Flexibility decline contributes to similarity of past and future thinking in Alzheimer's disease.
A striking similarity has been suggested between past and future thinking in Alzheimer's Disease (AD), a similarity attributable to abnormalities in common modular cognitive functions and neuroanatomical substrates. This study extends this literature by identifying specific executive function deficits underlying past and future thinking in AD. Twenty-four participants with a clinical diagnosis of probable (mild) AD and 26 older controls generated past and future events and underwent tests of binding and the executive functions of flexibility, inhibition, and updating. AD patients showed similar autobiographical performances in past and future event generation, and so did control participants. In each group, the similarity of past and future thinking was predicted by flexibility. Furthermore, AD patients with low flexibility showed higher similarity of past and future thinking than those with high flexibility. These findings are interpreted in terms of involvement of the hippocampus and frontal lobes in future thinking. Deficits in these brain regions in AD are likely to compromise the ability to recombine episodic information into novel and flexible configurations as scenarios for the future.


Adenosine A2A receptors in neuroadaptation to repeated dopaminergic stimulation: implications for the treatment of dyskinesias in Parkinson's disease.
The A2A receptor has recently attracted considerable interest as a potential target for Parkinson's disease (PD) therapy based on the motor-enhancing and neuroprotective effects of A2A antagonists in animal models of PD. The unique neuronal localization of the adenosine A2A receptor in the basal ganglia and its extensive interactions with dopaminergic and glutamatergic systems led the authors to investigate a potential role of the A2A receptor in the development of behavioral sensitization in response to repeated dopaminergic stimulation. Because dopamine-induced behavioral sensitization shares several neurochemical and behavioral features with dyskinesia, characterizing this novel aspect of A2A receptor function may enhance understanding and management of dyskinesia in PD. Recent studies from several laboratories suggest that the A2A receptor may be an important mediator of maladaptive changes in response to long-term dopamine stimulation. The authors summarize their investigation of the role of A2A receptors in two paradigms of behavioral sensitization elicited by daily treatment with either L-dopa in hemiparkinsonian mice or amphetamine in naive mice. The results demonstrate that the A2A receptor is required for the development of behavioral sensitization in response to repeated L-dopa treatment in hemiparkinsonian mice and repeated amphetamine administration in normal mice. Together with pharmacologic studies, these results raise the possibility that the maladaptive dyskinetic responses to long-term L-dopa management of PD may be attenuated by A2A receptor blockade. Potential presynaptic, postsynaptic (cellular), and trans-synaptic (network) mechanisms are discussed.


Production of 14C-labeled gas in BACTEC Neisseria Differentiation kits by Neisseria cinerea.
Six strains of Neisseria cinerea were tested in BACTEC Neisseria Differentiation kits (Johnston Laboratories, Inc., Towson, Md.), and all yielded positive glucose growth indices and negative maltose and fructose growth indices. These results were similar to those achieved with Neisseria gonorrhoeae. However, most of the N. cinerea isolates tested yielded 3-h glucose growth indices that were lower than those obtained with gonococci. 14C-labeled gas was produced significantly faster (P less than 0.02) by N. gonorrhoeae than by N. cinerea. Additional studies suggested that the 14C-labeled gas produced by N. cinerea was carbon dioxide. N. cinerea strains were similar to Branhamella catarrhalis strains because both species failed to produce detectable acid from glucose, maltose, sucrose, fructose, and lactose in cysteine-tryptic agar media. However, in contrast to N. cinerea strains, B. catarrhalis strains did not metabolize glucose in BACTEC Neisseria Differentiation kits.


Di-n-Butyl Phthalate and Its Monoester Metabolite Impairs Steroid Hormone Biosynthesis in Human Cells: Mechanistic In Vitro Studies.
The widespread environmental contaminant di-n-butyl phthalate (DBP) has been linked with reduced testosterone levels and adverse reproductive health outcomes in men. However, the underlying mechanisms of these anti-androgenic effects and the potential effects on other classes of steroid hormones remain to be elucidated. Here, we conducted mechanistic studies in human adrenocortical H295R cells exposed to 1-500 µM of DBP or its metabolite, mono-n-butyl phthalate (MBP), for 48 h. Quantification of steroid hormones in the cell medium by liquid chromatography-mass spectrometry revealed that both phthalates significantly decreased testosterone, androstenedione, corticosterone, and progesterone levels, in particular after dibutyryl-cyclic-AMP stimulation of steroidogenesis. Western blot analysis of key steroidogenic proteins showed that DBP induced a dose-dependent decrease of CYP11A1 and HSD3β2 levels, while MBP only significantly decreased CYP17A1 levels, indicating that the compounds affect early steps of the steroidogenesis differently. Both DBP and MBP exposure also lead to a dose-related decrease in HSD17β3, the enzyme which catalyzes the final step in the testosterone biosynthesis pathway, although these effects were not statistically significant. Interestingly, DBP increased the cortisol concentration, which may be due to the non-significant CYP11B1 increase in DBP-exposed cells. In contrast, MBP decreased cortisol concentration. Moreover, the analysis of superoxide generation and quantification of the protein oxidation marker nitrotyrosine demonstrated that DBP induced oxidative stress in H295R cells while MBP reduced protein nitrotyrosine levels. These findings confirm the anti-androgenic effects of DBP and MBP and reveal several differences in their toxicological mechanisms, with possible implications for future research on phthalate toxicity.


