Computer-assisted retinal vessel measurement in an older population: correlation between right and left eyes.
This study assessed the correlation between computer-assisted retinal vessel measurements of right and left eyes, from subjects in a defined, community-based older population. Retinal photographs from participants in the Blue Mountains Eye Study were digitized. All retinal arterioles and venules located 0.5-1.0 disc diameters from the optic disc margin were identified and a computer program measured their diameters. Pearson correlation (R2) statistic was used to assess the correlation in a random subsample of 1546 images. Substantial correlation between right and left eye measurements was found for summary indices of retinal arterioles (R2 = 0.70) and venules (R2 = 0.77). Higher correlation was found for intragrader (R2 0.75-079) than for intergrader assessment (R2 0.67-0.72). Moderate correlation was found in arteriole-to-venule ratio assessed by the same (R2 = 0.57) or different (R2 = 0.52) graders. Measurements from one eye can thus adequately represent the retinal vessel diameters of a person.


Do electronic cigarettes impart a lower potential disease burden than conventional tobacco cigarettes? Review on E-cigarette vapor versus tobacco smoke.
Development and utilization of electronic cigarettes (ECs) resulted from the search for healthier alternatives to conventional tobacco cigarettes (TCs) and the search for alternative methods for quitting TCs. This review compares the potential disease burden presented by TC smoke to that of EC vapor. Potential disease burden of EC vapor versus TC smoke was assessed by reviewing clinical studies that measured inhaled components. Chemicals and carcinogens produced by vapor versus smoke were compared. Studies show that EC vapors contain far less carcinogenic particles than TC smoke. Whereas ECs have the ability to reach peak serum cotinine/nicotine levels comparable to that of TCs, ECs do not cause an increase in total white blood cell count; thus, ECs have the potential to lower the risk of atherosclerosis and systemic inflammation. Use of ECs has been shown to improve indoor air quality in a home exposed to TC smoke. This reduces secondhand smoke exposure, thus having the potential to decrease respiratory illness/asthma, middle-ear disease, sudden infant death syndrome, and more. However, some studies claim that propylene glycol (PG) vapor can induce respiratory irritation and increase chances for asthma. To minimize risks, EC manufacturers are replacing PG with distilled water and glycerin for vapor production. Based on the comparison of the chemical analysis of EC and TC carcinogenic profiles and association with health-indicating parameters, ECs impart a lower potential disease burden than conventional TCs.


Use of propofol-isoflurane as an anesthetic regimen for cesarean section in dogs.
To evaluate use of propofol-isoflurane as an anesthetic regimen for cesarean section in dogs and to compare this protocol with epidural analgesia and anesthesia induced with thiopental sodium. Prospective study. 141 bitches admitted for cesarean section. General anesthesia was induced with propofol in 141 dogs undergoing cesarean section. After intubation, anesthesia was maintained by means of inhalation of isoflurane (0.5 to 2.0%), administered in a 65:35 mixture of oxygen:nitrous oxide. After induction, 20 minutes were allowed to elapse before delivery of puppies was begun. Viability of neonates was ascertained immediately after surgery. Owners were interviewed by telephone to determine survival of puppies during the postoperative period. Survival rates from this study were compared with those from cesarean section performed on dogs under epidural analgesia or under general anesthesia induced with thiopental sodium. Induction, maintenance, and recovery were problem free in all bitches. Of 412 puppies delivered by cesarean section, 293 (71%) survived, 13 (3%) were born alive but died within 20 minutes of delivery, and 106 (26%) were stillborn. Survival rate for puppies from dams induced with propofol-isoflurane was similar to that for puppies from dams receiving epidural analgesia. Survival rate for puppies delivered by cesarean section performed on dams under general anesthesia was higher for dams induced with propofol than for dams induced with thiopental sodium. General anesthesia induced with propofol and maintained with isoflurane is acceptable for performing cesarean section in dogs.


Supplementation with n3 fatty acid ethyl esters increases large and small artery elasticity in obese adults on a weight loss diet.
Increased arterial stiffness is associated with enhanced risk of cardiovascular disease in obese individuals. Whether n3 fatty acid ethyl ester (FAEE) supplementation improves arterial stiffness in obese participants on a weight loss diet has not yet been investigated. The objective of the study was to carry out a 12-wk randomized, single-blind trial to test the effect of a 25% energy deficit weight loss diet alone (WL) (n = 12) or WL plus 4 g/d Omacor (46% EPA and 38% DHA) supplementation (WL+FAEE) (n = 13) on arterial elasticity in obese adults. Large (C1) and small artery elasticity (C2) were measured by pulse contour analysis of the radial artery. WL alone reduced (P < 0.05 in all) body weight (-3%), waist circumference (-4%), systolic (-3%) and diastolic (-3%) blood pressures, cardiac output (-4%), plasma TG concentration (-25%), and the homeostasis model assessment (HOMA) score (-12%) and increased plasma HDL cholesterol (+9%) and adiponectin (+18%) concentrations. However, WL alone did not alter C1 and C2. The WL+FAEE intervention significantly reduced body weight (-4%), waist circumference (-4%), systolic (-8%) and diastolic (-5%) blood pressures, pulse pressure (-5%), heart rate (-8%), plasma TG concentration (-36%), and HOMA score (-12%) and increased stroke volume (+3%), plasma HDL cholesterol (+6%) and adiponectin concentrations (+28%), and C1 (+20%) and C2 (+22%) artery elasticity. The changes in systolic blood pressure, heart rate, plasma TGs, C1, and C2 were significantly greater in the WL+FAEE group than in the WL group. Supplementation with n3 FAEEs improves C1 and C2 independently of weight loss in obese adults.


Neurological consequences of protein and protein-calorie undernutrition.
Malnutrition is a worldwide problem of enormous magnitude. The growth of the central nervous system in human beings is retarded in case of malnutrition in the very early part of life. Likewise, the peripheral nerves in infants and children and young growing animals appear susceptible to nutritional deprivation including protein as well as protein-calorie deficiency. Motor weakness, hypotonia, and hyporeflexia in infants and children are the essential clinical neurological signs in protein-calorie malnutrition (PCM). Motor and sensory nerve conduction are significantly impaired in children with PCM as well as in animals subjected to protein or protein-calorie deficiency. Histological studies have revealed reduced diameter of myelinated nerve fibers, retardation of myelination, segmental demyelination and remyelination, axonal degeneration, and shortened longitudinal growth of internodes. Diffusion barrier by perineurium may be broken. There is reduction in myelin lipids and impaired synthesis of myelin as shown by the biochemical and radioisotope incorporation studies. Presence of cholesterol esters in the biochemical synthesis of nerves suggests degeneration changes. Experimental studies have revealed that most effects of PCM on peripheral nerves can be reversed by nutritional rehabilitation, although complete recovery in the sensory nerve action potential, fiber size of dorsal nerve roots, and myelin-specific lipids does not occur. Skeletal muscle also shows many changes including muscle fiber atrophy, reduction in duration and amplitude of motor unit potentials, and/or fibrillation on electromyography (EMG) and biochemical estimation of muscle enzymes. These changes may be the reflection of a direct effect of PCM on muscles or secondary to the abnormal structural or biochemical changes in the peripheral nerves. PCM affects the central nervous system, especially the neuropsychological functions, in a lasting manner. Learning deficits and impairment of manual dexterity are the most obtrusive features. Neurotransmitter abnormalities and maturation lag in electroencephalogram have been demonstrated in experimental animals. Spinal cord dysfunction sometimes manifests overtly as clinical myelopathy. Degenerative changes in the cerebellum have been noted.


Interns' experiences of disruptive behavior in an academic medical center.
The first year of graduate medical education is an important period in the professional development of physicians. Disruptive behavior interferes with safe and effective clinical practice. To determine the frequency and nature of disruptive behavior perceived by interns and attending physicians in a teaching hospital environment. All 516 interns at Partners HealthCare (Boston, MA) during the 2010 and 2011 academic years were eligible to complete an anonymous questionnaire. A convenience nonrandom sample of 40 attending physicians also participated. A total of 394 of 516 eligible interns (76.4%) participated. Attendings and interns each reported that their team members generally behaved professionally (87.5% versus 80.4%, respectively). A significantly greater proportion of attendings than interns felt respected at work (90.0% versus 71.5% respectively; P = .01). Disruptive behavior was experienced by 93% of interns; 54% reported that they experienced it once a month or more. Interns reported disruptive behavior significantly more frequently than attending physicians, including increased reports of condescending behavior (odds ratio [OR], 5.46 for interns compared with attendings; P < .001), exclusion from decision making (OR, 6.97; P < .001), and berating (OR, 4.84; P = .02). Inappropriate jokes, abusive language, and gender bias were also reported, and they were not significantly more frequent among interns than attending physicians. Interns most frequently identified nurses as the source of disruption, and were significantly more likely than faculty to identify nurses as the source of disruptive behavior (OR, 10.40; P < .001). Attendings reported other physicians as the most frequent source of disruption. Although interns generally feel respected at work, they frequently experience disruptive behavior. Interns described more disruptive behaviors than a convenience sample of attending physicians at our institution.


An audit of splenectomies in a teaching hospital in North India. Are postsplenectomy guidelines being complied with?
Patients with an absent or dysfunctional spleen are at risk of infection by encapsulated and other bacteria. Overwhelming postsplenectomy infection (OPSI) causes most concern because it can result in significant mortality. A retrospective review of splenectomised patients in a tertiary care setting over an eight year period was carried out to determine whether current postsplenectomy guidelines were being followed. The cases were identified from the medical records and pathology files and data such as the reason for splenectomy, the preventive measures taken regarding vaccination, and antibiotic prophylaxis, together with their documentation in the discharge notes were assessed. Fifty six patients were studied. Trauma, both blunt and penetrating, was the most common reason for splenectomy. Thirty six patients received pneumococcal vaccination, with 20 patients having no mention of vaccination in their case notes. The discharge notes of 50 patients mentioned their splenectomised status; however, documentation of vaccination details in the discharge summary was poor, with only three patients having the relevant information recorded. Documentation of the need for future vaccination and precautions required in the asplenic condition was also lacking. Nine patients had postsplenectomy complications, although there were no cases of OPSI. Adherence to standard guidelines for the management of splenectomised patients was unsatisfactory. There is a need for an improvement of the vaccination rate and careful documentation of this important health risk in the discharge summaries. Maintenance of a splenectomy registry could aid in optimising the management of these patients.


