centres near to the carbonyl group in idarubicin.


Specific detection of Salmonella enterica serotype Enteritidis using the polymerase chain reaction.
An assay was developed for the specific detection of Salmonella enterica serotype Enteritidis, using a novel application of the polymerase chain reaction (PCR). This PCR assay is based on the mismatch amplification mutation assay, an allele-specific reaction, and can discriminate Enteritidis from all other salmonella. PCR primers were selected to amplify a 351-base pair (bp) DNA fragment from the salmonella plasmid virulence A (spv A) gene of Enteritidis. A single base difference at position 272 is present between the nucleotide sequence of the spvA gene of Enteritidis and other salmonellae. The downstream PCR primer, that encompasses position 272 of the Enteritidis spvA gene, was designed to contain a single base mismatch at the penultimate position, resulting in a 1-base mismatch with Enteritidis and a 2-base mismatch with other salmonellae that harbour the virulence plasmid. The upstream primer was completely homologous with the region immediately 5' to the spvA gene. When these primers were used and the annealing and extension reactions were performed at the same temperature, the PCR assay was specific for Enteritidis; no PCR product was detected for 40 other serotypes and 28 different genera examined. In pure culture, 120 colony forming units (c.f.u.) could be detected; a PCR product was observed from template derived from a 5 h enrichment broth culture of chicken seeded with 1 c.f.u. per gram of Enteritidis. This PCR assay is specific, reproducible, and less time consuming than the standard bacteriological methods used to detect Enteritidis.


Vibrio spp. isolated from natural waters of the city of Yangon, Myanmar.
Virulence properties of the environmental isolate of vibrios from natural waters of Yangon, Myanmar were studied. Vibrio spp. were isolated for identification by the membrane filtration method and cultured on thio-sulphate-bile-sucrose media. No Vibrio cholerae O1 were isolated. V. cholerae non-O1 were the major vibrio species isolated from the samples. None of them were detected for cholera-toxin-like toxin, thermostable direct haemolysin, or heat-stable enterotoxin. Sixty-one isolates gave haemolytic activity; 27 V. cholerae non-O1 and 6 V. fluvialis isolates produced protease.


Virtual Reality Rehabilitation's Impact on Negative Symptoms and Psychosocial Rehabilitation in Schizophrenia Spectrum Disorder: A Systematic Review.
Schizophrenia is a chronic psychiatric disorder with symptoms that can severely affect patients' quality of life. While drug administration inhibits most of the positive symptoms, it fails to effectively treat the negative symptoms and in turn relies on rehabilitation therapies. With technological progress, virtual reality (VR) has been the target of recent studies in terms of mental health rehabilitation and has been shown to be a tool with ecological validity in order to introduce the individual to situations similar to their daily life. From July to August 2021, we conducted a systematic review with the purpose of understanding the impact of virtual reality rehabilitation on negative symptoms and psychosocial rehabilitation in the schizophrenia spectrum. The searches were performed in the databases Web of Science, Scopus, and PubMed. In our search, we identified 201 results, where 108 duplicates were excluded, resulting in a final balance of 93. After reading and assessing the titles and abstracts, 66 studies were excluded. Of the remaining 27 reports, 23 were excluded for not meeting the previously defined eligibility criteria, resulting in the inclusion of four studies in this systematic review. The available data on the specific topic was limited and could have been more complete. However, in our review, we were able to identify statistically relevant results demonstrating the effectiveness of intervention. We could find medium to large effects, allowing VR to be an ally for rehabilitation of symptoms related to schizophrenia.


[Local control of advanced breast cancer with mohs'paste].
We report two cases of primary advanced breast cancer that was locally controlled by using Mohs'paste. CASE 1: A 70- year-old woman was suffering massive exudates and offensive smell from her right giant breast tumor. Histopathological examination showed an invasive ductal carcinoma. However, she didn't have distant metastases. The patient received chemotherapy and the breast tumor has been fixed using Mohs'paste, and dissected. The giant tumor became flat and dry, so we could perform a radical operation. Then, she had contra-lateral axillary lymph node metastases. We performed a resection of left axillary lymph node and radiation therapy. After two years, we have not found a new lesion. CASE 2: A 54-year- old woman with right local advanced breast cancer discharged massive exudates and oozed blood. Histopathologically, she had an invasive ductal carcinoma. Moreover, she had lung and contra-lateral axillary lymph node metastases. She received chemotherapy and the breast tumor has been fixed using Mohs'paste, and dissected. The bleeding and exudates stopped almost completely, and the breast tumor became flat and dry. Both patients had experienced a mild pain, but their QOL improved remarkably. It is suggested that the patient with local advanced breast cancer may be controlled by using Mohs' paste.


Biomechanics of the Diabetic Foot: Consideration in Limb Salvage.
The biomechanics of the diabetic foot is altered and maladaptive. We lack a thorough understanding of the functional consequences of limb salvage. We currently rely on observation and descriptive data pertaining to the biomechanics of the diabetic foot. Technology has driven our ability to objectively describe biomechanics of the diabetic foot. Dynamic, segmental, gait analysis in conjunction with peak plantar pressure measurements have provided valuable insight. The biomechanical pathogenesis of a chronic ulceration that necessitates limb salvage is difficult to capture. The subsequent changes that occur after limb salvage are even more difficult to understand. However, methodical biomechanical analysis over the past several decades have provided a deeper understanding of diabetic foot function. Ultimately, a better understanding of the biomechanics of the diabetic foot would allow us to better select the most appropriate amputation level and maximize function after limb salvage attempt.


Failure to thrive, hyponatremia, and hyperkalemia in a neonate.
CME EDUCATIONAL OBJECTIVES: 1.Describe the varying clinical presentations of pseudohypoaldosteronism in the neonatal period.2.Review the physiology of aldosterone production and pathophysiology of pseudohypoaldosteronism.3.Identify treatment options for pseudohypoaldosteronism when identified in the neonatal period. Pseudohypoaldosteronism type I (PHA1) is a rare disease of mineralocorticoid resistance caused by defects in sodium transport in the distal tubule of the kidney. It presents in the neonate with life-threatening dehydration due to salt wasting, accompanied by hyperkalemia, acidosis, and, frequently, failure to thrive. Patients with PHA1 are often initially diagnosed with congenital adrenal hyperplasia, but their electrolyte abnormalities are resistant to treatment with glucocorticoids and mineralocorticoids. In these patients, an astute clinician will broaden his or her differential, resulting in life-saving treatment.