It All Just Clicks: Development of an Inpatient E-Consult Program.
Although the use of electronic consultations (e-consults) in the outpatient setting is commonplace, there is little evidence of their use in the inpatient setting. Often, the only choice hospitalists have is between requesting a time-consuming in-person consultation or requesting an informal, undocumented "curbside" consultation. For a new, remote hospital in our healthcare system, we developed an e-consult protocol that can be used to address simple consultation questions. In the first year of the program, 143 e-consults occurred; the top 5 consultants were infectious disease, hematology, endocrinology, nephrology, and cardiology. Over the first 4 months, no safety issues were identified in chart review audits; to date, no safety issues have been identified through the hospital's incident reporting system. In surveys, hospitalists were universally pleased with the quality of e-consult recommendations, though only 43% of consultantsagreed. With appropriate care for patient selection, e-consults can be used to safely and efficiently provide subspecialty expertise to a remote inpatient site Journal of Hospital Medicine 2017;12:332-334.


Desulfovibrio marinus sp. nov., a moderately halophilic sulfate-reducing bacterium isolated from marine sediments in Tunisia.
Two novel sulfate-reducing bacterial strains, designated E-2(T) and IMP-2, were isolated from geographically distinct locations. Strain E-2(T) was recovered from marine sediments near Sfax (Tunisia), whereas strain IMP-2 originated from oilfield production fluids in the Gulf of Mexico. Cells were Gram-negative, non-sporulated, motile, vibrio-shaped or sigmoid. They were strictly anaerobic, mesophilic and moderately halophilic. Sulfate, sulfite, thiosulfate and elemental sulfur served as electron acceptors, but not nitrate or nitrite. H(2) (with acetate as carbon source), formate, fumarate, lactate, malate, pyruvate, succinate and fructose were used as electron donors in the presence of sulfate as terminal electron acceptor. Lactate was oxidized incompletely to acetate. Fumarate and pyruvate were fermented. Desulfoviridin and c-type cytochromes were present. 16S rRNA gene sequence analysis of the two strains showed that they were phylogenetically similar (99.0 % similarity) and belonged to the genus Desulfovibrio, with Desulfovibrio indonesiensis and Desulfovibrio gabonensis as their closest phylogenetic relatives. The G+C content of the DNA was respectively 60.4 and 62.7 mol% for strains E-2(T) and IMP-2. DNA-DNA hybridization experiments revealed that the novel strains had a high genomic relatedness, suggesting that they belong to the same species. We therefore propose that the two isolates be affiliated to a novel species of the genus Desulfovibrio, Desulfovibrio marinus sp. nov. The type strain is strain E-2(T) (=DSM 18311(T) =JCM 14040(T)).


Clinical and molecular aspects of a pediatric metachronous adrenocortical tumor.
The occurrence of metachronous adrenocortical carcinoma has rarely been described. We report a case of a child with virilizing adrenocortical metachronous tumors that, despite several metastases, presented long-term survival (15 years). We analyzed in this tumor IGF2, IGF1R and FGFR4 gene expression, and evaluated the presence of p.R337H germline p53 mutation and somatic CTNNB1 mutation. IGF2 gene was over-expressed in both left (Weiss score 5) and right (Weiss 7) adrenocortical tumors. IGF1R expression levels were higher in the right adrenocortical tumor. FGFR4 over-expression was also detected in the right adrenocortical tumor. In addition, this patient harbors the germline p.R337H p53 mutation and loss of heterozygosity (LOH) was detected in the tumors. No somatic CTNNB1 mutations were found in both tumors. In conclusion, we demonstrated in this unusual case the over-expression of growth signaling pathways, which are molecular mechanisms previously related to adrenocortical tumorigenesis. Furthermore, the absence of somatic CTNNB1 mutations, which is a molecular marker of poor prognosis in adults, might be related to the long-term survival of this patient.


Screening of human serum proteins for uranium binding.
About 20% of uranyl ions in serum are associated with the protein pool. A few of them such as transferrin have been characterized, but most still have to be identified to obtain a better explanation of the biochemical toxicology and kinetics of uranium. We designed an in vitro sensitive procedure involving a combination of bidimensional chromatography with time-resolved fluorescence, coupled with proteomic analysis, to identify uranium-binding proteins in human serum fractions. Ten novel targets were identified and validated using purified proteins and inductively coupled plasma mass spectrometry. Of these, ceruloplasmin, hemopexin, and two complement proteins displayed the capacity to bind uranium with stoichiometry greater than 1 mole of uranium per mole of protein. Not all of these targets are metalloproteins, suggesting that uranyl ions can use a wide variety of binding sites and coordination strategies. These data provide additional insights into a better understanding of uranium chemical toxicity.