International Transporter Consortium commentary on clinically important transporter polymorphisms.
This Commentary focuses on genetic polymorphisms in membrane transporters. We present two polymorphisms for which there is a compelling body of literature supporting their clinical relevance: OATP1B1 (c.521T>C, p.V174A, rs4149056) and BCRP (c.421C>A, p.Q141K, rs2231142). The clinical evidence demonstrating their role in variation in pharmacokinetics and pharmacodynamics is described along with their allele frequencies in ethnic populations. Recommendations for incorporating studies of transporter polymorphisms in drug development are provided, along with the regulatory implications.


Ventricular tachycardia associated with non-freon aerosol propellants.
A previously well 2-year-old child presented with seizures and ventricular tachycardia shortly after playing with an aerosol can of a well-known proprietary deodorant. She required intensive care and survived without sequelae. The propellants used in this product were isobutane, n-butane, and propane. The propellants have been thought to be safer than the previously used Freons, which were known to be cardiotoxic and neurotoxic. Significant exposure was confirmed by the detection of n-butane and isobutane in the patient's serum. We conclude that unintentional exposure to non-Freon aerosol propellants in a nonconfined space can be hazardous to children. Aerosol cans should be considered to represent toxic hazards and should be kept out of reach of children.


Changes in the glucosinolate-myrosinase defense system in Brassica juncea cotyledons during seedling development.
Optimal defense theory (ODT) predicts that plant defenses will be allocated to plant organs and tissues in proportion to their relative fitness values and susceptibilities to attack. This study was designed to test ODT predictions on the myrosinase-glucosinolate defense system in Brassica juncea by examining the relationships between the fitness value of B. juncea cotyledons and the levels and effectiveness of cotyledon defenses. Specifically, we estimated fitness value of cotyledons during plant development by measuring plant growth and seed production after cotyledon damage or removal at successive seedling ages. Cotyledon removal within five days of emergence had a significant impact on growth and seed production, but cotyledon removal at later stages did not. Consistent with ODT, glucosinolate and myrosinase levels in cotyledons also declined with seedling age, as did relative defenses against a generalist herbivore, Spodoptera eridania, as estimated by bioassay. Declines in glucosinolates were as predicted by a passive, allometric dilution model based on cotyledon expansion. Declines in myrosinase activity were significantly more gradual than predicted by allometric dilution, suggesting active retention of myrosinase activity as young cotyledons expand.


Comparison of Modular Control during Side Cutting before and after Fatigue.
The purpose of this study was to clarify the coordination between the trunk and lower limb muscles during sidestep and to compare this coordination before and after fatigue intervention. The intervention was lateral jump until exhaustion. Nonnegative matrix factorization (NMF) was used to extract muscle synergies from electromyography. Subsequently, to compare the muscle synergies, a scalar product that evaluates the coincidence of synergies was calculated. Three muscle synergies were extracted before and after the intervention from the NMF analysis. In accordance with the evaluation of the scalar product, these synergies were the same before and after the intervention. One of these synergies that engaged the internal oblique/transversus abdominis, rectus femoris, and adductor muscle was activated from before landing to midstance during sidestep motion; therefore, this synergy is thought to suppress excessive hip abduction. However, the activation timing of this synergy was delayed after the intervention (P = 0.028, effect size: 0.54, Wilcoxon test). This delay is considered to decrease hip stability. Thus, this change may induce a reduction in hip control function.


Two DNA-binding and nick recognition modules in human DNA ligase III.
Human DNA ligase III contains an N-terminal zinc finger domain that binds to nicks and gaps in DNA. This small domain has been described as a DNA nick sensor, but it is not required for DNA nick joining activity in vitro. In light of new structural information for mammalian ligases, we measured the DNA binding affinity and specificity of each domain of DNA ligase III. These studies identified two separate, independent DNA-binding modules in DNA ligase III that each bind specifically to nicked DNA over intact duplex DNA. One of these modules comprises the zinc finger domain and DNA-binding domain, which function together as a single DNA binding unit. The catalytic core of ligase III is the second DNA nick-binding module. Both binding modules are required for ligation of blunt ended DNA substrates. Although the zinc finger increases the catalytic efficiency of nick ligation, it appears to occupy the same binding site as the DNA ligase III catalytic core. We present a jackknife model for ligase III that posits conformational changes during nick sensing and ligation to extend the versatility of the enzyme.


Antibody-drug conjugates, cancer immunotherapy, and metronomic chemotherapy as novel approaches in cancer management.
Treatment of cancer is a major challenge even though the pathophysiology is becoming clearer with time. A number of new chemical entities are developed to target cancer growth inhibition, but the targeted delivery of these products still needs novel research. This is of utmost importance not only for higher efficacy but also for a reduction in systemic toxicity and cost of treatment. Although multiple novel targets and molecules are being researched, most of them could not pass the regulatory approval process, due to low benefit-risk ratio and lack of target specificity. Failure of a majority of these drugs was in part due to their superiority claimed via surrogate markers. Despite these, currently, more than 100 chemotherapeutic agents are in practice. This review paper discusses in detail the molecular basis, drug discovery, and pros and cons over conventional treatment approaches of three novel approaches in cancer therapy, i.e., (i) antibody-drug conjugates, (ii) cancer immunotherapy, and (iii) metronomic chemotherapy. All the drugs developed using these three novel approaches were compared against the established treatment regimens in clinical trials with clinical end points, such as overall survival, progression-free survival, and quality of life.


Short telomere length, cancer survival, and cancer risk in 47102 individuals.
Recent meta-analyses have suggested that short telomere length was associated with increased risk of cancer. We therefore tested the hypotheses that short telomere length was associated with increased risk of cancer and with increased risk of early death after cancer. We measured leukocyte telomere length in a prospective study of 47 102 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 20 years for cancer diagnosis and death. Follow-up was 100% complete. All statistical tests were two-sided. Telomere length decreased linearly with increasing age (P <.001). During follow-up, we observed 3142 first cancers and, among these individuals, 1730 deaths. Decreasing quartiles of telomere length were associated with decreasing survival after cancer (log-rank P <.001). Multivariable-adjusted hazard ratios of early death were 1.31 (95% confidence interval [CI] = 1.14 to 1.52) in individuals in the quartile and 1.43 (95% CI = 1.13 to 1.80) in individuals in the decile with the shortest telomeres vs the longest. Unadjusted hazard ratios of cancer risk were 1.74 (95% CI = 1.58 to 1.93) and 2.00 (95% CI = 1.70 to 2.35) in individuals in the quartile and decile with the shortest vs longest telomeres; however, multivariable adjustment changed these hazard ratios to 0.98 (95% CI = 0.88 to 1.08) and 0.95 (95% CI = 0.80 to 1.11), mainly because of age adjustment. Short telomere length is associated with reduced survival after cancer but not with cancer risk. The latter contrasts with findings from recent meta-analyses.


Nanoscale optical properties of indium gallium nitride/gallium nitride nanodisk-in-rod heterostructures.
III-nitride based nanorods and nanowires offer great potential for optoelectronic applications such as light emitting diodes or nanolasers. We report nanoscale optical studies of InGaN/GaN nanodisk-in-rod heterostructures to quantify uniformity of light emission on the ensemble level, as well as the emission characteristics from individual InGaN nanodisks. Despite the high overall luminescence efficiency, spectral and intensity inhomogeneities were observed and directly correlated to the compositional variations among nanodisks and to the presence of structural defect, respectively. Observed light quenching is correlated to type I1 stacking faults in InGaN nanodisks, and the mechanisms for stacking fault induced nonradiative recombinations are discussed in the context of band structure around stacking faults and Fermi level pinning at nanorod surfaces. Our results highlight the importance of controlling III-nitride nanostructure growths to further reduce defect formation and ensure compositional homogeneity for optoelectronic devices with high efficiencies and desirable spectrum response.


Hypercalcemia of Malignancy and Colorectal Cancer.
Our aim is to describe the association between colorectal cancer (CRC) and humoral hypercalcemia of malignancy (HHM). Causes of hypercalcemia of malignancy include parathyroid hormone-related peptide (PTHrP) secretion, local osteolysis, calcitriol production and ectopic parathyroid hormone (PTH) secretion. Hypercalcemia of malignancy in patients with CRCs is a rare scenario. A patient with anal squamous cell carcinoma was admitted with hypercalcemia, suppressed PTH and hypophosphatemia. He was found to have metastatic anal squamous cell carcinoma to the liver. Further evaluation revealed elevated PTHrP and 1,25-dihydroxyvitamin D and low 25-hydroxyvitamin D. Over a 5-month course, the hypercalcemia responded poorly to bisphosphonates, transiently to prednisone, but showed marked improvement with chemotherapy. A review of English language publications in Pubmed and a reference search of retrieved articles revealed 29 cases of CRC causing PTHrP-mediated hypercalcemia. Most patients were middle-aged men (mean ± SD: 56.7 ± 13.4 years), with advanced metastatic cancer (85% with hepatic metastasis) and severe hypercalcemia (mean ± SD: 15.6 ± 1.9 mg/dL, 62% with Ca > 14). This condition is associated with high mortality (79%) and short survival (median 54.5 days, CI: 21 - 168). Despite being uncommon, HHM (PTHrP-mediated) should be considered in patients with metastatic CRC presenting with hypercalcemia. Clinicians should be aware that combined etiologies may be present, particularly in cases of resistant hypercalcemia. Treatment of the underlying malignancy is essential for calcium control.


A Bayesian model of lightness perception that incorporates spatial variation in the illumination.
The lightness of a test stimulus depends in a complex manner on the context in which it is viewed. To predict lightness, it is necessary to leverage measurements of a feasible number of contextual configurations into predictions for a wider range of configurations. Here we pursue this goal, using the idea that lightness results from the visual system's attempt to provide stable information about object surface reflectance. We develop a Bayesian algorithm that estimates both illumination and reflectance from image luminance, and link perceived lightness to the algorithm's estimates of surface reflectance. The algorithm resolves ambiguity in the image through the application of priors that specify what illumination and surface reflectances are likely to occur in viewed scenes. The prior distributions were chosen to allow spatial variation in both illumination and surface reflectance. To evaluate our model, we compared its predictions to a data set of judgments of perceived lightness of test patches embedded in achromatic checkerboards (Allred, Radonjić, Gilchrist, & Brainard, 2012). The checkerboard stimuli incorporated the large variation in luminance that is a pervasive feature of natural scenes. In addition, the luminance profile of the checks both near to and remote from the central test patches was systematically manipulated. The manipulations provided a simplified version of spatial variation in illumination. The model can account for effects of overall changes in image luminance and the dependence of such changes on spatial location as well as some but not all of the more detailed features of the data.


