Topoisomerase II inhibitor-induced apoptosis in thymocytes and lymphoma cells.
DNA topoisomerase II is a nuclear enzyme that modulates DNA topology during several metabolic processes and is the target of several antitumor drugs. The primary effect of anticancer agents is to induce apoptosis. The present study showed that etoposide, a topoisomerase II inhibitor which forms cleavable complexes, induced apoptosis in nonproliferative thymocytes and proliferative RVC cells, whereas ICRF-154, a bis(2,6-dioxopiperazine) derivative which does not form a cleavable complex, induced apoptosis only in thymocytes. Both etoposide and ICRF-154 inhibited topoisomerase II activity in thymocytes and RVC cells to a similar extent. Etoposide had no effect on the cell cycle of RVC cells, but ICRF-154 induced cell cycle arrest at the G2/M stage followed by cell death without forming a DNA ladder on an agarose gel. Incubation with ICRF-154 reduced the expression of topoisomerase IIa in thymocytes and IIb in RVC cells. These findings suggest that the catalytic inhibitor, ICRF-154, has a mechanism of cytotoxicity which differs from that of etoposide. In RVC cells exposed to etoposide, we identified two clones that were suppressed early in the incubation. One was highly homologous to hnRNP A1 which modulates splicing of selected transcripts or stabilizes mRNAs. The other was a novel gene of which the function remains unknown. These genes were also altered in RVC cells exposed to camptothecin, which underwent apoptosis, but not in those incubated with ICRF-154, indicating that the suppression of these genes is related to inhibitor-induced DNA breaks resulting in apoptosis. In thymocytes, however, a cleavable complex by topoisomerase II inhibitors is not essential for the induction of apoptosis, since it was induced by ICRF-154. This suggests that tissue-specific nuclear matrix proteins other than topoisomerase II, including SATP-1 in the thymus, should also be considered. The present findings also suggest that bis(2,6-dioxopiperazine) derivatives are useful agents with which to study the role of topoisomerase II in the regulation of gene expression as well as the role of the nuclear matrix.


Being overweight allows me to show empathy with my patients.
As an overweight nurse, I understand the concern about credibility when giving advice to patients on eating healthily (features February 8). But nurses who smoke give patients advice about the harmful effects of smoking and nurses who drink may advise people to stop drinking.


Some toxicological aspects of methamidophos exposure in mice.
Cholinesterase activity in the brain, RBC and plasma of Swiss mice was determined following different routes of administration of methamidophos. Continuous feeding with the insecticide caused a progressive inhibition of both plasma- and erythrocyte enzymes. The effect of methamidophos was more pronounced when applied in diet than when administered dermally or intraperitoneally. Following a single injection (i.p.) of methamidophos, the brain enzyme showed maximum inhibition 24 hr following treatment. At the appearance of tremors, the plasma and RBC-enzymes showed considerable inhibition, the former being more inhibited. The plasma enzyme appears to be the most sensitive enzyme and may be taken as a suitable index for exposure to methamidophos.


Positive attitude will aid treatment. A guide to rheumatoid arthritis.
Rheumatoid arthritis is a chronic destructive disease which can result in deformity and disability. While treatment can do much to aid sufferers, support and encouragement are equally vital to instil a positive attitude.


Estrogenic effects from household stoves.
With the application of a genetically modified yeast, estrogen receptor-activating compounds were detected in the soot and emission gas of a wood-burning household stove. The EC50 value of 17beta-estradiol was divided by the EC50 value of soot, and the obtained relative estrogenic value for raw soot was 2.37E-5, indicating that soot was about 100,000 times less estrogenic than 17beta-estradiol. Chemical analysis revealed that alkyl phenol, benzonic acid, and PAHs represented the major constituents in the most potent fractions of the soot. Along with PAHs, other constituents might also contribute to the estrogenicity of soot.


Serum glucocorticoids and adiponectin associate with insulin resistance in children born small for gestational age.
Altered glucocorticoid activity is one possible mechanism linking fetal growth restriction with later insulin resistance (IR) and type 2 diabetes. We aimed to investigate whether serum glucocorticoid parameters are related to IR in children born small for gestational age (SGA). A total of 110 children (55 age- and gender-matched pairs born SGA or appropriate for gestational age (AGA) in a case-control setting) were studied at the mean age of 12.2 (s.d. 0.2) years. Serum cortisol, corticosteroid-binding globulin (CBG), free cortisol index (FCI=cortisol/CBG), and glucocorticoid bioactivity (GBA, transactivation assay) were analyzed and related to serum adiponectin and insulin-like growth factor-binding protein 1 (IGFBP1) concentrations and homeostasis model assessment for IR (HOMA-IR) and QUICKI indices. In the pooled study population, GBA correlated well with cortisol and FCI (r=0.681 and 0.586 respectively; P<0.001 for both). Serum cortisol, CBG, FCI, GBA, HOMA-IR, or QUICKI did not differ between the SGA and AGA subjects, but the SGA children had lower body mass index (P=0.005) and waist circumference (WC) (P=0.001). The mean GBA in the highest GBA quartile was higher among the SGA subjects than among the AGA subjects (138.6 vs 96.4 nmol/l cortisol equivalents, P<0.001). In the SGA children, GBA correlated positively with HOMA-IR (r=0.522, P<0.001) and inversely with adiponectin (r=-0.278, P=0.042) (WC/height ratio adjustments), and in logistic regression analysis, higher GBA (odds ratio (OR) 1.3; P=0.013), lower adiponectin (OR 1.4; P=0.038), and lower IGFBP1 (OR 1.9; P=0.010) associated independently with higher HOMA-IR. These findings suggest that increased glucocorticoid activity and low serum adiponectin concentrations associate with IR in SGA children.


The effect of CAG repeat polymorphism in the glucocorticoid receptor on stress responses of mice exposed to water-immersion restraint stress.
Exposure to stress activates the hypothalamus-pituitary-adrenal (HPA) axis, which is followed by an increase in production of its end product, corticosterone, considered to be the most important glucocorticoid (GC) in rodents. Glucocorticoid receptor (GR) signaling has been suggested as a potential mechanism responsible for the pathogenesis of many clinical disorders. Here, we investigated the involvement of the GR polymorphism in stress response. ICR mice were screened by genomic PCR, bred, and divided into 3 groups according to the GR polymorphism, GRwt/wt, GRwt/Qn, and GRQn/Qn. Mice were exposed to water-immersion restraint stress (WRS), and then examined for gastric mucosal lesions, serum corticosterone, serum cytokines and serum Hsp70 levels. Male mice with GRQn/Qn exhibited a significantly greater gastric lesion index than those with GRwt/wt at 6 h of WRS. Stress-induced corticosterone output achieved peak levels at 3 h, after which it was downregulated. The serum level in the control group was GRwt/wt >GRwt/Qn >GRQn/Qn, whereas the order at 6 h of WRS was reversed, GRQn/Qn >GRwt/Qn >GRwt/wt, suggesting that the GRwt allele responded rapidly to stress. The IL-6 levels of each polymorphic line increased at 3 h and particularly at 6 h. On the contrary, the IL-10 levels in GRwt/wt and GRwt/Qn increased following exposure to WRS, whereas that in GRQn/Qn showed no change. The Hsp70 levels in mice with GRQn allele particularly increased at 6 h of WRS, and the concentration in GRQn/Qn significantly increased as compared to that in GRwt/wt. These results suggest that the GR gene polymorphism has a significant impact on the stress-induced output, including the gastric lesion index, corticosterone, cytokines, and Hsp70 levels in serum. The present study provides insights into the role of GR in individual responses to stress.


mlr3proba: an R package for machine learning in survival analysis.
As machine learning has become increasingly popular over the last few decades, so too has the number of machine-learning interfaces for implementing these models. Whilst many R libraries exist for machine learning, very few offer extended support for survival analysis. This is problematic considering its importance in fields like medicine, bioinformatics, economics, engineering and more. mlr3proba provides a comprehensive machine-learning interface for survival analysis and connects with mlr3's general model tuning and benchmarking facilities to provide a systematic infrastructure for survival modelling and evaluation. mlr3proba is available under an LGPL-3 licence on CRAN and at https://github.com/mlr-org/mlr3proba, with further documentation at https://mlr3book.mlr-org.com/survival.html.


[Opinions and experiences of healthcare professionals in the nutritional management of oncology patients: the ONA study].
Objectives: an inadequate approach to prevent malnutrition in cancer patients may worsen their quality of life and reduce their response to treatment. This study aims to describe the nutritional management of cancer patients in clinical practice, as well as the opinions of the healthcare professionals (HCPs) involved. Methods: this was an observational, descriptive, cross-sectional study addressed to HCPs in the Spanish healthcare setting. The online questionnaire was designed based on a literature review, one focus group of patients (n = 6), and the experience of the multidisciplinary scientific committee (n = 5), and was distributed by the scientific societies endorsing the study. Results: a total of 461 HCPs answered the survey. Most of them considered that a nutrition expert (95.0 %) is essential for the nutritional management of patients. However, 22.8 % of HCPs did not have access to this expert, and only 49.0 % had received training. Nutritional screening or patient referral for screening was performed by 58.4 % of HCPs. Of the total of HCPs, 86.6 % stated that nutritional information is provided to patients and considered them moderately satisfied with the information received. In malnourished patients or in those at risk of malnutrition, a complete nutritional assessment was performed by HCPs (73.1 %). Most HCPs (87.4 %) reported prescribing or recommending nutritional support if needed, and assessing adherence (86.8 %). Conclusions: despite malnutrition being a common problem in cancer patients, almost half of professionals do not perform any nutritional screening. In addition, patient information and assessment of nutritional adherence appear to be suboptimal.


Assessment of Genetic Polymorphisms in the Rewa Population of Central India Using Y-Chromosomal STR Markers.
The aim of the study was to analyze unrelated samples from the Rewa male population of Central India by targeting Y-short tandem repeats (STR) and then compare the results to previously published Y-STR haplotype data. A total of 181 unrelated male subjects from the Rewa population were genotyped for seventeen Y-STRs (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385a/b, DYS437, DYS438, DYS439, DYS448, DYS456, DYS458, DYS635, and Y-GATA-H4) by using an AmpFlSTR® Yfiler™ multiplex kit (Thermo Fisher Scientific, USA). The allele frequencies and forensic parameters were evaluated. A total of 111 distinct Y-STR alleles with corresponding frequencies ranging from 0.006 to 0.829 were identified. The gene diversity values ranged from 0.3092 at DYS437 to 0.8188 at DYS385b. The studied population showed a high level of haplotype diversity (0.9985) and discrimination capacity (0.927). A haplotype analysis was also conducted. Among the 181 unrelated male samples, 165 haplotypes and 153 unique haplotypes were found. Additionally, Rst (genetic distance) values were calculated using the analysis of molecular variance (AMOVA) for the studied population and for other 18 populations described in the literature. The Rst provides a convenient parameter for estimating the level of genetic differentiation from the microsatellite data. Based on these Rst values and using the multidimensional scaling plot, a neighbor-joining tree was constructed. The high values of haplotype diversity and discrimination capacity indicate a great potential for distinguishing between male individuals in the studied population. The present population data are expected to find their use in forensic caseworks and population genetics.


The Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) study: baseline characteristics of the population.
The Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient ischeMic attack (PERFORM) study is an international double-blind, randomized controlled trial designed to investigate the superiority of the specific TP receptor antagonist terutroban (30 mg/day) over aspirin (100 mg/day), in reducing cerebrovascular and cardiovascular events in patients with a recent history of ischemic stroke or transient ischemic attack. Here we describe the baseline characteristics of the population. Parameters recorded at baseline included vital signs, risk factors, medical history, and concomitant treatments, as well as stroke subtype, stroke-associated disability on the modified Rankin scale, and scores on scales for cognitive function and dependency. Eight hundred and two centers in 46 countries recruited a total of 19,119 patients between February 2006 and April 2008. The population is evenly distributed and is not dominated by any one country or region. The mean +/- SD age was 67.2 +/- 7.9 years, 63% were male, and 83% Caucasian; 83% had hypertension, and about half the population smoked or had quit smoking. Ninety percent of the qualifying events were ischemic stroke, 67% of which were classified as atherothrombotic or likely atherothrombotic (pure or coexisting with another cause). Modified Rankin scale scores showed slight or no disability in 83% of the population, while the scores on the Mini-Mental State Examination, Isaacs' Set Test, Zazzo's Cancellation Test, and the instrumental activities of daily living scale showed a good level of cognitive function and autonomy. The PERFORM study population is homogeneous in terms of demographic and disease characteristics. With 19,119 patients, the PERFORM study is powered to test the superiority of terutroban over aspirin in the secondary prevention of cerebrovascular and cardiovascular events in patients with a recent history of ischemic stroke or transient ischemic attack.


Burnout syndrome in pediatric practice.
Burnout is a common work-related syndrome consisting of emotional exhaustion, depersonalization and diminished feelings of personal accomplishment. Burnout influences the performance and efficiency of the healthcare professionals and therefore the quality of the care provided. This study aims to assess the burnout rates and potential determinants in pediatrics. A cross-sectional, descriptive study involving physicians practicing pediatrics in the Jeddah area of Saudi Arabia was conducted utilizing the Maslach Burnout Inventory in addition to questions regarding work-related and lifestyle-related factors. One hundred and thirty pediatricians (55% females) were included with age ranging between 25 and 45 years (mean: 30). Most (46%) were consultants and 54% practiced in a university based setting. Burnout scores were abnormal in 107 (82%) and in 45 (34%) the syndrome was severe. Males were more likely to reach a severe burnout category compared to females (40% vs. 31%; p=0.012). Academic pediatricians working in a university setting were much more likely to experience severe burnout compared to their counterparts working in other hospitals (50% vs. 19%; p=0.0005). Consultants were also more likely to experience severe burnout compared to residents and assistants (46% vs. 27%; p=0.03). At least one third of practicing pediatricians suffer from burnout syndrome. Specific strategies should be developed and implemented to limit and prevent professional burnout.


Healthcare organizations and patient transfers: a transportation industry perspective.
A major restructuring is underway in Ontario in the delivery of a wide range of public services, including healthcare, public transit and ambulance services. The resulting trends in these three industries have converged in a number of models for the delivery of non-emergency patient transfers. Hospitals find themselves involved in the business of transportation: engaged in new partnerships, and making new choices, to manage the movement of stable patients between sites, to medical procedures and to return home.


[Congenital mid-ureteral stricture: report of a case].
A rare case of congenital mid-ureteral stricture is reported. A 17-year-old woman was admitted with sudden onset of right flank pain. Intravenous urography demonstrated bilateral small renal calculi, left hydronephrosis and a stricture of the left ureter at the level of the pelvic brim. The diagnosis was determined as congenital mid-ureteral stricture because the ureter tapered smoothly from 25 mm to 5 mm in diameter at the stenotic site. She was successfully treated by partial ureterectomy with end-to-end anastomosis. Histopathologically, no dysplasia of muscular layer was recognized.


Chromosomal aberration and micronucleus studies of two topoisomerase (II) targeting anthracyclines.
Anthracycline antibiotics are widely used in cancer chemotherapy. Doxorubicin and Idarubicin, topoisomerase-targeting anthracyclines, were examined for their effect on chromosomal aberration and micronucleus induction in cultured human lymphocytes employing lymphocyte transformation test and cytokinesis-blocked micronucleus (CBMN) assay. A statistically significant dose-dependent increase in micronucleus frequency (p < 0.001) in binucleated cells was seen as well as a significant increase in chromosomal aberration frequency was also observed for both the drugs. A variety of aberrations were scored including terminal deletions, breaks, gaps, exchanges, fragment formation, ends rejoining, interstitial deletions etc. Nuclear division index was also calculated and showed a cell cycle delay towards higher doses. A number of necrotic and apoptotic cells were also observed at higher concentrations. This confirms the two drugs to be clastogenic and aneugenic.


Phototropins and associated signaling: providing the power of movement in higher plants.
Recent developments in phototropin biology have provided exciting new findings on the roles of these photoreceptor proteins in plants. Much of the recent work has focused on phototropin photochemistry and the structural alterations in both the chromophoric and peptide components of the molecule associated with light perception. In this review, specific aspects of phototropin action in higher plants will be discussed in the context of these new findings. Although, as their name suggests, phototropins play a key role in phototropic responses in plants, increasing evidence shows they have many other functions in plants. In this review, the roles of phototropins in additional plant "movement" responses will be addressed; in particular their roles in stomatal aperture control and chloroplast movements. In discussing these various movement responses special attention will be given to identified and hypothesized downstream signaling partners or events that enable the phototropins to selectively participate in any one or more of these responses in a given light condition.


[Surgical treatment of benign liver tumours--indications and results].
The authors present their results on the treatment of benign liver tumors. 65 patients were operated upon in the University Hospital in Pil-sen from 2000 until July 2006. Benign liver lesions were rather rare compared to malignant tumours, for which 273 patients were treated within the same period. The most often found benign -lesions were hepatocellular adenoma, focal nodular hyperplasia (FNH) and hemangioma. Sometimes, it was not possible to make a correct diagnosis preoperatively. The surgical procedures used for benign tumours were mostly enucleation and non-anatomic parenchyma-saving resection (55.4 %). Morbidity in this group was 26.5 %, mortality 0 %.


Unrecognized vertebral body fractures (VBFs) in chest radiographic reports in Taiwan: a hospital-based study.
Osteoporosis and its associated fragility fractures greatly impact the health-care system. VBF can be inadvertently overlooked on radiological examinations, which may delay diagnosis and treatment of osteoporosis. This hospital-based study evaluated chest radiographs to determine the prevalence rate of unrecognized VBF. Digitalized chest radiographs stored in the Taipei Veterans General Hospital Radiology Information System (TVGHRIS) were retrieved for study. One month of image data from 2009 was randomly obtained. All patients were over 55 years of age. Posterior-anterior (PA) and lateral chest radiographs were available for all patients. All selected chest radiographs were reviewed by two radiologists who were blinded to the official reports. Comparisons between official reports and the reference reports determined the prevalence of unrecognized VBF. Chest radiographs from 1655 patients (mean age 71.9 ± 10.4 years, 63.9% male) were reviewed. The prevalence of recognized VBF was significantly higher in consensus reports compared to the official reports (23.0% vs. 4.8%, p<0.001). Overall, 79% of VBFs were undiagnosed. The prevalence of unrecognized VBFs was 18.2% (19.6% in men, 15.7% in women). VBFs in men were more likely to be unrecognized than women (19.6% vs. 15.7%, p=0.04). Adjusted for age, gender was not an independent risk factor for unrecognized VBF in logistic regression. In conclusion, the high rate of unrecognized VBF in a tertiary medical center in Taiwan highlights the need to improve radiographic recognition of VBF, which could aid early treatment of osteoporosis in older adults.


The nitrate-inducible NAC transcription factor NAC056 controls nitrate assimilation and promotes lateral root growth in Arabidopsis thaliana.
Nitrate can affect many aspects of plant growth and development, such as promoting root growth and inhibiting the synthesis of secondary metabolites. However, the mechanisms underlying such effects and how plants can integrate nitrate signals and root growth needs further exploration. Here, we identified a nitrate-inducible NAC family transcription factor (TF) NAC056 which promoted both nitrate assimilation and root growth in Arabidopsis. NAC056 is a nuclear-localized transcription activator, which is predominantly expressed in the root system and hypocotyl. Using the yeast one-hybrid assay, we identified the NAC056-specific binding sequence (NAC56BM), T [T/G/A] NCTTG. We further showed that the nac056 mutant compromised root growth. NAC056 overexpression promotes LR Initiation and nitrate deficiency tolerance. Using RNA sequencing analysis and in vitro biochemical experiment, we found NAC056 regulated the expression of genes required for NO3- assimilation, directly targeting the key nitrate assimilation gene NIA1. In addition, mutation of NIA1 suppresses LR development and nitrate deficiency tolerance in the 35S::NAC056 transgenic plants. Therefore, NAC056 mediates the response of plants to environmental nitrate signals to promote root growth in Arabidopsis.


An Optimized Method to Assess Viable Escherichia coli O157:H7 in Agricultural Soil Using Combined Propidium Monoazide Staining and Quantitative PCR.
Agricultural soil contaminated by manure is becoming an important source for the transmission of foodborne pathogens. There is an urgent need for a rapid and accurate method for viable pathogen detection in agricultural soil samples. Propidium monoazide (PMA) is a DNA-binding dye that can inhibit the amplification of DNA from dead cells through subsequent quantitative polymerase chain reaction (qPCR), thus allowing for viable cells detection and quantification. The objective of this study was to detect viable Escherichia coli O157:H7 in the agricultural soils by PMA-qPCR. In this study, cell extraction and gradient density centrifugation were incorporated before PMA-qPCR to reduce the interference of soil particle including turbidity and a high ratio of dead cells. The optimized treatment conditions were determined as follows, the maximum removal of DNA from dead cells was achieved by 1.067 g/mL Percoll of centrifugation and 50 μM PMA treatment. Under these conditions, the turbidity of paddy soil suspensions decreased from 3500 to 28.4 nephelometric turbidity units (NTU), and the ratio of viable cells to dead cells increased from 0.001 to 1.025%. For typical agricultural soils collected in China, as low as 102colony-forming units (CFU)/g of viable cells could be accurately detected in the presence of a large number of dead cells (107 CFU/g) by the optimized PMA-qPCR. Significantly, with comparable accuracy, the optimized PMA-qPCR assay was more sensitive, accessible and rapid than conventional culture methods. In addition, the viable but non-culturable (VBNC) state of E. coli O157:H7 cells in paddy soils, which often escaped the detection by conventional culture methods, could be quantitatively characterized by the optimized PMA-qPCR method. Potentially, the optimized PMA-qPCR can be further applied for viable pathogens detection and give insight into the prevalence of VBNC E. coli O157:H7 in agricultural soil.