Cooperative cobinding of synthetic and natural ligands to the nuclear receptor PPARγ.
Crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPARγ ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (Ω)-loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative biochemical functional and cellular assays reveal that synthetic ligand and fatty acid cobinding can form a 'ligand link' to the Ω-loop and synergistically affect the structure and function of PPARγ. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand.


Inhibition of mTORC1 inhibits lytic replication of Epstein-Barr virus in a cell-type specific manner.
Epstein-Barr virus is a human herpesvirus that infects a majority of the human population. Primary infection of Epstein-Barr virus (EBV) causes the syndrome infectious mononucleosis. This virus is also associated with several cancers, including Burkitt's lymphoma, post-transplant lymphoproliferative disorder and nasopharyngeal carcinoma. As all herpesvirus family members, EBV initially replicates lytically to produce abundant virus particles, then enters a latent state to remain within the host indefinitely. Through a genetic screen in Drosophila, we determined that reduction of Drosophila Tor activity altered EBV immediate-early protein function. To further investigate this finding, we inhibited mTOR in EBV-positive cells and investigated subsequent changes to lytic replication via Western blotting, flow cytometry, and quantitative PCR. The student T-test was used to evaluate significance. mTOR, the human homolog of Drosophila Tor, is an important protein at the center of a major signaling pathway that controls many aspects of cell biology. As the EBV immediate-early genes are responsible for EBV lytic replication, we examined the effect of inhibition of mTORC1 on EBV lytic replication in human EBV-positive cell lines. We determined that treatment of cells with rapamycin, which is an inhibitor of mTORC1 activity, led to a reduction in the ability of B cell lines to undergo lytic replication. In contrast, EBV-positive epithelial cell lines underwent higher levels of lytic replication when treated with rapamycin. Overall, the responses of EBV-positive cell lines vary when treated with mTOR inhibitors, and this may be important when considering such inhibitors as anti-cancer therapeutic agents.


Increased incidence of cardiovascular conditions among older adults with pathological gambling features in a prospective study.
To evaluate the prospective associations between at-risk/problem/pathological gambling (ARPG) and incident medical conditions among older adults. Secondary data analysis of the National Epidemiologic Survey on Alcohol and Related Conditions, waves 1 and 2, collected from 2001 to 2002 and 2004 to 2005, respectively. Participants are adults aged 55 years and older (n = 10,231) who were selected from a nationally representative community sample of adults residing in the United States. Past-year diagnostic criteria for pathological gambling at wave 1 were evaluated with the Alcohol Use Disorder and Associated Disabilities Interview Schedule-Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition. Physical health conditions were assessed at wave 1 and wave 2. Logistic regression modeling was conducted on groups categorized as ARPG (participants endorsing 1 or more inclusionary criteria for pathological gambling) and non-ARPG (nongambling/low-frequency gambling or gambling without endorsement of pathological gambling criteria). Relative to non-ARPG, ARPG is prospectively associated with elevated incidences of arteriosclerosis and any heart condition, independently of wave-1 sociodemographic characteristics, psychiatric comorbidity, substance use, and body mass index. Older adults who demonstrate risky or problematic levels of gambling may be at particular risk for the onset of some physical health conditions. Individuals with at-risk/problem/pathological gambling features should be monitored more closely for the development of these conditions and encouraged to adopt activities that confer health benefits. Efforts should be made to educate older adults and their caretakers on the adverse incident physical health conditions associated with ARPG.


Risky families: family social environments and the mental and physical health of offspring.
Risky families are characterized by conflict and aggression and by relationships that are cold, unsupportive, and neglectful. These family characteristics create vulnerabilities and/or interact with genetically based vulnerabilities in offspring that produce disruptions in psychosocial functioning (specifically emotion processing and social competence), disruptions in stress-responsive biological regulatory systems, including sympathetic-adrenomedullary and hypothalamic-pituitary-adrenocortical functioning, and poor health behaviors, especially substance abuse. This integrated biobehavioral profile leads to consequent accumulating risk for mental health disorders, major chronic diseases, and early mortality. We conclude that childhood family environments represent vital links for understanding mental and physical health across the life span.


Preconception care of women with diabetes: the unrevealed obstacles.
In spite of the widely accepted knowledge that elevated blood glucose levels in early pregnancy are associated with a significantly increased risk of birth defects in infants of women with established diabetes, the majority of diabetic women do not plan their pregnancies and enter pregnancy with inadequate blood glucose control. This article reviews the current research on circumstances and factors associated with unplanned diabetic pregnancies and offers recommendations to encourage effective pregnancy planning and preconception care among women with diabetes.