Bcl-2 acts in a proangiogenic signaling pathway through nuclear factor-kappaB and CXC chemokines.
Vascular endothelial growth factor (VEGF) induces expression of Bcl-2 in tumor-associated microvascular endothelial cells. We have previously reported that up-regulated Bcl-2 expression in microvascular endothelial cells is sufficient to enhance intratumoral angiogenesis and to accelerate tumor growth. We initially attributed these results to Bcl-2-mediated endothelial cell survival. However, in recent experiments, we observed that conditioned medium from Bcl-2-transduced human dermal microvascular endothelial cells (HDMEC-Bcl-2) is sufficient to induce potent neovascularization in the rat corneal assay, whereas conditioned medium from empty vector controls (HDMEC-LXSN) does not induce angiogenesis. These results cannot be attributed to the role of Bcl-2 in cell survival. To understand this unexpected observation, we did gene expression arrays that revealed that the expression of the proangiogenic chemokines interleukin-8 (CXCL8) and growth-related oncogene-alpha (CXCL1) is significantly higher in HDMEC exposed to VEGF and in HDMEC-Bcl-2 than in controls. Inhibition of Bcl-2 expression with small interfering RNA-Bcl-2, or the inhibition of Bcl-2 function with small molecule inhibitor BL-193, down-regulated CXCL8 and CXCL1 expression and caused marked decrease in the angiogenic potential of endothelial cells without affecting cell viability. Nuclear factor-kappaB (NF-kappaB) is highly activated in HDMEC exposed to VEGF and HDMEC-Bcl-2 cells, and genetic and chemical approaches to block the activity of NF-kappaB down-regulated CXCL8 and CXCL1 expression levels. These results reveal a novel function for Bcl-2 as a proangiogenic signaling molecule and suggest a role for this pathway in tumor angiogenesis.


Simultaneous oral and inhalational intake of molecular hydrogen additively suppresses signaling pathways in rodents.
Molecular hydrogen (H2) is an agent with potential applications in oxidative stress-related and/or inflammatory disorders. H2 is usually administered by inhaling H2-containing air (HCA) or by oral intake of H2-rich water (HRW). Despite mounting evidence, the molecular mechanism underlying the therapeutic effects and the optimal method of H2 administration remain unclear. Here, we investigated whether H2 affects signaling pathways and gene expression in a dosage- or dose regimen-dependent manner. We first examined the H2 concentrations in blood and organs after its administration and found that oral intake of HRW rapidly but transiently increased H2 concentrations in the liver and atrial blood, while H2 concentrations in arterial blood and the kidney were one-tenth of those in the liver and atrial blood. In contrast, inhalation of HCA increased H2 equally in both atrial and arterial blood. We next examined whether H2 alters gene expression in normal mouse livers using DNA microarray analysis after administration of HCA and HRW. Ingenuity Pathway Analysis revealed that H2 suppressed the expression of nuclear factor-kappa B (NF-κB)-regulated genes. Western blot analysis showed that H2 attenuated ERK, p38 MAPK, and NF-κB signaling in mouse livers. Finally, we evaluated whether the changes in gene expression were influenced by the route of H2 administration and found that the combination of both HRW and HCA had the most potent effects on signaling pathways and gene expression in systemic organs, suggesting that H2 may act not only through a dose-dependent mechanism but also through a complex molecular network.


Djulis Hull Enhances the Efficacy of Ferric Citrate Supplementation via Restoring Normal Iron Efflux through the IL-6-Hepcidin-Ferroportin Pathway in High-Fat-Diet-Induced Obese Rats.
Obesity-related functional iron disorder remains a major nutritional challenge. We evaluated the effects of djulis hull (DH) on iron metabolism in 50% high-fat-diet-induced obese rats supplemented with ferric citrate (2 g iron/kg diet) for 12 weeks. DH supplementation (5, 10, 15% dry weight/kg diet) significantly increased serum and hepatic iron but decreased appetite hormones, body weight, hepcidin, and liver inflammation (all p < 0.05). The Spearman correlation showed that appetite hormones were negatively associated with iron but positively correlated with liver hepcidin (all p < 0.05). A Western blot analysis showed that DH significantly downregulated hepatic hepcidin through the IL-6-JAK-STAT3 and enhanced ferroportin (Fpn) via the Keap1-Nrf2 and PHD2-HIF-2α. An in vitro study revealed that major bioactive compounds of DH, hexacosanol, and squalene suppressed LPS-induced IL-6 and hepcidin but enhanced Fpn expression in activated THP-1 cells. In conclusion, DH may exert nutraceutical properties for the treatment of functional iron disorder and restoration of iron efflux may have beneficial effects on weight control.


Recurrent autoimmune hepatitis after orthotopic liver transplantation.
To determine the frequency, risk factors, and consequences of recurrent autoimmune hepatitis after liver transplantation, 41 patients with type 1 disease were monitored after surgery in accordance with a surveillance protocol. Tacrolimus or cyclosporine plus prednisone were administered to each patient, and liver biopsy examinations were performed at least annually according to protocol. Corticosteroid therapy was ultimately discontinued in only 2 patients. Recurrent disease was defined as the presence of lymphoplasmacytic infiltrates in liver tissue in the absence of other causes of allograft dysfunction. Autoimmune hepatitis recurred in 7 patients (17%), and the mean time to recurrence was 4.6 +/- 1 years. Recurrence was asymptomatic in 4 of 7 patients and detected only by surveillance liver biopsy assessment in 2 patients. Histological changes were mild, and there was no progression to cirrhosis during 4.9 +/- 0.9 years of observation. Five-year patient (86% v. 82%; P =.9) and graft (86% v. 67%; P =.5) survival rates were not statistically different between patients with and without recurrent disease. HLA-DR3 or HLA-DR4 occurred more commonly in patients with than without recurrence (100% v. 40%; P =.008) and healthy subjects (100% v. 49%; P =.01). Recurrent disease was unrelated to donor HLA status. In conclusion, recurrence after transplantation for type 1 autoimmune hepatitis is common. Its mild manifestations and favorable prognosis may reflect early detection by a surveillance protocol and/or continuous corticosteroid treatment. HLA-DR3- or HLA-DR4-positive recipients are at risk for recurrence regardless of donor HLA status.


Primary familial brain calcification with known gene mutations: a systematic review and challenges of phenotypic characterization.
In the past 2 years, 3 genes (SLC20A2, PDGFRB, and PDGFB) were identified as causative of primary familial brain calcification (PFBC), enabling genotype-specific phenotyping. To provide a systematic literature review on the neuroimaging and clinical phenotype of genetically confirmed PFBC and summarize known pathophysiological mechanisms, to improve and harmonize future phenotype description and reporting by addressing data gaps, and to develop uniform definitions for clinical characterization. We systematically searched the MEDLINE database among articles published from January 1, 2012, through May 31, 2014, for the 3 genes and selected 25 articles from all records (n=75) and from sources cited in the reference lists. Only genetically confirmed cases with individual clinical information were included, leaving 15 reports. Predefined categories for data extraction were different neurologic and psychiatric symptoms, imaging results, and age at onset (AAO). We also assessed availability of information to estimate possible bias. We included a total of 179 cases, 162 of which belong to 25 families. Availability of information ranged from 96.6% for ethnicity to 24.4% for AAO. All cases had calcifications on comprehensive cranial computed tomography, most frequently located in the basal ganglia (70.6%), subcortical white matter (40.8%), cerebellum (34.1%), or thalamus (28.5%). Mean (SD) AAO was 27.9 (22.3) years, and the AAO was comparable across genes (P=.77). The most frequently described signs were movement disorders, such as parkinsonism (12%) and dystonia (19%). Penetrance of the imaging phenotype was 100% compared with only 61% of the clinical phenotype. We propose a novel definition of disease status by specifying PFBC into genetic, clinical, and imaging phenotypes. Pathophysiological pathways converge on impaired phosphorus homeostasis and integrity of the blood-brain barrier. Especially in rare conditions, meta-analyses are the most suitable tool to extract reliable information on the natural course of a disease. For future analyses, we provide a minimal data set that can be used for systematic clinical and imaging data collection in PFBC and that will also improve informed counseling of patients.


Flow diverter devices in ruptured intracranial aneurysms: a single-center experience.
OBJECTIVE In this single-center series, the authors retrospectively evaluated the effectiveness, safety, and midterm follow-up results of ruptured aneurysms treated by implantation of a flow diverter device (FDD). METHODS The records of 17 patients (12 females, 5 males, average World Federation of Neurosurgical Societies score = 2.9) who presented with subarachnoid hemorrhage (SAH) due to the rupture of an intracranial aneurysm treated with an FDD were retrospectively reviewed. Of 17 ruptured aneurysms, 8 were blood blister-like aneurysms and the remaining 9 were dissecting aneurysms. The mean delay between SAH and treatment was 4.2 days. Intraprocedural and periprocedural morbidity and mortality were recorded. Clinical and angiographic follow-up evaluations were conducted between 6 and 12 months after the procedure. RESULTS None of the ruptured aneurysms re-bled after endovascular treatment. The overall mortality rate was 12% (2/17), involving 2 patients who died after a few days because of complications of SAH. The overall morbidity rate was 12%: 1 patient experienced intraparenchymal bleeding during the repositioning of external ventricular drainage, and 1 patient with a posterior inferior cerebellar artery aneurysm developed paraplegia due to a spinal cord infarction after 2 weeks. The angiographic follow-up evaluations showed a complete occlusion of the aneurysm in 12 of 15 surviving patients; of the 3 remaining cases, 1 patient showed a remnant of the aneurysm, 1 patient was retreated due to an enlargement of the aneurysm, and 1 patient was lost at the angiographic follow-up. CONCLUSIONS FDDs can be used in patients with ruptured aneurysms, where conventional neurosurgical or endovascular treatments can be challenging.