Circadian distribution of iron and ferritin in serum of healthy and type 2 diabetic males.
We examined the circulating levels of iron and ferritin in serum of seven healthy and three insulin non-dependent diabetic (Type 2) males in order to compare their circadian characteristics. Blood samples were collected every 3h over a 24h period and were analyzed for serum iron and ferritin. The mean Fe level was significantly higher in healthy than in diabetic subjects: 80.0 +/- 3.3 vs. 63.0 +/- 3.7 microg/dL. The ferritin level was significantly lower in healthy than in diabetic men: 79.8 +/- 4.7 vs. 186.3 +/- 110.5 microg/L. A significant (p < 0.001) time-effect was found by ANOVA and circadian rhythm was detected at p < 0.001 in all data sets when a 24h cosine was fitted to the normalized data. Acrophases were located in mid to late morning for Fe (11:30, vs. 09:22h) and for ferritin (11:10 vs. 11:46h). We concluded that there is significant circadian variation in both serum Fe and ferritin, with predictable peaks in the mid to late morning.


Maternal provisioning and fluctuating thermal regimes enhance immune response in a reptile with temperature-dependent sex determination.
The Charnov-Bull model of differential fitness is often used to explain the evolution and maintenance of temperature-dependent sex determination (TSD). Most tests of the model focus on morphological proxies of fitness, such as size traits, whereas early life physiological traits that are closely related to lifetime fitness might provide a framework for generalizing the Charnov-Bull model across taxa. One such trait is the strength of the early-life immune response, which is strongly linked to early-life survival and fitness. Here, we manipulated temperature, variance in temperature, and sex to test the Charnov-Bull model using a physiological trait, immune system strength, in the snapping turtle (Chelydra serpentina). We found no evidence of sex-specific differences in bactericidal capacity of hatchling blood, and no evidence that mean temperature influences bactericidal capacity. However, we did find that fluctuating incubation temperature (i.e. a more naturalized incubation regime) is associated with a greater bactericidal capacity compared with constant temperature incubation. We also found that egg mass, a proxy for maternal provisioning, is positively associated with bactericidal capacity. Our findings suggest that the evolution of temperature-dependent sex determination in reptiles is unrelated to our measure of early-life innate immunity. Our study also underlines how immune response is condition dependent in early life, and questions the biological relevance of constant temperature incubation in experimental studies on ectotherm development.


[Role of the Lutheran Non-Governmental Health Organization in tuberculosis control].
Ever since its establishment in Madagascar, the Lutheran Church has been very active in medical field. In 1983, the creation of a medical non governmental organization called SALFA (Sampanasa Loteriana momba ny Fahasalamana) gave a new impulse. Since 1987, the SALFA has been seriously involved in the management of tuberculous patients. This document is a synthesis of actions conducted by SALFA whose experience in tuberculosis control is widely recognized by the Health Department and specially by the National Tuberculosis Control Program (NTCP). With an annual average of 1250 tuberculosis taken in charge, this NGO assumes 10% of the whole of the Program work. The diagnosis work is good (more than 85% Of PMT+) and therapeutic follow up of patients is excellent (more than 80% of the cured); those two elements of screening-treatment, basis of all tuberculosis control program incited us to describe this exemplary program.


Regulation of human carbonyl reductase 3 (CBR3; SDR21C2) expression by Nrf2 in cultured cancer cells.
Carbonyl reduction is a central metabolic process that controls the level of key regulatory molecules as well as xenobiotics. Carbonyl reductase 3 (CBR3; SDR21C2), a member of the short-chain dehydrogenase/reductase (SDR) superfamily, has been poorly characterized so far, and the regulation of its expression is a complete mystery. Here, we show that CBR3 expression is regulated via Nrf2, a key regulator in response to oxidative stress. In human cancer cell lines, CBR3 mRNA was expressed differentially, ranging from very high (A549, lung) to very low (HT-29, colon; HepG2, liver) levels. CBR3 protein was highly expressed in SW-480 (colon) cells but was absent in HCT116 (colon) and HepG2 cells. CBR3 mRNA could be induced in HT-29 cells by Nrf2 agonists [sulforaphane (SUL, 7-fold) and diethyl maleate (DEM, 4-fold)] or hormone receptor ligand Z-guggulsterone (5-fold). Aryl hydrocarbon receptor agonist B[k]F failed to induce CBR3 mRNA after incubation for 8 h but elevated CBR3 levels after 24 h, most likely mediated by B[k]F metabolites that can activate Nrf2 signaling. Inhibition of Nrf2-activating upstream kinase MEK/ERK by PD98059 weakened DEM-mediated induction of CBR3 mRNA. Proteasome inhibitors MG-132 (5 μM) and bortezomib (50 nM) dramatically increased the level of CBR3 mRNA, obviously because of the increase in the level of Nrf2 protein. While siRNA-mediated knockdown of Nrf2 led to a decrease in the level of CBR3 mRNA in A549 cells (30% of control), Keap1 knockdown increased the level of CBR3 mRNA expression in HepG2 (9.3-fold) and HT-29 (2.7-fold) cells. Here, we provide for the first time evidence that human CBR3 is a new member of the Nrf2 gene battery.


Stabilization, birth waves, and the surge in the elderly.
This study examines the transition of a population to stability following a shift to a new fixed set of vital rates. Specifically, the authors develop a simple discrete population model and use it to derive an explicit solution for the birth trajectory. "The new vital rates interact with the population's initial age composition and generate birth waves whose amplitude and attenuation depend on the ratio of ultimate to initial growth and on the new pattern of stable net maternity. A greater change in growth and a later stable net maternity pattern produce larger fluctuations in the number of births. Stabilization begins at the youngest ages and proceeds upward. Sixty years after the shift, the birth waves have largely disappeared and the proportion under age 15 approximates the stable level implied by the new rates. Those patterns are manifest in the stabilization of both observed and Coale-Demeny model stable populations." (SUMMARY IN FRE)