HIV/STD prevalence, risk behavior, and substance use patterns and predictors in Russian and Hungarian sociocentric social networks of men who have sex with men.
This study recruited four sociocentric networks (n = 156) of men who have sex with men in Budapest, Hungary, and St. Petersburg, Russia. The sampling approach was based on identifying an initial "seed" in the community for each network, and then recruiting three successive friendship group waves out from the seed. HIV prevalence in the networks was 9%, and the composite rate of other sexually transmitted diseases was 6%. 57% of participants reported both main and casual male partners, and two thirds reported unprotected anal intercourse in the past 3 months. Fifty-five percent of men's most recent anal intercourse acts were with nonexclusive partners, and 56% of most recent anal intercourse acts were unprotected. Sexual risk predictors were generally consistent with behavioral science theory. In addition, risk was associated with more often talking with friends about AIDS, higher ecstasy use, and less often drinking. Sociocentric social network sampling approaches are feasible and constitute a modality for reaching hidden high-risk populations inaccessible through conventional methods.


Prevalence and Determinants of Stunting, Wasting, and Underweight Among School-Age Children Aged 6-12 Years in South Gondar Zone, Ethiopia.
Underweight, wasting, and stunting are the commonest nutritional disorders among children, especially in developing countries. The aim of this study was to assess the prevalence and determinant factors of underweight, wasting, and stunting among school-age children in 2019. A cross-sectional study was conducted in the five special districts of South Gondar Zone, among 314 school-age children. WHO AnthroPlus software was used to build Z-scores from anthropometric measurement. The data were analyzed by SPSS Version 20. The degrees of association were assessed using adjusted odds ratio (AOR) and 95% confidence interval during multivariable logistic regression. A P-value less than 0.05 was considered to be statistically significant. Of the total study participants, 232 (77.3%) were from public schools. The mean±standard deviation (SD) of height of children was 132.9±9.8 cm, and the mean±SD weight of children was 27.7±5.8 kg. The prevalence of stunting, wasting, and underweight was 11%, 6.3%, and 11.4%, respectively. Students who ate their breakfast rarely were 8-times more likely to be underweight than those who ate their breakfast always (AOR=7.9, 95% CI=4.8-14.8). Those who were sick in the past 2 weeks were more likely to be underweight than their counterparts (AOR=7.3, 95% CI=2.8-14.4). Those who never consume milk or milk products were 6.5 (AOR=6.5, 95% CI=1.7-23) times more likely to be stunted than those who consumed this always. Sickness in the past 2 weeks prior to data collection was significantly associated with thinness (AOR=6 0.9, 95% CI=4.1-10.1). The overall prevalence of wasting, stunting, and underweight was a mild public health problem in the study area.


Organization of nephron function.
Recent studies of mammalian nephron segments have revealed an unexpected diversity of renal transport functions. Most substances are transported by several segments, and the transport mechanisms differ from segment to segment. In this paper we review some of these findings in order to fit them into an integrated picture of kidney function. The main question we ask is what is the advantage of spatial separation of the various transporters along the nephron. We propose that spatial separation of transport functions allows independent and efficient control of the excretion of substances whose renal handling is interdependent. The organization of sodium and water handling along the nephron is considered in the greatest detail. Sodium and water play central roles in controlling the renal excretion of many other substances. Yet the excretion rates of sodium and water themselves are independently controlled. The intricate anatomical structure of the kidney not only provides spatial separation of transport processes along the nephron but also couples the function of different segments by juxtaposing them in specialized regions within the medulla and cortex. These anatomical arrangements provide a framework for integrating the complex array of renal functions.


Nutritional amblyopia associated with jejunoileal bypass surgery.
After jejunoileal bypass surgery for morbid obesity, metabolic complications including a nutritional amblyopia developed in a patient. Reanastomosis of the bypass and treatment with multivitamins resulted in a nearly complete return of vision. Any patient undergoing rapid weight loss after gastrointestinal surgery for morbid obesity should be followed up for possible decrease in vision. If nutritional amblyopia develops, immediate reversal of the previous surgery is indicated.