Uterus transplantation model in sheep with heterotopic whole graft and aorta and cava anastomoses.
Uterine transplantation in the sheep model has been described as a partial or whole orthotopic graft from a living donor with vascular anastomoses. As an alternative to surrogate pregnancy or adoption uterus transplantation might be indicated for cases of infertility of uterine origin. The main complications might be rejection and thrombosis. The objective of this work was to develop a model of whole uterus transplantation that was applicable to the human setting, using grafts obtained from brain-dead donors, and suitable for immunologic and viability follow-up with a reduced risk of thrombosis. Two donors and 1 recipient were operated. The first graft was used for an anatomic study; the second was used for transplantation. The donor operation consisted of an en bloc harvest of the uterus, adnexa, and proximal vagina with the distal aorta and cava. After harvest the donor sheep was humanely killed. In the recipient ewe, heterotopic implantation was performed in the lower abdomen. An End-to-side anastomoses of aorta and cava were performed below the recipient's renal vessels. A cutaneous vaginal stoma was performed in the right lower quadrant. The recipient ewe was humanely killed for an autopsy study. The anatomy of uterine veins of the ewe differs from the human. The uterine and ovarian veins join, forming the utero-ovarian vein, which drains at the confluence of the common iliac to the cava. En bloc harvesting allows for rapid graft preparation, with vascular cuffs easily anastomosed with a low risk of thrombosis. The vaginal stoma seems appropriate to facilitate follow-up and graft biopsy. This approach can be a suitable experimental model applicable to humans using grafts from brain-dead donors.


Controlling the bleeding of carmine colorant in crabstick.
Carmine used to color surimi seafood often seeps or bleeds from red-colored meat to white meat when vacuum-packed products go through high-temperature long-time pasteurization. Various physical and chemical treatments were examined to investigate means to inhibit or minimize carmine bleeding in surimi seafood products. Degree of bleeding was analyzed using L* (lightness) and a* (redness) as affected by carmine concentrations, pH, pasteurization conditions, and added calcium compounds. Bleeding was significantly affected by carmine concentrations. Optimum carmine concentration in color paste was 0.1%. Bleeding increased when pasteurization time and/or temperature increased. Color bleeding was also affected by moisture content of surimi paste. Carmine bleeding was minimized as pH of color solution decreased. The degree of bleeding was controlled as calcium compounds were added in color solution in a descending order of calcium chloride, calcium acetate, and calcium hydroxide. Minimal inhibition was obtained when color solutions contained calcium citrate, tricalcium phosphate, and calcium lactate. Practical Application: This manuscript addresses one of the long time problems in the surimi crabstick industry. Various means to control carmine bleeding or color transfer under high temperature for long time pasteurization were demonstrated. However, further study must continue to stop bleeding completely.


PTHrP regulates epidermal differentiation in adult mice.
Emerging evidence suggests that parathyroid hormone-related peptide (PTHrP) serves as a regulator of the development and/or differentiation of a number of organs, including endochondral bone, the tooth, and the mammary gland. Although disruption of the PTHrP gene by homologous recombination results in a lethal chondrodystrophy, PTHrP-knockout mice that have been rescued by the transgenic replacement of the peptide in cartilage display abnormalities in ectodermally derived structures including the skin. At 6-8 wk of age, these rescued PTHrP-knockout mice displayed a markedly thinned epidermis and striking hyperkeratosis, hypoplastic sebaceous glands, and a fibrotic dermis. In contrast, transgenic mice that overexpress PTHrP by virtue of the human keratin-14 promoter displayed a thickened ventral epidermis with marked acanthosis and papillomatosis, hyperplastic sebaceous glands, and a cellular dermis. The absence of PTHrP appeared to result in the reduction of the basal keratinocyte compartment and premature acquisition of suprabasal and granular differentiation markers, whereas overexpression of the peptide generated reciprocal findings. No difference in the epidermal proliferation rate was found in PTHrP-null skin and although an increase was observed in keratin 14-PTHrP transgenic animals, their epidermis did not express the hyperplasia marker K6. Finally, the replacement of PTHrP in the basal keratinocytes of rescued PTHrP-knockout mice under the direction of the keratin 14 promoter reversed the abnormalities seen in PTHrP-null skin. These findings suggest that PTHrP regulates the rate of keratinocyte differentiation in the skin of adult mice.


An Overview of Oncology Researches in Iran: A Scientometric Approach (1974 - February 2019).
With the growing rate of tumors, cancer has become one of the most important health concerns in Iran. The urgency with which Iranian researchers and health professionals address this challenge leads to a load of scientific materials. To reveal gaps in produced knowledge and suggest future research directions, applying well-validated scientometric tools, we assessed the trends of Iranian published scientific articles and citations in the field of oncology. The inclusion criteria consisted of all oncology-related articles that were data-based, and peer-reviewed; with at least an abstract published in English; and authored by at least one researcher affiliated with Iranian institutions. Amongst 5063525 oncology research records indexed in at least one of PubMed, Scopus, or Web of Science Core Collection (WoS) from the start to February 2019, Iranian researches accounted for about 24867 (0.49%). Published articles on all cancers by Iranian researchers had a sharp continuously ascending trend, with the same pattern for citations received. Some important topics such as complementary and alternative medicine (CAM) therapies have been missing and some such as diagnostic and pharmaceutical innovations have been less investigated. The most collaborative country was the United States, while no close collaboration was observed with China that was introduced as the most productive country in the field of oncology over the past decades. Despite the progressive trend in most oncology fields, some significant practical topics are still missing. Systematic reviews of produced theoretical innovations and translating them to functional knowledge can be of importance to fulfill the mentioned gaps.


Kinematic stride cycle asymmetry is not associated with sprint performance and injury prevalence in athletic sprinters.
The aims of this study were to (a) quantify the magnitude of kinematic stride cycle asymmetry in high-level athletic sprinters, (b) explore the association between kinematic asymmetry and maximal sprint running performance, and (c) investigate possible associations between kinematic asymmetry and injury prevalence. Twenty-two competitive sprinters (age 23 ± 3 year, height 1.81 ± 0.06 m, body mass 75.5 ± 5.6 kg, personal best 100 m 10.86 ± 0.22 seconds) performed 2-3 flying sprints over 20 m. Kinematics were recorded in 3D using a motion tracking system with 21 cameras at a 250 Hz sampling rate, allowing assessment of six consecutive steps for each athlete. Information about injuries sustained 1 year prior to and after the experiment was continuously registered (type, location, severity/duration, and time of year occurrence). The results showed that ≥11 of the 22 participating athletes displayed large or very large asymmetry for at least 11 of 14 variables, and all athletes displayed large or very large asymmetry for at least three variables. No correlations between individual magnitudes of asymmetry and sprint performance were significant (trivial to moderate). No significant changes in asymmetry between best and worst trial were observed for any of the analyzed variables. In addition, injured and non-injured athletes did not differ in asymmetry, neither for the time period 1 year prior to nor after the test. In conclusion, kinematic asymmetries in the stride cycle were not associated with neither maximal sprint running performance nor the prevalence of injury among high-level athletic sprinters.


Coexpression analysis of nine neuropeptides in the neurosecretory preoptic area of larval zebrafish.
The paraventricular nucleus (PVN) of the hypothalamus in mammals coordinates neuroendocrine, autonomic and behavioral responses pivotal for homeostasis and the stress response. A large amount of studies in rodents has documented that the PVN contains diverse neuronal cell types which can be identified by the expression of distinct secretory neuropeptides. Interestingly, PVN cell types often coexpress multiple neuropeptides whose relative coexpression levels are subject to environment-induced plasticity. Due to their small size and transparency, zebrafish larvae offer the possibility to comprehensively study the development and plasticity of the PVN in large groups of intact animals, yet important anatomical information about the larval zebrafish PVN-homologous region has been missing. Therefore we recently defined the location and borders of the larval neurosecretory preoptic area (NPO) as the PVN-homologous region in larval zebrafish based on transcription factor expression and cell type clustering. To identify distinct cell types present in the larval NPO, we also generated a comprehensive 3D map of 9 zebrafish homologs of typical neuropeptides found in the mammalian PVN (arginine vasopressin (AVP), corticotropin-releasing hormone (CRH), proenkephalin a (penka)/b (penkb), neurotensin (NTS), oxytocin (OXT), vasoactive intestinal peptide (VIP), cholecystokinin (CCK), and somatostatin (SST)). Here we extend this chemoarchitectural map to include the degrees of coexpression of two neuropeptides in the same cell by performing systematic pairwise comparisons. Our results allowed the subclassification of NPO cell types, and differences in variability of coexpression profiles suggest potential targets of biochemical plasticity. Thus, this work provides an important basis for the analysis of the development, function, and plasticity of the primary neuroendocrine brain region in larval zebrafish.


Isolation and characterization of rat liver mitochondrial ribosomes.
A procedure has been developed that allows characterization of mitochondrial ribosomes and quantitative analysis of the relative composition of constitutive ribosomal proteins. Purified mitochondrial ribosomes were isolated from two rat livers and shown to be active in catalyzing the polymerization of phenylalanine. They differ in sedimentation and spectral properties from cytoplasmic ribosomes isolated from the same livers. The number and relative composition of proteins present in active rat liver mitochondrial ribosomes were investigated using two-dimensional nonequilibrium pH gradient electrophoresis. There were 86 proteins found associated with mitochondrial ribosomes in contrast to 70 proteins found associated with cytoplasmic ribosomes. Comparison of electrophoretic patterns revealed that cytoplasmic ribosomal proteins were considerably more basic than their mitochondrial counterparts. Densitometry demonstrated that the relative changes in the concentrations of these proteins can be measured quantitatively. These procedures, developed for use with two rat livers, allow the rat to be used as an efficient model for further studies into disease states of mitochondrial translation.


Patient-perceived functional outcomes associated with elective hip and knee arthroplasties.
The purpose of this study was to determine the effect elective hip and knee arthroplasties had on functional activities of daily living and if the background variables of age, gender, and surgery location can be used to predict functional outcome after these types of surgeries. Data were collected from 43 subjects, 6 to 35 months after they had elective hip or knee arthroplasties. The subjects responded to a mail survey that defined before surgery and after recovery functioning in relation to 22 activities of daily living representing personal care, housework-yard work, and recreation-social activities. Approximately 65% of the subjects reported no change in their ability to perform the 22 surveyed activities. Psychosocial variables appeared to be significant determinants of function. When the selected background data were compared with surgery results, women performed significantly better than men (p less than .05), but age and surgery location were not significant variables affecting outcome.