Intramyocardial Mass with an Echo-Free Center as an Echocardiographic Presentation of Hypertrophic Cardiomyopathy.
A 43-year-old man presented to the emergency department with atypical chest pains. Physical examinations yielded no significant findings. Serial electrocardiography and high-sensitivity troponin measurements were normal. Transthoracic echocardiography in the emergency department revealed increased septal wall thickness; therefore, the patient was referred to the echocardiography ward for further evaluation. The echocardiographic findings were normal, except for an intramyocardial mass with an echo-free center in the base-to-mid portion of the inferior and inferoseptal walls (Figures 1. A, B & C). Additionally, the base and mid portions of the anteroseptal wall were hypertrophied. Cardiac magnetic resonance imaging demonstrated myocardial hypertrophy in the base and mid portions of the anteroseptal, inferoseptal, and inferior walls (Figures 2. A, B, C, D & E), as well as a patchy mid-wall appearance of late gadolinium enhancement, at the anterior and posterior junction of the right ventricle to the left ventricle (Figures 2. F, G & H). The findings were typical of hypertrophic cardiomyopathy. What was revealed in the late gadolinium-enhanced images was compatible with the echo-free space in echocardiography. Otherwise speaking, the cardiac magnetic resonance images delineated the background pathology (hypertrophic cardiomyopathy) and revealed fibrosis as the etiology of the echo-free space in echocardiography. Holter monitoring of electrocardiography was unremarkable. To our knowledge, intramyocardial masses with echo-free centers as an echocardiographic presentation of hypertrophic cardiomyopathy have not been reported yet. Accordingly, in the differential diagnosis of the aforementioned echocardiographic findings, hypertrophic cardiomyopathy should be included. Cardiac magnetic resonance imaging in this condition is helpful.


Combinational Analysis of FISH and Immunohistochemistry Reveals Rare Genomic Events in ALK Fusion Patterns in NSCLC that Responds to Crizotinib Treatment.
The purpose of this study was to explore the complicated rearrangement mechanisms underlying cases with atypical and negative anaplastic lymphoma receptor tyrosine kinase gene (ALK) fluorescence hybridization (FISH) and positive immunohistochemistry (IHC) results and to stress the importance of combinational assay of these two methods in current pathological diagnosis. A total of 3128 NSCLCs were screened for ALK fusions through both FISH analysis and IHC assays with Ventana-D5F3 antibody. Fourteen cases with atypical and negative FISH results with the current criteria and positive IHC results were analyzed with targeted next-generation sequencing (NGS). Of the 3128 cases tested, 228 (7.3%) and 214 (6.8%) were ALK positive by IHC and FISH, respectively. Fourteen cases with negative and atypical FISH results all demonstrated IHC positivity. Of 2991 cases, eight (0.27%) with negative FISH results demonstrated echinoderm microtubule associated protein like 4 gene (EML4)-ALK fusions revealed by targeted NGS, and the relative abundance of fusion ranged from 0.9% to 46.8%. Three of 2991 cases (0.1%) did not exhibit any type of ALK fusions. In addition, two patients showed an isolated 5' side signal and targeted NGS revealed two novel ALK partner genes, baculoviral IAP repeat containing 6 gene (BIRC6) and phosphatidylinositol binding clathrin assembly protein gene (PICALM). One patient showed an isolated and attenuated 3' red signal and demonstrated a novel translocation partner with CCAAT/enhancer binding protein zeta gene (CEBPZ). Of all the patients, four received crizotinib treatment and demonstrated partial responses at the end of follow-up. Our study showed that patients with negative and atypical ALK FISH patterns may have positive results for IHC testing and harbor the translocation partners of EML4 or other genes. Therefore, additional testing with NGS should be conducted to explore the molecular mechanisms underlying the complicated gene rearrangement events.


Bier's block: a change of injection site.
Bier's block or intravenous regional anesthesia is a well-proven technique that is useful in the traumatic setting to provide upper limb anesthesia in the manipulation of distal radial fractures. In this situation, the traditional injection site in the dorsum of the hand can present difficulties with subsequent plaster application and with venous access caused by swelling or pain. One hundred patients were randomly allocated into two groups of 50. The first group was injected into the dorsum of the hand and the second into the antecubital fossa, in each case on the injured side. Effectiveness of anesthesia at both the fractures site and the cuff was assessed using a visual analog scale. Results analyzed using Student's t test, showed no difference in anesthesia between the two groups. In addition, there were fewer technical problems associated with venous access and subsequent plaster application in the antecubital fossa group.


Albumin in Cirrhosis: More Than a Colloid.
Albumin has repeatedly been shown to be beneficial in treating patients with decompensated cirrhosis. We reviewed the medical literature regarding indications for the use of intravenous albumin in cirrhosis, with particular focus on the ways in which albumin can help mitigate hepatorenal physiology. Albumin has long been used as the preferred agent for volume expansion in patients with decompensated cirrhosis. It is used in conjunction with vasoconstrictors for the treatment of type 1 hepatorenal syndrome, and in combination with antibiotics for the treatment of spontaneous bacterial peritonitis. When given at the time of large volume paracentesis, albumin is known to help reduce the incidence of post-paracentesis circulatory dysfunction. Recently, albumin has been shown to improve outcomes in hospitalized patients with cirrhosis and hyponatremia, and has also shown promise in reducing mortality and hospitalizations in outpatients with both diuretic resistant and uncomplicated ascites. It is increasingly clear that these benefits derive from a combination of the oncotic and non-oncotic properties of albumin, and from the effects of albumin administration on effective arterial blood volume. Albumin is an effective treatment for multiple complications encountered in patients with decompensated cirrhosis.


Search for specific biomarkers of IFNβ bioactivity in patients with multiple sclerosis.
Myxovirus A (MxA), a protein encoded by the MX1 gene with antiviral activity, has proven to be a sensitive measure of IFNβ bioactivity in multiple sclerosis (MS). However, the use of MxA as a biomarker of IFNβ bioactivity has been criticized for the lack of evidence of its role on disease pathogenesis and the clinical response to IFNβ. Here, we aimed to identify specific biomarkers of IFNβ bioactivity in order to compare their gene expression induction by type I IFNs with the MxA, and to investigate their potential role in MS pathogenesis. Gene expression microarrays were performed in PBMC from MS patients who developed neutralizing antibodies (NAB) to IFNβ at 12 and/or 24 months of treatment and patients who remained NAB negative. Nine genes followed patterns in gene expression over time similar to the MX1, which was considered the gold standard gene, and were selected for further experiments: IFI6, IFI27, IFI44L, IFIT1, HERC5, LY6E, RSAD2, SIGLEC1, and USP18. In vitro experiments in PBMC from healthy controls revealed specific induction of selected biomarkers by IFNβ but not IFNγ, and several markers, in particular USP18 and HERC5, were shown to be significantly induced at lower IFNβ concentrations and more selective than the MX1 as biomarkers of IFNβ bioactivity. In addition, USP18 expression was deficient in MS patients compared with healthy controls (p = 0.0004). We propose specific biomarkers that may be considered in addition to the MxA to evaluate IFNβ bioactivity, and to further explore their implication in MS pathogenesis.