Evaluation of the drug monitoring programme of azelastine hydrochloride nasal spray in the treatment of allergic rhinitis in children under 13 years of age.
The efficacy and safety of a nasal spray containing azelastine (CAS 58581-89-8; e.g. Afluon, Allergadil, Rhinolast) in the treatment of both perennial and seasonal allergic rhinitis have been evaluated in two postmarketing drug surveillance programmes (PMS) conducted in Spain. The present analysis reports on the data from a subpopulation from these studies and includes 211 children aged less than 13 years of age. In 73% of children the administered dose of azelastine was one spray puff per nostril twice daily, corresponding to the recommended daily, dosage of 0.56 mg azelastine. Patients with seasonal rhinitis were treated for a period of two weeks, those perennial rhinitis were treated for four weeks. The efficacy of the azelastine was assessed by the changes in severity of the following 10 individual symptoms of rhinitis: sneezing, nose itching, nose congestion, rhinorrhoea, smell reduction, eye itching, lachrimation, photophobia, throat itching, and coughing. Symptoms were rated according to a four-point scale: 0 = absent, 1 = slight, 2 = moderate, and 3 = severe. Both the investigators and the patients were requested to evaluate efficacy and tolerance according to a four point scale: 1 = very good, 2 = good, 3 = moderate, 4 = bad. All of the 10 clinical symptoms underwent a statistically significant and clinically relevant reduction during the treatment period. Nose itching, sneezing, and rhinorrhoea were the symptoms which completely disappeared in the highest number of patients by the end of therapy. The mean sum of all 10 symptom scores pre-treatment (baseline visit) was 11.03 while at the completion of therapy (control visit) it was 3.21. Overall, a decrease of this score was seen in 112 (98%) patients for whom complete data was available, whereas an increase was registered only in 2 (2%) cases. The mean total of the five nasal scores at the baseline visit was 7.64, and at the control visit its value measured 2.31. One hundred and twenty-one (98%) patients exhibited a decrease in the total nasal score, and only 3 (2%) demonstrated an increase. The mean total of the three ocular symptoms scores at the baseline visit was 2.25, while at the control visit its value was only 0.48. A decrease in the total ocular score was observed in 78 (62%) patients, while an increase occurred in only one patient. Overall, 85% of doctors evaluated the efficacy of the drug as "very good/good". 90% of patients did not report adverse events (AEs) during treatment with azelastine and only four patients discontinued treatment due to AEs. General tolerance was evaluated as "very good or good" by 97% of the treating physicians. Local tolerance was rated as "very good or good" by 94%. The most positive characteristics of the therapy according to the physicians were: rapid onset of action in 56% of cases, good efficacy in 46%, simple application in 44%, no sedation in 34%, and long duration of action in 22% of cases. Based upon the excellent risk-benefit assessment of this PMS, our results confirm the suitability of azelastine nasal spray in the treatment of allergic rhinitis in juvenile patients.


Linear vection in virtual environments can be strengthened by discordant inertial input.
Visual and gravitoinertial sensory inputs are integrated by the central nervous system to provide a compelling and veridical sense of spatial orientation and motion. Although it's known that visual input alone can drive this perception, questions remain as to how vestibular/ proprioceptive (i.e. inertial) inputs integrate with visual input to affect this process. This was investigated further by combining sinusoidal vertical linear oscillation (5 amplitudes between 0m and +/-0.8m) with two different virtual visual inputs. Visual scenes were viewed in a large field-of-view head-mounted display (HMD), which depicted an enriched, hi-res, dynamic image of the actual test chamber from the perspective of a subject seated in the linear motion device. The scene either depicted horizontal (+/-0.7m) or vertical (+/-0.8m) linear 0.2Hz sinusoidal translation. Horizontal visual motion with vertical inertial motion represents a 90 degrees spatial shift. Vertical visual motion with vertical inertial motion whereby the highest physical point matches the lowest visual point and vice versa represents a 180 degrees temporal shift, i.e. opposite of what one experiences in reality. Inertial-only stimulation without visual input was identified as vertical linear oscillation with accurate reports of acceleration peaks and troughs, but a slight tendency to underestimate amplitude. Visual-only (stationary) stimulation was less compelling than combined visual+inertial conditions. In visual+inertial conditions, visual input dominated the direction of perceived self-motion, however, increasing the inertial amplitude increased how compelling this non-veridical perception was. That is, perceived vertical self-motion was most compelling when inertial stimulation was maximal, despite perceiving "up" when physically "down" and vice versa. Similarly, perceived horizontal self-motion was most compelling when vertical inertial motion was at maximum amplitude. "Cross-talk" between visual and vestibular channels was suggested by reports of small vertical components of perceived self-motion combined with a dominant horizontal component. In conclusion, direction of perceived self-motion was dominated by visual motion, however, compellingness of this illusion was strengthened by increasing discordant inertial input. Thus, spatial mapping of inertial systems may be completely labile, while amplitude coding of the input intensifies the percept.


Soybean allergy: characteristics, mechanisms, detection and its reduction through novel food processing techniques.
Human beings have consumed soybean as an excellent food source for thousand years due to its rich protein, fatty acids, minerals, and fibers. However, soybeans were recognized as one of the big eight allergens resulting in allergic symptoms and even could lead to death. With the increasing demand for soybean products, the challenges caused by soybean allergy need to be solved urgently. This review detailly described the pathogenesis and clinical characteristics of soybean allergy, and also the advantages and disadvantages of four different diagnostic methods were summarized. The major soybean allergens and their structures were summarized. Three types of soybean allergy including Type I, III, and IV, which could trigger allergic reactions were reported in this review. Summary in four different diagnostic methods showed that double-blind, placebo-controlled food challenge is recognized as a gold standard for diagnosing soybean allergy. Three types of processing techniques in reducing soybean allergy were discussed, and the results concluded that some novel food processing techniques such as ultrasound, cold-plasma treatment, showed potential application in the reduction of soybean allergenicity. Further, some suggestions regarding the management and treatment of food allergies were addressed in this review.


