Dysfunctional attitudes: measurement, significant constructs and links with depression.
Equivalent forms of Weissman's Dysfunctional Attitude Scale were assessed in 251 Australian patients routinely attending their general practitioner. Normative scores were strikingly similar to those reported in North America. The influences of demographic variables on scale scores were examined, and factor analyses suggested four key attributional constructs. In a second study of 43 clinically depressed patients we assessed the degree to which higher Dysfunctional Attitude scores might be an antecedent to, or a consequence of, greater depressive severity and found support favouring the latter explanation.


hPepT1 transports muramyl dipeptide, activating NF-kappaB and stimulating IL-8 secretion in human colonic Caco2/bbe cells.
Bacterial proteoglycan-derived muramyl dipeptide (MDP) activates the intracellular NOD2/CARD15 gene product. How intestinal epithelial cells take up MDP is poorly understood. We hypothesized that the intestinal apical di-/tripeptide transporter, hPepT1, transports MDP, thereby activating downstream pathways similar to nuclear factor kappa B (NF-kappaB). Time- and concentration-dependent (3)H-MDP uptakes were studied in Caco2/bbe (C2) cell monolayers where hPepT1 expression was either over- or underexpressed, using an inducible adenovirus system or silencing RNA (siRNA), respectively. NF-kappaB activation and interleukin (IL)-8 and monocyte chemoattractant protein-1 (MCP-1) release were determined by enzyme-linked immunosorbent assay. NOD2/CARD15 expression was inhibited by siRNA. MDP in human duodenal, cecal, and stool samples was measured. MDP, but not its isoforms, inhibited uptake of glycosylsarcosine in C2 cells, indicating stereoselective and competitive inhibition. Approximately 90% of the MDP was cytosolic, showing uptake rather than binding. The K m for MDP uptake was 4.3 mmol/L. Cells overexpressing hPepT1 showed increased Gly-Sar and MDP uptake, whereas decreased uptake was observed after hPepT1 siRNA-inhibition. MDP treatment activated NF-kappaB, resulting in IL-8 release, an effect blocked by siRNA-inhibited expression of NOD2/CARD15. MDP content in cecal and stool samples (in normal subjects) was 20-87 micromol/L, but undetectable in duodenal fluid. In colonic epithelial cells, MDP is taken up by hPepT1 and activates NF-kappaB and chemokine production. Because hPepT1 expression in chronic colonic inflammation is increased, this may play an important role in promoting colonocyte participation in host defense and pathogen clearance through increased uptake of MDP.


Signet ring cell carcinoma of bladder: a dilemma between primary and metastatic.
Signet ring cell carcinoma, in general, is a peculiar tumour. There is always a query regarding its exact site of origin. Even, immunohistochemistry shows overlapping staining patterns between various sites. On one hand, signet ring cell carcinoma of the bladder is a rare occurrence, but on the other hand metastatic signet ring cell carcinoma to the bladder is not uncommon. However, without prior knowledge of the primary site of tumour clinically and radiologically, definitive diagnosis is challenging based on morphology and immunohistochemistry.


Poor survival of cementless Biomet total hip: a report on 1,047 hips from the Finnish Arthroplasty Register.
In Finland, almost 50% of all hip replacements done after 1989 have been inserted without cement. Biomet components have been the most commonly used implants in cementless arthroplasties. Between 1985 and 1997, 4,300 prostheses were implanted because of primary osteoarthrosis. 4 different acetabular component designs have been identified as Biomet implants (Mallory-Head, Romanus, T-TAP, Universal) and were used in 1,047 hips. The 9-year survival of all arthroplasties using Biomet cups was only 65 (95% CI 61-69)% while that of arthroplasties using T-TAP-cups was only 58 (52-65)%. In contrast, the 7.5-year survival of arthroplasties using Romanus cups was 85 (79-91)%. The 98 (96-99)% 5-year survival of arthroplasties with Mallory-Head cups should be interpreted cautiously, since similar results of arthroplasties using the Universal cup with the same type of liner decline sharply to 93 (88-98)% only 1 year later. The poor survival of Biomet cementless prostheses in our series seems to be related to the poor survival of the cup. This finding was common to all metal shell designs using Hexloc liners. We recommend that Biomet cups with Hexloc liners should not be used and patients who have had them inserted should undergo regular clinical and radiographic follow-ups.


Pharmacokinetic modeling of species-dependent enhanced bioavailability of trifluorothymidine by thymidine phosphorylase inhibitor.
TAS-102, a new oral drug, is composed of an antitumor drug, alpha,alpha,alpha-trifluorothymidine (FTD), and its metabolic inhibitor, 5-chloro-6-(2-iminopyrrolidine-1-yl)methyl-2,4(1H,3H)-pyrimidinedione hydrochloride (TPI). It has been reported that the oral administration of TAS-102 increases the AUC of FTD in rodents and monkeys in different manners. In this study, a pharmacokinetic model was developed, in an attempt to evaluate the bioavailability of FTD in these animals after the co-administration of TPI. Since TPI inhibits FTD metabolism competitively, a time-dependent as well as concentration-dependent model for the hepatic intrinsic clearance of FTD was developed including the time courses of both FTD and TPI. Based on this modeling, we were able to quantitatively explain the TPI dose-dependent enhancement of AUC of FTD in monkeys, while little increase was observed in rats. These results are consistent to observations that thymidine phosphorylase (TPase) is predominantly expressed in monkeys; while uridine phosphorylase (UPase) is superior to TPase in rats. Since TPase is also predominantly expressed in humans, the pharmacokinetic model developed in this study can be used to explain the bioavailability of TAS-102 in humans.


Phase response relationships between light pulses and the melatonin rhythm in rats.
There is some controversy whether phase response curves constructed from studies conducted after acute release into constant darkness (Type II) or after prolonged constant darkness are comparable. This study investigated the effects of brief low-intensity light pulses on the onset of 6-sulphatoxymelatonin excretion in rats 48 to 60 h after lights-off and after 14 days of continuous darkness. In the former condition, maximum phase delays occurred between 4 and 6 h after expected lights-off, but no phase advances were observed within 2 days of the presentation of the stimulus. When the times of the pulses were plotted in relation to the individual onsets, peak light-induced phase delays occurred 0 to 2 h after melatonin onset. After 14 days in continuous darkness, the peak phase delays also occurred 0 to 2 h after melatonin onset and were slightly but significantly smaller. No significant phase advances were observed. In a separate small series of experiments, the temperature rhythm of rats was shown to be delayed by a comparable degree to that of melatonin by light pulses 2 and 4 h after expected lights-off under the Type II conditions. It is concluded that phase response curves conducted under Type I and Type II conditions are comparable.


Neuropsychological sequelae of Wernicke's encephalopathy in a 20-year-old woman: selective impairment of a frontal memory system.
This article reports the neuropsychological sequelae of Wernicke's Encephalopathy in a 20-year-old woman. After amelioration of acute symptoms, the patient showed a range of cognitive impairments the most marked of which was a severe impairment on free recall tasks involving both verbal and nonverbal material. In contrast, recognition memory appeared remarkably well preserved. Some evidence of frontal lobe and general intellectual impairment was also noted. The case is discussed in terms of the pathophysiology of Wernicke-Korsakoff Syndrome, criteria for its diagnosis, and the multicomponent nature of memory deficits.


Operant conditioning of primate prefrontal neurons.
An operant is a behavioral act that has an impact on the environment to produce an outcome, constituting an important component of voluntary behavior. Because the environment can be volatile, the same action may cause different consequences. Thus to obtain an optimal outcome, it is crucial to detect action-outcome relationships and adapt the behavior accordingly. Although prefrontal neurons are known to change activity depending on expected reward, it remains unknown whether prefrontal activity contributes to obtaining reward. We investigated this issue by setting variable relationships between levels of single-neuron activity and rewarding outcomes. Lateral prefrontal neurons changed their spiking activity according to the specific requirements for gaining reward, without the animals making a motor response. Thus spiking activity constituted an operant response. Data from a control task suggested that these changes were unlikely to reflect simple reward predictions. These data demonstrate a remarkable capacity of prefrontal neurons to adapt to specific operant requirements at the single-neuron level.


Transgenic mouse models for HTLV-I infection.
Human T-cell leukemia virus type I (HTLV-I) was the first human retrovirus isolated and is responsible for at least one form of human leukemia. The pathogenic mechanism(s) whereby HTLV transforms T lymphocytes in vivo is(are) obscure due to its long-term latency and the lack of practical representative animal models. The tax gene of HTLV-I has been implicated in this transformation process because of its ability to transactivate several cellular genes associated with T-cell replication and activation. Here, transgenic mouse models are discussed that express the Tax protein of HTLV-I and provide insights into its role in the cellular transformation process.


Ondansetron and probiotics in the management of pediatric acute gastroenteritis in developed countries.
Acute gastroenteritis (AGE) is a common and impactful disease, typically managed with supportive care. There is considerable interest in the role of adjunctive therapies, particularly ondansetron and probiotics in improving AGE outcomes. The purpose of this review is to present the latest evidence regarding the use of these agents in children with AGE in developed countries. Single-dose oral ondansetron is effective and safe in reducing hospital admissions and the use of intravenous rehydration in children with AGE in emergency-department-based trials. Ondansetron use has increased significantly; however, 'real-world' studies of effectiveness have documented less impressive clinical impacts. Similarly, probiotic consumption is growing rapidly. Although several strains appear to reduce the duration of diarrhea in hospitalized children, current data are insufficient to support the routine use of probiotics in outpatient pediatric AGE. Ondansetron and probiotics may improve patient outcomes in pediatric AGE. Appropriate strategies are needed to optimally integrate oral ondansetron into clinical practice to maximize its potential benefits. Although probiotics remain a promising option, there are challenges in generalizing the data available to patients presenting for outpatient care. Large randomized controlled trials are needed to definitively guide the clinical use of probiotics in outpatients in developed countries.


[Evaluation of the quality of life in patients with ischemic heart disease].
The aim of this study was to analyze quality-of-life parameters in patients with coronary heart disease in Chelyabinsk region. The number of patients with coronary heart disease who took part in this research was 830 people. The data were collected with using of application form that was supplemented by the Russian-language questionnaire SF-36. We determined the medical and social characteristics, the assessment of the conditions and lifestyle of patients with coronary heart disease, and the subjective assessment of the quality of life by themselves. We have been revealed statistically significant differences in assessing the quality of life by patients of different territorial groups. The data should be differentially use in developing of regional and territorial programs in order to reduce mortality from coronary heart disease.