Human macrophage foam cells degrade atherosclerotic plaques through cathepsin K mediated processes.
Proteolytic degradation of Type I Collagen by proteases may play an important role in remodeling of atherosclerotic plaques, contributing to increased risk of plaque rupture.The aim of the current study was to investigate whether human macrophage foam cells degrade the extracellular matrix (ECM) of atherosclerotic plaques by cathepsin K mediated processes. We 1) cultured human macrophages on ECM and measured cathepsin K generated fragments of type I collagen (C-terminal fragments of Type I collagen (CTX-I) 2) investigated the presence of CTX-I in human coronary arteries and 3) finally investigated the clinical potential by measuring circulating CTX-I in women with and without radiographic evidence of aortic calcified atherosclerosis. Immune-histochemistry of early and advanced lesions of coronary arteries demonstrated co-localization of Cathepsin-K and CTX-I in areas of intimal hyperplasia and in shoulder regions of advanced plaques. Treatment of human monocytes with M-CSF or M-CSF+LDL generated macrophages and foam cells producing CTX-I when cultured on type I collagen enriched matrix. Circulating levels of CTX-I were not significantly different in women with aortic calcifications compared to those without. Human macrophage foam cells degrade the atherosclerotic plaques though cathepsin K mediated processes, resulting in increase in levels of CTX-I. Serum CTX-I was not elevated in women with aortic calcification, likely due to the contribution of CTX-I from osteoclastic bone resorption which involves Cathepsin-K. The human macrophage model system may be used to identify important pathway leading to excessive proteolytic plaque remodeling and plaque rupture.


Efficacy and Safety of Programmed Death-1 (PD-1)/Programmed Death-Ligand 1 (PD-L1) Checkpoint Inhibitors in Patients With Metastatic Castration-resistant Prostate Cancer: A Systematic Review and Meta-analysis.
The aim of this systematic review with meta-analysis was to evaluate the efficacy and safety of programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors in patients with metastatic castration-resistant prostate cancer (mCRPC). We searched PubMed, Embase and Cochrane Library until 1 July 2022 for mCRPC trials testing PD-1/PD-L1 checkpoint inhibitors. We measured the efficacy and safety using overall survival, progression-free survival (PFS), overall response rates (ORR), prostate-specific antigen (PSA) response rate or treatment-related adverse events (TRAEs). When possible, data were meta-analysed. Thirteen studies involving 2533 participants were included in this meta-analysis. The pooled hazard ratio for overall survival was 0.81 (95% confidence interval 0.42-1.20, I2 = 80.3%, PHeterogeneity<0.001) and for PFS was 0.65 (95% confidence interval 0.38-0.92, I2 = 72.2%, PHeterogeneity = 0.013). Furthermore, better ORR (relative risk = 2.77, 95% confidence interval 1.25-6.13, I2 = 0%, PHeterogeneity = 0.699) was found in PD-L1-expressing tumours. However, no statistical trends between PD-L1 status on PSA response rate (relative risk = 0.79, 95% confidence interval 0.5-1.25, I2 = 0%, PHeterogeneity = 0.953) and tumour mutational burden on ORR (relative risk = 2.53, 95% confidence interval 0.49-13.12, I2 = 74.5%, PHeterogeneity = 0.02) were observed. The pooled proportions of TRAEs and ≥ grade 3 TRAEs were 85.1% (95% confidence interval = 71.7-98.5%) and 31.6% (95% confidence interval = 18.9-44.4%), respectively. This meta-analysis showed that among selected populations of men with mCRPC, anti-PD-1/PD-L1 combination treatment may significantly increase the PFS benefits. However, overall survival in mCRPC warrants further testing.


Natural variation in Arabidopsis shoot branching plasticity in response to nitrate supply affects fitness.
The capacity of organisms to tune their development in response to environmental cues is pervasive in nature. This phenotypic plasticity is particularly striking in plants, enabled by their modular and continuous development. A good example is the activation of lateral shoot branches in Arabidopsis, which develop from axillary meristems at the base of leaves. The activity and elongation of lateral shoots depends on the integration of many signals both external (e.g. light, nutrient supply) and internal (e.g. the phytohormones auxin, strigolactone and cytokinin). Here, we characterise natural variation in plasticity of shoot branching in response to nitrate supply using two diverse panels of Arabidopsis lines. We find extensive variation in nitrate sensitivity across these lines, suggesting a genetic basis for variation in branching plasticity. High plasticity is associated with extreme branching phenotypes such that lines with the most branches on high nitrate have the fewest under nitrate deficient conditions. Conversely, low plasticity is associated with a constitutively moderate level of branching. Furthermore, variation in plasticity is associated with alternative life histories with the low plasticity lines flowering significantly earlier than high plasticity lines. In Arabidopsis, branching is highly correlated with fruit yield, and thus low plasticity lines produce more fruit than high plasticity lines under nitrate deficient conditions, whereas highly plastic lines produce more fruit under high nitrate conditions. Low and high plasticity, associated with early and late flowering respectively, can therefore be interpreted alternative escape vs mitigate strategies to low N environments. The genetic architecture of these traits appears to be highly complex, with only a small proportion of the estimated genetic variance detected in association mapping.


Soothing the inflamed brain: effect of non-steroidal anti-inflammatory drugs on Alzheimer's disease pathology.
Epidemiological studies suggest that systemic use of non-steroidal anti-inflammatory drugs (NSAIDs) can prevent or retard the development of Alzheimer's disease (AD). However, clinical trials investigating the effects of NSAIDs on AD progression have yielded mixed or inconclusive results. The aim of this review is to distinguish the role of inflammation and the molecular targets of NSAIDs in the different stages of AD pathology. AD brains are characterized by extracellular deposits of β-amyloid protein and intraneuronal accumulation of hyperphosphorylated tau protein. Already in the early stages of AD pathology β-amyloid protein deposits are associated with inflammatory proteins and microglia, the brain resident macrophages. Recently, two genome-wide association studies identified new genes that are associated with an increased risk of developing AD. These genes include CLU and CR1 which encode for clusterin and complement receptor 1 respectively. Both genes are involved in the regulation of inflammation. This strongly indicates that inflammation plays a central role in the aetiology of AD. In this review we will show that the primary targets of NSAIDs are involved in a pathological stage that precedes the clinical appearance of AD. The early, preclinical involvement of inflammation in AD explains why patients with clinical signs of AD do not benefit from anti-inflammatory treatment and suggests that NSAIDs, rather than having a direct therapeutic effect, may have preventive effects.


Child meets word: "fast mapping" in preschool children.
"Fast mapping" (Carey & Bartlett, 1978) is a hypothesized process enabling children to rapidly create lexical representations for the unfamiliar words they encounter. In this study, 35 normal preschool children, ages 2:1-5:11 (years:months), were exposed to a monosyllabic nonsense word and its novel object referent. On first exposure, 91% of the subjects inferred the connection between the novel word and referent. After this single encounter, 81% correctly identified the referent on hearing its label a second time. After hearing the new word twice, 45% were able to produce at least two of its three phonemes in labeling the novel referent. Of those children who did not attempt to label the novel referent, a significant percentage recognized the correct label. In addition, a significant percentage of subjects recalled some nonlinguistic information associated with the referent. Normal preschoolers appear to create fast mappings containing a great deal of linguistic and nonlinguistic information on the basis of even brief, casual encounters with new words.


Holokinetic drive: centromere drive in chromosomes without centromeres.
Similar to how the model of centromere drive explains the size and complexity of centromeres in monocentrics (organisms with localized centromeres), our model of holokinetic drive is consistent with the divergent evolution of chromosomal size and number in holocentrics (organisms with nonlocalized centromeres) exhibiting holokinetic meiosis (holokinetics). Holokinetic drive is proposed to facilitate chromosomal fission and/or repetitive DNA removal (or any segmental deletion) when smaller homologous chromosomes are preferentially inherited or chromosomal fusion and/or repetitive DNA proliferation (or any segmental duplication) when larger homologs are preferred. The hypothesis of holokinetic drive is supported primarily by the negative correlation between chromosome number and genome size that is documented in holokinetic lineages. The supporting value of two older cross-experiments on holokinetic structural heterozygotes (the rush Luzula elegans and butterflies of the genus Antheraea) that indicate the presence of size-preferential homolog transmission via female meiosis for holokinetic drive is discussed, along with the further potential consequences of holokinetic drive in comparison with centromere drive.


Calcium-induced exposure of a hydrophobic surface on calmodulin.
Interactions between calmodulin (CaM) and several hydrophobic fluorescent probes were characterized in order to determine if CaM expresses hydrophobic binding sites in the presence of Ca2+. Several classes of fluorescent probes capable of sensing exposure of hydrophobic binding sites on proteins were found to bind to CaM, and these interactions were greatly enhanced by Ca2+. In the presence of Ca2+, the fluorescence intensity of 9-anthroylcholine (9AC) was increased 24-fold by CaM, with a shift in the fluorescence emission maximum from 514 to 486 nm. The fluorescence intensity of 8-anilino-1-naphthalenesulfonate (Ans) was enhanced 27-fold with an emission maximum shift from 540 to 488 nm in the presence of CaM and Ca2+. Similar results were obtained with the uncharged fluorescent ligand, N-phyenyl-1-naphthylamine. With all three fluorescent dyes, the fluorescence changes caused by CaM in the absence of Ca2+ were minor compared to those observed with CaM and Ca2+. Direct binding studies using equilibrium dialysis demonstrated that CaM can bind four to six molecules of 9AC or two to three molecules of Ans in a calcium-dependent manner. The effects of various amphiphilic compounds on the Ca2+-dependent complex formation between CaM and the Ca2+-sensitive phosphodiesterase or troponin I were investigated. Trifluoperazine (TFP) and 9AC inhibited CaM stimulation of the Ca2+-sensitive phosphodiesterase. The Ca2+-dependent binding of the phosphodiesterase to CaM-Sepharose was also inhibited by TFP, 9AC, and Ans. Furthermore, binding of CaM to troponin I-Sepharose was inhibited by these ligands. Consistent with these data was the observation that troponin I antagonized binding of 9AC to CaM. These data indicate that binding of Ca2+ to CaM results in exposure of a domain with considerable hydrophobic character, and binding of hydrophobic ligands to this domain antagonizes CaM-protein interactions. It is proposed that this hydrophobic domain may serve as the interface for the Ca2+-dependent binding of CaM to the phosphodiesterase or troponin I.


