Development and psychometric evaluation of a Positive Health measurement scale: a factor analysis study based on a Dutch population.
The My Positive Health (MPH) dialogue tool is increasingly adopted by healthcare professionals in the Netherlands as well as abroad to support people in their health. Given this trend, the need arises to measure effects of interventions on the Positive Health dimensions. However, the dialogue tool was not developed for this purpose. Therefore, this study aims to work towards a suitable measurement scale using the MPH dialogue tool as starting point. A cross-sectional study design. A total of 708 respondents, who were all members of the municipal health service panel in the eastern part of the Netherlands, completed the MPH dialogue tool. The factor structure of the MPH dialogue tool was explored through exploratory factor analysis using maximum likelihood extraction. Next, the fit of the extracted factor structure was tested through confirmatory factor analysis. Reliability and discriminant validity of both a new model and the MPH scales were assessed through Cronbach's alpha tests. Similar to the MPH dialogue tool, the extracted 17-item model has a six-factor structure but named differently, comprising the factors physical fitness, mental functions, future perspectives, contentment, social relations and health management. The reliability tests suggest good to very good reliability of the aimed measurement tool and MPH model (Cronbach's alpha values ranging from, respectively, 0.820 to 0.920 and 0.882 to 0.933). The measurement model shows acceptable discriminant validity, whereas the MPH model suggests overlap between domains. The results suggest that the current MPH dialogue tool seems reliable as a dialogue, but it is not suitable as a measurement scale. We therefore propose a 17-item model with improved, acceptable psychometric properties which can serve as a basis for further development of a measurement scale.


Selecting appropriate toys for young children: the pediatrician's role.
Play is essential for learning in children. Toys are the tools of play. Which play materials are provided and how they are used are equally important. Adults caring for children can be reminded that toys facilitate but do not substitute for the most important aspect of nurture-warm, loving, dependable relationships. Toys should be safe, affordable, and developmentally appropriate. Children do not need expensive toys. Toys should be appealing to engage the child over a period of time. Information and resources are provided in this report so pediatricians can give parents advice about selecting toys.


Increased prevalence of significant coronary artery calcification in patients with diabetes.
Coronary artery disease is the major cause of morbidity and mortality in patients with diabetes. Detection of coronary artery disease before the first myocardial infarction and before anginal symptoms will allow for strategies designed to reduce the cardiovascular event rate in this group of patients. Electron beam-computed tomography (EBCT) is a noninvasive technology for evaluating the extent of coronary artery atherosclerosis that relies on the detection of coronary artery calcium (CAC). We used EBCT to detect significant coronary artery atherosclerosis in diabetic patients without symptoms of heart disease. We used EBCT to evaluate calcium in the coronary arteries of 139 consecutive diabetic patients scanned over a 20-month period. The CAC scores in this group were compared with a randomly selected nondiabetic control group and a control group that was selected to match a number of established cardiovascular risk factors. Patients with diabetes had a significant increase in the prevalence of CAC scores > or =400 (25.9%) compared with the randomly selected (7.2%) and matched (14.4%) nondiabetic control groups. Scores in this range have been reported to be highly predictive for abnormal stress myocardial perfusion tomography and subsequent coronary events. Our results, therefore, indicate a substantial prevalence of significant coronary artery disease in an asymptomatic diabetic patient population compared with nondiabetic control subjects. They also suggest that EBCT may be a useful approach for selecting a group of diabetic subjects who would benefit most from additional evaluation for subclinical coronary artery disease.


Phylogenetic status of insect parasitism in the subfamily Entaphelenchinae Nickle with description of Peraphelenchus orientalis n. sp. (Tylenchomorpha: Aphelenchoididae).
The nematode family Aphelenchoididae is a highly divergent group that contains plant parasites, predators, fungal feeders, and insect parasites. It is taxonomically separated into 7 subfamilies. Although molecular phylogenetic relationships among 6 of the subfamilies have been clarified, the phylogenetic position of the subfamily Entaphelenchinae, which is composed of endoparasites of insects, remains unclear. Here, a new entaphelenchid species, Peraphelenchus orientalis n. sp., was isolated from the body cavities of burying beetles, Nicrophorus quadripunctatus, with a 14% prevalence (5 out of 36). The phylogenetic position of the subfamily within the family Aphelenchoididae was determined using morphological and molecular data for the new species. The rRNA sequences suggested that the new species belongs to Clade 3 of Aphelenchoididae, which mostly consists of predators and insect parasites. Although molecular sequences from other entaphelenchid species were not available, the subfamily appears to be monophyletic. The new species is characterized by the absence of a functional rectum and anus and by the presence of 3 pairs of male genital papillae, a loosely coiled male body, and a W-shaped male spicule. Compared with the original description of Peraphelenchus necrophori, P. orientalis n. sp. has significant typological differences, possibly because of misinterpretations during the original description of P. necrophori. Excluding these questionable characters, i.e., presence-absence of functional rectum and anus and number of male genital papillae, the new species is distinguished from P. necrophori by minor morphological characters and morphometric values.


[Anorexia nervosa: demographic, socio-economic and cultural data still too limited].
Although eating disorders are a public health issue, treating anorexia nervosa from a demographic and socio-economic perspective remains a challenge. Data are scarce, patchy and often of questionable quality. Such a lack of data on a somatopsychic illness with serious repercussions is a real problem, since reliable, longitudinal and detailed information could provide additional answers in understanding the illness, both in terms of age, sex and gender structure, and in terms of family, social and environmental factors.


The Phylum Bryozoa as a Promising Source of Anticancer Drugs.
Recent advances in sampling and novel techniques in drug synthesis and isolation have promoted the discovery of anticancer agents from marine organisms to combat this major threat to public health worldwide. Bryozoans, which are filter-feeding, aquatic invertebrates often characterized by a calcified skeleton, are an excellent source of pharmacologically interesting compounds including well-known chemical classes such as alkaloids and polyketides. This review covers the literature for secondary metabolites isolated from marine cheilostome and ctenostome bryozoans that have shown potential as cancer drugs. Moreover, we highlight examples such as bryostatins, the most known class of marine-derived compounds from this animal phylum, which are advancing through anticancer clinical trials due to their low toxicity and antineoplastic activity. The bryozoan antitumor compounds discovered until now show a wide range of chemical diversity and biological activities. Therefore, more research focusing on the isolation of secondary metabolites with potential anticancer properties from bryozoans and other overlooked taxa covering wider geographic areas is needed for an efficient bioprospecting of natural products.


Enhancing the utility of existing antibiotics by targeting bacterial behaviour?
The discovery of novel classes of antibiotics has slowed dramatically. This has occurred during a time when the appearance of resistant strains of bacteria has shown a substantial increase. Concern is therefore mounting over our ability to continue to treat infections in an effective manner using the antibiotics that are currently available. While ongoing efforts to discover new antibiotics are important, these must be coupled with strategies that aim to maintain as far as possible the spectrum of activity of existing antibiotics. In many instances, the resistance to antibiotics exhibited by bacteria in chronic infections is mediated not by direct resistance mechanisms, but by the adoption of modes of growth that confer reduced susceptibility. These include the formation of biofilms and the occurrence of subpopulations of 'persister' cells. As our understanding of these processes has increased, a number of new potential drug targets have been revealed. Here, advances in our ability to disrupt these systems that confer reduced susceptibility, and in turn increase the efficacy of antibiotic therapy, are discussed.


Low-energy short-term cold atmospheric plasma: Controlling the inactivation efficacy of bacterial spores in powders.
The present research work aims to elucidate kinetics and mechanisms of the inactivation of Bacillus subtilis spores by a surface micro-discharge (SMD) - cold atmospheric pressure plasma (CAPP). Regarding industrial applications, the inactivation of spores was also studied for a static layer of a biopolymer powder or film, with an air plasma and at ambient pressure. Close to 4 log10 cycles of inactivation of Bacillus subtilis spores were achieved when exposing spores on flat glass to the SMD-CAPP. This effect can be reached at a very low plasma power density of 5 mW/cm2 in 7 min exposure time. The maximum inactivation level of spores drops when treating corn-starch powder to 2.6 log10 cycles at 7 mW/cm2 plasma power density for 5 min and with a polymer load of 5 mg/cm2. Similar is true for films produced with hydroxymethyl cellulose (HMC). The inactivation efficacy can be tuned and is a function of applied surface energy (product of the plasma power density and the exposure time) and the polymer load. Plasma diagnostics reveal the fundamental importance of reactive nitrogen species (RNS) in the inactivation. Etching of spore hull is supposed to be triggered by the plasma density, while UV-C and UV-B radiation do not contribute directly and significantly to the inactivation effect at least in a biopolymer matrix. Fluidization of a fixed powder layer is supposed to overcome limitations of the inactivation efficacy by reducing the diffusion distance of active plasma species between the source and the sample. The combination of low plasma power density with short treatment time is supposed to reduce the risk of the formation of side-products from the matrix.


Long non-coding RNA LINC00675 inhibits tumorigenesis and EMT via repressing Wnt/β-catenin signaling in esophageal squamous cell carcinoma.
Long noncoding RNA LINC00675 (LINC00675) seems to play an anti-oncogenic role in cancers, though its exact function remains unknown. Up to date, little is known about the role of LINC00675 in esophageal squamous cell carcinoma (ESCC). In this study, we aimed to explore the expression pattern, clinical significance and biological function of LINC00675 in ESCC. RT-PCR was performed to detect the expression levels of LINC00675 in both ESCC tissue and cell lines. The association of LINC00675 expression with clinicopathological factors and prognosis was statistically analyzed. Cell growth was detected by MTT assay and colony formation assay. Cell apoptosis was evaluated with flow cytometry. Migration and invasion ability of ESCC cells were detected wound healing assay and transwell assays. The expressions of EMT-related proteins and Wnt/β-catenin-related proteins by Western blot were investigated. LINC00675 expression was significantly downregulated in both ESCC tissues and cell lines. Decreased LINC00675 expression was correlated with histological grade, lymph nodes metastasis and advanced clinical stage. Furthermore, LINC00675 could serve as an independent predictor for overall survival in ESCC. Importantly, in vitro experiments indicated that that forced LINC00675 expression significantly suppressed inhibited ESCC cell proliferation, colony formation, migration, invasion and EMT, and promoted cell apoptosis through suppressing Wnt/β-catenin signaling pathway. We suggested that LINC00675 acted as a tumor suppressor in ESCC via regulation of Wnt/β-catenin signaling pathway and may be a new prognostic biomarker and potential therapeutic target for ESCC intervention.