Sirolimus Associated with Tacrolimus at Low Doses in Elderly Kidney Transplant Patients: A Prospective Randomized Controlled Trial.
There is no consensus on the best immunosuppressive regimen for elderly renal transplant recipients. The objective of this study was to assess cytomegalovirus infection incidence and kidney transplant outcomes in elderly recipients treated with mammalian target of rapamycin inhibitors sirolimus/ tacrolimus at low doses compared with those receiving tacrolimus/mycophenolate sodium. In this single-center prospective randomized study (Trial Registration No. NCT02683291), kidney transplant recipients over 60 years of age were randomly allocated into 2 groups: tacrolimus-sirolimus (21 patients) and tacrolimus-mycophenolate (23 patients). Cytomegalovirus infection rate and patient survival, biopsy-proven acute rejection, and renal function at 12 months were assessed. Cytomegalovirus infection rate was higher in the mycophenolate group (60.9%) than in the sirolimus group (16.7%; P = .004). The rates of biopsy-proven acute rejection, patient survival, graft survival, and estimated glomerular filtration rate over 12 months did not significantly differ between groups. The incidence of cytomegalovirus infection was significantly lower in the sirolimus group. The use of tacrolimus combined with sirolimus in elderly kidney transplant recipients is safe.


Screening for Hyperparathyroidism by Measurement of Calcium in Patients Undergoing Thyroid Surgery: A Prospective Study.
This study screened for asymptomatic primary hyperparathyroidism (PHPT) by measuring calcium (Ca) before thyroid surgery. The study was prospective. A total of 676 patients without a suspicion of PHPT were studied. PHPT was defined as elevated Ca (in 2 measurements) in the presence of PTH>25 pg/ml and in the absence of hypocalciuria. PHPT was diagnosed in 5 patients (0.74%), all of them women. One of the 5 patients with PHPT had no indication for parathyroidectomy (PTx) according to current guidelines. Parathyroid adenoma was easily identified during perioperative assessment of thyroid surgery in 3 patients. In the other 2 patients (0.3%), localization of the adenoma required specific exploration, which was only performed because of the preoperative diagnosis of PHPT. Normalization of Ca and PTH was achieved in all 5 patients. In conclusion, in patients without a clinical or ultrasonographic suspicion of PHPT, approximately 300 individuals should be screened before thyroid surgery to avoid one reoperation (PTx) due to PHPT, which does not seem to be cost-effective.


Thermodynamics of Polypeptide Supramolecular Assembly in the Short-Chain Limit.
The self-assembly of peptides into ordered supramolecular structures, such as fibrils and crystals, is of relevance in such diverse areas as molecular medicine and materials science. However, little information is available about the fundamental thermodynamic driving forces of these types of self-assembly processes. Here, we investigate in detail the thermodynamics of assembly of diphenylalanine (FF). This dipeptide forms the central motif of the Aβ peptides, which are associated with Alzheimer's disease through their presence in amyloid plaques in the nervous systems of affected individuals. We identify the molecular origins of the self-assembly of FF in aqueous solution, and we evaluate these findings in the context of the aggregation free energies of longer peptides that are able to form amyloid fibrils. We find that the thermodynamics of FF assembly displays the typical characteristics of hydrophobic desolvation processes, and detailed analysis of the temperature dependence of the kinetics of assembly within the framework of crystallization theories reveals that the transition state from solution to crystalline aggregates is enthalpically unfavorable and entropically favorable, qualitatively similar to what has been found for longer sequences. This quantitative comparison of aggregating peptides of very different lengths is the basis of an in-depth understanding of the relationship between sequence and assembly behavior.


Review of the plant bug genus Fingulus Distant in Indochina (Hemiptera: Heteroptera: Miridae: Deraeocorini), with descriptions of two new species.
The deraeocorine plant bug genus Fingulus Distant from Indochina is reviewed, diagnosed and discussed. Seven species are currently recognized, including two new species described herein: F. angkorensis and F. rubricatus from Cambodia and Thailand. Behavior and habitat of F. angkorensis are documented, which was observed to be associated with two anthocorids and a thrips in leaf margin curl-galls produced by the thrips on a banyan tree Ficus microcarpa. A checklist including two species of the assumed sister genus Angerianus Distant is provided, with available distributional records; images of two Angerianus species are also shown for the first time.


Adherence to an (n-3) fatty acid/fish intake pattern is inversely associated with metabolic syndrome among Puerto Rican adults in the Greater Boston area.
Combinations of fatty acids may affect risk of metabolic syndrome. Puerto Ricans have a disproportionate number of chronic conditions compared with other Hispanic groups. We aimed to characterize fatty acid intake patterns of Puerto Rican adults aged 45-75 y and living in the Greater Boston area (n = 1207) and to examine associations between these patterns and metabolic syndrome. Dietary fatty acids, as a percentage of total fat, were entered into principle components analysis. Spearman correlation coefficients were used to examine associations between fatty acid intake patterns, nutrients, and food groups. Associations with metabolic syndrome were analyzed by using logistic regression and general linear models with quintiles of principal component scores. Four principal components (factors) emerged: factor 1, short- and medium-chain SFA/dairy; factor 2, (n-3) fatty acid/fish; factor 3, very long-chain (VLC) SFA and PUFA/oils; and factor 4, monounsaturated fatty acid/trans fat. The SFA/dairy factor was inversely associated with fasting serum glucose concentrations (P = 0.02) and the VLC SFA/oils factor was negatively related to waist circumference (P = 0.008). However, these associations were no longer significant after additional adjustment for BMI. The (n-3) fatty acid/fish factor was associated with a lower likelihood of metabolic syndrome (Q5 vs. Q1: odds ratio: 0.54, 95% CI: 0.34, 0.86). In summary, principal components analysis of fatty acid intakes revealed 4 dietary fatty acid patterns in this population. Identifying optimal combinations of fatty acids may be beneficial for understanding relationships with health outcomes given their diverse effects on metabolism.


Catastrophic antiphospholipid syndrome in pregnancy: a life-threatening condition.
Catastrophic antiphospholipid syndrome (CAPS) is a rare and potentially life-threatening variant of the antiphospholipid syndrome which is characterised by multiple small vessel thrombosis which can lead to multiorgan failure. CAPS is a clinical emergency which all clinicians need to be aware of because early diagnosis and treatment may improve maternal and fetal outcome. Here, we report a case of CAPS in pregnancy in a 31-year-old female patient who presented at 28 weeks of gestation. A literature review of CAPS in pregnancy and the puerperium is also included.


Adaptation of a deprescription intervention to the medication management of older people living in long-term care facilities.
Objectives: Inappropriate prescription is a problem related to aging and deprescription could be a possible strategy. The aim of this study was to adapt the available evidence on deprescribing to the medication management of older people living in long-term care facilities. Methods: The authors carried out a bibliographic search based on the most prevalent drugs in our context to develop a specific deprescribing intervention. A committee of experts reviewed this intervention which was later validated through an interobserver variability study. Finally, the authors evaluated it in a sample of patients through a controlled before-after study. Results: The authors included 119 subjects living in a public elderly long-term care center and 122 controls living in a center with similar clinical characteristics. The authors evaluated 852 medications, identifying a total of 175 (20.5%) potentially inappropriate medications and 162 (92.5%) drugs were deprescribed (1.4 per patient). The application of the intervention meant an annual saving of 9.525.25 €. Conclusion: The implementation of a deprescribing intervention aimed at the most prevalent drugs prescribed in a particular setting improves the appropriateness of pharmacotherapy in the patients.


Nck adaptors are positive regulators of the size and sensitivity of the T-cell repertoire.
The size and sensitivity of the T-cell repertoire governs the effectiveness of immune responses against invading pathogens. Both are modulated by T-cell receptor (TCR) activity through molecular mechanisms, which remain unclear. Here, we provide genetic evidence that the SH2/SH3 domain containing proteins Nck lower the threshold of T-cell responsiveness. The hallmarks of Nck deletion were T-cell lymphopenia and hyporeactivity to TCR-mediated stimulation. In the absence of the Nck adaptors, peripheral T cells expressing a TCR with low avidity for self-antigens were strongly reduced, whereas an overall impairment of T-cell activation by weak antigenic stimulation was observed. Mechanistically, Nck deletion resulted in a significant decrease in calcium mobilization and ERK phosphorylation upon TCR engagement. Taken together, our findings unveil a crucial role for the Nck adaptors in shaping the T-cell repertoire to ensure maximal antigenic coverage and optimal T cell excitability.


Person-Centered Care for Older Adults With Kidney Disease: Core Curriculum 2019.
This Core Curriculum article models a person-centered approach to care for older adults with kidney disease. We provide background information on the principles of person-centered care and outline ways in which this approach contrasts with the more disease-based approaches that dominate current medical education and practice. Using hypothetical cases, we discuss 3 clinical scenarios that arise commonly when caring for older adults with kidney disease: (1) a moderate reduction in estimated glomerular filtration rate, (2) new-onset nephrotic-range proteinuria, and (3) the prospect of starting dialysis. For each scenario, we summarize relevant available evidence and model what a person-centered approach might look like. In discussing each scenario, we highlight: (1) the considerable heterogeneity in clinical presentation, circumstances, priorities, and values that exist among older adults with kidney disease; (2) the importance of interpreting available evidence and clinical practice guidelines in the context of what is relevant to each patient; (3) methods for grounding discussions about care and treatment options in the realities of each patient's situation and what is most meaningful to them; and (4) the importance of setting aside one's own biases and practice style to ensure that patients' own values and goals guide their care.