Characteristics of platelet concentrates, with particular reference to Autopheresis C Plateletcell: correlation between dMPV and other tests for platelet function.
The quality of platelet concentrates (PC) collected by the Autopheresis C cell separator was assessed in two Regional Transfusion Centres taking part in a multicentre study. This study also enabled the assessment of a new simple, rapid test of platelet function and comparison with more established tests, such as aggregation to adenosine diphosphate, as a tool for the quality testing of PC. The new test, based upon the measurement of mean platelet volume using automated haematological cell analysers, is rapid and uses the same samples as those used to estimate the platelet and leucocyte content of the concentrates. The high correlation between this test and the other tests of platelet function used in the study suggests that it is an ideal tool in the quality testing of platelet concentrates.


Diastolic coronary artery pressure-flow velocity relationships in conscious man.
We characterised the diastolic pressure-flow velocity relationship in the normal left coronary artery of conscious man before and after vasodilatation with angiographic contrast medium. Phasic coronary artery pressure and flow velocity were measured in ten patients during individual diastoles (0.5 to 1.0 s) using a 20 MHz catheter-tipped, pulsed Doppler transducer. All pressure-flow velocity curves were linear over the diastolic pressure range of 110 +/- 15 (SD) mmHg to 71 +/- 7 mmHg (r = 0.97 +/- 0.01). In the basal state, values for slope and extrapolated zero flow pressure intercept averaged 0.35 +/- 0.12 cm X s-1 X mmHg-1 and 51.7 +/- 8.6 mmHg, respectively. Vasodilatation resulted in a 2.5 +/- 0.5 fold increase in mean flow velocity. The diastolic pressure-flow velocity relationship obtained during peak vasodilatation compared to that during basal conditions was characterised by a steeper slope (0.80 +/- 0.48 cm X s-1 X mmHg-1, p less than 0.001) and lower extrapolated zero flow pressure intercept (37.9 +/- 9.8 mmHg, p less than 0.05). Mean right atrial pressure for the group averaged 4.4 +/- 1.7 mmHg, while left ventricular end-diastolic pressure averaged 8.7 +/- 2.8 mmHg. These observations in man are similar to data reported in the canine coronary circulation which are consistent with a vascular waterfall model of diastolic flow regulation. In this model, coronary blood flow may be regulated by changes in diastolic zero flow pressure as well as in coronary resistance.


[Radionuclide diagnosis of vasculogenic impotence].
Pathogenesis of vasculogenic impotence is most adequately revealed by modern methods of the investigation of the hemodynamic mechanisms of erection with the enhancement of arterial perfusion of corpora cavernosa by artificial sexual stimulation. Radionuclide diagnostic methods effectively differ from the methods of radiocontrast phalloangiography by the simplicity of investigation and the absence of traumatism for a patient. The authors have proposed a mathematical model of a process of filling in the functioning volume of the penile vascular bed with a radiopharmaceutical preparation against the background of erection induced by intracavernous administration of papaverine hydrochloride solution. Parameters of the model determine the ratio of blood flow volumetric rates in the penis at rest and when erect.


Application of an Epac activator enhances neurotransmitter release at excitatory central synapses.
cAMP regulates secretory processes through both PKA-independent and PKA-dependent signaling pathways. Their relative contributions to fast neurotransmission are unclear at present, although forskolin, which is generally believed to enhance intracellular cAMP levels by stimulation of adenylyl cyclase activity, was shown to increase vesicular release probability (p) and the number of releasable vesicles (N) in various neuronal preparations. Using low-frequency (0.2 Hz) electrophysiological recordings in the presence of the Epac-selective cAMP analog 8-pCPT-2'-O-Me-cAMP (ESCA(1)), we find that Epac activation by this analog accounts on average for 38% of the forskolin-induced increase in evoked EPSC amplitudes and for 100% of the forskolin-induced increase in miniature EPSC (mEPSC) frequency in dissociated autaptic neuronal cultures from mouse hippocampus. From paired-pulse facilitation experiments, and considering the enhancement of mEPSC frequency, we conclude that ESCA(1)-induced Epac activity is presynaptic in origin and increases p. In addition, preapplication of ESCA(1) augmented a subsequent enhancement of evoked EPSC amplitudes by phorbol ester (PDBu). This effect was maximal when ESCA(1) application preceded the PDBu application by 3 min. Because the PDBu response was abolished after downregulation of intracellular PKC activity, we conclude that ESCA(1)-induced Epac activation leads to presynaptic changes involving Epac-to-PKC signaling.


Dynamics of a plant-herbivore model with toxin-induced functional response.
Traditional functional responses for plant-herbivore interactions do not take into account explicitly the effect of plant toxin. However, considerable evidence suggests that toxins set upper limits on food intake for many species of herbivorous vertebrates. In this paper, a mathematical model for plant-herbivore interactions mediated by toxin-determined functional response is studied. The model consists of three ordinary differential equations describing one herbivore population and two plant species with different toxicity levels. The effect of plant toxicity on herbivore's intake rate is incorporated explicitly in the model by assuming an increased handling time. The dynamical behaviors of the model are analyzed and the results are used to examine the influence of toxin-determined intake in the community composition of plant species. The bifurcation analysis presented in this paper suggests that the toxin-mediated functional response may have dramatic effects on plant-herbivore interactions.


Children and adolescents in the Psychiatric Emergency Department: a 10-year survey in Copenhagen County.
Knowledge on psychiatric emergencies in children and adolescents is limited. The Psychiatric Emergency Departments (PED) in Copenhagen enable the acute examination of children and adolescents 24 h a day, 7 days a week. However, very little is known about who presents to the PED, and the reason for their visit. To describe the prevalence and characteristics of presentations in PED and treatment provided. A retrospective population based study comprising data of more than 4000 visitors presenting to PED from 2001-2010. In 2003 and 2006, two randomly chosen years, a more thorough analysis was performed, based on the individual emergency charts. Inter-rater reliability was high. Visits increased nearly threefold during the period. Symptom score for 2003 and 2006 revealed that more than one third of the visitors had suicidal ideation. Depressive and anxiety symptoms together with suicidal ideation rose significantly (P < 0.001). Psychoses and suicidal attempts remained unchanged. In one third of the visits, the discharge diagnosis was anxiety and stress-related disorders, followed by personality, behavioural and emotional disorders. Between 15% and 20% of the visits resulted in admission and more than 50% in referral for outpatient follow-up. The number of presenting psychiatric emergencies has increased over the last 10 years. Comparing symptoms from 2003 and 2006 showed a significant rise in their severity. This study highlights the need for 24-h access for acute evaluation by physicians skilled in child and adolescent psychiatry, and raises concern that the severity could increase.