The MTHFR CT polymorphism confers a high risk for stroke in both homozygous and heterozygous T allele carriers with Type 2 diabetes.
Individuals with Type 2 diabetes are at increased risk of stroke. Plasma homocysteine (tHcy) is an independent risk factor for cardiovascular (CV) disease. The methylene-tetrahydrofolate reductase (MTHFR) gene polymorphism (thermolabile variant C(677)T) is associated with CV risk, partly as a result of increased Hcy, especially in homozygous subjects. To relate the occurrence of the MTHFR polymorphism with stroke prevalence by examining allelic frequency and genotype distribution in 165 subjects with Type 2 diabetes studied for the presence of thermolabile C(677)T MTHFR mutation. Mean age was 67.7 years, and tHcy 18.2 micromol/l. T allele frequency was 38.5%. MTHFR genotypes were: normal (CC) 40%; heterozygous (CT) 43%; homozygous (TT) 17%. Serum levels of folic acid and B12 vitamin were within normal limits. Stroke prevalence was 14%. Sixty-four per cent of stroke-free subjects had the normal C allele vs. 46% in stroke subjects. The frequencies of genotypes (CC-CT-TT) were (%): 44-41-15 in stroke-free vs. 17-57-26 in stroke patients. Coronary (CAD) and peripheral artery disease (PAD) were common in all groups, with no differences according to genotypes. Stroke prevalence was markedly higher in genotypes CT and TT (18 and 21%) compared with CC (6%). Mean tHcy levels were higher in TT subjects. The allelic frequency of C(677)T MTHFR mutation in Type 2 diabetes subjects with stroke is markedly different from that of subjects without stroke. Genotypic characteristics suggest that C(677)T MTHFR mutation confers a higher risk for stroke to both homozygous and heterozygous T allele carriers that cannot be ascribed solely to raised tHcy and/or lower folate status in CT subjects, nor to phenotypic expression of conventional risk factors for stroke. The impact of the MTHFR polymorphism on stroke may result from T allele-linked deleterious effects, or C allele-linked protection. Confirmatory studies are warranted, as this cohort was not randomly selected, and a type 1 error cannot be ruled out.


Induced pluripotent stem cell-derived extracellular vesicles: A novel approach for cell-free regenerative medicine.
In recent years, induced pluripotent stem cells (iPSCs) have been considered as a promising approach in the field of regenerative medicine. iPSCs can be generated from patients' somatic cells and possess the potential to differentiate, under proper conditions, into any cell type. However, the clinical application of iPS cells is restricted because of their tumorigenic potential. Recent studies have indicated that stem cells exert their therapeutic benefit via a paracrine mechanism, and extracellular vesicles have been demonstrated that play a critical role in this paracrine mechanism. Due to lower immunogenicity, easier management, and presenting no risk of tumor formation, in recent years, researchers turned attention to exosomes as potential alternatives to whole-cell therapy. Application of exosomes derived from iPSCs and their derived precursor provides a promising approach for personalized regenerative medicine. This study reviews the physiological functions of extracellular vesicles and discusses their potential therapeutic benefit in regenerative medicine.


[The biased information given to women about population screening for breast cancer makes a well considered informed choice to participate unlikely].
The 'Wet op de Geneeskundige Behandelingsovereenkomst' (Act on Agreement Concerning Medical Treatment) requires that patients are clearly informed about 'the risks and consequences that can be expected from an intended treatment or investigation'. The information received by women aged 50-74 years when invited for a biannual investigation for breast cancer does not satisfy the requirements: the available knowledge is presented too favourably and it is therefore not possible to make a well-considered informed choice to participate. For example, in the group to be screened, 4000 cases of breast cancer are diagnosed each year, yet in the information leaflet a figure of 9000 is stated, the number for all age categories. Furthermore, these 9000 cases include 1500 cases detected only as a result of screening. In the information leaflet no mention is made of the fact that 1 in 5 women will die despite screening and the risk of interval carcinomas is not examined; 40% of malignant mammary tumours are still found outside of the screening programme.


Effect of nebivolol on fracture healing: An experimental rat model.
Bone metabolism is a complex system, and fracture healing is one of its most important functions. Many circumstances can influence this process. Chronic drug use in elderly populations can affect bone healing, and inadequate tissue perfusion, increased free radicals and adverse drug effects can negatively influence fracture healing. Nebivolol, an anti-hypertensive drug that selectively blocks β1 receptors, effectively reduces blood pressure by inducing peripheral vasodilation. Nebivolol also exerts anti-oxidant effects by stimulating nitric oxide (NO) synthesis. Many studies show that NO protects the vascular endothelium and improves fracture healing. In this study, the histological and radiological effects of intraperitoneally administered nebivolol on fracture healing were evaluated. Twenty-one Sprague Dawley rats were divided into 3 (nebivolol 1, 2 and control) groups. Sterile nebivolol solution (1 mL = 0.017 mg nebivolol) was given to the rats in group 1 every day for 4 weeks, while the rats in nebivolol group 2 were given 2 mL per day, beginning after the production of an open, displaced unilateral femur fracture. Radiographic and histological studies were used to evaluate fracture healing. Histological and immunohistochemical analysis showed osseous healing with woven bone at the fracture site and only minimal amounts of cartilage in nebivolol 1 and 2 groups. Radiological grading was not different between the control and the nebivolol groups. This study suggests that nebivolol, a selective β blocker, has positive effects on fracture healing through anti-oxidative effects via the NO pathway and direct vasodilator effects.


The effect of gastric digestion on food allergy.
The role of the stomach as the primary location of protein digestion is very well recognized, leading to classification of proteins as digestion-resistant or digestion-labile. This review analyses the role of gastric digestion in food allergy. Hindrance of gastric digestion by elevation of the gastric pH, the therapeutic goal of anti-ulcer medication, was recently shown to trigger food allergy via oral sensitization in a murine food allergy model. The relevance in humans was assessed in an observational study of 152 gastroenterological patients who were medicated with anti-ulcer drugs due to dyspeptic disorders. Twenty-five percent of all patients developed a boost or de-novo IgE formation towards regular constituents of the daily diet. The clinical relevance of the induced antibodies was confirmed by positive skin and oral-provocation tests. Moreover, the importance of gastric digestion was also proven for food-allergic patients, as the allergenicity of allergens were reduced up to a 10,000-fold by gastric digestion. These recent studies indicate for the first time the important gate-keeping function of gastric digestion, both in the sensitization and the effector phases of food allergy.


Imaging methods for quantifying glenoid and Hill-Sachs bone loss in traumatic instability of the shoulder: a scoping review.
Glenohumeral instability is a common problem following traumatic anterior shoulder dislocation. Two major risk factors of recurrent instability are glenoid and Hill-Sachs bone loss. Higher failure rates of arthroscopic Bankart repairs are associated with larger degrees of bone loss; therefore it is important to accurately and reliably quantify glenohumeral bone loss pre-operatively. This may be done with radiography, CT, or MRI; however no gold standard modality or method has been determined. A scoping review of the literature was performed to identify imaging methods for quantifying glenohumeral bone loss. The scoping review was systematic in approach using a comprehensive search strategy and standardized study selection and evaluation. MEDLINE, EMBASE, Scopus, and Web of Science were searched. Initial selection included articles from January 2000 until July 2013, and was based on the review of titles and abstracts. Articles were carried forward if either reviewer thought that the study was appropriate. Final study selection was based on full text review based on pre-specified criteria. Consensus was reached for final article inclusion through discussion amongst the investigators. One reviewer extracted data while a second reviewer independently assessed data extraction for discrepancies. Forty-one studies evaluating glenoid and/or Hill-Sachs bone loss were included: 32 studies evaluated glenoid bone loss while 11 studies evaluated humeral head bone loss. Radiography was useful as a screening tool but not to quantify glenoid bone loss. CT was most accurate but necessitates radiation exposure. The Pico Method and Glenoid Index method were the most accurate and reliable methods for quantifying glenoid bone loss, particularly when using three-dimensional CT (3DCT). Radiography and CT have been used to quantify Hill-Sachs bone loss, but have not been studied as extensively as glenoid bone loss. Radiography can be used for screening patients for significant glenoid bone loss. CT imaging, using the Glenoid Index or Pico Method, has good evidence for accurate quantification of glenoid bone loss. There is limited evidence to guide imaging of Hill-Sachs bone loss. As a consensus has not been reached, further study will help to clarify the best imaging modality and method for quantifying glenohumeral bone loss.


[Relationship between HBeAg from HBsAg positive mothers and regulatory T cells in neonates and its influence on HBV intrauterine transmission].
Objective: To explore the relationship between HBeAg in HBsAg positive mothers and CD(4)(+)CD(25)(+)Foxp3(+)regulatory T cells (Treg) in newborns, as well as how they would influence the increasing risk on HBV intrauterine transmission. Methods: We collected information on general demographic characteristics and delivery on 270 HBsAg positive mothers and their newborns from the Third People's Hospital of Taiyuan. Fluorescence quantitative polymerase chain reaction (FQ-PCR) and chemiluminescence immunoassay (CLIA) were used to detect HBV DNA and HBV serological markers in peripheral blood from both mothers and neonates. The expression of Treg and other immune cells in peripheral blood of neonates were detected with flow cytometry (FCM). Results: Maternal HBeAg positive rates were associated with an increased risk of intrauterine transmission (OR=4.08, 95%CI: 1.89-8.82). Rates of Treg in newborns born to HBsAg-positive mothers were higher than that of the negative group (Z=2.29, P=0.022). Each pair of the subjects was assigned to five different groups according to the HBeAg titers of mothers. Frequencies of both Treg and HBeAg in newborns and HBV DNA in mothers between the above said 5 groups showed similar trends of changing patterns and the differences between groups were statistically significant(χ(2)=18.73, P<0.001; χ(2)=181.60, P<0.001; χ(2)=183.09, P<0.001). Results from partial correlation analysis showed that after adjusting for neonatal HBeAg and maternal HBV DNA, mother's HBeAg titers were positively related to the percentage of Treg in their newborns (r(s)=0.19, P=0.039). In addition, the frequencies of Treg were negatively correlated with pDC and CD(4)(+) T cell in their newborns (r(s)=-0.21, P=0.017; r(s)=-0.23, P=0.009). Conclusion: HBeAg from HBsAg positive mothers might have inhibited the function of neonatal DC cells and T cells to reduce the immune response to HBV by up-regulating the proportion of Treg and finally increased the risk of HBV intrauterine transmission.