Thrombin inhibition in an ex vivo model of porcine heart xenograft hyperacute rejection.
Prominent components of vascularized xenograft rejection such as platelet activation and microvascular thrombosis may be dependent upon thrombin generation in vivo. To study potential therapeutic benefits of a synthetic low-molecular-weight thrombin inhibitor, SDZ MTH 958, in hyperacute porcine heart rejection by human blood ex vivo, a working model of hyperacute rejection of porcine by fresh, heparinized (6 microM/ml) human blood with or without 1 microM SDZ MTH 958 was used. Thrombin-antithrombin complexes (TAT) and prothrombin fragment F1.2 levels as markers of thrombin activation were determined, and biopsies from rejected hearts were analyzed by immunohistopathology. Control porcine hearts (n=8) underwent a rapid and consistent decline in cardiac output, ceasing function by 60 min. Experimental cardiac output values of 14 ml/g (SEM 1.2) were significantly higher than seen in controls (5 ml/g SEM 0.6) after 5 min of cardiac work, and prolonged survival times up to 120 min were noted (P<0.05). Activity of SDZ MTH 958 was confirmed by functional assays throughout perfusion. Levels of TAT and F1.2 increased consistently in control samples when compared with plasma samples containing SDZ MTH 958. Immunohistopathological examination confirmed diminished fibrin deposition, reduced leukocyte adherence to endothelium, impaired diapedesis and less tissue necrosis in the hearts perfused with SDZ MTH 958. SDZ MTH 958, in this xenoperfusion model, prolonged survival, enhanced function of the explanted organ, and improved histological features at the time of rejection. Effective and specific antagonism of thrombin may be useful as an adjunct therapy to complement inhibition for xenograft rejection


Electrospray sample preparation for improved quantitation in matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.
The goal of this work is the development of a rapid and objective matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) method for the quantitation of peptides and proteins in human plasma suitable for use in the Good Laboratory Practices (GLP) environment, where the analytical method, validation and pharmacokinetic parameters derived from concentration data will be scrutinized by global regulatory agencies. Electrospray deposition has traditionally been used to prepare thin, uniform samples for a number of techniques, including Cf-252 plasma desorption and secondary ion mass spectrometry. Here the electrospray process of sample application is used to reduce the segregation of analyte from matrix during the sample drying step. The small droplets formed during the electrospray process are found to significantly improve the homogeneity of the sample surface prepared. Experiments comparing the traditional air dried and electrosprayed methods of sample preparation show that the increase in sample homogeneity from electrosprayed samples decreases both the within-sample spot and between-sample spot variability, resulting in a decrease in percent coefficient of variation (%CV) for the recorded MALDI mass spectra. The increase in sample homogeneity permits a more objective use of MALDI-TOFMS as a quantitative analytical method and has led to the development of an assay for the determination of desamino-[8-D-arginine] vasopressin (DDAVP) using arginine vasopressin (AVP) as internal standard in human plasma. The range of quantitation observed (2.0-10 micrograms/mL) is of limited value for bioanalytical application; however, the analysis of neat standards shows lower quantitation limits are easily achieved.


The F-actin content of multiple myeloma cells as a measure of their migration.
One of the main characteristics of multiple myeloma (MM) cells is their specific homing and growth in the bone marrow (BM). For their homing, MM cells need chemotactic signals to be attracted towards the BM and to be activated. Profound knowledge of the different chemokines for MM cells and their signal transduction pathways is necessary to interfere in this process. We studied here an extra possible tool for the investigation of the different chemokines and their pathways. The 5T experimental mouse model was used to investigate the migration of MM cells towards BM stromal cells. We studied the changes of the F-actin content in the 5TMM cells in the presence of BM stromal cell conditioned medium and we correlated this with their migratory capacity. F-actin became polarized when the cells were migrating, in contrast to nonmigrating cells. This polarization could not only be seen by fluorescence and confocal laser scanning microscopy, but also could be quantified by fluorometry and flow cytometry. The correlation between the F-actin content of the MM cells and their migration capacity thus makes its quantification a useful tool in studying their migratory behavior.


Loss of the metalloprotease ADAM9 leads to cone-rod dystrophy in humans and retinal degeneration in mice.
Cone-rod dystrophy (CRD) is an inherited progressive retinal dystrophy affecting the function of cone and rod photoreceptors. By autozygosity mapping, we identified null mutations in the ADAM metallopeptidase domain 9 (ADAM9) gene in four consanguineous families with recessively inherited early-onset CRD. We also found reduced photoreceptor responses in Adam9 knockout mice, previously reported to be asymptomatic. In 12-month-old knockout mice, photoreceptors appear normal, but the apical processes of the retinal pigment epithelium (RPE) cells are disorganized and contact between photoreceptor outer segments (POSs) and the RPE apical surface is compromised. In 20-month-old mice, there is clear evidence of progressive retinal degeneration with disorganized POS and thinning of the outer nuclear layer (ONL) in addition to the anomaly at the POS-RPE junction. RPE basal deposits and macrophages were also apparent in older mice. These findings therefore not only identify ADAM9 as a CRD gene but also identify a form of pathology wherein retinal disease first manifests at the POS-RPE junction.


Capsaicin Targets Lipogenesis in HepG2 Cells Through AMPK Activation, AKT Inhibition and PPARs Regulation.
Obesity, a major risk factor for chronic diseases such as type 2 diabetes (T2D), represents a serious primary health problem worldwide. Dietary habits are of special interest to prevent and counteract the obesity and its associated metabolic disorders, including lipid steatosis. Capsaicin, a pungent compound of chili peppers, has been found to ameliorate diet-induced obesity in rodents and humans. The purpose of this study was to examine the effect of capsaicin on hepatic lipogenesis and to delineate the underlying signaling pathways involved, using HepG2 cells as an experimental model. Cellular neutral lipids, stained with BODIPY493/503, were quantified by flow cytometry, and the protein expression and activity were determined by immunoblotting. Capsaicin reduced basal neutral lipid content in HepG2 cells, as well that induced by troglitazone or by oleic acid. This effect of capsaicin was prevented by dorsomorphin and GW9662, pharmacological inhibitors of AMPK and PPARγ, respectively. In addition, capsaicin activated AMPK and inhibited the AKT/mTOR pathway, major regulators of hepatic lipogenesis. Furthermore, capsaicin blocked autophagy and increased PGC-1α protein. These results suggest that capsaicin behaves as an anti-lipogenic compound in HepG2 cells.


A Bayesian approach to simultaneously adjusting for verification and reference standard bias in diagnostic test studies.
Verification bias arises in diagnostic test evaluation studies when the results from a first test are verified by a reference test only in a non-representative subsample of the original study subjects. This occurs, for example, when inclusion probabilities for the subsample depend on first-stage results and/or on a covariate related to disease status. Reference standard bias arises when the reference test itself has imperfect sensitivity and specificity, but this information is ignored in the analysis. Reference standard bias typically results in underestimation of the sensitivity and specificity of the test under evaluation, since subjects that are correctly diagnosed by the test can be considered as misdiagnosed owing to the imperfections in the reference standard. In this paper, we describe a Bayesian approach for simultaneously addressing both verification and reference standard bias. Our models consider two types of verification bias, first when subjects are selected for verification based on initial test results alone, and then when selection is based on initial test results and a covariate. We also present a model that adjusts for a third potential bias that arises when tests are analyzed assuming conditional independence between tests, but some dependence exists between the initial test and the reference test. We examine the properties of our models using simulated data, and then apply them to a study of a screening test for dementia, providing bias-adjusted estimates of the sensitivity and specificity.


Diagnosis and natural history of 17-hydroxylase deficiency in a newborn male.
We documented 17-hydroxylase deficiency in a newborn male infant with micropenis, perineoscrotal hypospadias, and a bifid scrotum containing two histologically normal testes. Mild hypertension developed at 20 months of age. The diagnosis was made on the basis of elevated serum levels of progesterone (180-475 ng/dl), corticosterone (1.8-20.2 micrograms/dl), and desoxycorticosterone (56-330 ng/dl). There was an exaggerated response of these steroids to ACTH-(1-24) and suppression by dexamethasone. Mass spectrometric analysis of urinary steroids showed an abnormally high ratio of C21 to C19 3 beta-hydroxy-5-ene steroids due to reduced C19 steroid formation. We suggest that this infant has a form of 17-hydroxylase deficiency which is less severe than previously reported cases in view of his partial prenatal virilization, the minimal testosterone response to CG the absence of hypokalemia, and the presence of normal cortisol levels after prolonged ACTH stimulation. Family studies suggest reduced 17-hydroxylase activity in the father. A surprising coincident finding of no apparent clinical significance was in vitro evidence of 5 alpha-reductase deficiency in genital skin fibroblasts.


PubMed Assistant: a biologist-friendly interface for enhanced PubMed search.
MEDLINE is one of the most important bibliographical information sources for biologists and medical workers. Its PubMed interface supports Boolean queries, which are potentially expressive and exact. However, PubMed is also designed to support simplicity of use at the expense of query expressiveness and exactness. Many PubMed users have never tried explicit Boolean queries. We developed a Java program, PubMed Assistant, to make literature access easier in several ways. PubMed Assistant provides an interface that efficiently displays information about the citations and includes useful functions such as keyword highlighting, export to citation managers, clickable links to Google Scholar and others that are lacking in PubMed.


Underlying pathophysiology of HCV infection in HIV-positive drug users.
HCV and HIV infections are very common among injection drug users (IDUs). It is well known that 80-90% of HIV-infected IDUs are also infected with HCV. Furthermore, patients with HCV/HIV co-infection are at a higher risk of progressing to end-stage liver disease, namely cirrhosis. Even though there is increasing global awareness of HCV/HIV co-infection and extended therapeutic programs for this infected population, little is known about the HCV/HIV pathophysiology that mediates the rapid progression to hepatic disease. Liver disease caused by HCV/HIV co-infection is characterized by inflammation and cell-death. Recent reports suggest that the HIV and HCV envelope proteins may induce apoptosis and inflammation in hepatocytes via a novel pathway involving collaborative signaling. Moreover, HCV/HIV co-infection may also alter the cytokine production in vivo. Further studies to elucidate the molecular mechanisms of HCV and HIV-mediated pathogenesis will help in the development of therapeutic strategies against HCV/HIV co-infection in these patients.


Surveillance of Outbreaks of SARS-CoV-2 Infections at School in the Veneto Region: Methods and Results of the Public Health Response during the Second and Third Waves of the Pandemic between January and June 2021.
During the COVID-19 pandemic, many countries adopted various non-pharmacological interventions to contain the number of infections. The most often used policy was school closures. We describe the strategy adopted by the Veneto Regional Authority to contain transmission in school settings. This included a detailed school surveillance system, strict contact tracing, and maintaining school attendance with self-monitoring for symptoms whenever possible. All analyzed COVID-19 cases among children, adolescents (0-19 years old), and school staff were registered using a web-based application between 4 January 2021 and 13 June 2021. During the study period, 6272 episodes of infection in schools were identified; 87% were linked to a student index case and 13% to school staff; 69% generated no secondary cases; 24% generated one or two; and only 7% caused more than two. Our data may help to clarify the role of school closures, providing useful input for decisions in the months to come. Good practice in public health management needs tools that provide a real-time interpretation of phenomena like COVID-19 outbreaks. The proposed measures should be easy to adopt and accessible to policymakers.