Typing of the pilus-protein-encoding FCT region and biofilm formation as novel parameters in epidemiological investigations of Streptococcus pyogenes isolates from various infection sites.
Streptococcus pyogenes is an important human pathogen for which an association between infection site and selected epidemiological or functional markers has previously been suggested. However, the studies involved often used strains with an insufficiently defined clinical background and laboratory history. Thus, the major goal of the present study was to investigate these relationships in 183 prospectively collected, well-defined, low-passage isolates from a North-East German centre for tertiary care. For each isolate the clinical background (91 respiratory, 71 skin and 21 invasive isolates) and antibiotic-resistance pattern was recorded. All isolates were classified according to their emm type, antibiotic-resistance and PFGE pattern ( SmaI restriction analysis of genomic DNA). As novel discriminatory methods we performed a PCR-based typing of the pilus-protein-encoding FCT region (FCT) and biofilm-formation phenotyping in various culture media. Forty-one isolates were found to be resistant to at least one of the tested antibiotics. emm typing revealed emm28, emm12 , emm1, emm4, emm89 and emm2 as the most frequent types in our collection. The novel FCT typing showed isolates encoding FCT types 4 and 2 to be the most common. Overall 113 strains with unique combinations of emm and FCT types, antibiotic-resistance and PFGE patterns were identified. The majority of all isolates revealed an association of biofilm-formation capacity with growth media. Comparing all results for potential associations, no correlation could be established between the anatomical site of isolation and the emm or the FCT type. There was no relationship between biofilm formation and emm type, antibiotic-resistance or PFGE patterns. However, a novel association between biofilm formation and FCT type became obvious among strains from our collection.


Amnesic patients' impaired category exemplar production priming.
This study examined the effect of varying the number of potential target words on amnesic patients' category exemplar production performance. In Experiment 1, 4 words from each of 6 categories were presented to amnesic patients and normal control participants. This was followed by an indirect task in which each participant produced the first 8 words that came to mind when presented with a category cue. On this task the amnesic patients were impaired. This outcome stands in sharp contrast to most other category exemplar production tasks that have been reported. However, these other paradigms tend to restrict participants' processing during target item presentation while our procedure allowed them to analyze the target words as they chose. Our procedure may have allowed the control participant more opportunity to "cluster" target words from the same category during list presentation and this, in turn, may have given them an advantage at the time of category exemplar production. Therefore, in Experiment 2, only 1 word per category was presented in the target list and only 2 words per category were requested during category exemplar production. Surprisingly, the amnesic patients still exhibited impaired performance. Therefore, it was suggested that perhaps amnesic patients' known inability to perform semantic levels of processing during individual target word presentation may have resulted in impaired priming for categorical features for these patients.


Prolonged Isotretinoin in Ultra High-Risk Neuroblastoma.
Patients with high-risk neuroblastoma remain a therapeutic challenge with significant numbers of patients failing to respond sufficiently to initial therapy. These patients with poor response to induction are considered as ultra high-risk and are in need of novel treatment strategies. Isotretinoin is part of the standard of care treatment for patients with high-risk disease who undergo high-dose chemotherapy with autologous stem cell rescue although some have questioned the optimal administration schedule. Prolonged use of isotretinoin was well tolerated and may have contributed to long-term survival in a group of patients with ultra high-risk neuroblastoma.


The shell matrix of the pulmonate land snail Helix aspersa maxima.
In mollusks, the shell mineralization process is controlled by an array of proteins, glycoproteins and polysaccharides that collectively constitute the shell matrix. In spite of numerous researches, the shell protein content of a limited number of model species has been investigated. This paper presents biochemical data on the common edible land snail Helix aspersa maxima, a model organism for ecotoxicological purposes, which has however been poorly investigated from a biomineralization viewpoint. The shell matrix of this species was extracted and analyzed biochemically for functional in vitro inhibition assay, for amino acid and monosaccharides compositions. The matrix was further analyzed on 1 and 2D gels and short partial protein sequences were obtained from 2D gel spots. Serological comparisons were established with a set of heterologous antibodies, two of which were subsequently used for subsequent immunogold localization of matrix components. Our data suggest that the shell matrix of Helix aspersa maxima may differ widely from the shell secretory repertoire of the marine mollusks studied so far, such as the gastropod Haliotis or the pearl oyster Pinctada. In particular, most of the biochemical properties generally attributed to soluble shell matrices, such as calcium-binding capability, or the capacity to interfere in vitro with the precipitation of calcium carbonate or to inhibit the precipitation of calcium carbonate, were not recorded with this matrix. This drastic change in the biochemical properties of the landsnail shell matrix puts into question the existence of a unique molecular model for molluscan shell formation, and may be related to terrestrialisation.


Methuselah's medicine: pharmaceutical innovation and mortality in the United States, 1960-2000.
Although there is a good deal of speculation surrounding the role of pharmaceutical innovation in late 20th century mortality improvements in the United States, there is little empirical evidence on the topic and there remains a good deal of doubt regarding whether pharmaceuticals matter at all for mortality. Using a reliable indicator of pharmaceutical innovation-yearly approvals of new molecular entities (NMEs) by the Food and Drug Administration, along with information on priority status and disease-category indication-this study examines the relationship between pharmaceutical innovation and life expectancy between 1960 and 2000. The study demonstrates a significant relationship between pharmaceutical innovation and life expectancy at birth, which is robust to controls for gross domestic product, as well as controls for various forms of medical spending. The relationship with life expectancy is robust, in part, because pharmaceutical innovation has a stronger relationship with early-life mortality (between 20 and 50) than with later-life mortality (65 and over), even though older persons consume more pharmaceuticals and many recently approved drugs target conditions more common in later life. There is, to be sure, another side to the results. There is some evidence, for example, that the relationship between pharmaceutical innovation and mortality has declined over time, suggesting a change in the kind of innovations now entering the market. Nevertheless, there is more to contemporary pharmaceutical innovation than the development of mere "halfway" technologies. The overall relationship between innovation and mortality is sufficiently strong to warrant further consideration as a key determinant of trends in mortality.