CRISPR and transposon in vivo screens for cancer drivers and therapeutic targets.
Human cancers harbor substantial genetic, epigenetic, and transcriptional changes, only some of which drive oncogenesis at certain times during cancer evolution. Identifying the cancer-driver alterations amongst the vast swathes of "passenger" changes still remains a major challenge. Transposon and CRISPR screens in vivo provide complementary methods for achieving this, and each platform has its own advantages. Here, we review recent major technological breakthroughs made with these two approaches and highlight future directions. We discuss how each genetic screening platform can provide unique insight into cancer evolution, including intra-tumoral heterogeneity, metastasis, and immune evasion, presenting transformative opportunities for targeted therapeutic intervention.


[Assessment of mitochondrial function in the surviving cytoplasts of cultured cells of pig embryonic kidney by using ethylrhodamine].
A study was made of the functional state of chondriome in cytoplasts previously cultivated for a long time under vital staining with fluorescent dye ethylrhodamine (10 micrograms/ml) which is known to accumulate preferentially in mitochondria. The energization was estimated by the intensity of mitochondrial fluorescence. It was realized that 30 minutes after enucleation cytoplasts retained the same fluorescence as did the untreated cells, and that the mitochondrial distribution within the cell was very similar. Such a high intensity of fluorescence seen within one day after enucleation gives a strong evidence on the high degree of independence on the cell nucleus of organelles that provide the energy to metabolic processes. In the course of survival in the cultivation medium for 1-4 days the intensity of fluorescence is shown to fall, especially on the second day after enucleation. All these changes coincide with the changes in cytoplast shape: originally well spread bodies transform into squeezed, ball-shaped or strongly deformed ones. The adhesive ability is going down, and in result only single units of cytoplast can hardly be found on the cover slips by the 4th day after enucleation. These changes give evidence on the enhanced degeneration of cultured cytoplasts.


Bypass blood flow during carotid endarterectomy.
The relationship of bypass shunt blood flow to arterial pressure and stump pressure was studied in 12 informed patients undergoing carotid endarterectomy. These patients were anesthetized with halothane plus nitrous oxide. Systemic arterial blood pressure was measured with a radial artery catheter, and stump pressure as well as distal shunt pressure (carotid pressure distal to the shunt) were measured with a 25-gauge needle inserted cephalad to the bypass shunt. From the pressure drop across the bypass shunt, blood viscosity, geometry of the bypass tubing and the use of Poiseullie's law, the shunt blood flow can be calculated. The calculated shunt flow shows a close correlation with the difference between arterial pressure and stump pressure (r = 0.91) as well as with the slope of arterial pressure increase following carotid occlusion (r = 0.82); but it is poorly correlated with the stump pressure. Administration of 100 ml low molecular weight dextran solution does not improve the shunt blood flow, whereas 500 ml low molecular weight dextran significantly decreases blood viscosity. The patency of the carotid artery as assessed by angiogram does not give a proper indication of the need for a bypass shunt. The shunt flow as well as the need of such a shunt might be predicted by the use of the difference of arterial pressure and stump pressure. If the slope of arterial pressure increases rapidly following carotid occlusion, it can also be used to determine the necessity of such a shunt.


Balancing task focus and relationship building: asking sleepy patients about traffic risk in treatment initiation consultations.
The use of traffic risk assessment questions is an understudied area in nursing research. Obstructive sleep apnoea is associated with an increased risk of traffic accidents. Therefore, traffic safety authorities demand adherent continuous positive airway pressure use. Nurses act as coaches to achieve treatment adherence, but they are also obliged to act as state agents by prohibiting obstructive sleep apnoea patients from drowsy driving. To examine how nurses and obstructive sleep apnoea patients manage traffic risk assessment questions in the relation-building context of treatment initiation consultations. To study, in detail, the actual practice of risk assessment, we used conversation analysis of 19 video-recorded initial treatment consultations with nurses and recently diagnosed obstructive sleep apnoea patients. The study received ethical approval from the Central Ethical Review Board in Linköping (registration number 214/231-32) and follows the ethical guidelines for qualitative research. Patients influence how nurses phrase questions about traffic risk by taking a stance to daytime sleepiness prior to the risk question. Nurses ask traffic risk questions in a way that assumes that driving is unproblematic if patients have not previously indicated problems. It may pose a significant problem when nurses, by accepting patients' prior stance when asking about traffic risk, orient to relationship building rather than task focus. To clarify the difference between their two potentially conflicting roles, nurses need to refer to existing laws and official guidelines when they raise the issue of risk in treatment initiation consultations. Nurses should also ask risk assessment questions in a problem-oriented communicative environment. Traffic risk assessment is sensitive yet important, as obstructive sleep apnoea is a highly prevalent problem causing excessive sleepiness. It is essential to acknowledge nurses' double roles with regard to coaching continuous positive airway pressure treatment and assessing traffic risk.


Sensorimotor neural dynamics during isochronous tapping in the medial premotor cortex of the macaque.
We determined the response properties of neurons in the primate medial premotor cortex that were classified as sensory or motor during isochronous tapping to a visual or auditory metronome, using different target intervals and three sequential elements in the task. The cell classification was based on a warping transformation, which determined whether the cell activity was statistically aligned to sensory or motor events, finding a large proportion of cells classified as sensory or motor. Two distinctive clusters of sensory cells were observed, i.e. one cell population with short response-onset latencies to the previous stimulus, and another that was probably predicting the occurrence of the next stimuli. These cells were called sensory-driven and stimulus-predicting neurons, respectively. Sensory-driven neurons showed a clear bias towards the visual modality and were more responsive to the first stimulus, with a decrease in activity for the following sequential elements of the metronome. In contrast, stimulus-predicting neurons were bimodal and showed similar response profiles across serial-order elements. Motor cells showed a consecutive activity onset across discrete neural ensembles, generating a rapid succession of activation patterns between the two taps defining a produced interval. The cyclical configuration in activation profiles engaged more motor cells as the serial-order elements progressed across the task, and the rate of cell recruitment over time decreased as a function of the target interval. Our findings support the idea that motor cells were responsible for the rhythmic progression of taps in the task, gaining more importance as the trial advanced, while, simultaneously, the sensory-driven cells lost their functional impact.


Regulation and Function of C-Type Natriuretic Peptide (CNP) in Gonadotrope-Derived Cell Lines.
C-type natriuretic peptide (CNP) is the most conserved member of the mammalian natriuretic peptide family, and is implicated in the endocrine regulation of growth, metabolism and reproduction. CNP is expressed throughout the body, but is particularly abundant in the central nervous system and anterior pituitary gland. Pituitary gonadotropes are regulated by pulsatile release of gonadotropin releasing hormone (GnRH) from the hypothalamus, to control reproductive function. GnRH and CNP reciprocally regulate their respective signalling pathways in αT3-1 gonadotrope cells, but effects of pulsatile GnRH stimulation on CNP expression has not been explored. Here, we examine the sensitivity of the natriuretic peptide system in LβT2 and αT3-1 gonadotrope cell lines to continuous and pulsatile GnRH stimulation, and investigate putative CNP target genes in gonadotropes. Multiplex RT-qPCR assays confirmed that primary mouse pituitary tissue express Nppc,Npr2 (encoding CNP and guanylyl cyclase B (GC-B), respectively) and Furin (a CNP processing enzyme), but failed to express transcripts for Nppa or Nppb (encoding ANP and BNP, respectively). Pulsatile, but not continuous, GnRH stimulation of LβT2 cells caused significant increases in Nppc and Npr2 expression within 4 h, but failed to alter natriuretic peptide gene expression in αT3-1 cells. CNP enhanced expression of cJun, Egr1, Nr5a1 and Nr0b1, within 8 h in LβT2 cells, but inhibited Nr5a1 expression in αT3-1 cells. Collectively, these data show the gonadotrope natriuretic peptide system is sensitive to pulsatile GnRH signalling, and gonadotrope transcription factors are putative CNP-target genes. Such findings represent additional mechanisms by which CNP may regulate reproductive function.


Prognostic significance of urinary neopterin levels in patients with hepatocellular carcinoma.
Urinary neopterin levels were measured by high-performance liquid chromatography in 15 patients with liver cirrhosis, 18 patients with hepatocellular carcinoma and 20 normal subjects. The mean levels of urinary neopterin in patients with hepatocellular carcinoma were significantly elevated (p less than 0.01) compared to those in cirrhotics and normal subjects, but did not significantly differ between cirrhotics and normal subjects. Urinary neopterin levels correlated significantly with tumor size in patients with hepatocellular carcinoma but not with serum alpha-fetoprotein. Hepatocellular carcinoma patients with high urinary neopterin levels appeared to have more serious hepatic dysfunction than those with normal urinary neopterin levels, and moreover, there was a significant difference (p less than 0.05) in survival between the two groups. These findings suggest that urinary neopterin excretion may be a good biochemical marker to assess the progression of tumor and a useful prognostic indicator in patients with hepatocellular carcinoma.


Ising model for neural data: model quality and approximate methods for extracting functional connectivity.
We study pairwise Ising models for describing the statistics of multineuron spike trains, using data from a simulated cortical network. We explore efficient ways of finding the optimal couplings in these models and examine their statistical properties. To do this, we extract the optimal couplings for subsets of size up to 200 neurons, essentially exactly, using Boltzmann learning. We then study the quality of several approximate methods for finding the couplings by comparing their results with those found from Boltzmann learning. Two of these methods--inversion of the Thouless-Anderson-Palmer equations and an approximation proposed by Sessak and Monasson--are remarkably accurate. Using these approximations for larger subsets of neurons, we find that extracting couplings using data from a subset smaller than the full network tends systematically to overestimate their magnitude. This effect is described qualitatively by infinite-range spin-glass theory for the normal phase. We also show that a globally correlated input to the neurons in the network leads to a small increase in the average coupling. However, the pair-to-pair variation in the couplings is much larger than this and reflects intrinsic properties of the network. Finally, we study the quality of these models by comparing their entropies with that of the data. We find that they perform well for small subsets of the neurons in the network, but the fit quality starts to deteriorate as the subset size grows, signaling the need to include higher-order correlations to describe the statistics of large networks.