Multiclonal pattern of Jaagsiekte sheep retrovirus integration sites in ovine pulmonary adenocarcinoma.
Insertional mutagenesis and envelope (Env)-mediated oncogenesis are hypothesized mechanisms by which Jaagsiekte sheep retrovirus (JSRV) causes ovine pulmonary adenocarcinoma (OPA). Twenty-eight JSRV integration sites in lung tumors (LTs) from four sheep with OPA were cloned and sequenced by a multiple step gene walking technique. Using nested PCR, clonal expansion of these integration sites could be detected, if at all, only in the localized regions of LT from which the integration sites were derived. One sheep had a viral integration site in a sequence with 85 and 81% identity, respectively, over 100 bp to exon 2 of the human and mouse receptor protein tyrosine phosphatase gamma genes. Clonal integration of Jaagsiekte sheep retrovirus in this gene was demonstrated by nested PCR and Southern blot hybridization in the DNA sample from which the integration site was cloned, but not in other LT or kidney DNA samples from the same sheep. OPA may develop from multiple independent oncogenic events and a role for insertional mutagenesis cannot be ruled out.


Preoperative monocyte count is a predictor of recurrence after Stage I lung adenocarcinoma resection.
High-grade tumours are observed even in Stage I lung adenocarcinomas. Tumour spread through air spaces (STAS) is a risk factor for recurrence after resection. However, there is no ideal predictive biomarker for STAS in high-grade Stage I lung adenocarcinoma. This study assessed the prognostic impact of the preoperative peripheral monocyte count in lung adenocarcinoma. We retrospectively analysed the data of 444 patients with resected Stage I lung adenocarcinoma during 2006-2016. Univariable and multivariable Cox proportional analyses of recurrence-free probability (RFP) and overall survival (OS) were used to analyze preoperative complete peripheral blood cell count data. Since monocyte count was associated with poor prognosis, the relationship between preoperative peripheral monocyte count and clinicopathological factors, including STAS, was assessed. In addition, immunohistochemical CD68 staining was performed to evaluate tumour-associated macrophages (TAMs). A higher preoperative peripheral monocyte count was a predictor of lower RFP (P = 0.004) and lower OS (P < 0.001). In multivariable analysis, a higher peripheral monocyte count was an independent prognostic factor for RFP and OS (hazard ratio: 1.88, 95% confidence interval: 1.07-3.31, P = 0.029; hazard ratio: 2.13, 95% confidence interval: 1.22-3.75, P = 0.008, respectively). A higher peripheral monocyte count was associated with a higher frequency of STAS (P = 0.017) and higher number of CD68+ TAMs (P = 0.013). A higher preoperative peripheral monocyte count was an independent marker for a poor prognosis in Stage I lung adenocarcinoma and was associated with a higher frequency of STAS.


The polypyrimidine tract-binding protein is required for efficient dengue virus propagation and associates with the viral replication machinery.
The polypyrimidine tract-binding protein (PTB) functions primarily as an IRES trans-acting factor in the propagation of hepatitis C virus and picornaviruses. PTB interacts with secondary structures within the 3'- and 5'-untranslated regions of these viral genomes to mediate efficient IRES-mediated viral translation. PTB has also been reported to bind to the untranslated region of the single-stranded RNA dengue virus (DENV), suggesting a similar function for PTB in flaviviruses. Indeed small interfering RNA-mediated PTB knockdown inhibited the production of infectious DENV, and this inhibition was specific to PTB knockdown and not due to a nonspecific anti-viral state. In fact, PTB depletion did not inhibit the production infectious yellow fever virus, another flavivirus. Nevertheless, whereas PTB knockdown led to a significant decrease in the accumulation of DENV viral RNAs, it did not impair translation. Moreover, PTB was shown to interact with the DENV nonstructural 4A protein, a known component of the viral replication complex, and with the DENV genome during infection. These data suggest that PTB interacts with the replication complex of DENV and is acting at the level of viral RNA replication.


[Modified Duplay technique in the treatment of hypospadias. Report of 585 cases].
The surgical repair of anterior hypospadias depends on the surgeon's custom and the anatomical variations of this anomaly. However, most publications agree nowadays on the one-stage surgery. We report on 585 hypospadias operated in our department. Our procedure is based on the Duplay technique, in addition to personal modifications in order to correct the frequently associated penis anomalies. The procedure is described herein. Aesthetic and functional results are reported and seem to be very satisfactory in comparison with the literature and permit the homologation of our technique.


Rethinking the bioavailability and cellular transport properties of S-adenosylmethionine.
S-adenosylmethionine (SAM) is a versatile metabolite that participates in a wide range of reactions such as methylation and transsulfuration. These capabilities allow SAM to influence cellular processes such as gene expression and redox balancing. The importance of SAM is highlighted by its widespread usage as an over-the-counter nutrient supplement and as an experimental reagent in molecular biology. The bioavailability and cellular transport properties of SAM, however, are often overlooked under these contexts, putting limits on SAM's therapeutic potential and complicating the interpretation of experimental results. In this article, we examined the chemical stability and cellular permeability of SAM, proposed a schematic for indirect SAM transport across the mammalian plasma membrane, and lastly discussed the implications arising from such transport schematic.


Modeling the effects of amiodarone on short QT syndrome variant 2 in the human ventricles.
The short QT syndrome (SQTS) is a new genetic disorder associated with atrial and ventricular arrhythmias and sudden death. The SQT2, SQTS variant, results from a gain-of-function mutation (V307L) in the KCNQ1-encoded potassium channel. Although pro-arrhythmogenic effects of SQTS have been characterized, less is known about the pharmacology of SQTS. Therefore, this study aims to assess the effects of amiodarone on SQT2. The ten Tusscher et al. model of the human ventricular action potential (AP) was modified to incorporate changes to IKs based on experimental data. Cell models were incorporated into heterogeneous one-dimensional (1D) tissue to compute the pseudo-ECG and the corresponding QT interval. The blocking effects of amiodarone on IKs, INa, INaK, ICaL, INaCa, and IKr were modeled using nH (Hill coefficient) and IC50 values from the literature. At the cellular level, amiodarone both at low and high doses prolonged the SQT2 AP duration (APD); at the tissue level, amiodarone at a high dose caused QT prolongation to the physiological range, but failed at a low dose. Amiodarone at a high dose produced better therapeutic effects on SQT2 than at a low dose. This study provides new evidence that amiodarone at a high dose may be a potential pharmacological treatment for SQT2.


Increased brain size and glial cell number in CD81-null mice.
A key issue in the development of the central nervous system (CNS) is understanding the molecular mechanisms regulating cell number. The present study examines the role of CD81 (previously known as TAPA, the target of the antiproliferative antibody) in the control of brain size and glial cell number. CD81 is a member of the tetraspanin family of proteins. This group of small membrane proteins is associated with the regulation of cell migration and mitotic activity. Glial cells express CD81, and antibodies directed against this protein suppress the mitotic activity of cultured cells. In this study, we examine the effects of the CD81 -/- mutation on the CNS of mature mice. These mice have extremely large brains, as much as 30% larger than the brains of wild-type (+/+) littermates. The increase in brain weight is accompanied by an increase in the number astrocytes and microglia, whereas the number of neurons and oligodendrocytes in the CD81 -/- animals appears to be normal. When the CD81 -/- mutation is placed on different genetic backgrounds, there is a remarkable range in the penetrance of the null allele phenotype, demonstrating that the mutation can be affected by modifier loci. This work provides support for the role of CD81 in the regulation of astrocyte and microglial number, perhaps by regulating cell proliferation by a contact inhibition-dependent mechanism.


Apathy and depression in Parkinson disease.
The purpose of this study was to investigate the prevalence and clinical correlates of apathy and depression in Parkinson disease (PD), and to clarify whether apathy can be dissociated from depression. One hundred fifty patients with PD completed the Beck Depression Inventory Second Edition (BDI-II), Starkstein's Apathy Scale (AS), and a quality of life (QOL) battery. Hoehn and Yahr (HY) staging, the Unified Parkinson's Disease Rating Scale (UPDRS), and the Mini-Mental State Examination (MMSE) were performed on the same day. Apathy (AS score > or = 16) was diagnosed in 60% of patients and depression (BDI-II score > or = 14) in 56%. Apathy coexisted with depression in 43% of patients, compared with depression without apathy in 13% and apathy without depression in 17%. Apathy scale score was significantly correlated with UPDRS scores, HY stage, and age, whereas BDI-II score was correlated only with UPDRS scores. Both AS and BDI-II scores were negatively correlated with QOL. However, multiple regression analysis revealed that depression was strongly and negatively associated with emotional well-being and communication, whereas apathy was mainly associated with cognition and stigma. These findings suggest that apathy and depression may be separable in PD, although both are common in patients with PD and are associated with QOL.


Congenital nephrosis, mesangial sclerosis, and distinct eye abnormalities with microcoria: an autosomal recessive syndrome.
We observed the occurrence of congenital nephrotic syndrome (CNS) and distinct ocular anomalies in two unrelated families. Eleven children from both families presented with a similar course of renal disease starting with nephrotic syndrome and renal failure prenatally or immediately after birth that resulted in death before the age of 2 months. Kidney histopathology showed diffuse mesangial sclerosis (DMS). Clinically obvious eye abnormalities were recognized in six of the eight patients in whom sufficient clinical data were available. Ocular anomalies included enlarged or large appearing corneae in some cases suggesting buphthalmos, and extremely narrow, nonreactive pupils (microcoria). Pathological examination of the eyes of two aborted fetuses revealed a more complex ocular maldevelopment including posterior lenticonus as well as anomalies of cornea and retina. On the basis of these observations and other cases in the literature, we delineate a previously unrecognized distinct entity characterized by congenital nephrotic syndrome, DMS, and eye abnormalities with microcoria as the leading clinical feature. Pedigrees of affected families with parental consanguinity support autosomal recessive inheritance. We propose that this syndrome should be designated microcoria-congenital nephrosis syndrome or Pierson syndrome. Possible overlap with Galloway-Mowat syndrome and relations to other oculo-renal syndromes are discussed.


How Chinese Employees' Voice Behavior Is Motivated: The Role of Perceived Overqualification.
Drawing on the conservation of resources theory (COR), we examined the effect of leader-member exchange (LMX) on the voice behavior via role breadth self-efficacy, and how the perceived overqualification moderates the relationship between LMX and voice behavior. We tested the theoretical model with data gathered from 407 individuals in China. The results revealed that LMX had an indirect effect on voice behavior through role breadth self-efficacy, and perceived overqualification moderated the positive association between LMX and role breadth self-efficacy. In addition, the mediating effect of LMX on voice behavior through role breadth self-efficacy was stronger when the level of perceived overqualification was low and weaker when it was high. The findings have theoretical and practical implications for increasing employees' voice behavior in organizations.