Acute phase proteins in psoriasis.
Psoriasis is a chronic, relapsing, inflammatory and hyperproliferative skin disorder. The levels of acute phase proteins are suggested to be elevated in those patients with acute disease. The expression of selected acute phase proteins as the parameters of humoral immunity has been analyzed in 70 patients with acute psoriasis and 40 healthy controls. The aim was to evaluate the inflammatory response in the exacerbation of psoriasis and to determine the correlation of these objective inflammatory parameters with clinical features of disease activity. Main demographic and epidemiologic features were, as well, analysed. The plasma levels of C-reactive protein (CRP) (chi2 = 23.61; p < 0.005), and alpha1-acid glycoprotein (alpha1-AGP) (chi2 = 7.42; p < 0.01) were significantly increased in those patients with acute phase of the disease compared to healthy controls. Our results suggest that psoriasis is an inflammatory disease and therefore its worsening seemed to be linked to the increase in the inflammatory response. It seems that CRP and al-AGP levels could serve as important prognostic factors for the worsening of psoriasis.


Modeling hydrolysis of slowly biodegradable organic compounds in biological nutrient removal activated sludge systems.
Hydrolysis is an important process in biological wastewater treatment and is known to be the rate-limiting step in organic carbon removal from municipal or industrial wastewater. The influence of the readily biodegradable chemical oxygen demand fraction in biological wastewater treatment systems has been extensively investigated, but little is known about the effects of slowly biodegradable substrate (XS) on denitrification and enhanced biological phosphorus removal. The biodegradation of XS is initiated by hydrolysis, which is an integral part of activated sludge models, such as the Activated Sludge Model no. 2d (ASM2d). This process is slower than heterotrophic growth and thus becomes the rate-limiting step for the biodegradation of organic compounds. The aim of this study was to evaluate different concepts of modeling the hydrolysis process using the original and modified version of ASM2d. Batch test results obtained at a large biological nutrient removal (BNR) plant in Gdansk (Poland) provided an experimental database for comparison of the two model predictions. Both models were compared in terms of their predictions for the most important process rates in BNR activated sludge systems. In comparison with the orginal ASM2d, the modified model had no or only minor effect on the predicted nitrate utilization rate, phosphate release rate and anoxic/aerobic phosphate uptake rate, but better predicted the oxygen uptake rate. The average ARDs (average relative deviations) were 19.0 and 29.3% (original ASM2d) vs. 13.4 and 20.4% (modified ASM2d), respectively, for the settled wastewater without pretreatment and after coagulation-flocculation.


[On-demand versus on-time dosing of tadalafil for erectile dysfunction: a prospective multi-center study].
To evaluate the safety and efficacy of tadalafil on demand and on time in men with erectile dysfunction. We conducted a multi-centered randomized controlled study on 120 ED males, who were assigned to take tadalafil at 10 mg/ 20 mg on demand before sexual activity and at the same dose on time twice a week for 8 weeks. Before and at 4 and 8 weeks after treatment, and 1 month after withdrawal, we obtained the scores on IIEF-5, ED Inventory of Treatment Satisfaction (EDITS) and the short form of Psychological and Interpersonal Relationship Scales (SF-PAIRS) , and compared the safety and efficacy of medication between the two groups of patients. Totally, 110 patients accomplished the trial, 56 in the on-time and 54 in the on-demand group. At 4 and 8 weeks of medication and 1 month after withdrawal, the IIEF-5 scores were improved in both the on-time and on-demand groups, even more significantly in the former than in the latter at 8 weeks of treatment (21.6 +/- 2.9 vs 18.5 +/- 1.7) and 1 month after withdrawal (20.9 +/- 2.1 vs 17.9 +/- 2.3) (P < 0.05). The EDITS scores were significantly higher in the on-time than in the on-demand group at 8 weeks of treatment (31.7 +/- 6.9 vs 28.6 +/- 5.8) and 1 month after withdrawal (30.6 +/- 4.7 vs 27.9 +/- 6.5) (P < 0.05). The scores on the sexual self-confidence, spontaneity and time-concern domains of SF-PAIRS were remarkably improved after medication as compared with the baseline (P < 0.05), even more significantly in the on-time than in the on-demand group at 1 month after withdrawal. Both dosing schedules were well tolerated and no significant differences were observed in safety between the two groups. On-time dosing of tadalafil is efficacious and well tolerated in the treatment of ED, and has an even better effect than on-demand dosing at 8 weeks of medication and 1 month after withdrawal.


Visual analysis of concerted cleavage by type IIF restriction enzyme SfiI in subsecond time region.
Many DNA regulatory factors require communication between distantly separated DNA sites for their activity. The type IIF restriction enzyme SfiI is often used as a model system of site communication. Here, we used fast-scanning atomic force microscopy to monitor the DNA cleavage process with SfiI and the changes in the single SfiI-DNA complex in the presence of either Mg²⁺ or Ca²⁺ at a scan rate of 1-2 fps. The increased time resolution allowed us to visualize the concerted cleavage of the protein at two cognate sites. The four termini generated by the cleavage were released in a multistep manner. The high temporal resolution enabled us to visualize the translocation of a DNA strand on a looped complex and intersegmental transfer of the SfiI protein in which swapping of the site is performed without protein dissociation. On the basis of our results, we propose that the SfiI tetramer can remain bound to one of the sites even after cleavage, allowing the other site on the DNA molecule to fill the empty DNA-binding cleft by combining a one-dimensional diffusion-mediated sliding and a segment transfer mechanism.


Phenolic Compounds and Bioactivity of Healthy and Infected Grapevine Leaf Extracts from Red Varieties Merlot and Vranac (Vitis vinifera L.).
We investigated the phenolic composition, radical scavenging activity, and antimicrobial activity of grapevine leaf extracts from two red grape varieties, Vranac and Merlot (Vitis vinifera L.). The extracts were prepared from healthy grapevine leaves and those infected by Plasmopara viticola (downy mildew). The phenolic composition of the grapevine leaf extracts was determined using spectrophotometric assays and reverse-phase high performance liquid chromatography (RP-HPLC). The radical scavenging activity of grapevine leaf extracts was determined by the 2,2-diphenyl-1-picrylhydrazyl assay, and their antimicrobial activity was determined by microwell dilution tests. The total phenolic content was higher in healthy grapevine leaf extracts than in infected grapevine leaf extracts. The RP-HPLC analysis detected significant amounts of flavonols, phenolic acids, and flavan-3-ols, and small amounts of stilbenes in the grapevine leaf extracts. Compared with the infected grapevine leaf extracts, the healthy grapevine leaf extracts were richer in flavonols, phenolic acids, and flavan-3-ols, but had lower stilbenes contents. All extracts showed strong free radical scavenging activity, which was strongly correlated with the total phenolic content (R(2) = 0.978). The extracts showed a stronger antimicrobial activity towards Gram-positive bacterial strains than towards Gram-negative bacterial strains and yeast. The phenolic compounds in grapevine leaves were responsible for their strong radical scavenging and antimicrobial activities. Together, these results demonstrate that grapevine leaves have high nutritional value and can be used as a fresh food and to prepare extracts that can be used as additives in food and medicines.