Risk factors for chronic kidney disease: a prospective study of 23,534 men and women in Washington County, Maryland.
Chronic kidney disease (CKD) is an increasing cause of morbidity and mortality in the United States. Prospective data on risk factors for CKD are limited to men, and few studies examine the importance of smoking. The authors performed a community-based, prospective observational study of 20-yr duration to examine the association between hypertension and smoking on the future risk of CKD in 23,534 men and women in Washington County, Maryland. CKD was identified as end-stage renal disease in the Health Care Financing Administration database or kidney disease listed on the death certificate. All cases were confirmed as CKD by medical chart review. Adjusted relative hazards of CKD were modeled using Cox proportional hazards regression including age as the time variable and baseline BP, cigarette smoking, gender, and diabetes status as risk factors. The adjusted hazard ratio (95% confidence interval) of developing CKD among women was 2.5 (0.05 to 12.0) for normal BP, 3.0 (0.6 to 14.4) for high-normal BP, 3.8 (0.8 to 17.2) for stage 1 hypertension, 6.3 (1.3 to 29.0) for stage 2 hypertension, and 8.8 (1.8 to 43.0) for stages 3 or 4 hypertension compared with individuals with optimal BP. In men, the relationship was similar but somewhat weaker than in women, with corresponding hazard ratios of 1.4 (0.2 to 12.1), 3.3 (0.4 to 25.6), 3.0 (0.4 to 22.2), 5.7 (0.8 to 43.0), and 9.7 (1.2 to 75.6), respectively. Current cigarette smoking was also significantly associated with risk of CKD in both men and women (hazard ratio in women 2.9 [1.7 to 5.0] and in men 2.4 [1.5 to 4.0]). A large proportion of the attributable risk of CKD in this population was associated with stage 1 hypertension (23%) and cigarette smoking (31%). In conclusion, CKD risk shows strong graded relationships to the sixth report of the Joint National Committee (JNC-VI) on Prevention, Detection Evaluation and Treatment of High BP criteria for BP, to diabetes, and to current cigarette smoking that are at least as strong in women as in men.


B-type natriuretic peptide and wall stress in dilated human heart.
Background Although B-type natriuretic peptide (BNP) is used as complimentary diagnostic tool in patients with unknown thoracic disorders, many other factors appear to trigger its release. In particular, it remains unresolved to what extent cellular stretch or wall stress of the whole heart contributes to enhanced serum BNP concentration. Wall stress cannot be determined directly, but has to be calculated from wall volume, cavity volume and intraventricular pressure of the heart. The hypothesis was, therefore, addressed that wall stress as determined by cardiac magnetic resonance imaging (CMR) is the major determinant of serum BNP in patients with a varying degree of left ventricular dilatation or dysfunction (LVD). Methods A thick-walled sphere model based on volumetric analysis of the LV using CMR was compared with an echocardiography-based approach to calculate LV wall stress in 39 patients with LVD and 21 controls. Serum BNP was used as in vivo marker of a putatively raised wall stress. Nomograms of isostress lines were established to assess the extent of load reduction that is necessary to restore normal wall stress and related biochemical events. Results Both enddiastolic and endsystolic LV wall stress were correlated with the enddiastolic LV volume (r = 0.54, P < 0.001; r = 0.81, P < 0.001). LV enddiastolic wall stress was related to pulmonary pressure (capillary: r = 0.69, P < 0.001; artery: r = 0.67, P < 0.001). Although LV growth was correlated with the enddiastolic and endsystolic volume (r = 0.73, P < 0.001; r = 0.70, P < 0.001), patients with LVD exhibited increased LV wall stress indicating an inadequately enhanced LV growth. Both enddiastolic (P < 0.05) and endsystolic (P < 0.01) wall stress were increased in patients with increased BNP. In turn, BNP concentration was elevated in individuals with increased enddiastolic wall stress (>8 kPa: 587 +/- 648 pg/ml, P < 0.05; >12 kPa: 715 +/- 661 pg/ml, P < 0.001; normal < or =4 kPa: 124 +/- 203 pg/ml). Analysis of variance revealed LV enddiastolic wall stress as the only independent hemodynamic parameter influencing BNP (P < 0.01). Using nomograms with "isostress" curves, the extent of load reduction required for restoring normal LV wall stress was assessed. Compared with the CMR-based volumetric analysis for wall stress calculation, the echocardiography based approach underestimated LV wall stress particularly of dilated hearts. Conclusions In patients with LVD, serum BNP was increased over the whole range of stress values which were the only hemodynamic predictors. Cellular stretch appears to be a major trigger for BNP release. Biochemical mechanisms need to be explored which appear to operate over this wide range of wall stress values. It is concluded that the diagnostic use of BNP should primarily be directed to assess ventricular wall stress rather than the extent of functional ventricular impairment in LVD.


An Integrative Approach to Neuroinflammation in Psychiatric disorders and Neuropathic Pain.
Neuroinflammation is a complex process involving both the peripheral circulation and the Central Nervous System (CNS) and is considered to underlie many CNS disorders including depression, anxiety, schizophrenia, and pain. Stressors including early-life adversity, psychosocial stress, and infection appear to prime microglia toward a pro-inflammatory phenotype. Subsequent inflammatory challenges then drive an exaggerated neuroinflammatory response involving the upregulation of pro-inflammatory mediators that is associated with CNS dysfunction. Several pharmacologic inhibitors of pro-inflammatory cytokines including TNF-α and IL-1β show good clinical efficacy in terms of ameliorating neuroinflammatory processes. Mind/body and plant-based interventions such as yoga, breathing exercises, meditation, and herbs/spices have also been demonstrated to reduce pro-inflammatory cytokines and have a positive impact on depression, anxiety, cognition, and pain. As the intricate connections between the immune system and the nervous system continue to be elucidated, successful therapies for reducing neuroinflammation will likely involve an integrated approach combining drug therapy with nonpharmacologic interventions.


Targeting Thioredoxin Reductase by Parthenolide Contributes to Inducing Apoptosis of HeLa Cells.
Parthenolide (PTL), a major active sesquiterpene lactone from the herbal plant Tanacetum parthenium, has been applied in traditional Chinese medicine for centuries. Although PTL demonstrates potent anticancer efficacy in numerous types of malignant cells, the cellular targets of PTL have not been well defined. We reported here that PTL interacts with both cytosolic thioredoxin reductase (TrxR1) and mitochondrial thioredoxin reductase (TrxR2), two ubiquitous selenocysteine-containing antioxidant enzymes, to elicit reactive oxygen species-mediated apoptosis in HeLa cells. PTL selectively targets the selenocysteine residue in TrxR1 to inhibit the enzyme function, and further shifts the enzyme to an NADPH oxidase to generate superoxide anions, leading to reactive oxygen species accumulation and oxidized thioredoxin. Under the conditions of inhibition of TrxRs in cells, PTL does not cause significant alteration of cellular thiol homeostasis, supporting selective target of TrxRs by PTL. Importantly, overexpression of functional TrxR1 or Trx1 confers protection, whereas knockdown of the enzymes sensitizes cells to PTL treatment. Targeting TrxRs by PTL thus discloses an unprecedented mechanism underlying the biological activity of PTL, and provides deep insights to understand the action of PTL in treatment of cancer.


The utility of positron emission tomography in staging of potentially operable carcinoma of the thoracic esophagus: results of the American College of Surgeons Oncology Group Z0060 trial.
The American College of Surgeons Oncology Group trial Z0060 is a prospective multi-institutional trial with a primary objective to evaluate whether positron emission tomography (PET) with F-18 fluorodeoxyglucose (FDG) detects evidence of metastastic disease that precludes esophagectomy in patients with esophageal cancer who are surgical candidates after routine staging. Patients with resectable, biopsy-proven carcinoma were enrolled after computed tomography of chest and abdomen demonstrated no evidence of metastasis. FDG-PET was performed according to specified standards. FDG-PET findings suggesting metastases required confirmation and patients without metastases on PET were expected to proceed to surgery. A total of 262 patients were registered. Of these, 199 were deemed eligible and of these, 189 patients were evaluable. Seventy-three patients were ineligible or unevaluable. Reasons for ineligibility included nonresectable disease by routine staging (39), missing or outdated staging procedures (12), PET technical protocol violations (10), no cancer (4), pre-PET induction therapy (3), claustrophobia (1), and other causes (4). There were 145 (78%) patients who went on to have surgery, 42 (22%) who did not, and 2 patients for whom the surgical status was not determined. The reasons for no resection included the following: M1 disease found by PET and confirmed (9), M1 disease found by PET and not confirmed (2), M1 disease at exploration not found by PET (7), decline or death before surgery (10), patient refusal of surgery (7), unresectable local tumor at exploration (5), and extensive N1 disease precluding operation (2). Eight (4.2%) patients undergoing resection had a recurrence in the first 6 months. Although 22% of eligible patients did not undergo esophagectomy, FDG-PET after standard clinical staging for esophageal carcinoma identified confirmed M1b disease in at least 4.8% (95% confidence interval: 2.2%-8.9%) of patients before resection. Unconfirmed PET evidence of M1 disease and regional adenopathy (N1 disease) led to definitive nonsurgical or induction therapy in additional patients.


[Physico-chemical properties of DNA from representatives of a population of Pseudomonas bacteriophages].
Twenty-four bacteriophages of Pseudomonas similar in terms of their morphology and structure were studied. The genomes of 23 bacteriophages from a population widespread in Belorussia and of one bacteriophage from the Krasnodar Region were shown to be double-helical DNAs with the content of GC base pairs from 46.8 to 66.7%. Four endonucleases (Eco R1, Hind III, Bam H1, and Eco RV) were used in the restriction analysis. Phage 8 which differed from the other phages in the area of its distribution was found to represent an individual group. The other phages were subdivided into eight related groups and had an identical restriction map within each group. The mean molecular masses of phage DNAs calculated by the method of summing the molecular masses of restricts ranged from 27.8 to 31.0 MDa.


Interfering with a memory without erasing its trace.
Previous research has shown that performance of a novice skill can be easily interfered with by subsequent training of another skill. We address the open questions whether extensively trained skills show the same vulnerability to interference as novice skills and which memory mechanism regulates interference between expert skills. We developed a recurrent neural network model of V1 able to learn from feedback experienced over the course of a long-term orientation discrimination experiment. After first exposing the model to one discrimination task for 3480 consecutive trials, we assessed how its performance was affected by subsequent training in a second, similar task. Training the second task strongly interfered with the first (highly trained) discrimination skill. The magnitude of interference depended on the relative amounts of training devoted to the different tasks. We used these and other model outcomes as predictions for a perceptual learning experiment in which human participants underwent the same training protocol as our model. Specifically, over the course of three months participants underwent baseline training in one orientation discrimination task for 15 sessions before being trained for 15 sessions on a similar task and finally undergoing another 15 sessions of training on the first task (to assess interference). Across all conditions, the pattern of interference observed empirically closely matched model predictions. According to our model, behavioral interference can be explained by antagonistic changes in neuronal tuning induced by the two tasks. Remarkably, this did not stem from erasing connections due to earlier learning but rather from a reweighting of lateral inhibition.