Maternal Risk Factors for Lactation Mastitis: A Meta-analysis.
This meta-analysis was conducted to identify maternal risk factors for lactational mastitis. Studies published in English or Chinese were retrieved from Medline (PubMed), Embase, Cochrane Library, Web of Science, CNKI, WANFANG, and VIP databases according to predefined inclusion and exclusion criteria. Study quality was assessed by the Newcastle-Ottawa Scale. A random-effects model was used for data pooling and I2 tests to assess study heterogeneity. Pooled data from 8 cohorts and 10 case-control studies identified previous mastitis during breastfeeding (P<0.00001), cesarean section (P=0.001), breast trauma (P<0.001), anemia (P=0.0001), latch problems ≤ 8 weeks post-delivery (P=0.003), milk overproduction (P=0.002), blocked duct (P<0.0001), cracked nipple (especially ≤ 4 weeks post-delivery) (P=0.0001), use of nipple shields (P<0.00001), nipple cream (P<0.0001), brassieres (P<0.0001), and breast pumps (P<0.00001), and breastfeed duration > 30 min (P=0.008) as significant risk factors. Washing nipples before breastfeeding decreased lactational mastitis risk. Identification of these risk factors may facilitate the development of nursing care protocols for reducing lactational mastitis.


Melanocytoma of ciliary body and choroids simulating melanoma.
Melanocytoma is a rare intraocular tumor. There are some reports in the literature dealing with primary melanocytomas of the choroid and ciliary body. It is believed that most of these tumors are clinically diagnosed as nevi or melanoma, and are followed up or treated without surgical resection, respectively. Some clinical features can give a clue as to the correct diagnosis. We report on a 47-year-old white female with progressive visual loss of 2 months and right painful eye. Her visual acuity of finger counting was confined to 3.0m OD and 20/20 OS. Biomicroscopy OD showed a 360 degrees posterior synechia, and fundoscopy was not conclusive due to vitreous opacity. No alterations were seen on OS. Intraocular pressure was normal, and the pupillary reflex was present in both eyes. An ultrasound of the OD showed an elevated tumor on topography of the ciliary body and anterior choroid at the ora serrata level. Melanoma was the main diagnosis considered, and enucleation was indicated due to poor prognosis for visual acuity. Gross and histopathologic examinations of the OD showed a heavily pigmented tumor. The brownish pigment obscured the morphology of the tumor cells that could not be visualized by conventional H&E stain. Bleached slides showed that tumor was composed of melanocytoma cells type I.


Wearable Sensor for Assessing Gait and Postural Alterations in Patients with Diabetes: A Scoping Review.
Background and Objectives: Diabetes mellitus is considered a serious public health problem due to its high prevalence and related complications, including gait and posture impairments due to neuropathy and vascular alterations and the subsequent increased risk of falls. The gait of patients with diabetes is characterized by alterations of the main spatiotemporal gait parameters such as gait velocity, cadence, stride time and length, which are also known to worsen with disease course. Wearable sensor systems can be used for gait analysis by providing spatiotemporal parameters and postural control (evaluated from the perspective of body sway), useful for investigating the disease progression. Thanks to their small size and low cost of their components, inertial measurement units (IMUs) are easy to wear and are cheap tools for movement analysis. Materials and Methods: The aim of this study is to review articles published in the last 21 years (from 2000 to 2021) concerning the application of wearable sensors to assess spatiotemporal parameters of gait and body postural alterations in patients with diabetes mellitus. Relevant articles were searched in the Medline database using PubMed, Ovid and Cochrane libraries. Results: One hundred and four articles were initially identified while searching the scientific literature on this topic. Thirteen were selected and analysed in this review. Wearable motion sensors are useful, noninvasive, low-cost, and objective tools for performing gait and posture analysis in diabetic patients. The IMUs can be worn at the lumber levels, tibias or feet, and different spatiotemporal parameters of movement and static posture can be assessed. Conclusions: Future research should focus on standardizing the measurement setup and selecting the most informative spatiotemporal parameters for gait and posture analysis.


Photodynamic therapy as adjunctive therapy for morpheaform basal cell carcinoma.
The authors decided to evaluate the possible use of methyl-aminolevulinate photodynamic therapy (MAL-PDT) as adjunctive therapy for morpheaform basal cell carcinoma prior to standard surgical excision in order to reduce tumor size and volume and to facilitate surgical treatment. It was observed that MAL-PDT may be an option as an adjunctive therapy prior to standard surgical excision of morpheaform basal cell carcinoma, leading to less invasive surgery.


Synthesis of (+)-(1'R,2'S) and (1'S,2'R)-6,11-dimethyl-1,2,3,4,5,6 -hexahydro-3-[[2'-(alkoxycarbonyl)-2'-phenylcyclopropyl]methyl]-2 ,6 -methano-3-benzazocin-8-ol. Comparison of the affinities for sigma 1 and opioid receptors with in the diastereoisomeric MPCB and CCB.
The synthesis and the in vitro receptor affinity for sigma 1 and opiod receptors of the two diastereoisomers of (+)-cis-MPCB namely, (+)-cis-(1'S,2'R)-6,11-Dimethyl-1,2,3,4,5,6 -hexahydro-3-[[2'-(methoxycarbonyl)-2'-phenylcyclopropyl]methyl]-2 ,6 -methano-3-benzazocin-8-ol, (1'S,2'R)6a and (+)-cis-(1'R,2'S)-6,11-Dimethyl-1,2,3,4,5,6-hexahydro-3- [[2-(methoxycarbonyl)-2'-phenylcyclopropyl]methyl]-2,6-methano-3-+ ++benzazocin-8 -ol, (1'R,2'S)6a are reported. Affinities of (1'S,2'R)6a and (1'R,2'S)6a were compared with those of the (-)-cis-diastereoisomers of MPCB(1), and of its p-Cl phenyl derivative CCB(2). The (+)-cis-N-normetazocine derivatives showed higher affinity for the sigma 1 sites, labeled with [3H]-(+)-pentazocine than the corresponding (-)-cis- analogs. In particular, compound (1'S,2'R)6a showed a Ki = 66.7 nM for sigma 1 receptor, associated with a good selectivity for sigma 1 with respect to kappa, mu, delta opioid receptors subtypes (Ki = > 1,000 nM). Analysis of the data seem to support the hypothesis that the (+)-cis-N-normetazocine nucleus posses a specific enantioselectivity for sigma 1 sites, when supporting bulkier N-substituents functionalized with a carboxy ester group.


Nordihydroguaiaretic acid potently breaks down pre-formed Alzheimer's beta-amyloid fibrils in vitro.
Inhibition of the accumulation of amyloid beta-peptide (Abeta) and the formation of beta-amyloid fibrils (fAbeta) from Abeta, as well as the degradation of pre-formed fAbeta in the CNS would be attractive therapeutic objectives for the treatment of Alzheimer's disease (AD). We previously reported that nordihydroguaiaretic acid (NDGA) inhibited fAbeta formation from Abeta(1-40) and Abeta(1-42) dose-dependently in the range of 10-30 micromin vitro. Utilizing fluorescence spectroscopic analysis with thioflavin T and electron microscopic study, we show here that NDGA dose-dependently breaks down fAbeta(1-40) and fAbeta(1-42) within a few hours at pH 7.5 at 37 degrees C. At 4 h, the fluorescence of fAbeta(1-40) and fAbeta(1-42) incubated with 50 microm NDGA was 5% and 10% of the initial fluorescence, respectively. The activity of NDGA to break down these fAbetas was observed even at a low concentration of 0.1 microm. At 1 h, many short, sheared fibrils were observed in the mixture incubated with 50 microm NDGA, and at 4 h, the number of fibrils reduced markedly, and small amorphous aggregates were observed. We next compared the activity of NDGA to break down fAbeta(1-40) and fAbeta(1-42), with other molecules reported to inhibit fAbeta formation from Abeta and/or to degrade pre-formed fAbeta both in vivo and in vitro. At a concentration of 50 microm, the overall activity of the molecules examined in this study was in the order of: NDGA >> rifampicin = tetracycline > poly(vinylsulfonic acid, sodium salt) = 1,3-propanedisulfonic acid, disodium salt > beta-sheet breaker peptide (iAbeta5). In cell culture experiments, fAbeta disrupted by NDGA were less toxic than intact fAbeta, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Although the mechanisms by which NDGA inhibits fAbeta formation from Abeta, as well as breaking down pre-formed fAbetain vitro, are still unclear, NDGA could be a key molecule for the development of therapeutics for AD.


A patch of surface-exposed residues mediates negative regulation of immune signaling by tomato Pto kinase.
Tomato (Lycopersicon esculentum) Pto kinase specifically recognizes the Pseudomonas effector proteins AvrPto and AvrPtoB, leading to induction of defense responses and hypersensitive cell death. Structural modeling of Pto combined with site-directed mutagenesis identified a patch of surface-exposed residues required for native regulation of signaling. Mutations in this area resulted in constitutive gain-of-function (CGF) forms of Pto that activated AvrPto-independent cell death via the cognate signaling pathway. The patch overlaps the peptide binding region of the kinase catalytic cleft and is part of a broader region required for interaction with bacterial effectors. We propose that the negative regulatory patch is normally occupied by a peptide that represses Pto signaling. Furthermore, we found that Pto kinase activity was required for Avr-dependent activation but dispensable for signaling by CGF forms of Pto. This suggests that Pto signals by a conformational change rather than phosphorylation of downstream substrates in the defense signaling pathway.


The association between injury severity and psychological morbidity, hand function, and return to work in traumatic hand injury with major nerve involvement: A one-year follow-up study.
We aimed to investigate the association between the severity of the injury and psychological morbidities, hand functions, and return to work (RTW) in traumatic hand injury (THI) with major nerve involvement. Thirty-two patients had THI with major nerve involvement were enrolled in this study. The demographic and clinical characteristics of the patients were recorded after the injury. The severity of the injury was evaluated using the modified Hand Injury Severity Score (MHISS). The Disabilities of the Arm, Shoulder, and Hand (Q-DASH) score and Duruöz Hand Index (DHI) were used to assess the hand function. Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), and Impact of Event Scale-Revised (IES) were performed to assess psychological morbidity. These assessments were performed after injury and at the end of the first year. Time to RTW was recorded in the first year after the injury. Jamar Hand Dynamometer and pinch meter were used for the measurement of hand and finger grip strength at the end of the first year. There were significant improvements in IES-R, BDI, BAI, Q-DASH, and DHI scores at the end of the first year compared with baseline scores. We found a significant correlation between MHISS and time of RTW, Q-DASH, and pinch strengths. We found no significant correlation between MHISS and IES-R, BDI, BAI, and grip strength. The severity of the injury is significantly associated with hand functions, pinch strengths, and RTW in THIs with major nerve involvement. The findings showed that there was no association between the severity of the injury and psychological morbidities in the present study.