Mosques against malaria.
In a community-based malaria control project covering a predominantly Muslim population in the United Republic of Tanzania, difficulty was encountered in motivating people to have their mosquito nets reimpregnated with insecticide at six-monthly intervals. Education on this subject was therefore provided in mosques during Friday noon prayers. People who attended these services considered them an appropriate forum for discussing health concerns and viewed them as a credible source of information.


Effects of digital devices and online learning on computer vision syndrome in students during the COVID-19 era: an online questionnaire study.
Computer vision syndrome (CVS) describes a group of eye and vision-related problems that result from prolonged digital device use. This study aims to assess the prevalence and associated factors of CVS among students during the lockdown resulting from the COVID-19 pandemic. A cross-sectional, online, questionnaire-based study performed among high school students in Thailand. A total of 2476 students, with mean age of 15.52±1.66 years, were included in this study. The mean number of hours of digital device use per day (10.53±2.99) increased during the COVID-19 pandemic compared with before its advent (6.13±2.8). The mean number of hours of online learning was 7.03±2.06 hours per day during the pandemic. CVS was found in 70.1% of students, and its severity correlated with both the number of hours of online learning and the total number of hours of digital device usage (p<0.001). Multiple logistic regression analysis revealed that the factors associated with CVS included age ≤15 years (adjusted OR (AOR)=2.17), overall digital device usage >6 hours per day (AOR=1.91), online learning >5 hours per day (AOR=4.99), multiple digital device usage (AOR=2.15), refractive errors (AOR=2.89), presence of back pain (AOR=2.06) and presence of neck pain (AOR=2.36). The number of hours of digital device usage increased during lockdown. Over 70% of children had CVS, whose associated factors, including hours of digital device usage, hours of online learning, ergonomics and refractive errors, should be adjusted to decrease the risk of acquiring this condition. Online learning will remain, along with CVS, after this pandemic, and we hope our research will be taken into account in remodelling our education system accordingly.


Radionuclide diagnosis of splenic rupture in infectious mononucleosis.
Spontaneous splenic rupture is a rare but serious complication of infectious mononucleosis. Although radionuclide spleen imaging is a well accepted method for diagnosis of traumatic rupture, interpretation can be difficult in the setting of mononucleosis, as tears may be ill-defined and diagnosis hampered by inhomogeneous splenic uptake. Four proven cases of spontaneous rupture are presented, three of which illustrate these diagnostic problems.


Lens aging in relation to nutritional determinants and possible risk factors for age-related cataract.
To investigate whether nutritional factors and possible risk factors for cataract influence the lens optical density (LOD). Three hundred seventy-six subjects, aged 18 to 75 years, were recruited. In a cross-sectional design, serum was analyzed for lutein, zeaxanthin, vitamin C, alpha-tocopherol, and cholesterol levels. Adipose tissue (n = 187) was analyzed for lutein level. The LOD and the macular pigment optical density (MPOD) were measured by spectral fundus reflectance. The mean +/- SD LOD at 420 nm was 0.52 +/- 0.17. It showed a significant association with age (beta =.008, P<001) and MPOD (beta = -.096, P =.02). For subjects 50 years and younger (mean +/- SD LOD, 0.45 +/- 0.11), we found only a single significant beta coefficient, for age (beta =.006, P<.001). For subjects older than 50 years (mean +/- SD LOD, 0.68 +/- 0.16), we found significant beta coefficients for age (beta =.011, P<.001) and MPOD (beta = -.240, P =.005). Controlling for age, we found no associations between LOD and other possible risk factors for age-related cataract or serum or adipose tissue concentrations of carotenoids, vitamin C, and alpha-tocopherol. Macular pigment is composed of lutein and zeaxanthin, the only carotenoids found in human lenses. The inverse relationship between LOD and MPOD suggests that lutein and zeaxanthin may retard aging of the lens.


Midline Brain Abnormalities Across Psychotic and Mood Disorders.
Patients with schizophrenia are known to have increased prevalence of abnormalities in midline brain structures, such as a failure of the septum pellucidum to fuse (cavum septum pellucidum) and the absence of the adhesio interthalamica. This is the first study to investigate the prevalence of these abnormalities across a large multidiagnostic sample. Presence of cavum septum pellucidum and absence of the adhesio interthalamica was assessed in 639 patients with chronic schizophrenia, delusional disorder, schizoaffective disorder, bipolar disorder, major depressive disorder, or a first episode of psychosis, mania or unipolar depression. This was compared with 223 healthy controls using logistic-regression-derived odds ratios (OR). Patients with psychotic or mood disorders showed an increased prevalence of both abnormalities (OR of cavum septum pellucidum = 2.1, OR of absence of the adhesio interthalamica = 2.6, OR of both cavum septum pellucidum and absence of the adhesio interthalamica = 3.8, all P < .001). This increased prevalence was separately observed in nearly all disorders as well as after controlling for potential confounding factors. This study supports a general increased prevalence of midline brain abnormalities across mood and psychotic disorders. This nonspecificity may suggest that these disorders share a common neurodevelopmental etiology.


Tungsten targets the tumor microenvironment to enhance breast cancer metastasis.
The number of individuals exposed to high levels of tungsten is increasing, yet there is limited knowledge of the potential human health risks. Recently, a cohort of breast cancer patients was left with tungsten in their breasts following testing of a tungsten-based shield during intraoperative radiotherapy. While monitoring tungsten levels in the blood and urine of these patients, we utilized the 66Cl4 cell model, in vitro and in mice to study the effects of tungsten exposure on mammary tumor growth and metastasis. We still detect tungsten in the urine of patients' years after surgery (mean urinary tungsten concentration at least 20 months post-surgery = 1.76 ng/ml), even in those who have opted for mastectomy, indicating that tungsten does not remain in the breast. In addition, standard chelation therapy was ineffective at mobilizing tungsten. In the mouse model, tungsten slightly delayed primary tumor growth, but significantly enhanced lung metastasis. In vitro, tungsten did not enhance 66Cl4 proliferation or invasion, suggesting that tungsten was not directly acting on 66Cl4 primary tumor cells to enhance invasion. In contrast, tungsten changed the tumor microenvironment, enhancing parameters known to be important for cell invasion and metastasis including activated fibroblasts, matrix metalloproteinases, and myeloid-derived suppressor cells. We show, for the first time, that tungsten enhances metastasis in an animal model of breast cancer by targeting the microenvironment. Importantly, all these tumor microenvironmental changes are associated with a poor prognosis in humans.