Behavioral economic decision making and alcohol-related sexual risk behavior.
The discipline of behavioral economics integrates principles from psychology and economics to systematically characterize decision-making preferences. Two forms of behavioral economic decision making are of relevance to HIV risk behavior: delay discounting, reflecting preferences for immediate small rewards relative to larger delayed rewards (i.e., immediate gratification), and probability discounting, reflecting preferences for larger probabilistic rewards relative to smaller guaranteed rewards (i.e., risk sensitivity). This study examined questionnaire-based indices of both types of discounting in relation to sexual risk taking in an emergency department sample of hazardous drinkers who engage in risky sexual behavior. More impulsive delay discounting was significantly associated with increased sexual risk-taking during a drinking episode, but not general sexual risk-taking. Probability discounting was not associated with either form of sexual risk-taking. These findings implicate impulsive delay discounting with sexual risk taking during alcohol intoxication and provide further support for applying this approach to HIV risk behavior.


Digitise this! A quick and easy remote sensing method to monitor the daily extent of dredge plumes.
Technological advancements in remote sensing and GIS have improved natural resource managers' abilities to monitor large-scale disturbances. In a time where many processes are heading towards automation, this study has regressed to simple techniques to bridge a gap found in the advancement of technology. The near-daily monitoring of dredge plume extent is common practice using Moderate Resolution Imaging Spectroradiometer (MODIS) imagery and associated algorithms to predict the total suspended solids (TSS) concentration in the surface waters originating from floods and dredge plumes. Unfortunately, these methods cannot determine the difference between dredge plume and benthic features in shallow, clear water. This case study at Barrow Island, Western Australia, uses hand digitising to demonstrate the ability of human interpretation to determine this difference with a level of confidence and compares the method to contemporary TSS methods. Hand digitising was quick, cheap and required very little training of staff to complete. Results of ANOSIM R statistics show remote sensing derived TSS provided similar spatial results if they were thresholded to at least 3 mg L(-1). However, remote sensing derived TSS consistently provided false-positive readings of shallow benthic features as Plume with a threshold up to TSS of 6 mg L(-1), and began providing false-negatives (excluding actual plume) at a threshold as low as 4 mg L(-1). Semi-automated processes that estimate plume concentration and distinguish between plumes and shallow benthic features without the arbitrary nature of human interpretation would be preferred as a plume monitoring method. However, at this stage, the hand digitising method is very useful and is more accurate at determining plume boundaries over shallow benthic features and is accessible to all levels of management with basic training.


Assessment of four enzyme immunoassay kits for serum beta-hCG screening.
This pilot study evaluates four qualitative serum beta-human chorionic gonadotropin (beta-hCG) enzyme immunoassay kits for both routine pregnancy testing and screening for ectopic pregnancy. We found that the Tandem-E HCG assay had the lowest limit of detection, and longest turnaround time. Tandem ICON HCG assay had the shortest turnaround time. The Vis-Con II was the most economical batch test. The Quest assay kit was both fast and simple and had the lowest cost for stat testing.


A case of aspergillosis outbreak in a broiler duck farm in Kelantan, Malaysia.
This case report aims to discuss the veterinary approach taken to control a case of aspergillosis outbreak on a duck farm. A broiler duck farm with a population of 900 Muscovy ducks was having a complaint of a 5% mortality rate in their 3-week-old ducklings. Upon presentation, 10% of the ducks appeared to be listless, dyspneic, ruffled feathers, and cyanotic. Postmortem examination of the dead birds was conducted. The collected samples were subjected to isolation and identification of the associated Aspergillus fumigatus under the microscope using the scotch tape method. Postmortem examination revealed whitish to creamy caseous nodules in the lungs, thoracic air sacs, gizzard, proventriculus, and intestines. Granuloma lesions and infiltration of inflammatory cells were observed in the lung and liver tissues. As for therapeutic management, all ducks were treated with copper sulfate, erythromycin, and multivitamins as the fungicide, antibiotic, and supplement, respectively, via drinking water. There is no effective treatment for Aspergillosis as the spores are difficult to destroy completely. Nonetheless, the disease can be controlled and prevented effectively with proper farm sanitation and providing a suitable feed storage environment to inhibit the growth of this opportunistic fungus.


Breast Self-Examination Practice and Associated Factors Among Secondary School Female Teachers in Gammo Gofa Zone, Southern, Ethiopia.
Nowadays, breast self-examination (BSE) is a breast cancer screening method that identifies breast mass by the woman herself. However, it is not widely practiced due to various problems. This study aimed to assess the magnitude of BSE practice and associated factors among female secondary school teachers in Gammo Gofa Zone, South Ethiopia. An institution-based cross-sectional study was conducted among 247 female secondary school teachers, from March 1 to 30, 2018. Participants were selected using the lottery method. A self-administered questionnaire was used for data collection. Data were cleaned, coded, and entered into Epi data manager 4.4 and analyzed using SPSS version 21. Binary logistic regression was employed. Of 82 respondents, 34.3% had ever performed BSE. Among these, only 32 (13.4%) had practiced BSE monthly (regularly). Being knowledgeable on BSE [AOR=2.84, 95% CI (1.41, 5.72)], ever heard about BSE [AOR=2.26, 95% CI (1.07, 4.77)], being married [AOR=4.09, 95% CI (1.64, 10.22)], having less perceived barrier to BSE [AOR=2.62, 95% CI (1.26, 5.46)], having high perceived confidence [AOR=3.63, 95% CI (1.79, 7.39)] and motivation to BSE [AOR=3.29, 95% CI (1.15, 9.45)] were significant predictors of BSE practice. In this study, one in three women had ever practiced BSE, whereas about one in seven women regularly practiced BSE. The main reasons for not practicing BSE were: not knowing how to perform BSE and forgetfulness (for regular practice). Therefore, integrated work on behavioral change communication and interferences that focus on improving knowledge of BSE, and skills on how to perform BSE is needed. Additionally, the identified domains of the health belief model (perceived barrier, perceived confidence, and perceived motivation) may be the most effective strategies that should be considered by Gammo Gofa Zonal health and educational offices.


Prolonged fasting in humans results in diminished plasma choline concentrations but does not cause liver dysfunction.
Choline is a major donor of methyl groups, a precursor for membrane synthesis, and a component of the neurotransmitter acetylcholine. Choline-deficient diets deplete humans of choline and cause hepatic dysfunction and steatosis. In this study we determined whether acute starvation also depletes choline, as indicated by changes in plasma choline or phosphatidylcholine. Healthy humans (n = 10) fasted for 7 d, ingesting only water and mineral-vitamin supplements. Their mean (+/- SEM) plasma choline concentration was 9.5 +/- 0.5 micromol/L at the start of the study and dropped to 7.8 +/- 0.3 micromol/L after 1 wk of fasting (P < 0.01). The plasma phosphatidylcholine concentration did not change significantly (2.2 +/- 0.1 mmol/L at the start of the study and 2.4 +/- 0.2 mmol/L after 1 wk of fasting). Capacity of the liver to secrete lipoproteins was not affected by prolonged fasting. The mean plasma concentration of low-density-lipoprotein cholesterol was 3.3 +/- 0.2 mmol/L (126 +/- 8 mg/dL) at the start of the study and 4.9 +/- 0.5 mmol/L (188 +/- 19 mg/dL) after 1 wk of fasting. Liver damage assessed by serum alanine aminotransferase activity occurred in only 1 of 10 subjects. We conclude that prolonged fasting in humans modestly diminished plasma choline but was not associated with signs of choline deficiency, such as perturbed lipoprotein secretion and liver damage.


IP-10 contributes to the inhibition of mycobacterial growth in an ex vivo whole blood assay.
Interferon-γ inducible protein 10 (IP-10), is a potent chemoattractant that promotes migration of monocytes and activated T-cells to inflammation foci. IP-10 is elevated in serum of patients with chronic hepatitis C virus (HCV) and tuberculosis (TB) infections, although it remains to be determined the contribution of IP-10 in restricting Mycobacterium tuberculosis (Mtb) replication. Here, we investigated the impact of IP-10 on mycobacteria replication using the ex vivo model of human whole-blood (WB) assay. In particular, we compared the levels of IP-10 upon infection with different Mtb clinical strains and species of non-tuberculous mycobacteria (NTM) and evaluated how IP-10 may contain bacterial replication. Interestingly, we observed that the inhibition of the host enzyme dipeptidyl peptidase IV (DPP-IV), which inactivates IP-10 through cleavage of two amino acids at the chemokine N-terminus, restricted mycobacterial persistence in WB, supporting the critical role of full length IP-10 in mediating an anti-Mtb response. Addition of recombinant IP-10 expressed in eukaryotic cells enhanced the anti-mycobacterial activity in WB, although no differences were observed when IP-10 containing different proportions of cleaved and non-cleaved forms of the chemokine were added. Moreover, recombinant IP-10 did not exert a direct anti-mycobacterial effect. Our results underscore the clinical relevance of IP-10 in mycobacteria pathogenesis and support the potential outcomes that may derive by targeting the IP-10/CXCR3 pathway as host directed therapies for the treatment of Mtb or NTM infections.


Abnormal retinal projections alter GAP-43 patterns in the diencephalon.
In Syrian hamsters, mature retinal terminals contain only low levels of the growth-associated protein, GAP-43, whereas the lateral posterior nucleus (LP) of the thalamus contains high levels of this protein. Damage to the superior colliculus in neonatal hamsters induces retinal terminals to form dense patches of innervation in the LP, an area which otherwise receives little if any direct retinal input. The present study used GAP-43 antibodies to examine the interaction between abnormally routed optic fibers and the cells in the anomalous thalamic target zone. Immunohistochemistry revealed very little GAP-43 in the abnormal retinal projection to the LP, indicating that the normal developmental decline in GAP-43 levels occurs even in an inappropriate extracellular environment. Moreover, retinal fibers were found to exclude the protein from its normal territory, forming negatively-stained islands in those regions of the LP containing the retinal terminals. In order to identify the normal source of GAP-43-positive terminals in the LP, we surgically removed two major extrinsic afferents to this region, or we chemically eliminated local interneurons. Whereas removing projections from the SC or posterior cortex did not alter GAP-43 immunoreactivity in the LP, destruction of local interneurons with ibotenic acid resulted in markedly diminished levels of this protein. These results show that retinal terminals induced to form in an abnormal target area undergo their normal diminution of GAP-43, and that these retinal projections displace other GAP-43-rich terminals in the LP that appear to arise from local interneurons.