[Guidelines for interaction by the therapeutic team in inpatient treatment of patients with chronic neurotic disorders].
In treatment of in-patients with chronic neurotic disorders we tried both to reduce distress in the therapeutic team (doctors, nurses, other therapists) as usually caused by those patients, and to improve outcome of treatment. Therefore, three to five guidelines on how to deal with the patient were given to the therapeutic team, and illustrated by possible literal statements to the patient. The guidelines aimed at a general interactional approach to the patient and did not determine specific therapeutic interventions. They were set up following principles of Brief Therapy as developed at the Mental Research Institute in Palo Alto. Results of our intervention in treatment of ten patients are reported. The therapeutic team rated the guidelines generally as positive. The therapeutic outcome varied greatly. A comparison with a matched pair control group showed a favourable tendency. Initial ratings by the team of the prescriptions predicted eventual improvement of the patients.


Induction of Apoptosis, Autophagy and Ferroptosis by Thymus vulgaris and Arctium lappa Extract in Leukemia and Multiple Myeloma Cell Lines.
Thymus vulgaris and Arctium lappa have been used as a folk remedy in the Iraqi Kurdistan region to deal with different health problems. The aim of the current study is to investigate the cytotoxicity of T. vulgaris and A. lappa in leukemia and multiple myeloma (MM) cell lines and determine the mode of cell death triggered by the most potent cytotoxic fractions of both plants in MM. Resazurin assay was used to evaluate cytotoxic and ferroptosis activity, apoptosis, and modulation in the cell cycle phase were investigated via Annexin V-FITC/PI dual stain and cell-cycle arrest assays. Furthermore, we used western blotting assay for the determination of autophagy cell death. n-Hexane, chloroform, ethyl acetate, and butanol fractions of T. vulgaris and A. lappa exhibited cytotoxicity in CCRF-CEM and CEM/ADR 5000 cell lines at concentration range 0.001-100 μg/mL with potential activity revealed by chloroform and ethyl acetate fractions. NCI-H929 displayed pronounced sensitivity towards T. vulgaris (TCF) and A. lappa (ACF) chloroform fractions with IC50 values of 6.49 ± 1.48 and 21.9 ± 0.69 μg/mL, respectively. TCF induced apoptosis in NCI-H929 cells with a higher ratio (71%), compared to ACF (50%) at 4 × IC50. ACF demonstrated more potent autophagy activity than TCF. TCF and ACF induced cell cycle arrest and ferroptosis. Apigenin and nobiletin were identified in TCF, while nobiletin, ursolic acid, and lupeol were the main compounds identified in ACF. T. vulgaris and A. lappa could be considered as potential herbal drug candidates, which arrest cancer cell proliferation by induction of apoptosis, autophagic, and ferroptosis.


Association of urinary nerve growth factor levels with erectile function in young men with type 2 diabetes mellitus.
We investigated urine nerve growth factor (NGF) levels and erectile dysfunction in diabetic men <45 years of age. Urinary NGF levels were measured in 72 diabetic men and 20 control subjects without lower urinary tract symptoms or erectile dysfunction. Participants were evaluated using the International Prostate Symptom Score, quality of life index, Overactive Bladder Symptom Score (OABSS), the five-item version of the International Index of Erectile Function questionnaire (IIEF-5), the patient perception of bladder condition questionnaire, measurement of flow rate and post-void residual urine volume. The results showed that the diabetic men had significantly higher urinary normalized NGF/creatinine (Cr) levels compared to the healthy controls (0.48±1.2 vs 0.01±0.01, P=0.04). The increased urinary NGF/Cr levels correlated negatively with the IIEF-5 total score (P=0.03, coefficient=-0.26, -0.02 to -0.47). The 42 patients with urinary NGF/Cr levels <0.05 had higher IIEF-5 scores than the 30 patients with urinary NGF/Cr level ⩾0.05 (20.2±4.6 vs 16.9±6.7, P=0.03). We conclude that urinary NGF levels were associated with erectile dysfunction in the men with type 2 <45 years of age.


New paradigms in thrombosis: novel mediators and biomarkers platelet RNA transfer.
Platelets, anucleated cells with a central role in hemostasis and inflammation, contain messenger RNAs and microRNAs of unknown functionality and clinical relevance. Historically, platelet RNA was viewed as merely a remnant of platelet biogenesis; however, several studies now refute this assumption. Studies have shown that platelets can actively translate RNA to protein and that specific RNA profiles correlate with select human clinical phenotypes. These studies support a more fluid role for platelet RNA in platelet function and disease development. Our lab and others have recently studied the platelet's unique ability to transfer RNA to recipient cells and the effect this transfer has on the recipient cells' functions. This transfer may represent a previously unknown form of vascular cell communication and modulation. Unlike the well-characterized thrombotic properties of platelets, the nature and purpose of platelet RNA transfer has not been determined, partly due to limitations in techniques used to manipulate platelet RNA profiles. Defining the mechanism of RNA transfer and its role in the vascular system will allow for the better understanding of how platelets function in both their traditional thrombotic role and non-traditional functions, potentially having widespread implications in several fields.


[Testicular sertolioma].
Sertolioma accounts for 4.5% of all non-herminogenic testicular tumors. Sertolioma presents clinically with local symptoms (enlarged testis) which may be associated with dyshormonal symptoms. Most sertoliomas are benign, only 16.7% of them are malignant. Metastatic process is primarily lymphogenic and involves first retroperitoneal lymph nodes. Accurate histological criteria of malignancy for sertolioma have not been determined yet. The treatment should be started with orchofuniculectomy. Organ-saving operations may be performed in metastases-free children with bilateral sertoliomas. Surgical treatment is the only treatment effective in malignant sertolioma. Retroperitoneal and (or) solitary distant metastases should be removed surgically. Sertolioma is resistant to chemotherapy and is low sensitive to radiotherapy. Contrary to benign sertolioma, malignant one has poor prognosis.


[Development of breath movement reverse tracking system for tumor precision radiotherapy].
To reduce the influence of breathing movement on the location precision of the tumor target in precise radiotherapy for thoraco-abdominal tumors. An inverse tracking system was developed to track the path of the breathing movement of the tumor target via image guiding. With this system, the displacement of the target in a given time period was tracked and quickly transformed in signals that drove the tracking couch to move inversely relative to the tumor target. This system can effectively reduce the influence of tumor target breath movement during radiotherapy. Compared with other breath movement control methods, this method avoids prolonged exposure time, allows the patient to breathe at ease and shortens the time of CT scanning.


Factors Affecting Detection of Hepatitis E Virus on Canadian Retail Pork Chops and Pork Livers Assayed Using Real-Time RT-PCR.
We collected 599 Canadian retail pork chops and 283 pork livers routinely (usually weekly) from April 2011 to March 2012 using the Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS) retail sampling platform. Samples were assayed using validated real-time (q) reverse transcriptase polymerase chain reaction (RT-PCR) and nested classical RT-PCR for the detection of hepatitis E virus (HEV), porcine enteric calicivirus (PEC) and rotavirus (RV). The presence of Escherichia coli, Salmonella spp. and Campylobacter spp. was measured on a subset of our samples. Exact logistic regression models were fitted for predictors for HEV detection, for each assay. For both assays, sample type (pork chop versus liver) was a significant predictor for HEV RNA detection. For nested classical RT-PCR but not qRT-PCR, region of sample collection was a significant predictor (P = 0.008) of HEV detection. Odds of HEV detection were greatest in spring relative to other seasons. E. coli was a significant predictor for HEV RNA detection using the qRT-PCR (P = 0.03). Overall, the prevalence of E. coli, Salmonella spp. and Campylobacter spp. was significantly greater than HEV, PEC or RV on our retail pork samples. Our sparse data set for the detection of PEC and RV precluded modelling of risk factors for the detection of these viruses.


The association of maternal smoking and other sociobehavioral factors with dental caries in toddlers: A cross-sectional study.
Severe early childhood caries (S-ECC) is a form of dental caries in toddlers, which can strongly affect general health and quality of life. Studies on factors that can contribute to the development of caries immediately after tooth eruption are sparse. The aim of this study was to assess the role of sociobehavioural factors and pre- and postnatal exposure to tobacco smoke in the aetiology of dental caries in children up to 3 years old. A cross-sectional study was conducted between 2011 and 2017 to assess oral health and teething in urban children 0-4 years of age. The number of teeth and surfaces with white spot lesions (d1,2), as well as decayed (d), missing (m), and filled (f) teeth classified according to ICDAS II was evaluated in a dental office setting. d1,2dmft and d1,2dmfs were calculated. Severe early childhood caries was diagnosed for d1,2dmfs > 0. Parents completed a self-administered questionnaire on socioeconomic factors, maternal health, course of pregnancy, child's perinatal parameters, hygiene and dietary practices, as well as maternal smoking during and after pregnancy. Data on children aged 12-36 months were collected and analysed statistically using the t-test, Spearman rank correlations and Poisson regression. Significance level was set at 0.05. Dental caries was found in 46% of 496 children aged 12-36 months. Mean d1,2dmft and d1,2dmfs were 2.62 ± 3.88 and 4.46 ± 8.42, respectively. Tobacco smoking during and after pregnancy was reported by 8.9% and 24.8% of women, respectively. Spearman's rank correlation analysis confirmed a relationship between S-ECC and parental education, maternal smoking, bottle feeding, avoiding springy foods, number of meals, and the age of tooth brushing initiation. Pre- and postnatal exposure to tobacco smoke increased the risk of S-ECC especially in children in age 19-24 months. Maternal smoking was correlated with the level of education and dietary practices. Our study confirmed that prenatal smoking is associated with increased risk of severe-early childhood caries (S-ECC) while the association with post-natal smoking is also evident, the increase in risk is not statistically clear. Both maternal smoking and the child's tooth decay are associated with poor parental education and other improper oral health behaviours. The positive impact of quitting smoking on the oral health in children should be part of anti-smoking advice.