[Genetic basis of Cushing's disease in children and targeted therapeutic future perspectives].
Cushing's disease (CD) is a multisystem disorder of a cortisol excess caused by ACTH -secreting pituitary tumor (corticotropinoma). CD in children is due to somatic or germline mutations with the late onset causing multiple endocrine tumors. If not treated, hypercortisolism leads to severe decrease in quality of life and life-threating conditions. The first-line treatment for CD is pituitary surgery, which might be followed by complications and relapse with necessity of additional surgery or initiations of second-line treatment. Recent studies of molecular basis of corticotropinoma development made it possible to employ medical therapy in CD. Understanding of corticotropinoma etiology and pathogenesis is an important part of education for pediatric endocrinologists since we need to keep in mind possibility of multisystem disorder in case of CD in children and because medical therapy might gain more important role for CD treatment in future.The most actual genetic aspects of corticotroph adenomas growth and the medical treatment opportunities are present in this review.


Mating suppresses splenic natural killer cell activity in male golden hamsters.
The possibility that sexual behavior is associated with changes in natural killer cell activity was explored using a 4-h chromium-51 release assay. Mated male Golden Hamsters (Mesocricetus auratus) showed a significant suppression of natural killer cell activity 2 h after sexual activity relative to matched Virgin controls. Natural killer cell activity returned to control levels by 16 h postmating. The suppression of natural killer cell activity did not correlate with changes in plasma cortisol, transcortin, or testosterone levels, or with ejaculatory or intromissive behaviors. Administration of 0.40 mg/100 g of testosterone also suppressed natural killer activity at 2 h.


It takes a village: Neurons partner with vascular pericytes to make memories.
Neurons have a central role in memory formation, but emerging work points to the critical role that non-neuronal cells play in this process. In this issue of Neuron, Pandey and colleagues1 show that hippocampal neurons communicate with vascular pericytes during memory consolidation. Through this dialogue, pericyte-derived growth factors support long-term memory.


Synthetic flavonoids cross the placenta in the rat and are found in fetal brain.
The synthetic flavonoid EMD-49209 is a potent inhibitor of the in vivo and in vitro binding of thyroxine (T4) to transthyretin (TTR). We studied the distribution of 125I-labeled EMD-49209 in maternal tissues, intestinal contents, and fetal tissues in rats that were 20 days pregnant (from 1 to 24 h after intravenous injection). The percent dose of EMD decreased quickly with time. In maternal brain no radioactive flavonoid could be detected. EMD was excreted very rapidly from the intestines. In the fetal compartment the percent dose of EMD increased with time; after 24 h it contained 17% of the EMD. The flavonoid was found in all fetal tissues investigated and also in the fetal brain. Because TTR concentrations are high in the fetal rat, especially in the brain, the transfer of flavonoid to the fetal brain might be linked to TTR expression. The presence of flavonoid in the fetal brain raises the possibility of an essential interference of flavonoids with the availability of T4 in the fetal compartment.


Bowel Obstruction and Peritoneal Dialysis: A Case Report of a Patient with Complications from a Broad Ligament Hernia.
Abdominal hernias are a common cause of bowel obstruction. The major types of abdominal hernias are external or abdominal wall hernias, which occur at areas of congenital or acquired weakness in the abdominal wall. An alternative entity is internal hernias, which are characterized by a protrusion of viscera through the peritoneum or mesentery. We herein present the case of a female peritoneal dialysis patient with bowel obstruction due to an internal hernia. Although an initial work-up did not lead to a correct diagnosis, an exploratory laparotomy revealed that she had intestinal herniation due to a defect in the broad ligament of the uterus, which was promptly corrected by surgery. The concerns about the perioperative dialytic management as well as the diagnostic problems regarding the disease that arose in our experience with the present patient are also discussed.


Fechner's elusive parallel law.
Weber's Law states that the differential threshold or just-noticeable-difference (jnd) is proportional to the physical intensity of the stimulus. Fechner built up his logarithmic law of sensation intensity from Weber's Law and the assumption that all jnds are subjectively equal. He thought it important that the Parallel Law should also hold. The Parallel Law states that, when perceived stimulus intensity is changed by something other than physical intensity (such as adaptation), Weber's Law continues to hold: discrimination should be unchanged provided the perceived values of the two stimuli change in the same ratio. Fechner claimed that weight discrimination was unaffected by weight adaptation; he was unsure about light adaptation; and he claimed that tactile length discrimination was unaffected by perceived changes caused by the bodily location of the stimulus. Modern research on adaptation for weights and other sensory stimuli shows that changes occur both in perceived intensity and in discrimination. Discrimination between stimuli is usually finest when the adaptation level is appropriate to the test level. There is insufficient evidence concerning the discrimination of tactile length and visual length when perceived length is changed. However, the Parallel Law may be untestable because of the difficulty of obtaining measures in the same experiment both for changes in discrimination and for the ratios of the perceived changes of the stimuli.


Pseudotumour Cerebri Presentation in a Child Under the Gonadotropin-Releasing Hormone Agonist Treatment.
Gonadotropin-releasing hormone analogues are common treatment option in central precocious puberty in childhood as well as in endometriosis, infertility, and prostate cancer in adults. Pseudotumor cerebri is a rare side effect observed in adults. We present the case of a girl with precocious puberty treated with triptorelin acetate who developed pseudotumor cerebri after the 4th dose. She had headaches, and her blood pressure was detected to be above the 99 percentile. There were no causes underlying of hypertension such as cardiac, renal, or endocrine. Neurological examination was normal except bilateral papilledema. Cranial magnetic resonance imaging was normal. Cerebrospinal fluid (CSF) opening pressure was elevated. Triptorelin therapy was ceased and acetazolamide was applied; CSF pressure returned to normal. We observed pseudotumor cerebri after precocious puberty treatment, a finding for the first time ever seen in childhood.