Nephrosplenic space closure significantly decreases recurrent colic in horses: a retrospective analysis.
Nephrosplenic space closure is commonly used to reduce relapse of nephrosplenic space entrapment in cases of left dorsal displacement of the left colon (LDDLC). Nevertheless, studies documenting the effectiveness of this surgery are sparse in the literature. The aim of this study was to analyse clinical data of horses presented for LDDLC and evaluate the effect of nephrosplenic space closure on the incidence of colic recurrence. Medical records of 156 horses diagnosed with LDDLC at the Equine Clinic of the University of Liège between 2004 and 2016 were retrieved for analysis. Extracted data included horse breed, sex, age and weight, initial treatment, and if a subsequent preventive surgical closure of the nephrosplenic space was carried out or not. Follow-up information was obtained by telephone interview. Statistical analyses were performed using a chi-squared test with significance set at P<0.05. Follow-up data were available for 65 per cent of horses. The mean follow-up was 35 months. There was a significant decrease in the total incidence of colic after closure surgery compared with non-operated horses. No horse was diagnosed with LDDLC after closure of the nephrosplenic space. Closure of the nephrosplenic space significantly decreases recurrent colic in horses compared with non-operated horses.


Eplerenone improved hypokalemia in a patient with Gitelman's syndrome.
A 47-year-old woman presented with hypokalemia (2.4 mmol/L). She also had hypomagnesemia, hypocalciuria, and hyperreninemic hyperaldosteronism. Sequence analysis revealed a compound heterozygous mutation, R655C and R955Q, in the SLC12A3 gene. These findings were compatible with Gitelman's syndrome (GS). Eplerenone, a selective aldosterone blocker, in combination with oral potassium chloride improved serum potassium level (3.6 mmol/L) with no apparent adverse effect. Although eplerenone has an advantage over spironolactone for its selective affinity for the aldosterone receptor, the efficacy and safety of eplerenone for GS is little understood. Our observation suggests that eplerenone is a useful treatment option for GS.


Noninvasive diagnostic assessment of peripheral vascular disease.
Noninvasive techniques have assumed an increasingly important role in the management of patients with vascular disease. Both ultrasonic and plethysmographic instruments allow objective evaluation of vascular disorders by the measurement of segmental limb blood pressures, analysis of blood velocity disturbances, recording of digit or limb pulse waveforms, or imaging of vascular disease, with or without Doppler flow analysis or color-flow mapping. These techniques have been applied for screening asymptomatic individuals, diagnosis of symptomatic patients, monitoring of interventional or surgical procedures, and follow-up of the natural history or the efficacy of medical, interventional, or surgical therapy of vascular disease. This article reviews the clinical application of these modalities to patients with peripheral arterial disease and briefly discusses cost-effectiveness and potential abuses of noninvasive technology.


Complete and durable response of choroid metastasis from non-small cell lung cancer with systemic bevacizumab and chemotherapy.
Ocular metastasis from lung cancer is uncommon. We report a patient with metastatic non-small cell lung cancer who was found to have a metastatic lesion in the choroid at the time of presentation. The patient was treated with carboplatin, gemcitabine, and bevacizumab. After three cycles of chemotherapy, radiologic imaging and ophthalmologic examination demonstrated complete resolution of the choroid lesion. This case report demonstrates the durable response of choroidal metastasis from non-small cell lung cancer to systemic bevacizumab and chemotherapy.


Cyanobacterial formation of intracellular Ca-carbonates in undersaturated solutions.
Cyanobacteria have long been thought to induce the formation of Ca-carbonates as secondary by-products of their metabolic activity, by shifting the chemical composition of their extracellular environment to conditions favoring mineral precipitation. Some cyanobacterial species forming Ca-carbonates intracellularly were recently discovered. However, the environmental conditions under which this intracellular biomineralization process can occur and the impact of cyanobacterial species forming Ca-carbonates intracellularly on extracellular carbonatogenesis are not known. Here, we show that these cyanobacteria can form Ca-carbonates intracellularly while growing in extracellular solutions undersaturated with respect to all Ca-carbonate phases, that is, conditions thermodynamically unfavorable to mineral precipitation. This shows that intracellular Ca-carbonate biomineralization is an active process; that is, it costs energy provided by the cells. The cost of energy may be due to the active accumulation of Ca intracellularly. Moreover, unlike cyanobacterial strains that have been usually considered before by studies on Ca-carbonate biomineralization, cyanobacteria forming intracellular carbonates may slow down or hamper extracellular carbonatogenesis, by decreasing the saturation index of their extracellular solution following the buffering of the concentration of extracellular calcium to low levels.


[Prenatal diagnosis of cystic fibrosis with recombinant DNA methods].
Cystic fibrosis is one of the commonest genetic disorders with about 1 in 3000 newborns being affected. The molecular etiology of the disease is still not known. In spite of improved therapy the life expectancy is markedly reduced. Many parents of a child affected by CF request a prenatal diagnosis, when a further child is expected. By using molecular genetic methods the prenatal detection of CF is possible now with great accuracy in most families. This review describes the principles of the genetics and the diagnosis of the disease. Case reports illustrate risk figure ascertainment. Preconditions for performing the diagnosis in individual cases are outlined, and a guide to the practical approach is given.


[The distaff philosophy in folk medicine animal science].
Spinning, distaffs and spinning-rooms are used to be closely linked with superstitious thinking and behavior. The so-called distaff philosophy reflects the wisdom of the old black magic spinners. Their wisdom was known by the popular veterinary medicine. With the help of the collections of distaff philosophical thoughts the relation between distaff philosophy and popular veterinary medicine is shown.


Isolation, partial characterization and translation of mRNAs for chymosin and pepsin, the two main aspartyl proteinases of bovine stomach.
Poly(A) RNA from the mucosa of the fundal region of the fourth stomach of suckling calf and adult cattle was isolated by the phenol or guanidine thiocyanate procedure. The mRNAs for chymosin and pepsin were present in the 15S fraction of poly(A) RNA. They were active both in cell-free translation systems and in oocytes of Xenopus laevis and directed the synthesis of either chymosin or pepsin precursor, depending upon the age of the donor animal. In the reticulocyte and wheat germ system only preprochymosin or prepepsinogen were synthesized. In the oocyte system only the synthesis and secretion of prochymosin or pepsinogen could be detected. Both proenzymes, prochymosin and pepsinogen, present in oocytes or secreted into the medium, were converted to active enzymes, chymosin and pepsin, respectively, at pH 3.0, as shown by their proteolytic and milk-clotting activity.


Pharmacokinetic comparisons of benzoylmesaconine in rats using ultra-performance liquid chromatography-tandem mass spectrometry after administration of pure benzoylmesaconine and Wutou decoction.
Wutou decoction is widely used in China because of its therapeutic effect on rheumatoid arthritis. Benzoylmesaconine (BMA), the most abundant component of Wutou decoction, was used as the marker compound for the pharmacokinetic study of Wutou decoction. The aim of the present study was to compare the pharmacokinetics of BMA in rats after oral administration of pure BMA and Wutou decoction. Pure BMA (5 mg/kg) and Wutou decoction (0.54 g/kg, equivalent to 5 mg/kg BMA) were orally administered to rats with blood samples collected over 10 h. Quantification of BMA in rat plasma was achieved using sensitive and validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Specifically, the half-life (T1/2) and mean residence time values of pure BMA were 228.3 ± 117.0 min and 155.0 ± 33.2 min, respectively, whereas those of BMA in Wutou decoction were decreased to 61.8 ± 35.1 min and 55.8 ± 16.4 min, respectively. The area under the curve (AUC) of BMA after administration of Wutou decoction was significantly decreased (five-fold) compared with that of pure BMA. The results indicate that the elimination of BMA in rats after the administration of Wutou decoction was significantly faster compared with that of pure BMA.


A complete mapping of the proteins in the small ribosomal subunit of Escherichia coli.
The relative positions of the centers of mass of the 21 proteins of the 30S ribosomal subunit from Escherichia coli have been determined by triangulation using neutron scattering data. The resulting map of the quaternary structure of the small ribosomal subunit is presented, and comparisons are made with structural data from other sources.


Biomarkers in functional movement disorders: a systematic review.
Functional movement disorders (FMD) are proposed to reflect a specific problem with voluntary control of movement, despite normal intent to move and an intact neural capacity for movement. In many cases, a positive diagnosis of FMD can be established on clinical grounds. However, the diagnosis remains challenging in certain scenarios, and there is a need for predictors of treatment response and long-term prognosis.In this context, we performed a systematic review of biomarkers in FMD. Eighty-six studies met our predefined criteria and were included.We found fairly reliable electroencephalography and electromyography-based diagnostic biomarkers for functional myoclonus and tremor. Promising biomarkers have also been described for functional paresis, gait and balance disorders. In contrast, there is still a lack of diagnostic biomarkers of functional dystonia and tics, where clinical diagnosis is often also more challenging. Importantly, many promising findings focus on pathophysiology and reflect group-level comparisons, but cannot differentiate on an individual basis. Some biomarkers also require access to time-consuming and resource-consuming techniques such as functional MRI.In conclusion, there are important gaps in diagnostic biomarkers in FMD in the areas of most clinical uncertainty. There is also is a lack of treatment response and prognostic biomarkers to aid in the selection of patients who would benefit from rehabilitation and other forms of treatment.


3-Methyl-N-(4-methyl-phen-yl)benzamide.
In the title compound, C(15)H(15)NO, the two aromatic rings make a dihedral angle of 70.06 (3)°, while the central amide core -NH-C(=O)- is twisted by 30.24 (4) and 40.16 (3)° out of the planes of the 3-methyphenyl and 4-methyphenyl rings, respectively. The methyl groups are disordered over two equally occupied positions. In the crystal, inter-molecular N-H⋯O hydrogen bonds link the mol-ecules into infinite chains running along the a axis.


Residential segregation in Australian cities: a literature review.
"In this review of literature dealing with the postwar immigrant experience in urban Australia, some of the key interpretations of residential segregation are assessed. The article focuses on studies which have examined ethnic clusters formed by southern Europeans in Sydney and Melbourne and more recently by Indochinese refugees. Much of the analysis to date has been based on measuring static residential patterns rather than social interaction, and the need to question the significance of ethnic concentrations which sometimes characterize the early stages of immigrant adaptation is suggested."