Amylases StAmy23, StBAM1 and StBAM9 regulate cold-induced sweetening of potato tubers in distinct ways.
Cold-induced sweetening (CIS) in potato is detrimental to the quality of processed products. Conversion of starch to reducing sugars (RS) by amylases is considered one of the main pathways in CIS but is not well studied. The amylase genes StAmy23, StBAM1, and StBAM9 were studied for their functions in potato CIS. StAmy23 is localized in the cytoplasm, whereas StBAM1 and StBAM9 are targeted to the plastid stroma and starch granules, respectively. Genetic transformation of these amylases in potatoes by RNA interference showed that β-amylase activity could be decreased in cold-stored tubers by silencing of StBAM1 and collective silencing of StBAM1 and StBAM9. However, StBAM9 silencing did not decrease β-amylase activity. Silencing StBAM1 and StBAM9 caused starch accumulation and lower RS, which was more evident in simultaneously silenced lines, suggesting functional redundancy. Soluble starch content increased in RNAi-StBAM1 lines but decreased in RNAi-StBAM9 lines, suggesting that StBAM1 may regulate CIS by hydrolysing soluble starch and StBAM9 by directly acting on starch granules. Moreover, StBAM9 interacted with StBAM1 on the starch granules. StAmy23 silencing resulted in higher phytoglycogen and lower RS accumulation in cold-stored tubers, implying that StAmy23 regulates CIS by degrading cytosolic phytoglycogen. Our findings suggest that StAmy23, StBAM1, and StBAM9 function in potato CIS with varying levels of impact.


[Contractile function and antioxidative system of the myocardium of the intact rabbit during hyperbaric oxygenation].
Daily exposures of rabbits to the HBO (2 ata, 1 hr) enhanced activity of glutathione-peroxidase for all 28 days of exposure. Other parameters of the antioxidative defence and the contractile function remained unchanged. The 2.5-ata oxygenation sharply reduced the activity of antioxidative enzymes, the antioxidative activity of lipids, and the tissue resistance against the induced peroxide oxidation of lipids. The heart contractile function was obviously worsened. Sites of necrosis appeared in the myocardium tissue. Increase in oxygenation seems to lead to changes of adaptation of the antioxidative system, but the exhaustion of the latter's power reserves potentiates the toxic effect of hyperoxia.


Episodic-like memory is preserved with age in cuttlefish.
Episodic memory, remembering past experiences based on unique what-where-when components, declines during ageing in humans, as does episodic-like memory in non-human mammals. By contrast, semantic memory, remembering learnt knowledge without recalling unique what-where-when features, remains relatively intact with advancing age. The age-related decline in episodic memory likely stems from the deteriorating function of the hippocampus in the brain. Whether episodic memory can deteriorate with age in species that lack a hippocampus is unknown. Cuttlefish are molluscs that lack a hippocampus. We test both semantic-like and episodic-like memory in sub-adults and aged-adults nearing senescence (n = 6 per cohort). In the semantic-like memory task, cuttlefish had to learn that the location of a food resource was dependent on the time of day. Performance, measured as proportion of correct trials, was comparable across age groups. In the episodic-like memory task, cuttlefish had to solve a foraging task by retrieving what-where-when information about a past event with unique spatio-temporal features. In this task, performance was comparable across age groups; however, aged-adults reached the success criterion (8/10 correct choices in consecutive trials) significantly faster than sub-adults. Contrary to other animals, episodic-like memory is preserved in aged cuttlefish, suggesting that memory deterioration is delayed in this species.


SVA retrotransposons as modulators of gene expression.
Endogenous mobile genetic elements can give rise to de novo germline or somatic mutations that can have dramatic consequences for genome regulation both local and possibly more globally based on the site of integration. However if we consider them as "normal genetic" components of the reference genome then they are likely to modify local chromatin structure which would have an effect on gene regulation irrelevant of their ability to further transpose. As such they can be treated as any other domain involved in a gene × environment interaction. Similarly their evolutionary appearance in the reference genome would supply a driver for species specific responses/traits. Our recent data would suggest the hominid specific subset of retrotransposons, SINE-VNTR-Alu (SVA), can function as transcriptional regulatory domains both in vivo and in vitro when analyzed in reporter gene constructs. Of particular interest in the SVA element, were the variable number tandem repeat (VNTR) domains which as their name suggests can be polymorphic. We and others have previously shown that VNTRs can be both differential regulators and biomarkers of disease based on the genotype of the repeat. Here, we provide an overview of why polymorphism in the SVA elements, in particular the VNTRs, could alter gene expression patterns that could be mechanistically associated with different traits in evolution or disease progression in humans.


Biochemical characterization of the mouse muscle-specific enolase: developmental changes in electrophoretic variants and selective binding to other proteins.
The glycolytic enzyme enolase (EC 18.104.22.168) is active as dimers formed from three subunits encoded by different genes. The embryonic alphaalpha isoform remains distributed in many adult cell types, whereas a transition towards betabeta and gammagamma isoforms occurs in striated muscle cells and neurons respectively. It is not understood why enolase exhibits tissue-specific isoforms with very close functional properties. We approached this problem by the purification of native betabeta-enolase from mouse hindlimb muscles and by raising specific antibodies of high titre against this protein. These reagents have been useful in revealing a heterogeneity of the beta-enolase subunit that changes with in vivo and in vitro maturation. A basic carboxypeptidase appears to be involved in generating an acidic beta-enolase variant, and may regulate plasminogen binding by this subunit. We show for the first time that pure betabeta-enolase binds with high affinity the adjacent enzymes in the glycolytic pathway (pyruvate kinase and phosphoglycerate mutase), favouring the hypothesis that these three enzymes form a functional glycolytic segment. betabeta-Enolase binds with high affinity sarcomeric troponin but not actin and tropomyosin. Some of these binding properties are shared by the alphaalpha-isoenolase, which is also expressed in striated muscle, but not by the neuron-specific gammagamma-enolase. These results support the idea that specific interactions with macromolecules will address muscle enolase isoforms at the subcellular site where ATP, produced through glycolysis, is most needed for contraction. Such a specific targeting could be modulated by post-translational modifications.


Preferential Mixture-of-Experts: Interpretable Models that Rely on Human Expertise As Much As Possible.
We propose Preferential MoE, a novel human-ML mixture-of-experts model that augments human expertise in decision making with a data-based classifier only when necessary for predictive performance. Our model exhibits an interpretable gating function that provides information on when human rules should be followed or avoided. The gating function is maximized for using human-based rules, and classification errors are minimized. We propose solving a coupled multi-objective problem with convex subproblems. We develop approximate algorithms and study their performance and convergence. Finally, we demonstrate the utility of Preferential MoE on two clinical applications for the treatment of Human Immunodeficiency Virus (HIV) and management of Major Depressive Disorder (MDD).


Group II metabotropic glutamate receptors regulate the vulnerability to hypoxic brain damage.
We examined the expression of metabotropic glutamate (mGlu) receptors in species of fish that differ for their vulnerability to anoxic brain damage. Although expression of mGlu1a and mGlu5 receptors was similar in the brain of all species examined, expression of mGlu2/3 receptors was substantially higher in the brain of anoxia-tolerant species (i.e., the carp Carassius carassius and the goldfish Carassius auratus) than in the brain of species that are highly vulnerable to anoxic damage, such as the trouts Salmo trutta and Oncorhynchus mykiss. This difference was confirmed by measuring the mGlu2/3 receptor-mediated inhibition of forskolin-stimulated cAMP formation in slices prepared from the telencephalon of C. auratus and S. trutta. We exposed the goldfish C. auratus to water deprived of oxygen for 4 hr for the induction of hypoxic brain damage. Although the goldfish survived this treatment, the occurrence of apoptotic cell death could be demonstrated by terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling staining and by the assessment of caspase-3 activity in different brain region. The extent of cell death was highest in the medulla oblongata, followed by the optic tectum, cerebellum, and hypothalamus. No cell death was found in the telencephalon. This regional pattern of hypoxic damage was inversely related to the expression of mGlu2/3 receptors, which was lowest in the medulla oblongata and highest in the telencephalon. Treatment of the goldfish with the brain permeant mGlu2/3 receptor antagonist LY341495 (1 mg/kg, i.p.) amplified anoxic damage throughout the brain and enabled the induction of cell death by anoxia in the telencephalon. In contrast, treatment of the goldfish with the mGlu2/3 receptor agonist LY379268 (0.5 or 1 mg/kg, i.p.) was highly protective against anoxic brain damage. Finally, exposure to the antagonist LY341495 (0.5 microm) greatly amplified the release of glutamate induced by hypoxia in slices prepared from the medulla oblongata and the telencephalon of the goldfish. We conclude that expression of mGlu2/3 receptors provides a major defensive mechanism against brain damage in anoxia-tolerant species.


Osteoporosis screening using computed tomography for men with prostate cancer: results of a prospective study.
We performed a prospective study using both FRAX and computed tomography to screen for osteoporosis in men undergoing radiation for prostate cancer. We found that implementing routine computed tomography (CT)-based screening was feasible in the setting of a prospective study, but the yield of osteoporosis identification was low in this population. Men with prostate cancer (PCa) are at increased risk of hip fracture for multiple reasons. Estimation of hip fracture risk with the FRAX tool is currently recommended, but FRAX alone may not identify a portion of men with osteoporosis. We hypothesized that adding bone mineral density (BMD) screening using CT to FRAX is feasible and would identify more men with osteoporosis. Men with PCa scheduled to undergo CT simulation for radiation treatment were enrolled in a single-arm prospective study. The mean attenuation of the mid-L5 vertebral body trabecular bone (L5CT) was calculated on a single slice using the radiation simulation CT scan. The 10-year risk of hip fracture was calculated using the FRAX tool. Dual energy X-ray absorptiometry (DXA) was performed for men whose L5CT measurement was less than 130 Hounsfield units (HU). A total of 98 eligible men were enrolled and underwent FRAX and CT screening. The median 10-year risk of hip fracture was 1.1% and exceeded 3% in 16 cases; the median L5CT was 162.28 HU (range 55.6-526.1 HU). DXA scan was completed in 15 men who had L5CT < 130 HU but 10-year calculated hip fracture risk < 3%, 1 of whom was found to have osteoporosis (T-score ≤ -2.5). Implementing CT-based BMD screening was feasible in the setting of a prospective study for men receiving radiation for PCa, but fewer cases than anticipated of osteoporosis were identified.