The recombinant dihydropyridine receptor II-III loop and partly structured 'C' region peptides modify cardiac ryanodine receptor activity.
A physical association between the II-III loop of the DHPR (dihydropryidine receptor) and the RyR (ryanodine receptor) is essential for excitation-contraction coupling in skeletal, but not cardiac, muscle. However, peptides corresponding to a part of the II-III loop interact with the cardiac RyR2 suggesting the possibility of a physical coupling between the proteins. Whether the full II-III loop and its functionally important 'C' region (cardiac DHPR residues 855-891 or skeletal 724-760) interact with cardiac RyR2 is not known and is examined in the present study. Both the cardiac DHPR II-III loop (CDCL) and cardiac peptide (C(c)) activated RyR2 channels at concentrations >10 nM. The skeletal DHPR II-III loop (SDCL) activated channels at < or =100 nM and weakly inhibited at > or =1 microM. In contrast, skeletal peptide (C(s)) inhibited channels at all concentrations when added alone, or was ineffective if added in the presence of C(c). Ca2+-induced Ca2+ release from cardiac sarcoplasmic reticulum was enhanced by CDCL, SDCL and the C peptides. The results indicate that the interaction between the II-III loop and RyR2 depends critically on the 'A' region (skeletal DHPR residues 671-690 or cardiac 793-812) and also involves the C region. Structure analysis indicated that (i) both C(s) and C(c) are random coil at room temperature, but, at 5 degrees C, have partial helical regions in their N-terminal and central parts, and (ii) secondary-structure profiles for CDCL and SDCL are similar. The data provide novel evidence that the DHPR II-III loop and its C region interact with cardiac RyR2, and that the ability to interact is not isoform-specific.


Fast algorithm for generating long self-affine profiles.
We introduce a fast algorithm for generating long self-affine profiles. The algorithm, which is based on the fast wavelet transform, is faster than the conventional Fourier filtering algorithm. In addition to increased performance for large systems, the algorithm, named the wavelet filtering algorithm, a priori gives rise to profiles for which the long-range correlation extends throughout the entire system independently of the length scale.


[Regulatory effect of glucagon-like peptide-1 on cell proliferation of skeletal myoblast strain L6 and its possible signal mechanism].
To study the regulatory effect of glucagon-like peptide-1 (GLP-1) on cell proliferation of skeletal myoblast strain L6 and its possible signal mechanism. L6 cells cultured in DMEM high glucose culture medium containing 10% FBS were divided into control group (C, without addition), GLP-1 group (G, added with 10 nmol/L GLP-1), PI3K inhibitor group (W, added with 50 nmol/L PI3K specific inhibitor wortmannin), and GLP-1 + PI3K inhibitor group (GW, added with 10 nmol/L GLP-1 and 50 nmol/L wortmannin) according to the random number table. Cell proliferation activity was detected with MTT assay at post culture hour (PCH) 24, 48, 72 (denoted as absorbance value). At PCH 24, the change in cell cycle was evaluated with flow cytometer, the expression level of proliferating cell nuclear antigen (PCNA) was determined with immunohistochemical staining, the protein levels of phosphorylated PI3K (p-PI3K) and p-Akt were determined with Western blotting. Data were processed with multi-group analysis of variance. (1) The cell proliferation activity at PCH 48, 72 in G group was respectively 0.660 +/- 0.120, 0.870 +/- 0.240, all significantly higher than those in C group (0.530 +/- 0.060, 0.700 +/- 0.100, with F value respectively 5.46, 5.90, P < 0.05 or P < 0.01). The cell proliferation activity in W group at each time point was lower than that in C group. The cell proliferation activity in GW group at PCH 48, 72 was respectively 0.510 +/- 0.080, 0.740 +/- 0.160, all lower than those in G group (with F value respectively 5.46, 5.90, P < 0.05 or P < 0.01). (2) The percentage of S phase cell in G group at PCH 24 [(15.7 +/- 0.4)%] was significantly higher than that in C group [(13.6 +/- 0.6)%] and GW group [(10.1 +/- 0.6)%], while that in W group [(6.8 +/- 1.2)%] was lower than that in C group (with F values all equal to 15.39, P values all below 0.01). (3) PCNA level in G group at PCH 24 [(51.24 +/- 1.18)%] was markedly higher than that in C group [(36.72 +/- 1.56)%] and GW group [(25.90 +/- 1.22)%], and while in W group [(21.70 +/- 0.09)%] was lower than that in C group (with F values equal to 783.80, P values all below 0.05). (4) The protein level of p-Akt in G group at PCH 24 was significantly higher than that in the other 3 groups, while that in W group was lower than that in C group (with F values equal to 94.43, P values all below 0.01). There was no obvious difference in protein level of p-PI3K at PCH 24 among G, GW, and C groups ( F = 20.94, P > 0.05). The protein level of p-PI3K at PCH 24 in W group was lower than that in C group (F = 20.94, P < 0.05). GLP-1 can promote cell proliferation of skeletal myoblast by accelerating the progression of cell cycle and increasing the synthesis of DNA, which can be attributed to PI3K/Akt signal pathway.


Tenebrio molitor (Coleoptera: Tenebrionidae)-Optimization of Rearing Conditions to Obtain Desired Nutritional Values.
The present study dealt with the influence of temperature and feed on the nutritional value of Tenebrio molitor, especially on the content of crude protein, amino acids, fat, and fatty acid profile. Tenebrio molitor larvae were kept in 15, 20, and 25°C and fed with wheat bran, lentil flour, and mixture. The parameters were analyzed by international standard methods. Generally, with an increase of the lentils in the feed, the crude protein content increased. The changes in the temperature and the feed were most pronounced on the essential amino acids Val, Arg, and Leu. The highest average fat content was determined at 20°C in insects fed with wheat bran. The lowest fat content was determined at 15°C in bran-fed insects. The dependency of fat content on the temperature in feeding with lentil flour and a mixture of wheat bran and lentil flour was statistically insignificant (P > 0.05, Kruskal-Wallis, Mann-Whitney post hoc tests). The highest content of polyene fatty acids was achieved at a rearing temperature of 15°C and the bran diet. It was concluded that a higher proportion of protein diet could increase the content of crude protein in the insects. An increase in the temperature generally leads only to a slight increase in the content of nitrogenous substances. The influence of feed on this nutritional parameter is therefore much more significant than the effect of the rearing temperature. In general, it can be stated that the feed and the temperature also significantly affect the fat content.