Theophylline-loaded compritol microspheres prepared by ultrasound-assisted atomization.
Nine solid dispersions were prepared by the melting method in the form of particles containing theophylline at 10%, 20%, and 30% (w/w) in three Compritols (Compritol 888 ATO, HD5 ATO, E ATO) to compare their efficiency in controlling theophylline release. After solidification the mass was ground and granules were evaluated by thermal [differential scanning calorimetry, hot stage microscopy (HSM)] and spectroscopic [Fourier transform infrared (FTIR), Raman, X-ray powder diffraction (XRD)] analysis and the solubility parameters. Another nine samples of the same composition were obtained as microspheres by ultrasound-assisted (US) atomization. XRD confirmed the presence of crystalline theophylline inside the solid dispersions. FTIR and Raman microspectroscopy revealed that crystals of the drug were present on the granule surface. On the contrary, the surface of the final microspheres did not present free drug crystals. The granules do not work so efficiently as microspheres in controlling the release of theophylline: 888 ATO ≈ HD5 ATO > E ATO represents the order of the ability of the Compritols to control the theophylline release from microspheres. HSM revealed that, on aging, the dissolved drug crystallizes, considerably modifying the granule formulation and that US vibration, speeding up the crystallization of the drug during the preparation of microspheres, greatly reduces the changes associated with aging.


Phylogenetic differentiation between Awassi and Hamdani sheep using the mitochondrial 12S rRNA.
This study was conducted to assess the role of the mitochondrial 12S rRNA variations in the phylogenetic discrimination between two Iraqi breeds of sheep that differ in geographical distribution. A total of 122 animals (68 Awassi and 54 Hamdani) were included in the study. Direct sequencing of amplicons followed by the construction of a median-joining network and several trees were performed to identify the possible phylogenetic differences between both involved breeds. Genetic diversity, relative frequencies, and analysis of molecular variance (AMOVA) were performed to assess the genetic correlation between both populations. The median-joining network and minimized tree values showed that all observed haplotypes were separated into two groups according to their breed. Comprehensive phylogenetic data revealed only one Asian ancestor for all observed haplotypes. As indicated by AMOVA, the observed diversity was mostly due to between-population variation (1.24836%), while within-population variation (0.91221%) accounted for much less. The currently investigated rRNA amplicons exhibited different mitochondrial manifestations between Awassi and Hamdani breeds. Due to the ability of these 12S rRNA amplicons to mimic the geographical diversity for the currently investigated breeds, it is highly recommended to be used as potent mitochondrial genetic markers among broader ovine sequences.


Pseudomonas spp. and Serratia liquefaciens as Predominant Spoilers in Cold Raw Milk.
The storage of fresh raw milk at low temperature does not prevent proliferation of psychrotrophic bacteria that can produce heat-resistant proteolytic enzymes contributing to the reduced shelf life of dairy products. This study aimed to identify the dominant psychrotrophic proteolytic enzyme-producing population of raw milk from Brazil. Raw milk samples collected in 3 different cooling tanks in Brazil were stored at optimal (45 h at 4 °C followed by 3 h at 7 °C) and suboptimal (45 h at 7 °C followed by 3 h at 10 °C) conditions to simulate farm storage and transportation allowed by Brazilian laws. The highly proteolytic enzyme-producing strains isolated from stored cold raw milk were characterized by repetitive sequence-based Polymerase Chain Reaction (PCR) analysis. This clustering resulted in 8 different clusters and 4 solitary fingerprints. The most proteolytic isolates from each rep-cluster were selected for identification using miniaturized kit, 16S rDNA and rpoB gene sequencing. Serratia liquefaciens (73.9%) and Pseudomonas spp. (26.1%) were identified as the dominant psychrotrophic microorganisms with high spoilage potential. The knowledge of milk spoilage microbiota will contribute to improved quality of milk and dairy products.


Changes in serum levels of bone morphogenic protein 4 and inflammatory cytokines after bariatric surgery in severely obese korean patients with type 2 diabetes.
Serum bone morphogenic protein- (BMP-) 4 levels are associated with human adiposity. The aim of this study was to investigate changes in serum levels of BMP-4 and inflammatory cytokines after Roux-en-Y gastric bypass (RYGB). Fifty-seven patients with type 2 diabetes underwent RYGB. Serum levels of BMP-4 and various inflammatory markers, including high-sensitivity C-reactive protein (hsCRP), free fatty acids (FFAs), and plasminogen activator inhibitor- (PAI-) 1, were measured before and 12 months after RYGB. Remission was defined as glycated hemoglobin <6.5% for at least 1 year in the absence of medications. Levels of PAI-1, hsCRP, and FFAs were significantly decreased at 1 year after RYGB. BMP-4 levels were also significantly lower at 1 year after RYGB than at baseline (P = 0.024). Of the 57 patients, 40 (70%) had diabetes remission at 1 year after surgery (remission group). Compared with patients in the nonremission group, patients in the remission group had lower PAI-1 levels and smaller visceral fat areas at baseline. There was a difference in the change in the BMP-4 level according to remission status. Our data demonstrate a significant beneficial effect of bariatric surgery on established cardiovascular risk factors and a reduction in chronic nonspecific inflammation after surgery.


Sequence and properties of mecA, a negative regulator of genetic competence in Bacillus subtilis.
The development of competence in Bacillus subtilis is regulated by growth conditions and several regulatory genes. In complex media competence development is poor, and there is little or no expression of late competence genes. mec mutations permit competence development and late competence gene expression in complex media, and bypass the requirements for many of the competence regulatory genes. In this paper we describe the cloning and characterization of mecA. The mecA gene product acts negatively in the development of competence. Null mutations in mecA allowed expression of a late competence gene comG, under conditions where it is not normally expressed, including in complex media and in cells mutant for several competence regulatory genes. Overexpression of MecA from a multicopy plasmid resulted in inhibition of comG transcription. The DNA sequence of mecA was determined and the predicted gene product showed no significant similarity to any protein in the database. Expression of a mecA-lacZ translational fusion was constitutive during growth and did not vary significantly in the different media tested. The role of mecA in competence development and other stationary phase phenomena is discussed.


Comparative pharmacokinetics of macrolides.
The search for erythromycin derivatives with improved antibacterial and/or pharmacokinetic properties, has led to the synthesis of several new agents. Roxithromycin, an ether oxime derivative of erythromycin, is one of the more promising. The main differences between erythromycin and roxithromycin are their kinetics, roxithromycin giving higher serum concentrations than erythromycin at equimolar oral doses. Its elimination half-life is also longer, about 12 h compared to 2-3 h for erythromycin. As their tissue distributions and antibiotic profiles are similar, roxithromycin can be administered in lower daily doses and at less frequent intervals. A suitable dosage regimen for roxithromycin seems to be 150 mg every 12 h. From a pharmacokinetic point of view, daily dosing with roxithromycin would be equivalent to the administration of erythromycin every 6 h.


Hygromorphs: from pine cones to biomimetic bilayers.
We consider natural and artificial hygromorphs, objects that respond to environmental humidity by changing their shape. Using the pine cone as an example that opens when dried and closes when wet, we quantify the geometry, mechanics and dynamics of closure and opening at the cell, tissue and organ levels, building on our prior structural knowledge. A simple scaling theory allows us to quantify the hysteretic dynamics of opening and closing. We also show how simple bilayer hygromorphs of paper and polymer show similar behaviour that can be quantified via a theory which couples fluid transport in a porous medium and evaporative flux to mechanics and geometry. Our work unifies varied observations of natural hygromorphs and suggests interesting biomimetic analogues, which we illustrate using an artificial flower with a controllable blooming and closing response.


Liquid water: from symmetry distortions to diffusive motion.
Water deviates from tetrahedral symmetry on different scales, creating "defects" that are important for its dynamics. In this Account, I trace the manifestations of these distortions from the isolated molecule through gas-phase clusters to the liquid phase. Unlike the common depiction, an isolated water molecule has a nonsymmetric charge distribution: although its positive charge is localized at the hydrogens, the negative charge is smeared between the lone-pair sites. This creates a "negativity track" along which a positive charge may slide. Consequently, the most facile motion within the water dimer is a reorientation of the hydrogen-bond (HB) accepting molecule (known as an "acceptor switch"), such that the donor hydrogen switches from one lone pair to the other. Liquid water exhibits asymmetry between donor and acceptor HBs. Molecular dynamics simulations show that the water oxygens accepting HBs from the central molecule are spatially localized, whereas water hydrogens donating HBs to it are distributed along the negativity track. This asymmetry is manifested in a wider acceptor- versus donor-HB distribution. There is a higher probability for a water molecule to accept one (trigonal symmetry) or three HBs than to donate one or three HBs. A simple model can explain semiquantitatively how these distributions evolve by distorting perfectly tetrahedral water. Just two reactions are required: the dissociation of a HB between a double-donor donating to a double-acceptor, D(2)···A(2), followed by a switching reaction in which a HB donor rotates its hydrogen between two double-acceptor molecules. The preponderance of D(2)···A(2) dissociation events is in line with HB "anticooperativity", whereas positive cooperativity is exhibited by conditional HB distributions: a molecule with more acceptor bonds tends to have more donor bonds and vice versa. Quantum mechanically, such an effect arises from intermolecular charge transfer, but it is observed even for fixed-charge water models. Possibly, in the liquid state this is partly a collective effect, for example, a more ordered hydration shell that enhances the probability for both acceptor and donor HBs. The activation energy for liquid water self-diffusion is considerably larger than its HB strength, pointing to the involvement of collective dynamics. The remarkable agreement between the temperature dependence of the water self-diffusion coefficient and its Debye relaxation time suggests that both share the same mechanism, likely consisting of coupled rotation and translation with collective rearrangement of the environment. The auto-correlation function of a hydrogen-bonded water molecule pair is depicted quantitatively by the solution of the diffusion equation for reversible geminate recombination, up to long times where the ubiquitous t(-3/2) power law prevails. From the model, one obtains the HB dissociation and formation rate coefficients and their temperature dependence. Both have a similar activation enthalpy, suggesting rapid formation of HBs with alternate partners, perhaps by the HB switching reaction involving the trigonal site. A detailed picture of how small fluctuations evolve into large-scale molecular motions in water remains elusive. Nonetheless, our results demonstrate how the plasticity of water can be traced to its asymmetric charge distribution, with duality between tetrahedral and trigonal ligation states.