Assessing daily stress processes in social surveys by combining stressor exposure and salivary cortisol.
This article presents a research method for assessing stress and mental health in ongoing population-based social surveys that combines self-reports of naturally occurring daily stressors with a primary marker of stress physiology, salivary cortisol. We first discuss the relevance of stress processes to mental health and introduce a model for examining daily stress processes, which highlights multiple components of daily stressor exposure. A primary aim of this approach is to capture variability across stressful situations, between persons of different groups, or within persons over a period of time. Next, we describe how the assessment of diurnal salivary cortisol is a promising approach to examining naturally occurring stress physiology in large social surveys. We then present findings from the National Study of Daily Experiences (a substudy of the Midlife in the United States Study) that document the feasibility and reliability of the collection of daily stressors and salivary cortisol and provide examples of research findings linking stressor exposure to cortisol. The final portion of the article describes ways that this approach can leverage the strengths of various features of longitudinal social surveys to extend research on stress and mental health.


[Interrelationship between protein synthesis and mRNA metabolism in rat liver cells].
It is demonstrated that RNA isolated from polyribosomes and postmitochondrial fraction of rat liver cells and bound to nitrocellulose filters (Milliport) represent mRNA. RNA taken from the nitrocellulose filters sedimented in sucrose concentration gradient with a wide peak within the range of 18--6S, attaining a maximum at 12S. The (A+U)/(G+C) ratio of this RNA was equal to 1.04. On the other hand, the same ratio for rRNA was 0.64. Specific radioactivity of polysomal mRNA containing poly-A sequences, was significantly lower at 14-hour labelling with 14C-orotate than at 4-hour labelling (control). Inhibitors (cycloheximide, puromycin, ethionine, actinomycin D) stabilized polysomal mRNA. Specific radioactivity of postmitochondrial fraction mRNA was higher at 14-hour labelling than at 4-hour labelling. Specific radioactivity of postmitochondrial fraction mRNA during protein synthesis blocking by different inhibitors was comparable to those of control animals. It is hypothesized that active translation is necessary for the initiation of rat liver mRNA degradation.


Lifestyle changes for prehypertension with other cardiovascular risk factors: findings from Thailand.
To evaluate a model for community pharmacists to screen and recommend lifestyle changes for patients with prehypertension/hypertension and other elevated modifiable cardiovascular risk factors. Descriptive, exploratory, nonexperimental study. One accredited community pharmacy in Hat Yai, Thailand, between October 2008 and January 2009. Individuals 35 years or older without any previous diagnosis of hypertension and other cardiovascular disease. Measurement of blood pressure, blood glucose, total cholesterol, and body mass index; history taking for smoking and physical exercise; laboratory referral; assessment of readiness to adopt lifestyle changes; and provision of verbal advice and an education pamphlet on cardiovascular risk factors and recommended lifestyle modifications. Number of prehypertensive/hypertensive participants, patient return rate at 3-month follow-up, rate of laboratory referral uptake, confirmed glucose intolerance and dyslipidemia, and changes from baseline in blood pressure level. 263 of 400 people eligible for screening were found to have prehypertension or hypertension. Of these patients, 57% returned at 3-month follow-up. Mean (±SE) systolic (6.5 ± 0.89 mm Hg [95% CI 4.7-8.2], P < 0.001) and diastolic (2.2 ± 0.82 [0.54-3.77], P = 0.009) blood pressure were lowered. Compared with baseline (39.3%), the percentage of normotensive participants increased significantly at 3-month follow-up (51.8%; P < 0.001). The overall laboratory referral uptake was 36% (50 of 138). Glucose intolerance was confirmed in 2 of 21 participants. Of the 42 patients accepting laboratory confirmation, total and low-density lipoprotein cholesterol were confirmed to be above the normal range in 100% and 78.6%, respectively. Among these participants, those who returned at follow-up were rescreened for blood glucose and total cholesterol. Both values were found to be in the normal range. Although more participants reported lifestyle changes at 3 months, the smoking rate and amount of physical exercise were not changed. Community pharmacists, through the use of point-of-care testing and referrals for laboratory testing, can detect patients who are at risk of developing or already have hypertension, diabetes, and/or dyslipidemia. Lifestyle advice from pharmacists can have a positive effect on these risk factors.