Vesicular stomatitis New Jersey virus RNA persists in cattle following convalescence.
To test the hypothesis that vesicular stomatitis New Jersey virus (VSV-NJ) persists in convalescent cattle, we used explant cultures and reverse transcription nested polymerase chain reactions to probe for viral genomic, replicative intermediate, and mRNA in two cows experimentally inoculated in the tongue 5 months earlier and three cows naturally infected 4-14 months previously. Virus was not isolated from any tissues of any animal. Sequences of the viral polymerase and nucleocapsid genes were consistently identified in the tongue and lymph nodes draining the tongue of both experimentally infected animals but not in the three naturally infected animals. Replicative intermediate but not messenger RNA sequences were detected. These results showed for the first time the long term persistence of VSV-NJ RNA in its bovine host.


Hydrophilic Polymer-associated Ischemic Enterocolitis.
Hydrophilic polymer coating of medical devices serves to lubricate the device and prevent device-related complications. The coating can be mechanically disrupted and result in downstream injury via presumed thromboembolism. This process has been reported in the brain, heart, lung, and skin, and has been replicated through animal studies and in vitro histologic processing of the polymer coating. We report the first description of hydrophilic polymer-associated ischemic enterocolitis in a series of 7 specimens (small bowel=2, colon=4, aortic thrombus=1) from 3 patients. We report a 4% incidence among all patients with an ischemic bowel resection between April 29, 2014 and August 8, 2016. All patients developed bowel ischemia within 1 day of aortic repair, and all bowel resection specimens showed polymers, mainly in the submucosal vessels in areas of extensive ischemia. The polymers appeared as basophilic, intravascular, serpiginous structures. In a patient who developed acute paralysis after the aortic repair, identical polymers were identified in the aortic thrombus and the ischemic bowel segment. We demonstrate that the polymers display an altered morphology over time and with various graft types, and that the degrading polymers are associated with a foreign body giant cell reaction. Special stains can aid in diagnosis, with the polymers turquoise on a colloidal iron stain, pink on von Kossa and mucicarmine stains, and pale blue on trichrome. Clinical follow-up was available up to 115 weeks: 1 patient died, and 2 are alive and well. In summary, we report a new diagnostic entity to be considered in the differential diagnosis of iatrogenic ischemic injuries in the gastrointestinal tract. Awareness of this entity is important to elucidate the cause of ischemia and to prevent misdiagnosis of the polymers and their associated giant cell reaction as a parasitic infection, granulomatous vasculitis, sarcoidosis, and idiopathic inflammatory bowel disease.


CCL2 regulates angiogenesis via activation of Ets-1 transcription factor.
Although recent studies have suggested that CC chemokine CCL2 may directly affect the angiogenesis, the signaling events involved in such regulation remain to be determined. This study investigated a potential signal mechanism involved in CCL2-induced angiogenesis. Our in vitro and in vivo (hemangioma model of angiogenesis) experiments confirmed earlier findings that CCL2 can induce angiogenesis directly. Using a gene array analysis, CCL2 was found to induce expression of several angiogenic factors in brain endothelial cells. Among the most prominent was an up-regulation in Ets-1 transcription factor. CCL2 induced a significant increase in Ets-1 mRNA and protein expression as well as Ets-1 DNA-binding activity. Importantly, Ets-1 antisense oligonucleotide markedly abrogated in vitro CCL2-induced angiogenesis, suggesting that Ets-1 is critically involved in this process. Activation of Ets-1 by CCL2 further regulated some of Ets-1 target molecules including beta(3) integrins. CCL2 induced significant up-regulation of beta(3) mRNA and protein expression, and this effect of CCL2 was prevented by the Ets-1 antisense oligonucleotide. The functional regulation of Ets-1 activity by CCL2 was dependent on ERK-1/2 cascade. Inhibition of ERK1/2 activity by PD98509 prevented CCL2-induced increases in Ets-1 DNA-binding activity and Ets-1 mRNA expression. Based on these findings, we suggest that Ets-1 transcription factor plays a critical role in CCL2 actions on brain endothelial cells and CCL2-induced angiogenesis.


Endoscopic treatment of biliary complications in donors after living donor liver transplantation in a high volume transplant center.
Although living donor liver transplantation (LDLT) has been accepted as a primary treatment for adults with end-stage liver disease, concerns about donor health have been emerged. As LDLT is technically complex, it creates perioperative morbidity and mortality risk in donors. Biliary complications such as stricture and leakage are seen most frequently in donors after liver transplantation. While some of these complications get treated with conservative approach, endoscopic, surgical, and percutaneous interventions may be required in some others. We aimed to present endoscopic retrograde cholangiography (ERC) results in donors who developed biliary complications after LDLT. Between June 2010 and January 2018, a total of 1521 donors (1291 right lobe grafts, 230 left lobe grafts) of patients who underwent LDLT, were retrospectively reviewed. 63 donors who underwent ERC due to biliary complication, were included in the study. Biliary stricture was found in 1.6% (25/1521), biliary leakage in 2.1% (33/1521), and stricture and leakage together in 0.3% (5/1521) donors. Our endoscopic success rates in patients with biliary leakage, biliary stricture, and stricture and leakage were 85% (28/33), 92% (23/25), and 80% (4/5), respectively. Surgical treatment was performed on 12.6% (8/63) donors who failed ERC. We found that ERC is a successful treatment for post-LDLT donors who have biliary complications.


[Integrating demographic and socioeconomic policies].
"The article offers a theoretical model of integration between demographic and socioeconomic policy [in Bulgaria].... The author examines the changes in the population's demographic structures: changes in the sex ratio; ageing; [and] family nuclearisation.... The conclusion is drawn that in order to boost the effectiveness of the demographic policy, social practice and its scientific back-up should be even more fully integrated." (SUMMARY IN ENG)


Conserved MicroRNA miR-8/miR-200 and its target USH/FOG2 control growth by regulating PI3K.
How body size is determined is a long-standing question in biology, yet its regulatory mechanisms remain largely unknown. Here, we find that a conserved microRNA miR-8 and its target, USH, regulate body size in Drosophila. miR-8 null flies are smaller in size and defective in insulin signaling in fat body that is the fly counterpart of liver and adipose tissue. Fat body-specific expression and clonal analyses reveal that miR-8 activates PI3K, thereby promoting fat cell growth cell-autonomously and enhancing organismal growth non-cell-autonomously. Comparative analyses identify USH and its human homolog, FOG2, as the targets of fly miR-8 and human miR-200, respectively. USH/FOG2 inhibits PI3K activity, suppressing cell growth in both flies and humans. FOG2 directly binds to p85alpha, the regulatory subunit of PI3K, and interferes with the formation of a PI3K complex. Our study identifies two novel regulators of insulin signaling, miR-8/miR-200 and USH/FOG2, and suggests their roles in adolescent growth, aging, and cancer.


Validation of commercially available ELISAs for the detection of circulating sclerostin in hemodialysis patients.
Sclerostin is an endocrine regulator in chronic kidney disease - mineral and bone disorder (CKD-MBD). Validation of assay comparability and pre-analytical handling is mandatory for establishment of sclerostin as a biomarker. Blood samples (serum, EDTA, heparin and citrate plasma) were obtained from 12 hemodialysis (HD) patients after the long dialysis interval. Passing-Bablok regression analysis and Bland-Altman difference plots were used to evaluate the agreement between sclerostin levels measured with two commercially available ELISAs from TECOmedical and Biomedica. Independent of the sample type, the agreement of the two assays was poor with a strong proportional but no systematic bias. Compared to the TECOmedical assay, the Biomedica test yielded almost 2-fold higher sclerostin values throughout all sample types. Spike recovery and linear dilution studies revealed a higher accuracy of the TECOmedical assay (97% and 96%) compared to the Biomedica assay (118% and 78%). Sclerostin levels were stable within 4 hours after sample collection, in particular when analyzed in plasma. In contrast to the Biomedica assay, the TECOmedical showed a systematic but no proportional bias between serum and plasma samples with higher values for plasma samples. Among the 3 different plasma samples no systematic error could be documented. Careful consideration of the pre-analytical handling and comparative assay validation are necessary to facilitate a more differentiated interpretation of studies reporting circulating sclerostin levels. The presence of a proportional bias demonstrates that in HD patients the two ELISAs for measuring sclerostin should not be used interchangeably. Furthermore, caution is necessary when comparing sclerostin results obtained from different blood sample types.


Cofactor-induced reversible folding of Flavodoxin-4 from Lactobacillus acidophilus.
Flavodoxins in combination with the flavin mononucleotide (FMN) cofactor play important roles for electron transport in prokaryotes. Here, novel insights into the FMN-binding mechanism to flavodoxins-4 were obtained from the NMR structures of the apo-protein from Lactobacillus acidophilus (YP_193882.1) and comparison of its complex with FMN. Extensive reversible conformational changes were observed upon FMN binding and release. The NMR structure of the FMN complex is in agreement with the crystal structure (PDB ID: 3EDO) and exhibits the characteristic flavodoxin fold, with a central five-stranded parallel β-sheet and five α-helices forming an α/β-sandwich architecture. The structure differs from other flavoproteins in that helix α2 is oriented perpendicular to the β-sheet and covers the FMN-binding site. This helix reversibly unfolds upon removal of the FMN ligand, which represents a unique structural rearrangement among flavodoxins.


Cytoplasmic aspartyl-tRNA synthetase from Saccharomyces cerevisiae. Study of its functional organisation by deletion analysis.
Aspartyl-tRNA synthetase (AspRS) from yeast, a homodimer of 125 kDa, was shortened by several residues from the C- and N-termini, via site-directed mutagenesis, to examine the contribution of the removed peptides to the enzyme properties. This study showed that the N-terminal sequence up to amino acid 70 (which confers peculiar ionic properties to the protein) is dispensable for activity. Domains located beyond amino acid 70 appeared to have increasing catalytic importance; the removal of 80 or 90 residues affected the Km values for ATP and deletions of 101 or 140 amino acids profoundly modified the physiochemical properties of AspRS, and by consequence, its structural organisation (extraction of the mutated proteins out of the cells required the presence of SDS). On the C-terminal side, very limited modifications readily affected the enzyme properties. Deletion of as few as three residues increased the Km for ATP and reduced the aminoacylation kcat as well as the thermostability of the adenylate synthesis activity; the kcat of this step was impaired after deletion of two further residues. Finally, shortening the C-terminal decapeptide completely inactivated AspRS, whilst affecting neither its affinity for tRNAAsp nor its dimerisation capacity. These data reveal the role of the C-terminal decapeptide as a determinant in both reactions catalysed by AspRS. This peptide is involved in ATP binding, stabilising the functional conformation of the amino-acid-activating domain and probably maintaining the tRNA-acceptor end in a reactive position with regard to the activated amino acid.