Cardiac response during trumpet playing.
Heart rate, heart rate variability, stroke volume, and cardiac output were measured while six college students and six professionals played trumpet. One-minute rest periods were followed by 1 minute of playing exercises designed to assess the effects of pitch and articulation. Heart rate and heart rate variability increased during playing, but stroke volume decreased. Changes in heart rate between resting and playing were greater for students, although beat-to-beat variability was larger for professionals in the upper register. These results suggest that expertise is characterized by greater physiological efficiency.


[Better acceptance of measures for induction of anesthesia after rectal premedication with midazolam in children. Comparison of results of an open and placebo-controlled study].
The rectal administration of midazolam for premedication of children before induction of anesthesia by mask was investigated in two clinical studies. In 62 children aged between 2 and 10 years, midazolam was given by open design at various dosages (0.15 mg.kg-1, 0.25 mg.kg-1, 0.30 mg.kg-1, 0.35 mg.kg-1, 0.40 mg.kg-1) to evaluate the most effective dose for optimal acceptance of the mask and gas mixture. An additional 40 children between 3 and 9 years received 0.2 mg midazolam.kg-1 body weight or placebo in a double-blind design to estimate the lower limit of efficacy of midazolam. All children were classified as ASA I and had to undergo a surgical procedure. Within the two studies the children were not different with respect to their general data, age, weight, and sex. In both studies more boys than girls were included. Parameters of efficacy were the degree of sedation before and at 10, 20, and 30 min after midazolam as well as acceptance of the mask and the gas mixture at induction of anesthesia. In all groups, including placebo, a sedative and tranquilizing effect of the premedication was found. The rectal administration of 0.35-0.4 mg midazolam.kg-1 is most suitable for the preoperative medication of children between 2 and 10 years. Due to the degree of sedation and the relief of anxiety toward the surroundings and the operation, the induction of anesthesia is optimally accepted by the child. In contrast, the effect of a dose around 0.2 mg midazolam.kg-1 body weight is not much different from that of placebo and is not sufficient for effective premedication.


Comparison of autochthonous and imported cases of hepatitis A or hepatitis E.
Hepatitis A and hepatitis E are not limited to tropical countries but are also present in industrialized countries. Both infections share similar clinical features. There is no comparative study evaluating the clinical parameters of autochthonous and imported hepatitis A virus and hepatitis E virus infections. The aim of this study was to determine differences between autochthonous and imported hepatitis A virus (HAV) and hepatitis E virus (HEV) infections. Medical charts of all patients at our center with acute HAV and HEV infections were analyzed retrospectively (n = 50, study period 01/2009 - 08/2013). Peak bilirubin (median 8.6 vs. 4.4 mg/dL, p = 0.008) and ALT levels (median 2998 vs. 1666 IU/mL, p = 0.04) were higher in patients with hepatitis A compared to hepatitis E. In comparison to autochthones hepatitis E cases, patients with imported infections had significantly higher peak values for AST, ALT, bilirubin and INR (p = 0.009, p = 0.002, p = 0.04 and p = 0.049, respectively). In HAV infection, AST levels tended to be higher in imported infections (p = 0.08). (i) It is not possible to differentiate certainly between acute HAV and HEV infections by clinical or biochemical parameters, however, HAV infections might be associated with more cholestasis and higher ALT values. (ii) Imported HEV infections are associated with higher transaminases, INR and bilirubin levels compared to autochthonous cases and (iii) imported HAV infections tend to be associated with higher transaminases in comparison to autochthonous cases.


Expression and regulation of Bradyrhizobium japonicum and Xanthobacter flavus CO2 fixation genes in a photosynthetic bacterial host.
Calvin cycle carbon dioxide fixation genes encoded on DNA fragments from two nonphotosynthetic, chemolithoautotrophic bacteria, Bradyrhizobium japonicum and Xanthobacter flavus, were found to complement and support photosynthetic growth of a ribulose 1,5-bisphosphate carboxylase-oxygenase (RubisCO) deletion mutant of the purple nonsulfur bacterium Rhodobacter sphaeroides. The regulation of RubisCO expression was analyzed in the complemented R. sphaeroides RubisCO deletion mutant. Distinct differences in the regulation of RubisCO synthesis were revealed when the complemented R. sphaeroides strains were cultured under photolithoautotrophic and photoheterotrophic growth conditions, e.g., a reversal in the normal pattern of RubisCO gene expression. These studies suggest that sequences and molecular signals which regulate the expression of diverse RubisCO genes may be probed by using the R. sphaeroides complementation system.


Children's early approaches to learning and academic trajectories through fifth grade.
Children's early approaches to learning (ATL) enhance their adaptation to the demands they experience with the start of formal schooling. The current study uses individual growth modeling to investigate whether children's early ATL, which includes persistence, emotion regulation, and attentiveness, explain individual differences in their academic trajectories during elementary school. Using data from the Early Childhood Longitudinal Study - Kindergarten Cohort (ECLS-K), the present investigation examined the association between ATL at kindergarten entry and trajectories of reading and math achievement across 6 waves of data from kindergarten, 1st, 3rd, and 5th grade (n = 10,666). The current study found a positive link between early ATL and individual trajectories of reading and math performance. Overall, children's early ATL was equally beneficial for children regardless of their race/ethnicity and dimensions of their socioeconomic background. However, links between early ATL and academic trajectories differed by their gender and initial levels of math and reading achievement.


Low-Temperature Detection of Sulfur-Hexafluoride Decomposition Products Using Octahedral Co3O4-Modified NiSnO3 Nanofibers.
Sulfur hexafluoride (SF6) is widely used in electrical equipment because of its excellent insulating properties. The type of internal fault in the power system can be identified by detecting SF6 decomposition products. In this manuscript, we report a novel sensing material based on octahedral Co3O4-modified NiSnO3 nanofibers synthesized via a two-step process based on electrospinning followed by a hydrothermal method for detecting the SF6 decomposition products. From the evaluation of various characterization techniques, it was determined that the Co3O4 octahedra adhered inflexibly to the surface of the NiSnO3 nanofibers, which consist of smaller particles and provide a huge surface area for the adsorption of an enormous amount of gas species. Planar-type chemical gas sensors were devised, and their gas detecting performance against SF6 decomposition products was systematically investigated. A comparison of the sensitivity properties of different amounts of charged Co3O4 octahedra in NiSnO3 nanofibers shows that the S-2-based Co3O4@NiSnO3 composite has a high selectivity for 100 ppm SO2F2 gas with a high sensing response of 22.5 at a relatively low temperature of 50 °C with a moderate response/recovery interval (∼200/∼268 s) and a low detection limit (5 ppm) over other interfering gases, such as SOF2, SO2, and H2S. Interestingly, the sensing properties of the fabricated sensors based on the Co3O4@NiSnO3 composites for the SO2F2 gas were improved in terms of lower operating temperatures, higher gas responses, and mild response/recovery intervals, which could be attributed to the unique microstructure effect, the catalytic influence of Co3O4 octahedra, and the creation of p/n junctions to increase the charge transfer and diffusion rate within the catalytic assembly of the sensor materials. This work highlights the importance of the heterostructure design in the construction of high-performance gas sensors for the real-time detection of SF6 decomposition products.


A metagenomic DNA sequencing assay that is robust against environmental DNA contamination.
Metagenomic DNA sequencing is a powerful tool to characterize microbial communities but is sensitive to environmental DNA contamination, in particular when applied to samples with low microbial biomass. Here, we present contamination-free metagenomic DNA sequencing (Coffee-seq), a metagenomic sequencing assay that is robust against environmental contamination. The core idea of Coffee-seq is to tag the DNA in the sample prior to DNA isolation and library preparation with a label that can be recorded by DNA sequencing. Any contaminating DNA that is introduced in the sample after tagging can then be bioinformatically identified and removed. We applied Coffee-seq to screen for infections from microorganisms with low burden in blood and urine, to identify COVID-19 co-infection, to characterize the urinary microbiome, and to identify microbial DNA signatures of inflammatory bowel disease in blood.


[Radiochemotherapy of bladder cancer with/without tissue-organ protection]
The authors report the results of radiochemotherapy for bladder cancer, both advanced and early with a poor prognosis, on the basis of their own material as well as based on the literature. More than half of the patients received radioprotective madication at the same time. The short follow-up does not allow for far-reaching conclusions, but early results and limited complications appear hopeful. The authors emphasise that, if indicated, radiochemotherapy can serve as an alternative to cystectomy.


Biological functions of glucolipids in Bacillus subtilis.
Glyceroglycolipids are very important in Gram-positive bacteria and cyanobacteria. In Bacillus subtilis, a model organism for the Gram-positive bacteria, the ugtP mutant, which lacks glyceroglucolipids, shows abnormal morphology. Lack of glucolipids has many consequences: abnormal localization of the cytoskeletal protein MreB and activation of some extracytoplasmic function (ECF) sigma factors (σM, σV and σX) in the log phase are two examples. Conversely, the expression of monoglucosyldiacylglycerol (MGlcDG) by 1,2-diacylglycerol 3-glucosyltransferase from Acholeplasma laidlawii (alMGS) almost completely suppresses the ugtP disruptant phenotype. Activation of ECF sigmas in the ugtP mutant is decreased by alMGS expression, and is suppressed to low levels by MgSO4 addition. When alMGS and alDGS (A. laidlawii 1,2-diacylglycerol-3-glucose (1-2)-glucosyltransferase producing diglucosyldiacylglycerol (DGlcDG)) are simultaneously expressed, σX activation is repressed to wild type level. These observations suggest that MGlcDG molecules are required for maintenance of B. subtilis cell shape and regulation of ECF sigmas, and that DGlcDG regulates σX activity. The activation of ECF sigmas is not accompanied by proteolysis of anti-σ. Thus, glyceroglucolipids may have the specific role of helping membrane proteins function by acting in the manner of chaperones.


Modeling the atmospheric transport and deposition of PCDD/F to the Great Lakes.
Atmospheric deposition is a significant loading pathway for polychlorinated dibenzo-p-dioxins and dibenzofurans (dioxin) to the Great Lakes. An innovative approach using NOAA's HYSPLIT atmospheric fate and transport model was developed to estimate the 1996 dioxin contribution to each lake from each of 5,700 point sources and 42,600 area sources in a U.S./Canadian air emissions inventory. These unusually detailed source-receptor modeling results show that deposition to each lake arises from a broad geographical region, with significant contributions from up to 2,000 km away. The source categories contributing most significantly to 1996 dioxin deposition appear to be municipal waste incineration, iron sintering, medical waste incineration, and cement kilns burning hazardous waste. Model-predicted air concentrations and deposition fluxes were consistent with ambient measurement data, within the uncertainties in each, but there may be a moderate tendency toward underestimation using midrange emissions estimates. The most likely reason for this tendency appears to be missing or underestimated emissions sources, but in-situ atmospheric formation of octachlorinated dibenzo-p-dioxin (OCDD) and heptachlorinated dibenzo-p-dioxin (HpCDD) may have also contributed. Despite uncertainties, the findings regarding the relative importance of different sources types and source regions appear to be relatively robust and may be useful in prioritizing pollution prevention efforts.