MDM2 Antagonists Induce a Paradoxical Activation of Erk1/2 through a P53-Dependent Mechanism in Dedifferentiated Liposarcomas: Implications for Combinatorial Strategies.
The MDM2 gene is amplified in dedifferentiated liposarcoma (DDLPS). Treatment with MDM2 antagonists is a promising strategy to treat DDLPS; however, drug resistance is a major limitation when these drugs are used as a single agent. This study examined the impact of MDM2 antagonists on the mitogen-activated protein kinase (MAPK) pathway in DDLPS and investigated the potential synergistic activity of a MAPK kinase (MEK) inhibitor in combination with MDM2 antagonists. We identified a synergistic effect and identified the mechanism behind it. Combination effects of MDM2 antagonists and a MEK inhibitor were analyzed in a patient-derived xenograft mouse model and in DDLPS and leiomyosarcoma cell lines using different cell proliferation assays and immunoblot analysis. MDM2 antagonist (RG7388)-resistant IB115 [P4] cells and p53-silenced DDLPS cells were also established to understand the importance of functional p53. We found that MDM2 antagonists induced an upregulation of phosphorylated extracellular signal-regulated kinase (p-ERK) in DDLPS cells. The upregulation of p-ERK occurred due to mitochondrial translocation of p53, which resulted in increased production of reactive oxygen species, causing the activation of receptor tyrosine kinases (RTKs). Activated RTKs led to the activation of the downstream MEK/ERK signaling pathway. Treatment with a MEK inhibitor resulted in decreased expression of p-ERK, causing significant anti-tumor synergy when combined with MDM2 antagonists. Our results provide a framework for designing clinical studies of combination therapies in DDLPS patients.


[Cognitive-behavioral therapy in prevention of depression relapses and recurrences: a review].
To revise theories and the available evidence about Cognitive Behavioral Therapy (CBT) role on the relapse and recurrence prevention of depressive episodes. Review of random and controlled clinical trials that investigated CBT efficacy on the relapse and recurrence prevention of depressive episodes. The following databases were used: Medline, Lilacs, Cochrane, Biosis and Embase. The reference sections of the selected articles, review articles and specialized books were consulted. Fifteen studies with different experimental design were found, several with methodological problems. The majority of them compared CBT with antidepressants at the acute treatment phase. In 12 studies CBT significantly lowered the relapse/recurrence rate. Recent papers pointed to the CBT usefulness for treating residual depressive symptoms as a recurrence prevention strategy. CBT was effective for the depression relapse reduction. Its relationship with antidepressants as a prevention tool and CBT strategies (using it only in the acute phase, or during acute and maintenance phases, or after antidepressants withdrawal as a maintenance treatment, or focusing residual symptoms) need to be better investigated.


[Relationship between blocking the erythrocyte surface and the quantity of IgG molecules bound in the process of hemosensitization].
Under different conditions of the IgG-sensitization of the tannin-treated erythrocytes a determination was made of the degree of blocking the cell surface. There was shown a reverse relationship between the amount of the bound IgG molecules and their portions bound by the surface with the maximal cross-section. Fixation of the IgG by means of CH2O at the end of sensitization led to the additional blocking of the erythrocyte surface. The limit of the erythrocyte saturation with the IgG molecules was controlled by the greatest possible density of the globulin molecules localization.


Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity.
The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis, and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintenance of weight loss and reduction of dyslipidemia in experimental and human obesity. The molecular mechanism by which CB1R blockade reverses dyslipidemia in obesity has not yet been clarified. In this study, we showed that CB1R blockade with the systemic CB1R blocker rimonabant enhanced whole-body energy expenditure and activated brown adipose tissue (BAT), indicated by increased expression of genes involved in BAT thermogenesis and decreased lipid droplet size in BAT. This was accompanied by selectively increased triglyceride (TG) uptake by BAT and lower plasma TG levels. Interestingly, the effects on BAT activation were still present at thermoneutrality and could be recapitulated by using the strictly peripheral CB1R antagonist AM6545, indicating direct peripheral activation of BAT. Indeed, CB1R blockade directly activated T37i brown adipocytes, resulting in enhanced uncoupled respiration, most likely via enhancing cAMP/PKA signaling via the adrenergic receptor pathway. Our data indicate that selective targeting of the peripheral CB1R in BAT has therapeutic potential in attenuating dyslipidemia and obesity.


Students and Doctors are Unaware of the Cost of Drugs they Frequently Prescribe.
Given the increasing healthcare costs of an ageing population, there is growing interest in rational prescribing, which takes costs of medication into account. We aimed to gain insight into the attitude to and knowledge of medication costs of medical students and doctors in daily practice. This was a cross-sectional electronic survey among medical students (bachelor/master) and doctors (consultants/registrars). Attitude to costs was evaluated using a cost-consciousness scale. In open questions, the participants estimated the cost of commonly prescribed (generic/non-generic) drugs (including separate pharmacy dispensing costs). They were asked where they could find information about drug costs. Overall, a reasonable cost-consciousness was found. Students were less conscious of the cost than were doctors (15.56 SD 3.25 versus 17.81 SD 2.25; scale 0-24; p = 0.001). In contrast to this consciousness, actual estimated drug costs were within a 25% margin for only 5.4% of generic and 13.7% of proprietary drugs (Wilcoxon signed-rank, p < 0.001). The price of generic drugs was frequently overestimated (77.5%) and that of proprietary drugs was underestimated (51.4%). The dispensing costs were estimated correctly for 30% of the drugs. Most doctors (84%) and a minority of students (40%) were able to identify at least one source of information about drug costs. While doctors and students considered it important to be aware of the cost of drugs, this attitude is not reflected in their ability to estimate the cost of frequently prescribed drugs. Cost awareness is important in therapeutic reasoning and cost-effective prescribing. Both should be better addressed in (undergraduate) pharmacotherapy education.


Situations Leading to Reduced Effectiveness of Current Hand Hygiene against Infectious Mucus from Influenza Virus-Infected Patients.
Both antiseptic hand rubbing (AHR) using ethanol-based disinfectants (EBDs) and antiseptic hand washing (AHW) are important means of infection control to prevent seasonal influenza A virus (IAV) outbreaks. However, previous reports suggest a reduced efficacy of ethanol disinfection against pathogens in mucus. We aimed to elucidate the situations and mechanisms underlying the reduced efficacy of EBDs against IAV in infectious mucus. We evaluated IAV inactivation and ethanol concentration change using IAV-infected patients' mucus (sputum). Additionally, AHR and AHW effectiveness against infectious mucus adhering to the hands and fingers was evaluated in 10 volunteers. Our clinical study showed that EBD effectiveness against IAV in mucus was extremely reduced compared to IAV in saline. IAV in mucus remained active despite 120 s of AHR; however, IAV in saline was completely inactivated within 30 s. Due to the low rate of diffusion/convection because of the physical properties of mucus as a hydrogel, the time required for the ethanol concentration to reach an IAV inactivation level and thus for EBDs to completely inactivate IAV was approximately eight times longer in mucus than in saline. On the other hand, AHR inactivated IAV in mucus within 30 s when the mucus dried completely because the hydrogel characteristics were lost. Additionally, AHW rapidly inactivated IAV. Until infectious mucus has completely dried, infectious IAV can remain on the hands and fingers, even after appropriate AHR using EBD, thereby increasing the risk of IAV transmission. We clarified the ineffectiveness of EBD use against IAV in infectious mucus.IMPORTANCE Antiseptic hand rubbing (AHR) and antiseptic hand washing (AHW) are important to prevent the spread of influenza A virus (IAV). This study elucidated the situations/mechanisms underlying the reduced efficacy of AHR against infectious mucus derived from IAV-infected individuals and indicated the weaknesses of the current hand hygiene regimens. Due to the low rate of diffusion/convection because of the physical properties of mucus as a hydrogel, the efficacy of AHR using ethanol-based disinfectant against mucus is greatly reduced until infectious mucus adhering to the hands/fingers has completely dried. If there is insufficient time before treating the next patient (i.e., if the infectious mucus is not completely dry), medical staff should be aware that effectiveness of AHR is reduced. Since AHW is effective against both dry and nondry infectious mucus, AHW should be adopted to compensate for these weaknesses of AHR.


Conjugated hyperbilirubinemia after surgery. A diagnosis of Dubin-Johnson syndrome confirmed by genetic testing.
Dubin-Johnson syndrome is a rare benign inherited disorder, caused by mutations in ABCC2 gen, and it is characterized by predominantly conjugated hyperbilirubinemia that can be increased by intercurrent infectious illnesses or surgical procedures. We report the case of a 10 year-old patient who showed, after a surgical procedure for peritonitis due to appendicitis, jaundice and predominantly conjugated hyperbilirubinemia, and he was diagnosed with Dubin-Johnson syndrome by genetic testing.


Evaluation of TCR Vbeta subfamily T cell expansion in NOD/SCID mice transplanted with human cord blood hematopoietic stem cells.
Examination of the T cell receptor (TCR) gene repertoire is important in the analysis of the immune status of models, because clonal expansion of T cells permits the identification of specific antigen responses of T cells. Little is known about T-cell immunity in the humanized NOD/SCID mouse model. TCR Vbeta repertoire usage and clonality were analyzed to investigate the distribution and clonal expansion of TCR Vbeta subfamily T cells in NOD/SCID mice transplanted with human cord blood (CB) hematopoietic stem cells. The NOD/SCID mice were sublethally irradiated ((60)Co, 300cGy) to eliminate residual innate immunity in the host. The experimental mice were transplanted intravenously with CB CD34(+) cells sorted by MACS. After 6 weeks, RNA was obtained from peripheral blood, bone marrow and thymus of the study animals. The gene expression and clonality of the TCR Vbeta repertoire were determined by RT-PCR and GeneScan techniques. A restricted range of TCR Vbeta usage was exhibited in the bone marrow of mice, which included TCR Vbeta 1, 2, 9, 13 and 19. Further, oligoclonal expression of some TCR Vbeta subfamilies (Vbeta9, 13, 19) was identified by GeneScan technique. To investigate the reason for oligoclonal expansion of the TCR Vbeta subfamily T cells from CB in mouse models, the T-cell culture with tissue-antigen of NOD/SCID mouse was performed in vitro. The cells from peripheral blood mononuclear cells and bone marrow, spleen, thymus in NOD/SCID mice were frozen and thawed, and used as tissue-antigen. CB mononuclear cells were separately cultured with the component from those murine cells for 15-20 days. Oligoclonal expression or oligoclonal trend of some TCR Vbeta subfamilies (Vbeta10, 11 and Vbeta2, 15, 16, 19) was detected in T cells after stimulation with tissue-antigen of NOD/SCID mouse. Interestingly, a similar clonal expansion of the TCR Vbeta11 subfamily was found in T cells cultured with peripheral blood, bone marrow and spleen respectively. The TCR Vbeta subfamily T cells could be reconstituted in humanized NOD/SCID mouse transplanted with CD34(+) cells from CB. The restricted expression and clonal expansion of some CB T cell clones may be induced by tissue-antigens of NOD/SCID mice.