Acceleration of K+ channel inactivation by MEK inhibitor U0126.
Voltage-dependent (Kv)4.2-encoded A-type K+ channels play an important role in controlling neuronal excitability and are subject to modulation by various protein kinases, including ERK. In studies of ERK modulation, the organic compound U0126 is often used to suppress the activity of MEK, which is a kinase immediately upstream from ERK. We have observed that the inactivation time constant of heterologously expressed Kv4.2 channels was accelerated by U0126 at 1-20 microM. This effect, however, was not Kv4 family specific, because U0126 also converted noninactivating K+ currents mediated by Kv1.1 subunits into transient ones. To determine whether U0126 exerted these effects through kinase inhibition, we tested U0125, a derivative of U0126 that is less potent in MEK inhibition. At the same concentrations, U0125 had effects similar to those of U0126 on channel inactivation. Finally, we expressed a mutant form of Kv4.2 in which three identified ERK phosphorylation sites (T602, T607, and S616) were replaced with alanines. The inactivation of K+ currents mediated by this mutant was still accelerated by U0126. Our data favor the conclusion that the increase in the rate of channel inactivation by U0126 is likely to be independent of protein kinase inhibition and instead represents a direct action on channel gating.


Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation.
Cannabidiol (CBD), a nonpsychoactive marijuana constituent, was recently shown as an oral antihyperalgesic compound in a rat model of acute inflammation. We examined whether the CBD antihyperalgesic effect could be mediated by cannabinoid receptor type 1 (CB1) or cannabinoid receptor type 2 (CB2) and/or by transient receptor potential vanilloid type 1 (TRPV1). Rats received CBD (10 mg kg(-1)) and the selective antagonists: SR141716 (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) for CB1, SR144528 (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide) for CB2 and capsazepine (CPZ) for TRPV1 receptors. The intraplantar injection of carrageenan in rats induced a time-dependent thermal hyperalgesia, which peaked at 3 h and decreased at the following times. CBD, administered 2 h after carrageenan, abolished the hyperalgesia to the thermal stimulus evaluated by plantar test. Neither SR141716 (0.5 mg kg(-1)) nor SR144528 (3 and 10 mg kg(-1)) modified the CBD-induced antihyperalgesia; CPZ partially at the lowest dose (2 mg kg(-1)) and fully at the highest dose (10 mg kg(-1)) reversed this effect. These results demonstrate that TRPV1 receptor could be a molecular target of the CBD antihyperalgesic action.


Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin.
The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.


Fetal megacystis: prediction of spontaneous resolution and outcome.
To investigate the natural history of fetal megacystis from diagnosis in utero to postnatal outcome, and to identify prognostic indicators of spontaneous resolution and postnatal outcome after resolution. This was a national retrospective cohort study. Fetal megacystis was defined in the first trimester as a longitudinal bladder diameter (LBD) ≥ 7 mm, and in the second and third trimesters as an enlarged bladder failing to empty during the entire extended ultrasound examination. LBD and gestational age (GA) at resolution were investigated with respect to likelihood of resolution and postnatal outcome, respectively. Sensitivity, specificity and area under the receiver-operating characteristics curve (AUC) were calculated. In total, 284 cases of fetal megacystis (93 early megacystis, identified before the 18th week, and 191 late megacystis, identified at or after the 18th week) were available for analysis. Spontaneous resolution occurred before birth in 58 (20%) cases. In cases with early megacystis, LBD was predictive of the likelihood of spontaneous resolution (sensitivity, 80%; specificity, 79%; AUC, 0.84), and, in the whole population, GA at regression was predictive of postnatal outcome, with an optimal cut-off at 23 weeks (sensitivity, 100%; specificity, 82%; AUC, 0.91). In the group with early megacystis, the outcome was invariably good when resolution occurred before the 23rd week of gestation, whereas urological sequelae requiring postnatal surgery were diagnosed in 3/8 (38%) cases with resolution after 23 weeks. In the group with late megacystis, spontaneous resolution was associated with urological complications after birth, ranging from mild postnatal hydronephrosis in infants with resolution before 23 weeks, to more severe urological anomalies requiring postnatal surgery in those with resolution later in pregnancy. This supports the hypothesis that an early resolution of megacystis is often related to a paraphysiological bladder enlargement that resolves early in pregnancy without consequences, while antenatal resolution occurring later in pregnancy (after the 23rd week of gestation) should suggest a pathological condition with urological sequelae. In fetal megacystis, LBD and GA at regression can be used as predictors of resolution and outcome, respectively. These parameters could help in fine-tuning the prognosis and optimizing the frequency of follow-up scans. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.


Development of Nanocrystal Ziprasidone Orally Disintegrating Tablets: Optimization by Using Design of Experiment and In Vitro Evaluation.
The objective of the current study was to develop ziprasidone hydrochloride monohydrate (ZHM) nanocrystal-based orally dispersible tablet (ODT) formulations. Design of experiment approach was used to develop ODTs. The tablets were compressed using direct compression method and characterized with quality control tests. In vitro dissolution studies and Caco-2 cell permeability tests were executed. The hardness and friability values of nanocrystal-based ODTs were found 31.2 N and 1.05%, respectively. The disintegration time was below 10 s. Dissolution profile in pH 7.4 phosphate buffer showed that nanocrystal-based ODTs and commercial product were dissolved in 120 min 58.98% and 16%, respectively. In pH 7.4 phosphate buffer with SLS, sample groups dissolved above 85% at the end of the study. Permeability value and cumulative ZHM amount on the cells were improved with nanocrystals. In conclusion, the novel formulation of ZHM nanocrystal-based ODTs was successfully developed for alternative dosage form.


Carboxypeptidase M is a positive allosteric modulator of the kinin B1 receptor.
Ligand binding to extracellular domains of G protein-coupled receptors can result in novel and nuanced allosteric effects on receptor signaling. We previously showed that the protein-protein interaction of carboxypeptidase M (CPM) and kinin B1 receptor (B1R) enhances B1R signaling in two ways; 1) kinin binding to CPM causes a conformational activation of the B1R, and 2) CPM-generated des-Arg-kinin agonist is efficiently delivered to the B1R. Here, we show CPM is also a positive allosteric modulator of B1R signaling to its agonist, des-Arg(10)-kallidin (DAKD). In HEK cells stably transfected with B1R, co-expression of CPM enhanced DAKD-stimulated increases in intracellular Ca(2+) or phosphoinositide turnover by a leftward shift of the dose-response curve without changing the maximum. CPM increased B1R affinity for DAKD by ∼5-fold but had no effect on basal B1R-dependent phosphoinositide turnover. Soluble, recombinant CPM bound to HEK cells expressing B1Rs without stimulating receptor signaling. CPM positive allosteric action was independent of enzyme activity but depended on interaction of its C-terminal domain with the B1R extracellular loop 2. Disruption of the CPM/B1R interaction or knockdown of CPM in cytokine-treated primary human endothelial cells inhibited the allosteric enhancement of CPM on B1R DAKD binding or ERK1/2 activation. CPM also enhanced the DAKD-induced B1R conformational change as detected by increased intramolecular fluorescence or bioluminescence resonance energy transfer. Thus, CPM binding to extracellular loop 2 of the B1R results in positive allosteric modulation of B1R signaling, and disruption of this interaction could provide a novel therapeutic approach to reduce pathological B1R signaling.


Airway tissue mast cells in persistent asthma: predictor of treatment failure when patients discontinue inhaled corticosteroids.
To determine if persistent airway tissue mast cells are associated with treatment failure when patients discontinue inhaled corticosteroids (ICS). Double-blind, randomized, placebo-controlled trial. Multicenter, tertiary referral centers. Forty-five subjects with asthma recruited from six medical centers in the United States. The Asthma Clinical Research Network undertook a 28-week, randomized, multicenter, double-blind, placebo-controlled trial of 164 subjects with clinically stable, persistent asthma. A subset of subjects (n = 45) underwent bronchoscopy with endobronchial biopsy and BAL at the end of a 6-week run-in period, during which all subjects received triamcinolone acetonide (TAA), 400 microg bid. Airway tissue mast cells, eosinophils, neutrophils, macrophages, and T cells were quantified morphometrically along with determination of BAL tryptase. At the end of the run-in period, subjects were then randomized to receive salmeterol (42 micro g bid), placebo, or continue TAA for 16 weeks followed by a second bronchoscopy. Outcome variables included airway tissue mast cells, eosinophils, neutrophils, macrophages, and T cells that were quantified morphometrically and BAL tryptase. Thirty-five subjects completed the treatment phase; an additional 10 subjects, who were randomized to either salmeterol or placebo after the run-in, had treatment failure. When the bronchoscopy results performed at the end of the run-in, prior to randomization, were analyzed, the treatment failure group demonstrated significantly more tissue mast cells as compared to the nontreatment failure group despite 6 weeks of therapy with TAA (p = 0.04). BAL tryptase was also significantly higher in the treatment failure group (p < 0.0001). Of those subjects who completed the study, tissue mast cells and BAL tryptase did not change significantly within any of the treatment groups during the treatment phase (p > 0.05). Persistent elevations in airway tissue mast cells and BAL tryptase after treatment with TAA predict treatment failure in patients for whom discontinuation of ICS is being considered.


Increasing glucagon secretion could antagonize the action of exogenous insulin for glycemic control in streptozocin-induced diabetic rhesus monkeys.
Although intraislet insulin signaling is known to play a critical role in regulating glucagon secretion, it is unknown whether abnormal glucagon secretion influences the hypoglycemic effect of exogenous insulin with intraislet insulin deletion. We performed a longitudinal study using 16 streptozocin (STZ)-induced diabetic rhesus monkeys to explore α-cell function under the absence β-cells and to assess whether increasing glucagon secretion antagonizes the action of exogenous insulin for glycemic control. We found that although the α-cells were impaired and the basal secretion levels of glucagon decreased rapidly after STZ (80-90 mg/kg) administration, as based on long-term observation post-STZ injection, glucagon secretion and the number of α-cells were increased. Glycemic control was increasingly difficult, the insulin resistance (HOMA-IR) index was significantly higher, and the triglycerides (TG) levels were gradually decreased. Moreover, a significant correlation between the levels of glucagon and HOMA-IR was found. Under the long-term absence of β-cells, the inhibitory effect on α-cell activity is profoundly attenuated, leading to an increase in glucagon secretion and the amount of α-cells and even α-cell dysfunction. Increased glucagon levels have a serious impact on the insulin sensitivity in vivo and result in an antagonization of the hypoglycemic effect of exogenous insulin.