Resource utilization in patients with brain metastases managed with best supportive care, radiotherapy and/or surgical resection: a Markov analysis.
In spite of the large number of patients and increasing financial pressure on health care budgets worldwide, limited data on resource utilization after diagnosis of brain metastases are available. Prospective data were collected on all patients diagnosed with brain metastases during a time period of 2 years (n = 53). Treatment was best supportive care (BSC), primary radiotherapy (RT) and/or surgical resection. Eighty-five percent of patients had active extracranial disease. Costs were calculated from the hospital and nursing home's point of view. Overall, 11,532 patient days were analyzed. Treatment per patient amounted to 0.8 courses of whole-brain RT, 0.2 neurosurgical procedures, 0.1 radiosurgical procedures and 1.3 cycles of chemotherapy. Median survival in the BSC, RT and neurosurgery groups was 1.4, 4.6 and 11.0 months, respectively. Chemotherapy was associated with longer median survival. Four percent of the remaining lifetime was spent in nursing homes and 8% within hospitals. Forty-three percent of all hospital days and 47% of deaths were related to non-neurologic causes. The total cost per patient was 24,649 EUR (34,841 USD) and the corresponding cost per life year was 43,955 EUR (62,130 USD). Hospital care was the main cost factor. A considerable amount of resources is utilized in this patient group. Better tools for avoiding overtreatment and selecting patients for appropriate therapy are needed to achieve maximum value for money.


Hematological and biochemical abnormalities associated with severe forms of COVID-19: A retrospective single-center study from Morocco.
Since December 2019, the coronavirus disease (COVID-19) pandemic has catapulted the world into a marked health crisis, with over 29 million cases and >930,000 deaths. To better detect affected individuals at an early stage and stop disease progression to an advanced stage, several studies have been conducted to identify the clinical, biological, and radiological characteristics of COVID-19. This study aimed to enrich the literature by critically analyzing the clinical and biological characteristics of 134 patients from the North African Mediterranean region, including numerous genetic, epigenetic, and environmental factors that may influence disease evolution. This single-center retrospective study included all patients older than 18 years confirmed to have COVID-19 and hospitalized at the Cheikh Khalifa University Hospital affiliated with Mohammed VI University of Health Sciences, Casablanca, Morocco. Clinical, demographic, and biological data were analyzed in a cohort of severe and non-severe patients. Univariate analysis was performed to identify factors predictive of severity. There were 134 patients: the median age was 53 years, and 54.5% were male. Of these, 89 had mild to moderate disease; 45 had severe to critical disease, of which 14 died and 31 survived. Advanced age, presence of comorbidities, male sex, and infection in ethnic or family groups were risk factors for progression to severe disease. The presence of abnormalities in the following parameters were strongly associated with progression to severe disease: white blood cells (WBC), neutrophils, lymphocytes, C-reactive protein (CRP), procalcitonin, D-dimers, lactate dehydrogenase (LDH), ferritin, creatinine, aspartate aminotransferase (ASAT), and alanine aminotransferase (ALAT) during both admission and hospitalization. Based on these results and an extensive literature review, we recommend that clinicians closely monitor the biological parameters identified herein and perform immunological and genetic studies.


[Periventricular leukomalacia].
The present knowledge on periventricular leucomalacia is reviewed. Its incidence is about 10% in preterms infants < 32 gestational weeks. By careful ultrasonographic scanning four stages can be distinguished: Prolonged flares, resolution, cystic leucomalacia, ventriculomegaly. Periventricular leucomalacia (PVL) is much more correlated with later neurologic impairment than intraventricular haemorrhage (apart from grade IV). PVL is caused by ischemia of the periventricular white matter mainly due to arterial hypotension and disturbed regulation of cerebral blood flow. The interactions between blood pressure, pCO2, pO2 and cerebral blood flow are complex and poorly understood. Regarding the clinical management it seems important to avoid hypotension, fluctuating pCO2 and hypoxemia/anemia in order to prevent white matter ischemia. Research should be focussed on the development of monitoring methods (doppler sonography, near infrared spectroscopy, time compressed electroencephalography), which allow to detect ischemic events to prevent neurologic impairment in about 1000 preterm infants per year in Germany.


DFT study of the monomers and dimers of 2-pyrrolidone: equilibrium structures, vibrational, orbital, topological, and NBO analysis of hydrogen-bonded interactions.
A computational study of the monomers and hydrogen-bonded dimers of 2-pyrrolidone was executed at different DFT levels and basis sets. The above dimeric complexes were treated theoretically to elucidate the nature of the intermolecular hydrogen bonds, geometry, thermodynamic parameters, interaction energies, and charge transfer. The processes of dimer formation from monomers and concerted reactions of double proton transfer were considered. The evolution of geometry, vibrational frequencies, charge distribution, and AIM properties in going from monomers to dimers was systematically followed. The solvent effects upon dimer formation were investigated in terms of the self-consistent reaction field (SCRF Onsager model). For the monomers and three dimers, vibrational frequencies were calculated and the changes in frequencies of the vibrations most sensitive to complexation were discussed. The orbital interactions were shown to lengthen the X-H (X = N, O) bond and lower its vibrational frequency (a red shift). To better understand the nature of the corresponding intermolecular interactions, we performed natural bond orbital (NBO) analysis. Topological analysis of electron density at bond critical points (BCP) was executed for complex molecules using the Bader's atoms in molecules (AIM) theory. The interaction energies were calculated, and the basis set superposition errors (BSSE) were estimated systematically. Satisfactory correlations between the structural parameters, interaction energies, and electron density characteristics at BCP were found.


The effect of temperature on the development and reproduction of Busseola fusca (Lepidoptera: Noctuidae).
The effect of temperature on the reproduction and development of Busseola fusca was studied under laboratory conditions. Single male-female pairs were confined to oviposition chambers kept at 15, 20, 26 and 30 ± 1°C and a 14L:10D photoperiod. Data on reproduction parameters were captured daily. Oviposition occurred at all the mentioned temperatures but no fertility was recorded at 30°C. The total number of eggs laid per female moth was between 300 and 400 and the optimum temperature for oviposition and fertility was between 20 and 26°C. Larval development was studied at five different temperature regimes, i.e. 15, 18, 20, 26 and 30 ± 1°C and a 14L:10D photoperiod. The most favourable temperature as well as the upper threshold temperature for larval development was between 26 and 30°C. Total development period was 152.6-52.6 days, respectively, at 15°C, and 26-30°C. The thermal constants for B. fusca was 99.50, 536.48, 246.25 and 893.66°D and lower temperature thresholds were 10.36, 8.14, 8.99 and 8.84°C, for completion of the egg, larval, pupal and egg-to-adult stages, respectively. Results on the thermal constants and lower and upper threshold temperatures of B. fusca can be used to predict the impact of climate change on the distribution and population growth of this pest.


Evidence for two components of delayed rectifier K+ current in human ventricular myocytes.
Previous voltage-clamp studies have suggested that the delayed rectifier current (IK) is small or absent in the human ventricle and, when present, consists only of the rapid component (IKr); however, molecular studies suggest the presence of functionally important IK in the human heart, specific IKr blockers are known to delay ventricular repolarization and cause the long QT syndrome in humans, and we have shown that the expression of IK is strongly influenced by cell isolation techniques. The present experiments were designed to assess the expression of IK in myocytes obtained by arterial perfusion of right ventricular tissue from explanted human hearts. Of 35 cells from three hearts, 33 (94%) showed time-dependent currents typical of IK. The envelope-of-tails test was not satisfied under control conditions but became satisfied in the presence of the benzenesulfonamide E-4031 (5 micromol/L). E-4031 suppressed a portion of IK in 32 of 33 cells, with properties of the drug-sensitive and -resistant components consistent with previous descriptions of IKr and the slow component (IKs), respectively. Action potential duration to 95% repolarization at 1 Hz was prolonged by E-4031 from 336+/-16 (mean +/- SEM) to 421 +/- 19ms (n = 5, P < .01), indicating a functional role for IK. Indapamide, a diuretic agent previously shown to inhibit IKs selectively, suppressed E-4031-resistant current. The presence of a third type of delayed rectifier, the ultrarapid delayed rectifier current (IKur), was evaluated with the use of depolarizing prepulses and low concentrations (50 micromol/L) of 4-aminopyridine. Although these techniques revealed clear IKur in five of five human atrial cells, no corresponding component was observed in any of five human ventricular myocytes. We conclude that a functionally significant IK, with components corresponding to IKr and IKs, is present in human ventricular cells, whereas IKur appears to be absent. These findings are important for understanding the molecular, physiological, and pharmacological determinants of human ventricular repolarization and arrhythmias.


Preliminary Validity of the Eyberg Child Behavior Inventory With Filipino Immigrant Parents.
Filipinos are an understudied minority affected by significant behavioral health disparities. We evaluate evidence for the reliability, construct validity, and convergent validity of the Eyberg Child Behavior Inventory (ECBI) in 6- to 12- year old Filipino children (N = 23). ECBI scores demonstrated high internal consistency, supporting a single-factor model (pre-intervention α =.91; post-intervention α =.95). Results document convergent validity with the Child Behavior Checklist Externalizing scale at pretest (r = .54, p < .01) and posttest (r = .71, p < .001). We conclude that the ECBI is a promising tool to measure behavior problems in Filipino children.


Arterial compression of the right common iliac vein; an unusual anatomical variant.
Compression of the left common iliac vein by the right common iliac artery has been well described (Cockett's syndrome). The authors describe a case report of compression of the right common iliac vein by the right internal iliac artery. The patient presented with ipsilateral lower limb oedema. Venography showed smooth extrinsic compression of the right common iliac vein. The CT scan was initially interpreted as showing no extrinsic mass or obvious compressing lesion and lymphography was normal. It was the duplex scan which showed the bifurcation of the right common iliac artery crossing the right common iliac vein and causing significant extrinsic compression.