Aberrant structural and functional connectivity and neurodevelopmental impairment in preterm children.
Despite advances in antenatal and neonatal care, preterm birth remains a leading cause of neurological disabilities in children. Infants born prematurely, particularly those delivered at the earliest gestational ages, commonly demonstrate increased rates of impairment across multiple neurodevelopmental domains. Indeed, the current literature establishes that preterm birth is a leading risk factor for cerebral palsy, is associated with executive function deficits, increases risk for impaired receptive and expressive language skills, and is linked with higher rates of co-occurring attention deficit hyperactivity disorder, anxiety, and autism spectrum disorders. These same infants also demonstrate elevated rates of aberrant cerebral structural and functional connectivity, with persistent changes evident across advanced magnetic resonance imaging modalities as early as the neonatal period. Emerging findings from cross-sectional and longitudinal investigations increasingly suggest that aberrant connectivity within key functional networks and white matter tracts may underlie the neurodevelopmental impairments common in this population. This review begins by highlighting the elevated rates of neurodevelopmental disorders across domains in this clinical population, describes the patterns of aberrant structural and functional connectivity common in prematurely-born infants and children, and then reviews the increasingly established body of literature delineating the relationship between these brain abnormalities and adverse neurodevelopmental outcomes. We also detail important, typically understudied, clinical, and social variables that may influence these relationships among preterm children, including heritability and psychosocial risks. Future work in this domain should continue to leverage longitudinal evaluations of preterm infants which include both neuroimaging and detailed serial neurodevelopmental assessments to further characterize relationships between imaging measures and impairment, information necessary for advancing our understanding of modifiable risk factors underlying these disorders and best practices for improving neurodevelopmental trajectories in this high-risk clinical population.


Specific Intensity Direct Current (DC) Electric Field Improves Neural Stem Cell Migration and Enhances Differentiation towards βIII-Tubulin+ Neurons.
Control of stem cell migration and differentiation is vital for efficient stem cell therapy. Literature reporting electric field-guided migration and differentiation is emerging. However, it is unknown if a field that causes cell migration is also capable of guiding cell differentiation--and the mechanisms for these processes remain unclear. Here, we report that a 115 V/m direct current (DC) electric field can induce directional migration of neural precursor cells (NPCs). Whole cell patching revealed that the cell membrane depolarized in the electric field, and buffering of extracellular calcium via EGTA prevented cell migration under these conditions. Immunocytochemical staining indicated that the same electric intensity could also be used to enhance differentiation and increase the percentage of cell differentiation into neurons, but not astrocytes and oligodendrocytes. The results indicate that DC electric field of this specific intensity is capable of promoting cell directional migration and orchestrating functional differentiation, suggestively mediated by calcium influx during DC field exposure.


Diagnoses and interactive patterns of infants referred to a community-based infant mental health clinic.
To describe the distribution of symptoms and diagnoses in a community-based infant mental health clinic and to compare play and feeding interactions of referred and nonreferred infants. The Diagnostic Classification of Mental Health and Developmental Disorders of Infancy and Early Childhood (DC 0-3) was used to diagnose 113 referred infants (60% were boys). Thirty additional dyads were matched with 30 nonreferred dyads. Feeding, play interactions, and home environment were compared. Two peaks of referral were found: 0 to 6 and 12 to 18 months. The main reasons for referral were eating problems, sleep problems, aggressive behavior, irritability, and maternal depression. The most common DC 0-3 diagnosis was a combination of primary infant disorder, parent-child relationship disorder, and parental psychopathology. Mothers of referred children provided lower levels of sensitivity, support, and structuring of the interaction, and less optimal home environment. The dyadic relationship showed a lower degree of mutuality and higher negative exchanges. Feeding interactions elicited more negative interactions than play. Infants referred by community health workers showed less optimal mother-infant interactions and had less optimal environment, compared with nonreferred dyads. Symptoms of emotional distress in infancy are best apprehended when assessed in multi-institutional contexts and formulated in a multiaxial approach.


The thread that links: continuity of patient care.
With managed care shortening hospital stays, nurses at the bedside are challenged to come up with innovative ways to utilize time wisely. Our critical care transport team has implemented a strategy that assists in this endeavor. An universal admission data sheet is completed when each patient arrives on the unit. This form takes about 45 minutes to 1 hour to complete. It identifies several issues that impact on patient teaching and discharge planning. By completing this form enroute, we provide the bedside nurse with more time to concentrate on discharge planning and teaching. Follow up indicates that early implementation of this form leads to a shorter, more productive stay for the patient. We have also observed an improvement in the continuity of patient care, since the transport nurse completing the form communicates the information to the primary nurse receiving the patient. This has also led to a strong link between the outside satellite staff and the base hospital staff through better relationships between the transporting and receiving nurses.


Thymosin beta(4) reduces lethality and down-regulates inflammatory mediators in endotoxin-induced septic shock.
Thymosin beta(4) (Tbeta(4)), a highly conserved peptide with immunomodulatory properties, is the major actin-sequestering peptide in mammalian cells. Recent studies have established that Tbeta(4) can accelerate wound healing in full thickness skin wounds and following burn injuries to the cornea. In the eye studies, the accelerated healing due to Tbeta(4) was accompanied by a significant reduction in polymorphonuclear leukocyte (PMN) infiltration and a several-fold decrease in interleukin-1beta (p< or =0.015) and 6-keto-prostaglandin F(1alpha) (6-keto-PGF1alpha, p< or =0.05). Given the recognized role of proinflammatory cytokines in septic shock and of extracellular F- and G-actin in the pathophysiology of multiple organ dysfunction, we have investigated the role of Tbeta(4) in sepsis. We report that an LD(50) dose of LPS (24 mg/kg) in rats resulted in a significant reduction of Tbeta(4) levels in the blood. Furthermore, administration of 100 microg of Tbeta(4) immediately following and at 2 and 4 h after an LD(50) dose of LPS (60 mg/kg) in mice significantly reduced mortality rates (p< or =0.024) and lowered blood levels of a number of inflammatory cytokines, eicosanoids, and other molecules that are highly elevated following endotoxin administration. In studies in human subjects given low doses of endotoxin (4 ng/kg LPS) and in patients with septic shock, we have also observed significant decreases in blood levels of Tbeta(4). The rapid disappearance of Tbeta(4) in the blood following LPS administration or during septic shock suggests that Tbeta(4) may be involved in early events leading to activation of the inflammatory cascade and ultimately the clinical sequelae of sepsis. The results of this study indicate that Tbeta(4) may have utility in the clinic in the treatment of septic shock and in syndromes associated with actin toxicities.


Susceptibility of Mycobacterium ulcerans to a combination of amikacin/rifampicin.
The effectiveness of rifampicin (RIF), amikacin (AMK) and their combination were estimated in the treatment of mice experimentally infected by Mycobacterium ulcerans and the risk of relapse after the treatment was evaluated. After 7 weeks of treatment with RIF or with the combination of AMK/RIF and 8 weeks with AMK alone, no viable bacilli were found in the infected tissues and these remained uninfected during the following 6 months. Among the mice treated with AMK alone, three mice relapsed, but the minimal inhibitory concentration of AMK for these isolates remained unchanged. With RIF alone, two mice relapsed and the minimal inhibitory concentration of these isolated strains was higher. However, with all the mice treated with both RIF and AMK, no relapse was observed.


Physicians' perspectives on estimating and communicating prognosis in palliative care: a cross-sectional survey.
Advance care planning (ACP) can help to enhance the care of patients with limited life expectancy. Despite physicians' key role in ACP, the ways in which physicians estimate and communicate prognosis can be improved. To determine how physicians in different care settings self-assess their performance in estimating and communicating prognosis to patients in palliative care, and how they perceive their communication with other physicians about patients' poor prognosis. A survey study was performed among a random sample of GPs, hospital physicians (HPs), and nursing home physicians (NHPs) in the southwest of the Netherlands (n = 2212). A questionnaire was developed that had three versions for GPs, HPs, and NHPs. Each specialism filled in an appropriate version. A total of 547 physicians participated: 259 GPs, 205 HPs, and 83 NHPs. In the study, 61.1% of physicians indicated being able to adequately estimate whether a patient will die within 1 year, which was associated with use of the Surprise Question (odds ratio [OR] = 1.65, P = 0.042). In the case of a prognosis of <1 year, 75.0% of physicians indicated that they communicate with patients about preferences regarding treatment and care, which was associated with physicians being trained in palliative care (OR = 2.02, P=0.007). In cases where patients with poor prognosis are discharged after hospital admission, 83.4% of HPs indicated that they inform GPs about these patients' preferences compared with 29.0% of GPs, and 21.7% of NHPs, who indicated that they are usually adequately informed about the preferences. The majority of physicians indicated that they believe they can adequately estimate patients' limited life expectancy and that they discuss patients' preferences for care. However, more physicians should be trained in communicating about patients' poor prognosis and care preferences.