Masticatory lubrication. The role of carbohydrate in the lubricating property of a salivary glycoprotein-albumin complex.
We report for the first time a masticatory-lubrication assay system to assess the lubricating properties of salivary constituents. The lubricating ability of the proline-rich glycoprotein (PRG) of parotid saliva was enhanced by human serum albumin. The interactive effect of albumin was abolished by chemically deglycosylating the glycoprotein. Fluorescence spectroscopy with a hydrophobic probe verified the existence of a PRG-albumin complex and demonstrated that deglycosylation of the PRG altered the nature of its interaction with albumin.


Corticosteroid therapy in regressive autism: Preliminary findings from a retrospective study.
Some children with autism spectrum disorders (ASD; 15% to 30% of patients) show a significant and persistent regression in speech and social function during early childhood. There are no established treatments for the regressive symptoms. However, there are some known causes of this type of regression, such as Rett syndrome and Landau-Kleffner syndrome (LKS). In LKS, steroids have been used as a treatment. Some evidence suggests an autoimmune contribution to the pathophysiology of autism (Chez MG, Guido-Estrada N: Immune therapy in autism: historical experience and future directions with immunomodulatory therapy. Neurotherapeutics 2010, 7:293-301, Wasilewska J, Kaczmarski M, Stasiak-Barmuta A, Tobolczyk J, Kowalewska E: Low serum IgA and increased expression of CD23 on B lymphocytes in peripheral blood in children with regressive autism aged 3-6 years old. Arch Med Sci 2012, 8:324-331, Stefanatos G: Changing perspectives on Landau-Kleffner syndrome. Clin Neuropsychol 2011, 25:963-988), raising the possibility that steroids might be a useful therapy for regression in ASD. A retrospective study published in BMC Neurology by Duffy et al. (Duffy, et al: Corticosteroid therapy in regressive autism: A retrospective study of effects on the Frequency Modulated Auditory Evoked Response (FMAER), language, and behavior. BMC Neurol 2014, 14:70) reviewed 20 steroid treated R-ASD (STAR) patients and 24 ASD control patients not treated with steroids (NSA). Improvements in clinical function and in a neurophysiological biomarker were seen in the steroid-treated children pre- to post-prednisolone treatment. This research provides a rationale for a randomized trial with steroid therapy to determine the longer term benefits and complications of steroids in this population.


The construction of autobiographical memories in the self-memory system.
The authors describe a model of autobiographical memory in which memories are transitory mental constructions within a self-memory system (SMS). The SMS contains an autobiographical knowledge base and current goals of the working self. Within the SMS, control processes modulate access to the knowledge base by successively shaping cues used to activate autobiographical memory knowledge structures and, in this way, form specific memories. The relation of the knowledge base to active goals is reciprocal, and the knowledge base "grounds" the goals of the working self. It is shown how this model can be used to draw together a wide range of diverse data from cognitive, social, developmental, personality, clinical, and neuropsychological autobiographical memory research.


Ionic current rectification at a nanofluidic/microfluidic interface with an asymmetric microfluidic system.
A nanofluidic-microfluidic interface is reported that rectifies ionic current using uncoated symmetric nanocapillaries. Previously, ionic current rectification has been achieved by other groups with nanochannels with differential coatings and in nanopores that are conical in shape. This simple device uses nanocapillary membranes (NCMs) with uncoated symmetric channels to connect a microfluidic channel and a larger solution reservoir. The conductivity of the solution in the microchannel appears to be critical in the formation of the low "off" state current and the high "on" state current. It is hypothesized that the "off" state current is low due to the formation of an ion depletion zone in the microchannel while the higher "on" state currents are produced by a zone of enhanced ionic concentration in the microchannel.


Mitochondrial Pathology and Glycolytic Shift during Proximal Tubule Atrophy after Ischemic AKI.
During recovery by regeneration after AKI, proximal tubule cells can fail to redifferentiate, undergo premature growth arrest, and become atrophic. The atrophic tubules display pathologically persistent signaling increases that trigger production of profibrotic peptides, proliferation of interstitial fibroblasts, and fibrosis. We studied proximal tubules after ischemia-reperfusion injury (IRI) to characterize possible mitochondrial pathologies and alterations of critical enzymes that govern energy metabolism. In rat kidneys, tubules undergoing atrophy late after IRI but not normally recovering tubules showed greatly reduced mitochondrial number, with rounded profiles, and large autophagolysosomes. Studies after IRI of kidneys in mice, done in parallel, showed large scale loss of the oxidant-sensitive mitochondrial protein Mpv17L. Renal expression of hypoxia markers also increased after IRI. During early and late reperfusion after IRI, kidneys exhibited increased lactate and pyruvate content and hexokinase activity, which are indicators of glycolysis. Furthermore, normally regenerating tubules as well as tubules undergoing atrophy exhibited increased glycolytic enzyme expression and inhibitory phosphorylation of pyruvate dehydrogenase. TGF-β antagonism prevented these effects. Our data show that the metabolic switch occurred early during regeneration after injury and was reversed during normal tubule recovery but persisted and became progressively more severe in tubule cells that failed to redifferentiate. In conclusion, irreversibility of the metabolic switch, taking place in the context of hypoxia, high TGF-β signaling and depletion of mitochondria characterizes the development of atrophy in proximal tubule cells and may contribute to the renal pathology after AKI.


Relationship between representation of hindpaw and hindpaw barrel subfield (HBS) in layer IV of rat somatosensory cortex.
We describe the organization of the hindpaw barrel subfield (HBS) in layer IV of rat somatosensory cortex (SI) and relate this organization to the representation of the hindpaw. The ovoid-shaped, HBS is oriented anterior to posterior and comprises barrels and barrel-like structures, the most prominent of which consist of at least five anteriorly-located elongated barrel bands. Posterior to these elongated bands is a cluster of four barrels. Two additional barrels are found, one lateral, the other medial. The lateral border is formed by a nearly continuous band that overlaps portions of the anterior elongated bands and posterior barrels. The HBS shows considerable variability in size and shape; nevertheless, the overall pattern reflects a common plan of organization. Electrophysiological mapping confirmed that hindpaw representation is somatotopically organized. The glabrous toes are represented anteriorly, the pads posteriorly, and the dorsal hairy skin of the toes and hindpaw laterally. By aligning physiological and morphological (HBS) maps according to lesion sites, our data suggest that the elongated anteriorly-located barrel bands represent the hindpaw toes, the four toe pads are represented immediately posterior followed by barrels representing the plantar pads. The representations of dorsal hairy skin of toe and dorsal hindpaw form the lateral border; the heel and ankle are represented most posterior. We interpret our findings as support that individual barrels in the HBS are associated with discrete regions of the hindpaw; however, the precise relationship of structure and function reported between the vibrissae and posteromedial barrel subfield (PMBSF) and between the forepaw and the forepaw barrel subfield (FBS) were not observed.


Inhibition of O-GlcNAc transferase (OGT) by peptidic hybrids.
O-GlcNAc transferase (OGT) attaches a GlcNAc moiety on specific substrate proteins using UDP-GlcNAc as the sugar donor. This modification can alter protein function by regulating cellular signaling and transcription pathways in response to altered nutrient availability and stress. Specific inhibitors of OGT would be valuable tools for biological studies and lead structures for therapeutics. The existing OGT inhibitors are mainly derived from the sugar donor substrate, but poor cell permeability and off-target effects limit their use. Here, we describe our progress on OGT inhibition based on substrate peptides identified by array screening. Subsequently, bisubstrate inhibitors were prepared by conjugating these peptides to uridine in various ways. In parallel, an in silico fragment screening was conducted to obtain small molecules targeting the UDP binding pocket. After evaluation of the initial hits, one of these small molecules was elaborated into a novel OGT hybrid inhibitor, as the replacement of uridine. The novel compounds inhibit OGT activity with IC50 values in the micromolar range.


EphB2 as a therapeutic antibody drug target for the treatment of colorectal cancer.
Analysis of human colorectal cancer specimens revealed overexpression of the EphB2 receptor tyrosine kinase. Monoclonal antibodies (MAbs) to extracellular sequence of EphB2 were raised and tested for activity against colorectal cancer cells. One of the MAbs, 2H9, effectively blocked the interaction of ephB2 with ephrin ligands and inhibited the resulting autophosphorylation of the receptor. However, this antibody did not affect the proliferation of cancer cells expressing ephB2. Immunocytochemical analysis revealed rapid internalization of the MAb 2H9 on binding ephB2, suggesting that target-dependent cell killing could be achieved with an antibody-drug conjugate. When MAb 2H9 was conjugated to monomethylauristatin E through a cathepsin B-cleavable linker, it specifically killed ephB2-expressing cancer cells in vitro and in vivo. Our results suggest that ephB2 is an attractive target for immunoconjugate cancer therapy.