Maroteaux-Lamy syndrome associated with growth hormone deficiency.
Growth retardation is a common feature of mucopolysaccharide storage disorders, mostly considered to be a consequence of skeletal changes, Maroteaux-Lamy disease is a subtype of mucopolysaccharidosis, demonstrating somatic changes and skeletal deformities. We present a case with Maroteaux-Lamy disease associated with growth hormone deficiency. Magnetic resonance imaging study revealed marked signal changes in white matter due to the storage in brain and empty sella appearance in sellar region. In the presence of empty sella syndrome, hypothalamic-pituitary dysfunction due to the storage material may have led to growth hormone deficiency in this patient. Therefore, we recommend patients with mucopolysaccharidosis, especially those who have growth retardation, to be evaluated by hormonal and radiological studies.


Potential Role of the Renal Arterial Resistance Index in the Differential Diagnosis of Diabetic Kidney Disease.
To investigate the potential role of renal arterial resistance index (RI) in the differential diagnosis between diabetic kidney disease (DKD) and non-diabetic kidney disease (NDKD) and establish a better-quantified differential diagnostic model. We consecutively reviewed 469 type 2 diabetes patients who underwent renal biopsy in our center. According to the renal biopsy results, eligible patients were classified into the DKD group and the NDKD group. The diagnostic significance of RI was evaluated by receiver operating characteristic (ROC) curve analysis. Logistic regression analysis was used to search for independent risk factors associated with DKD. Then a novel diagnostic model was established using multivariate logistic regression analysis. A total of 332 DKD and 137 NDKD patients were enrolled for analysis. RI was significantly higher in the DKD group compared with those in the NDKD group (0.70 vs. 0.63, p< 0.001). The optimum cutoff value of RI for predicting DKD was 0.66 with sensitivity (69.2%) and specificity (80.9%). Diabetic retinopathy, diabetes duration ≥ 60 months, HbA1c ≥ 7.0(%), RI ≥ 0.66, and body mass index showed statistical significance in the multivariate logistic regression analysis. Then, we constructed a new diagnostic model based on these results. And the validation tests indicated that the new model had good sensitivity (81.5%) and specificity (78.6%). RI has a potential role in discriminating DKD from NDKD. The RI-based predicting model can be helpful for differential diagnosis of DKD and NDKD.


Cannabinoid Receptor Subtype 2 (CB2R) in a Multitarget Approach: Perspective of an Innovative Strategy in Cancer and Neurodegeneration.
The cannabinoid receptor subtype 2 (CB2R) represents an interesting and new therapeutic target for its involvement in the first steps of neurodegeneration as well as in cancer onset and progression. Several studies, focused on different types of tumors, report a promising anticancer activity induced by CB2R agonists due to their ability to reduce inflammation and cell proliferation. Moreover, in neuroinflammation, the stimulation of CB2R, overexpressed in microglial cells, exerts beneficial effects in neurodegenerative disorders. With the aim to overcome current treatment limitations, new drugs can be developed by specifically modulating, together with CB2R, other targets involved in such multifactorial disorders. Building on successful case studies of already developed multitarget strategies involving CB2R, in this Perspective we aim at prompting the scientific community to consider new promising target associations involving HDACs (histone deacetylases) and σ receptors by employing modern approaches based on molecular hybridization, computational polypharmacology, and machine learning algorithms.


Perceptions of marital interaction among black and white newlyweds.
Perceptions of marital interactions were gathered from a representative sample of urban newlywed couples (199 Black and 174 White). A factor analysis of the reports found 6 factors common to husbands and wives: Disclosing Communication, Affective Affirmation, Negative Sexual Interaction, Traditional Role Regulation, Destructive Conflict, and Constructive Conflict. Avoiding Conflict was specific to men and Positive Coorientation was specific to women. Wives reported fewer constructive and more destructive conflict behaviors. Compared with Whites, Blacks reported more disclosure, more positive sexual interactions, and fewer topics of disagreement. They also more often reported leaving the scene of conflict and talking with others more easily than with the spouse. As hypothesized, perceptions that marital interactions affirm one's sense of identity strongly predicted marital well-being. Although regression analyses predicting marital happiness yielded few interactions with race or gender, those that are significant, coupled with race and gender differences in perceiving interaction, suggest taking a contextual orientation to the meaning of marital interaction.


Review on skeletal disorders caused by Staphylococcus spp. in poultry.
Lameness or leg weakness is the main cause of poor poultry welfare and serious economic losses in meat-type poultry production worldwide. Disorders related to the legs are often associated with multifactorial aetiology which makes diagnosis and proper treatment difficult. Among the infectious agents, bacteria of genus Staphylococcus are one of the most common causes of bone infections in poultry and are some of the oldest bacterial infections described in poultry. Staphylococci readily infect bones and joints and are associated with bacterial chondronecrosis with osteomyelitis (BCO), spondylitis, arthritis, tendinitis, tenosynovitis, osteomyelitis, turkey osteomyelitis complex (TOC), bumblefoot, dyschondroplasia with osteomyelitis and amyloid arthropathy. Overall, 61 staphylococcal species have been described so far, and 56% of them (34/61) have been isolated from clinical cases in poultry. Although Staphylococcus aureus is the principal cause of poultry staphylococcosis, other Staphylococcus species, such as S. agnetis, S. cohnii, S. epidermidis, S. hyicus, S. simulans, have also been isolated from skeletal lesions. Antimicrobial treatment of staphylococcosis is usually ineffective due to the location and type of lesion, as well as the possible occurrence of multidrug-resistant strains. Increasing demand for antibiotic-free farming has contributed to the use of alternatives to antibiotics. Other prevention methods, such as better management strategies, early feed restriction or use of slow growing broilers should be implemented to avoid rapid growth rate, which is associated with locomotor problems. This review aims to summarise and address current knowledge on skeletal disorders associated with Staphylococcus spp. infection in poultry.


Acoustic attenuation, phase and group velocities in liquid-filled pipes II: simulation for Spallation Neutron Sources and planetary exploration.
This paper uses a finite element method (FEM) to compare predictions of the attenuation and sound speeds of acoustic modes in a fluid-filled pipe with those of the analytical model presented in the first paper in this series. It explains why, when the predictions of the earlier paper were compared with experimental data from a water-filled PMMA pipe, the uncertainties and agreement for attenuation data were worse than those for sound speed data. Having validated the FEM approach in this way, the versatility of FEM is thereafter demonstrated by modeling two practical applications which are beyond the analysis of the earlier paper. These applications model propagation in the mercury-filled steel pipework of the Spallation Neutron Source at the Oak Ridge National Laboratory (Tennessee), and in a long-standing design for acoustic sensors for use on planetary probes. The results show that strong coupling between the fluid and the solid walls means that erroneous interpretations are made of the data if they assume that the sound speed and attenuation in the fluid in the pipe are the same as those that would be measured in an infinite volume of identical fluid, assumptions which are common when such data have previously been interpreted.


Substitution behaviour of amine-bridged dinuclear Pt(II) complexes with bio-relevant nucleophiles.
Complexes of the type [Pt2(N,N,N',N'-tetrakis(2-pyridylmethyl)diamine(HO)2]4+ and [Pt2(N,N,N',N'-tetrakis(2-pyridylmethyl)diamine(Cl)2]2+ were used to study their reactions with a series of bio-relevant nucleophiles, viz. thiourea, L-methionine and guanosine-5'-monophosphate (5'-GMP2-) as a function of nucleophile concentration and temperature. The reactions with the sulfur containing nucleophiles (thiourea and L-methionine) were followed under pseudo-first-order conditions by stopped-flow and UV-Vis spectrophotometry. The reaction with 5'-GMP2- was carried out under second order conditions and studied by NMR spectroscopy. The results indicate that the bridged dinuclear complexes remain intact after coordination of the studied nucleophiles for an extended period of time, which differs significantly from that reported for other multinuclear platinum complexes in the literature.


Indirect sympatholytic actions at β-adrenoceptors account for the ocular hypotensive actions of cannabinoid receptor agonists.
Intraocular pressure (IOP) is the primary risk factor for glaucoma, a blinding eye disease. Cannabinoid agonists have long been known to decrease IOP, suggesting they may be useful in glaucoma treatment. However, the specific mechanism by which cannabinoids generate this ocular hypotensive effect remains unknown. The current evidence suggests the cannabinoids reduce IOP through actions at cannabinoid 1 (CB(1)) receptors within the eye, and adrenergic receptors (ARs) may also contribute to this action of cannabinoids. Considering this, the present study aimed to elucidate the mechanism behind the ocular hypotensive properties of cannabinoids through the use of mice genetically lacking either cannabinoid receptors or βARs. Cannabinoid agonists, βAR antagonists, and βAR agonists decreased IOP in wild-type mice and CB(2)(-/-) mice. In contrast, none of these compounds were found to reduce IOP in βAR(-/-) or CB(1)(-/-) mice. Desensitization of the βARs and depletion of catecholamines in wild-type mice also eliminated the ability of the cannabinoid agonist (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone mesylate (WIN 55,212-2) to reduce IOP, strongly implicating a role for both βARs and catecholamines in the ocular hypotensive properties of cannabinoids. Finally, CB(1) receptors were shown to colocalize with tyrosine hydroxylase, a marker for adrenergic neurons. Taken together, these findings suggest that βARs are required for the ocular hypotensive properties of cannabinoids, and cannabinoids reduce IOP by acting as indirect sympatholytics and inhibiting norepinephrine release within the eye.


Quantification of Arm Swing during Walking in Healthy Adults and Parkinson's Disease Patients: Wearable Sensor-Based Algorithm Development and Validation.
Neurological pathologies can alter the swinging movement of the arms during walking. The quantification of arm swings has therefore a high clinical relevance. This study developed and validated a wearable sensor-based arm swing algorithm for healthy adults and patients with Parkinson's disease (PwP). Arm swings of 15 healthy adults and 13 PwP were evaluated (i) with wearable sensors on each wrist while walking on a treadmill, and (ii) with reflective markers for optical motion capture fixed on top of the respective sensor for validation purposes. The gyroscope data from the wearable sensors were used to calculate several arm swing parameters, including amplitude and peak angular velocity. Arm swing amplitude and peak angular velocity were extracted with systematic errors ranging from 0.1 to 0.5° and from -0.3 to 0.3°/s, respectively. These extracted parameters were significantly different between healthy adults and PwP as expected based on the literature. An accurate algorithm was developed that can be used in both clinical and daily-living situations. This algorithm provides the basis for the use of wearable sensor-extracted arm swing parameters in healthy adults and patients with movement disorders such as Parkinson's disease.