A Region-Based Gauss-Newton Approach to Real-Time Monocular Multiple Object Tracking.
We propose an algorithm for real-time 6DOF pose tracking of rigid 3D objects using a monocular RGB camera. The key idea is to derive a region-based cost function using temporally consistent local color histograms. While such region-based cost functions are commonly optimized using first-order gradient descent techniques, we systematically derive a Gauss-Newton optimization scheme which gives rise to drastically faster convergence and highly accurate and robust tracking performance. We furthermore propose a novel complex dataset dedicated for the task of monocular object pose tracking and make it publicly available to the community. To our knowledge, it is the first to address the common and important scenario in which both the camera as well as the objects are moving simultaneously in cluttered scenes. In numerous experiments-including our own proposed dataset-we demonstrate that the proposed Gauss-Newton approach outperforms existing approaches, in particular in the presence of cluttered backgrounds, heterogeneous objects and partial occlusions.


The role of neutropenia on outcomes of cancer patients with community-acquired pneumonia.
Although the presence of neutropenia may predispose cancer patients to develop community-acquired pneumonia, the role of neutropenia on their outcomes has not been investigated. The purpose of the present study was to compare clinical outcomes of cancer community-acquired pneumonia patients with and without neutropenia. Patients with cancer, identified in the Community-Acquired Pneumonia Organization database, were divided into two groups according to the type of cancer and the presence of neutropenia: patients with solid cancer without neutropenia versus those with functional or absolute neutropenia. Among the 3,106 community-acquired pneumonia patients enrolled, 135 had cancer without neutropenia and 75 had cancer with neutropenia. No significant difference was found between patients with and without neutropenia regarding mean time to clinical stability (5.4+/-2.7 versus 4.9+/-2.7 days, respectively), mean length of hospital stay (9.2+/-7.7 versus 9.9+/-9.6 days) and in-hospital mortality (18 versus 15%, respectively). Using a multiple logistic regression model, neutropenia was not associated with mortality in cancer patients when adjusting for significant covariates (odds ratio 1.30). Lack of neutropenia, during the initial evaluation of a cancer community-acquired pneumonia patient, should not be considered an indicator of better clinical outcome.


Bloch oscillations in organic and inorganic polymers.
The transport of polarons above the mobility threshold in organic and inorganic polymers is theoretically investigated in the framework of a one-dimensional tight-binding model that includes lattice relaxation. The computational approach is based on parameters for which the model Hamiltonian suitably describes different polymer lattices in the presence of external electric fields. Our findings show that, above critical field strengths, a dissociated polaron moves through the polymer lattice as a free electron performing Bloch oscillations. These critical electric fields are considerably smaller for inorganic lattices in comparison to organic polymers. Interestingly, for inorganic lattices, the free electron propagates preserving charge and spin densities' localization which is a characteristic of a static polaron. Moreover, in the turning points of the spatial Bloch oscillations, transient polaron levels are formed inside the band gap, thus generating a fully characterized polaron structure. For the organic case, on the other hand, no polaron signature is observed: neither in the shape of the distortion-those polaron profile signatures are absent-nor in the energy levels-as no such polaron levels are formed during the simulation. These results solve controversial aspects concerning Bloch oscillations recently reported in the literature and may enlighten the understanding about the charge transport mechanism in polymers above their mobility edge.


Total Release of 21 Indicator Pharmaceuticals Listed by the Swedish Medical Products Agency from Wastewater Treatment Plants to Surface Water Bodies in the 1.3 Million Populated County Skåne (Scania), Sweden.
In 2017, the Swedish Environmental Protection Agency published a report on advanced wastewater treatment for the removal of pharmaceutical residues and stated that advanced treatment should be implemented where it will make the largest difference from an environmental perspective. However, the report also concluded that this need cannot be specified with existing data, but consideration must be made of local conditions. Two considerations are (1) the discharged amount of pharmaceutical into receiving water bodies and (2) the turnover of water in the recipient, where the highest risks are related to recipients with a low water turnover and low dilution. The current project comprised eight different WWTPs distributed throughout the entire County Skåne (Scania) in Sweden, with a population of ca. 1,300,000 persons. In total, 21 of 22 pharmaceuticals were analyzed according to the list proposed by the Swedish Medical Products Agency 2015. The results show that large amounts of pharmaceuticals are released from the WWTPs yearly to Scanian recipients. The total discharge of pharmaceuticals from the eight treatment plants adds up to 71 kg of these 21 substances alone, mainly comprising metoprolol, which is a drug that lowers blood pressure, and the analgesic drug diclofenac. Additionally, carbamazepine, losartan, naproxen and oxazepam were present in significant concentrations. These represented three illnesses that are very common: high blood pressure, inflammation/pain and depression/anxiety. The concentrations were generally in line with previous national Swedish screenings. It was estimated that, when one million cubic meters (1,000,000 m3) of wastewater is discharged, almost 4 kg of the 21 pharmaceuticals is released. The total volume wastewater release by the >90 WWTPs in Scania was estimated to 152,887,000 m3, which corresponded to 590 kg/year. The investigated 21 drugs cover only a small part of many hundred pharmaceuticals that are in use in Sweden. Thus, most likely, one or several tons of pharmaceuticals leak out to the Scanian recipients annually. The analysis of river samples shows that the dilution of wastewater is a key parameter in reducing concentrations. However, some locations have remarkably high concentrations, which occur when the volume wastewater is large in relation to the flow in the river. These kinds of regional results are of importance when selecting where advanced treatment should be prioritized in a first instance, as requested by the Swedish EPA.


[Role of adrenergic mechanisms in the cerebrovascular effect of thyroliberin].
Thyroliberin increases the cerebral blood flow both in anesthesized cats and unanesthetized rabbits under hemorrhagic shock. At the same time the increase of the arterial pressure is observed, caused by activation of the sympathoadrenal system. This is confirmed by experiments with the removal of the hypertensive reaction to thyroliberin after the use of the alpha-adrenoblockers. Analysis of the action mode of thyroliberin on the cerebral circulation with the use of atropine, dihydroergotoxin and propranolol allowed one to establish the involvement of beta-adrenoreceptors of the cerebral vessels in mediation of the cerebrovascular effect of the drug. The thyroliberin ability to improve the cerebral circulation under pronounced hypotension as well as to make the arterial pressure return to normal underlies its positive effect on the lifespan of animals under hemorrhagic shock.


Pathogenesis of ascites in cirrhosis and portal hypertension.
Disturbance of the circulatory system frequently occurs in patients with cirrhosis. Cardiac index and plasma volume increase whereas mean arterial blood pressure and systemic vascular resistance decrease. Marked disturbance in vasoconstrictor and natriuretic systems also exist with activation mediators such as plasma renin, plasma noradrenaline, antidiuretic hormone and endothelin. Renal factors contribute to the pathogenesis of ascites formation although the exact mechanisms are yet to be elucidated. Several theories exist in relation to pathogenesis although none to date fully explain all of the findings observed in clinical practice. In this review, we examine the mechanisms that contribute to the development of ascites in patients with cirrhosis and portal hypertension.


Outcome of children of parents with atopic asthma and transient childhood wheezy bronchitis.
Childhood asthma and wheeze only in the presence of respiratory infection (wheezy bronchitis) appear to have different prognoses and may differ in their aetiology and heritability. In particular, slight reductions in lung function may be associated with episodes of wheezing associated with intercurrent viral infection. Outcomes for wheezing symptoms and lung function were studied in 133 offspring of three distinct groups of 69 middle aged probands with childhood histories of (1) atopic asthma (n = 18), (2) wheeze associated with upper respiratory tract infection (wheezy bronchitis, n = 24), and (3) no symptoms (n = 27). Probands were selected from a previously studied cohort in which outcomes of wheezy bronchitis and asthma had been shown to differ. Children of probands with wheezy bronchitis had a lower prevalence of current wheezing symptoms. Forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) in boys of probands with a history of wheezy bronchitis were significantly reduced compared with either of the other two groups (p < 0.0001). In a multivariate analysis, grouping based on parent proband had a significant effect on lung function, independent of factors such as symptoms, atopy or smoking history. The different symptomatic and lung function outcome in children of probands with wheezy bronchitis and asthma provides further evidence that wheezy bronchitis and asthma differ in their natural history and heritability, and suggests that there may be familial factors specific to each wheezing syndrome.


Hypothalamic dysfunction; a review of experimental and clinical observation of cardiac and renal aspects.
The nuclear cell masses of the hypothalamus act as autonomic regulators for visceromotor function. Through the correlation of impulses arising in or about the hypothalamus with the changes in cellular chemistry, there is provided, by mediation of the endocrines, a balanced control of water metabolism, renal function and cardiac action. Derangement of hypothalamic regulation causes specific clinical syndromes described by the general term "diencephalohypophyseal dystrophy." Cardiac abnormalities attributable to hypothalamic dysfunction include alterations in rate and various arrhythmias. Alteration in renal function includes hematuria, polyuria or relative anuria, and specific effects on electrolyte and nitrogen output.


Epidemiological and clinical characteristics of rotaviral diarrhoea in children from Gdańsk, Gdynia and Sopot.
The aim of the present work was to analyse clinical picture of rotaviral diarrhoea and its incidence in children from Tri-city. The study was conducted on 773 children aged 1 month-11 years, who were treated in selected hospitals in 1997 due to acute diarrhoea. Apart from physical examination and collecting patients' medical history, each child was subjected to routine laboratory investigations in accordance with clinical indications. Rotaviral aetiology of the infection was confirmed in 275 out of 773 patients with acute diarrhoea. In 80.7% cases, the disease affected children aged 7-36 months old and it was more frequent in boys than in girls. Acute diarrhoea was diagnosed mainly during cold months of the year, and the increase of its incidence was recorded between March and May. The duration of the disease usually did not exceed 3 days and its symptoms included fever, vomiting and dehydration which normally required parenteral administration of fluids. Statistical analysis was performed in order to estimate the differences in the incidence and intensity of the symptoms of rotaviral and bacterial diarrhoea. The present study showed that clinical picture of rotaviral diarrhoea in children from Tri-city was similar to that reported in literature on the subject, but there were differences regarding the seasonal occurrence of the infection which was probably related to the climate of analysed region.


The Evolution of a Radiation Safety Audit Program for a Research Institution.
Possibly two of the greatest challenges of a radiation safety program are to ensure that all regulatory requirements are being met and to involve the users in maintaining compliance. At the Fred Hutchinson Cancer Research Center (FHCRC), the radiation safety office has developed an audit program that accomplishes these two challenges for the FHCRC ionizing radiation safety program, which has resulted in quality improvements in the laboratory environment and culminated in an excellent State inspection.