Delay-slope-dependent stability results of recurrent neural networks.
By using the fact that the neuron activation functions are sector bounded and nondecreasing, this brief presents a new method, named the delay-slope-dependent method, for stability analysis of a class of recurrent neural networks with time-varying delays. This method includes more information on the slope of neuron activation functions and fewer matrix variables in the constructed Lyapunov-Krasovskii functional. Then some improved delay-dependent stability criteria with less computational burden and conservatism are obtained. Numerical examples are given to illustrate the effectiveness and the benefits of the proposed method.


[Clinical application of PGA-tube for regeneration of intrapelvic nerves during extended surgery for intrapelvic recurrent rectal cancer].
For the regeneration of injured peripheral nerves, we have devised a PGA-tube that is composed of a tube of polyglycolic acid containing collagen sponge. This PGA-tube was applied clinically to reconstruct a peripheral nerve that had been resected during extended surgical resection of for intrapelvic recurrent rectal cancer. Four months after the surgical resection, the function of the left hip joint has improved remarkably, whereas the function had been lost just after the operation. It is suggested that the PGA-tube will be useful for regeneration of peripheral nerves that are resected during operation for intrapelvic malignancy.


Polymerase chain reaction--based sequence-specific oligonucleotide hybridization analysis of HLA class II antigens in pulmonary tuberculosis: relevance to chemotherapy and disease severity.
HLA antigens were studied by serology and polymerase chain reaction-based sequence-specific oligonucleotide hybridization techniques in 153 patients with pulmonary tuberculosis (PTB) and 289 healthy controls. HLA-DR2 was present more frequently in PTB patients than in controls (51% vs. 36.3%; corrected P[Pc]=.029, relative risk [RR] = 1.8). The DR2 association was stronger in patients in the drug-failure group (n=56; Pc=.000012, RR=3.7) than in healthy controls and in patients in the drug-responder group. No significant deviation was observed in HLA allelic frequencies in various patient groups, as determined by radiographs of lung lesions. Molecular subtyping of DR2 revealed that the bulk of the allele was DRB1*1501 and DRB1*1502 in patients and controls. There was no skewing of the frequency of these molecular subtypes of DR2 in patients, suggesting that the whole DR2 molecule or its closely linked gene(s) may be involved in governing patient susceptibility to PTB and, particularly, development of the severe drug-resistant form of the disease.


Visualizing Peroxynitrite in Microvessels of the Brain with Stroke Using an Engineered Highly Specific Fluorescent Probe.
Stroke is one of the leading causes of death and disability in the world, which is associated with malfunction of reactive oxygen species and reactive nitrogen species (ROS/RNS) in cerebral microvessels. In vivo monitoring these species, such as ONOO-, with high selectivity in stroke process is of great significance for early diagnoses and therapies of the disease. Herein, by engineering an indoline-2,3-dione moiety as the recognizing domain, we proposed a novel fluorescence probe Rd-PN2 with highly specific response toward ONOO-, even in the coexistence of other ROS/RNS with high concentration. Rd-PN2 showed high sensitivity and reaction speed in response to ONOO- and exhibited satisfying performances in tracking the endogenously generated ONOO- in living cells and zebrafish. Accordingly, Rd-PN2 can furnish real-time and in vivo visualizing of ONOO- in cerebral microvessels of mice with ischemic and hemorrhagic strokes under two-photon microscopy. This work presented a precisely modulated fluorescence probe for real-time visualizing of ONOO- production in cerebral micovessels, which will also help to acquire more accurate information in the studies of ONOO- functions in the future.


Dual functions of silver nanoparticles in F9 teratocarcinoma stem cells, a suitable model for evaluating cytotoxicity- and differentiation-mediated cancer therapy.
Silver nanoparticles (AgNPs) exhibit strong antibacterial and anticancer activity owing to their large surface-to-volume ratios and crystallographic surface structure. Owing to their various applications, understanding the mechanisms of action, biological interactions, potential toxicity, and beneficial effects of AgNPs is important. Here, we investigated the toxicity and differentiation-inducing effects of AgNPs in teratocarcinoma stem cells. AgNPs were synthesized and characterized using various analytical techniques such as UV-visible spectroscopy, X-ray diffraction, energy-dispersive X-ray spectroscopy, and transmission electron microscopy. The cellular responses of AgNPs were analyzed by a series of cellular and biochemical assays. Gene and protein expressions were analyzed by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively. The AgNPs showed typical crystalline structures and spherical shapes (average size =20 nm). High concentration of AgNPs induced cytotoxicity in a dose-dependent manner by increasing lactate dehydrogenase leakage and reactive oxygen species. Furthermore, AgNPs caused mitochondrial dysfunction, DNA fragmentation, increased expression of apoptotic genes, and decreased expression of antiapoptotic genes. Lower concentrations of AgNPs induced neuronal differentiation by increasing the expression of differentiation markers and decreasing the expression of stem cell markers. Cisplatin reduced the viability of F9 cells that underwent AgNPs-induced differentiation. The results showed that AgNPs caused differentially regulated cytotoxicity and induced neuronal differentiation of F9 cells in a concentration-dependent manner. Therefore, AgNPs can be used for differentiation therapy, along with chemotherapeutic agents, for improving cancer treatment by targeting specific chemotherapy-resistant cells within a tumor. Furthermore, understanding the molecular mechanisms of apoptosis and differentiation in stem cells could also help in developing new strategies for cancer stem cell (CSC) therapies. The findings of this study could significantly contribute to the nanomedicine because this study is the first of its kind, and our results will lead to new strategies for cancer and CSC therapies.


The CKD Outcomes and Practice Patterns Study (CKDopps): Rationale and Methods.
Minimizing clinical complications in patients with advanced chronic kidney disease (CKD) and improving the transition to dialysis therapy and transplantation represents a challenge, requiring reliable evidence regarding the effects of CKD care on outcomes. The CKD Outcomes and Practice Patterns Study (CKDopps) is a new international prospective cohort study designed to describe and evaluate variation in nephrologist-led CKD practices. CKDopps is underway in Brazil, France, Germany, Japan, and the United States. Diverse national samples of nephrology clinics are being recruited based on random selection stratified by geographic region and clinic characteristics. CKDopps aims to enroll 12,200 non-dialysis-dependent patients with CKD (75% and 25% with estimated glomerular filtration rates < 30 and 30-<60mL/min/1.73m(2), respectively) to be followed up for 3 to 5 years. Demographic, comorbid condition, laboratory, and treatment-related variables are collected at 6-month intervals; patient-reported data are collected annually and more frequently near the transition to end-stage kidney disease; nephrologist practice surveys are collected annually. Outcomes include mortality, end-stage kidney disease, other clinical events (eg, acute kidney injury, hospitalizations, infections, cardiovascular events, and transplant wait-listing), and patient-reported outcomes. For the targeted sample size of 12,200 patients and 160 clinics, CKDopps has 80% power to detect HRs of 1.31 for mortality and 1.19 for mortality or transition to end-stage kidney disease. CKDopps does not capture care provided in settings outside nephrology clinics (eg, primary care) or patients with CKD not receiving medical care. CKDopps is designed to characterize nephrology clinic practice variation and identify practices associated with better outcomes, with particular focus on advanced CKD, transition to end-stage kidney disease, and the patient experience. Because data will be collected during routine clinical care in real-world practice, analyses may yield practical readily implementable findings. CKDopps aims to establish a multinational infrastructure for research, collaboration, and ancillary investigation. Additional countries are encouraged to join.


[News in hemodynamic monitoring, resuscitation and intensive care of patients after cardiac surgery: "Guidelines for resuscitation in cardiac arrest after cardiac surgery" of the European Association for Cardio-Thoracic Surgery].
In order to simplify and to standardize procedures during cardiac arrest in patients after cardiac surgery and for professional medical staff education, working group of the European Association for Cardio-Thoracic Surgery issued in 2009 "Guideline for resuscitation in cardiac arest after cardiac surgery". There are several differences between these guidelines and guidelines for general population: in ventricular fibrillation, three sequential attempts at defibrillation should precede external cardiac massage; in asystole or extreme bradycardia, pacing should precede external cardiac massage. Where the above measures fail, and in pulseless electrical activity, early resternotomy is advocated. Adrenaline should not be routinely given. Also protocols for excluding reversible airway and breathing complications and for safe emergency resternotomy are given. These guidelines in very simple and professional way define rules for resuscitation of patients after cardiac surgery. It is a useful manual which will certainly find its place in daily work of professional medical staff involved in healthcare of these patients.


Successful prolonged treatment of a carbapenem-resistant Acinetobacter baumannii hip infection with cefiderocol: A case report.
We report a 50-year-old Caucasian male with a complicated past medical history who developed extensive polymicrobial osteomyelitis, including a carbapenem-resistant Acinetobacter baumannii (CRAB). In order to streamline therapy, the patient received compassionate use cefiderocol for 6 weeks which was well tolerated. In addition, the patient's infection was considered cured at end of treatment. Few cases on the use of prolonged cefiderocol for treatment of osteomyelitis due to CRAB have been published. Our patient did not report adverse reactions, nor did he develop laboratory abnormalities which were assessed throughout and at the end of the 6-week course.


[A bull's eye subtraction polar map for assessing thallium redistribution (1). Comparison with quantitative redistribution].
A new bull's eye subtraction polar (BS) map has been developed for quantitative assessment of redistribution on stress-delayed thallium-201 SPECT studies. BS map was created after subtraction of a normalized stress bull's eye polar map from a normalized delayed polar map in 10 normal subjects and 33 patients with coronary artery disease to compare BS map with qualitative redistribution scores. The BS map showed less than 15% in all of the 50 segments in the normal subjects. Of 27 segments exhibiting persistent defect without redistribution, the BS map showed less than 10% in 20 segments (74%) and 10-15% in 6 segments (22%). On the other hand, of 34 segments exhibiting redistribution, the BS map showed greater than or equal to 15% in 25 segments (74%) and 10-15% in the remaining 9 segments (26%). Thus, significant redistribution was evident in the areas showing greater than or equal to 10-15% on the BS map. We conclude that the BS map is valuable for quantitative assessment of redistribution on stress-delayed thallium-201 SPECT imaging.


Overweight: The Overlooked Risk Factor.
At the conclusion of this activity, the family physician should be able to: Describe the epidemiology of overweight and obesity in the United States. Describe the disease burden associated with being overweight (body mass index 25-30 kg/m2) and how to broach the topic of weight management with patients. Differentiate the safety and efficacy of 2 nonprocedural device treatments for people with overweight.