Treatment of children with protein - losing enteropathy after fontan and other complex congenital heart disease procedures in condition with limited human and technical resources.
Protein-losing enteropathy (PLE) is a disorder characterized by abnormal and often profound enteric protein loss. It's relatively uncommon complication of Fontan and other complex congenital heart disease (CCHD) procedures. Because of the complexity and rarity of this disease process, the pathogenesis and pathophysiology of protein-losing enteropathy remain poorly understood, and attempts at treatment seldom yield long-term success. is to describe single centre experience in diagnosis, evaluation, management and treatment of children with protein-losing enteropathy after Fontan and other CCHD procedures in the current era and in centre with limited human and technical resources, follows with a comprehensive review of protein-losing enteropathy publications, and concludes with suggestions for prevention and treatment. Retrospectively we analyzed patients with CCHD and protein-losing enteropathy in our institution, starting from January 2000 to December 2012. The including criteria were age between two and 17 years, to have a complex congenital heart disease and available complete documentation of cardiac surgery under cardiopulmonary bypass. Of all patients we evaluated 18 cases with protein-losing enteropathy, aged 6 to 19 years (mean 14±9); there were three children who had undergone screening procedure for D-transposition, one Tetralogy of Fallot, and remaining 14 patients had undergone Fontan procedures; (anatomic diagnosis are: six with tricuspid atresia, seven with d-transposition, double outlet right ventricle and pulmonary atresia and two with hypoplastic left heart syndrome). The diagnosis of protein-losing enteropathy was made at median age of 5.6 years, ranging from 13 months to 15 years. Diagnosis was made using alpha 1-antitrypsin as a gold marker in stool. By physical examination in 14 patients edema was found, in three ascites, and six patients had pleural effusion. Laboratory findings at the time of diagnosis are: abnormal enteric protein loss was documented at the time of diagnosis in all 18 patients. At the time of diagnosis all patients receiving some form of anticoagulation, 17 patients receiving other medication: 17 - diuretics and ACE inhibitors, 12 digoxin, 9 antiarrhytmics. Cross-sectional echocardiography was performed for all patients and different abnormalities were registered. In 14 patients also magnetic resonance was performed. Therapeutic approach was based on the non-specific medication (diet, diuretics, digoxin, ACE inhibitors, and anticoagulants), heparin and corticosteroids therapy. Long-term response to this type of therapy was registered in three patients. Nine patients underwent treatment with heparin and corticosteroids and no one experienced long term benefit. Despite of needs for catheter therapy or surgical intervention in our study, in the absent of technical and human resources now any one had underwent those procedures. Six patients has been transferred abroad and in five of them surgical intervention was perform. Protein-losing enteropathy remains a devastating complication of Fontan procedure and despite in advantages in surgical and medical therapy there is no evidence that protein-losing enteropathy is less common in the current area.


Minimally Invasive Mitral Valve Surgery I: Patient Selection, Evaluation, and Planning.
Widespread adoption of minimally invasive mitral valve repair and replacement may be fostered by practice consensus and standardization. This expert opinion, first of a 3-part series, outlines current best practices in patient evaluation and selection for minimally invasive mitral valve procedures, and discusses preoperative planning for cannulation and myocardial protection.


Brain damage and associated behavioral deficits following the administration of L-cysteine to infant rats.
L-cysteine in doses of 1.2-1.3 mg/g, was administered to 4-day-old rats which were tested throughout development and as adults on a variety of behavioral tasks. Lesions of the type previously described from L-cysteine treatment were confirmed in several cortical and limbic structures. No neurodegenerative changes were observed in NaCl (10 mmoles/kg) controls. Surviving L-cysteine treated animals displayed no obvious impairments in motor ability or growth rate, but did show behavioral deficits when tested as adults on 3 behavioral tasks: spontaneous alternation; Lashley III maze; and pattern discrimination. Activity in the open field was significantly higher in the L-cysteine group at 20 days of age. Amphetamine, administered in doses of 1.5 to 3.0 mg/kg, had no differential effects on open-field activity in the two groups. The behavioral changes observed in L-cysteine treated animals is similar to that which has been reported in adult rats with extensive hippocampal damage.


Acceptability, Tolerability, and Estimates of Putative Treatment Effects of Probiotics as Adjunctive Treatment in Patients With Depression: A Randomized Clinical Trial.
The microbiota-gut-brain axis is a promising target for novel treatments for mood disorders, such as probiotics. However, few clinical trials have been conducted, and further safety and efficacy data are needed to support this treatment approach. To provide acceptability and tolerability data and estimates of intervention effect size for probiotics as adjunctive treatment for patients with major depressive disorder (MDD). In this single-center, double-blind, placebo-controlled pilot randomized clinical trial, adults aged 18 to 55 years with MDD taking antidepressant medication but having an incomplete response were studied. A random sample was recruited from primary and secondary care services and general advertising in London, United Kingdom. Data were collected between September 2019 and May 2022 and analyzed between July and September 2022. Multistrain probiotic (8 billion colony-forming units per day) or placebo daily for 8 weeks added to ongoing antidepressant medication. The pilot outcomes of the trial were retention, acceptability, tolerability, and estimates of putative treatment effect on clinical symptoms (depression: Hamilton Depression Rating Scale [HAMD-17] and Inventory of Depressive Symptomatology [IDS] scores; anxiety: Hamilton Anxiety Rating Scale [HAMA] and General Anxiety Disorder [GAD-7] scores) to be used as indicators for a definitive trial. Of 50 included participants, 49 received the intervention and were included in intent-to-treat analyses; of these, 39 (80%) were female, and the mean (SD) age was 31.7 (9.8) years. A total of 24 were randomized to probiotic and 25 to placebo. Attrition was 8% (1 in the probiotic group and 3 in the placebo group), adherence was 97.2%, and there were no serious adverse reactions. For the probiotic group, mean (SD) HAMD-17 scores at weeks 4 and 8 were 11.00 (5.13) and 8.83 (4.28), respectively; IDS, 30.17 (11.98) and 25.04 (11.68); HAMA, 11.71 (5.86) and 8.17 (4.68); and GAD-7, 7.78 (4.12) and 7.63 (4.77). For the placebo group, mean (SD) HAMD-17 scores at weeks 4 and 8 were 14.04 (3.70) and 11.09 (3.22), respectively; IDS, 33.82 (9.26) and 29.64 (9.31); HAMA, 14.70 (5.47) and 10.95 (4.48); and GAD-7, 10.91 (5.32) and 9.48 (5.18). Standardized effect sizes (SES) from linear mixed models demonstrated that the probiotic group attained greater improvements in depressive symptoms according to HAMD-17 scores (week 4: SES, 0.70; 95% CI, 0.01-0.98) and IDS Self Report scores (week 8: SES, 0.64; 95% CI, 0.03-0.87) as well as greater improvements in anxiety symptoms according to HAMA scores (week 4: SES, 0.67; 95% CI, 0-0.95; week 8: SES, 0.79; 95% CI, 0.06-1.05), but not GAD-7 scores (week 4: SES, 0.57; 95% CI, -0.01 to 0.82; week 8: SES, 0.32; 95% CI, -0.19 to 0.65), compared with the placebo group. The acceptability, tolerability, and estimated effect sizes on key clinical outcomes are promising and encourage further investigation of probiotics as add-on treatment for people with MDD in a definitive efficacy trial. ClinicalTrials.gov Identifier: NCT03893162.


Comparison of lidocaine and 2-chloroprocaine in paracervical block: clinical effects and drug concentrations in mother and child.
2-Chloroprocaine (CP) has recently been recommended as a less toxic alternative to amide-type local anesthetics due to its rapid metabolism. A double-blind, randomized study comparing CP to lidocaine when used for paracervical block was carried out. Twenty-nine patients received CP, while 31 received lidocaine. None of the 60 mothers developed adverse side effects. Adequate pain relief was achieved in 28 cases in each group, with a mean duration of 40 min regardless of the anesthetic. No change in uterine activity was observed. In the CP group one fetus had mild bradycardia, while two in the lidocaine group had severe, and three mild bradycardia within 5-7 min after the block. Low concentrations of CP were detected in the venous blood of 2 of 29 mothers and in the umbilical venous blood of their babies. Measurable amounts of its metabolite, 2-chloro-4-aminobenzoic acid (CABA), were found in all 13 samples of maternal blood 5 min after PCB and in 6 of 27 maternal samples at birth. Traces of CABA were found in umbilical venous blood in three neonates; in a fourth, a level of 1,000 ng/ml was found. In contrast, unmetabolized lidocaine was found in all maternal samples and in all but one of the cord samples at birth. Concentration of lidocaine in cord blood at delivery ranged from less than 100 to 4,000 ng/ml and were similar for both arterial and venous samples. No correlation could be demonstrated between levels of local anesthetics in the cord samples and the frequency or severity of fetal bradycardia regardless of the anesthetic.


Isolation and identification of phosphate solubilizing bacteria from chinese cabbage and their effect on growth and phosphorus utilization of plants.
Phosphate solubilizing bacteria (PSB) were isolated from the rhizosphere of Chinese cabbage and screened on the basis of their solubilization of inorganic tricalcium phosphate in liquid cultures. Ten strains that had higher solubilization potential were selected, and they also produced indole-3-acetic acid, 1-aminocyclopropane-1-carboxylate (ACC) deaminase, and siderophores. The strains were identified to be members of Pseudomonas, by 16S rDNA sequence analysis. Seed bacterization with PSB strains increased the root elongation and biomass of Chinese cabbage in seedling culture, although they had no effect on phosphorus uptake of plants. The plant growth promotion by PSB in this study could be due to the production of phytohormones or mechanisms other than phosphate solubilization, since they had no effect on P nutrition.


[Information on Death Certificates: Comparison Between Inpatient and Outpatient Sectors].
The death of a person and the circumstances of death are documented on the death certificate in Germany. The path of the corpse to burial as well as the quality of the cause of death statistics are significantly influenced by the information in the official death certificate. The quality of the information in the death certificates has been repeatedly criticized. The aim of the present study was to identify typical sources of error in death certificates and to obtain information on whether qualitative differences exist between death certificates completed in the outpatient and inpatient sectors. A retrospective evaluation was performed of 218 death certificates of deaths examined by the Institute of Legal Medicine as part of a second postmortem examination prior to cremation. Of these, 118 death certificates were issued in the hospital and 100 death certificates were issued on an outpatient basis by the family physician or a physician on duty in the outpatient sector. All but one of the death certificates issued on an outpatient basis were legible. The information on the underlying disease was plausible. More than one-third of the epicrises had no significant findings or were not completed at all. The entry on the immediate causes of death in the designated field on the death certificate (Ia in the causal chain) were inadequate in one third of the cases. The error rate in the entries was higher in outpatient than in inpatient deaths. In the future, therefore, it will be necessary to prepare for the special situation of a post-mortem examination by means of further and advanced training events and to convey the importance of the diagnoses determined in the process, in order to eliminate these avoidable sources of error.


Compression Freezing Kinetics of Water to Ice VII.
Time-resolved x-ray diffraction (XRD) of compressed liquid water shows transformation to ice VII in 6 nsec, revealing crystallization rather than amorphous solidification during compression freezing. Application of classical nucleation theory indicates heterogeneous nucleation and one-dimensional (e.g., needlelike) growth. These first XRD data demonstrate rapid growth kinetics of ice VII with implications for fundamental physics of diffusion-mediated crystallization and thermodynamic modeling of collision or impact events on ice-rich planetary bodies.