ASCT2 silencing regulates mammalian target-of-rapamycin growth and survival signaling in human hepatoma cells.
System ASC amino acid transporter-2 (ASCT2) was previously demonstrated to be essential for human hepatoma cell growth and survival, as its silencing via inducible antisense RNA expression results in complete apoptosis within 48 h by a mechanism that transcends its role in amino acid delivery. To gain mechanistic insights into the reliance of cancerous liver cells on ASCT2, the aim of this study was to determine the early consequences of its silencing on the growth and survival signaling that presage apoptosis. Induced antisense ASCT2 RNA in SK-Hep1 cells led to >90% suppression of ASCT2 mRNA by 6 h and inhibition of mammalian target-of-rapamycin (mTOR)/raptor (mTOR complex-1; mTORC1) signaling by 8 h, as manifested by diminished p70 ribosomal protein S6 kinase-1 and eukaryotic initiation factor-4E (eIF4E) binding protein-1 phosphorylation, while protein synthesis rates declined by nearly 50% despite no measurable decreases in the cap binding protein eIF4G or cellular ribosomal protein content. Depressed mTORC1 signaling occurred before detectable reduction in ASCT2 activity but coincided with a 30% decline in total cellular ASCT2 protein. By 12 h after ASCT2 silencing, further decrements were observed in protein synthesis rates and ASCT2 protein and activity, each by approximately 50%, while signaling from mTOR/rictor (mTOR complex-2; mTORC2) was stimulated as indexed by enhanced phosphorylation of the Akt/PKB kinase on serine-473 and of its proapoptotic substrate Bad on serine-136. These results suggest that ASCT2 silencing inhibits mTORC1 signaling to the translational machinery followed by an mTORC2-initiated survival response, establishing a link between amino acid transporter expression and mTOR function.


Effect of Selective Laser Melting Process Parameters on the Quality of Al Alloy Parts: Powder Characterization, Density, Surface Roughness, and Dimensional Accuracy.
Additive manufacturing (AM) of high-strength Al alloys promises to enhance the performance of critical components related to various aerospace and automotive applications. The key advantage of AM is its ability to generate lightweight, robust, and complex shapes. However, the characteristics of the as-built parts may represent an obstacle to the satisfaction of the parts' quality requirements. The current study investigates the influence of selective laser melting (SLM) process parameters on the quality of parts fabricated from different Al alloys. A design of experiment (DOE) was used to analyze relative density, porosity, surface roughness, and dimensional accuracy according to the interaction effect between the SLM process parameters. The results show a range of energy densities and SLM process parameters for AlSi10Mg and Al6061 alloys needed to achieve "optimum" values for each performance characteristic. A process map was developed for each material by combining the optimized range of SLM process parameters for each characteristic to ensure good quality of the as-built parts. This study is also aimed at reducing the amount of post-processing needed according to the optimal processing window detected.


Comparison of triple image area using panoramic radiography of child and adult dry skull.
The objective of this study was to compare the zone of simple, double and triple images in a dry infant cranium against an adult completely formed one when panoramic X-ray photography's were taken. We took 96 panoramic X-ray photography's to a dry infant cranium placing a metallic spherical object of 8mm in different anatomical points for later to observe, identify and analyse the image of the object in each of them and determine if the images appeared as simple, double or triple. The 57.15% of images obtained were simple, 16.66 % were double and 26.19% triple. The area of triple and double images in the infant cranium did not involve anatomical important structures. The area where triple and double images appear was located in the occipital part in the infantile cranium with respect to the adult skull. On the basis of these results we can suggest that the X-ray photography must not be used as the main radiological support in the making of decisions in patients with craniofacial alterations.


Paclitaxel-hyaluronic acid for intravesical therapy of bacillus Calmette-Guérin refractory carcinoma in situ of the bladder: results of a phase I study.
Carcinoma in situ represents high grade anaplasia of the bladder mucosa. Intravesical immunotherapy with bacillus Calmette-Guérin is the gold standard treatment for patients with carcinoma in situ. Patients with carcinoma in situ refractory to bacillus Calmette-Guérin are candidates for major surgery such as radical cystectomy. We identified the maximum tolerated dose and the recommended dose, and evaluated the safety profile of paclitaxel-hyaluronic acid bioconjugate given by intravesical instillation to patients with carcinoma in situ refractory to bacillus Calmette-Guérin. A total of 16 patients with carcinoma in situ refractory to bacillus Calmette-Guérin were enrolled in a phase I, open label, single institution study. A minimum of 3 eligible patients were included per dose level. Paclitaxel-hyaluronic acid solution (ONCOFID-P-B™) was administered for 6 consecutive weeks. The primary objective was to identify the maximum tolerated dose and the recommended dose. As secondary objectives the safety profile of ONCOFID-P-B, the pharmacokinetic profile after each instillation and the tumor response were also evaluated. No dose limiting toxicity occurred at any drug level evaluated. The plasma levels of the study drug were always below the lower limit of quantification at all tested doses after each instillation. A total of 11 adverse events were reported by 7 patients and 9 (60%) showed complete treatment response. Intravesical instillation of ONCOFID-P-B for carcinoma in situ refractory to bacillus Calmette-Guérin showed minimal toxicity and no systemic absorption in the first human intravesical clinical trial to our knowledge. Finally, satisfactory response rates were observed.


Population-Based Study of Risk of AKI with Levetiracetam.
Regulatory agencies warn about the risk of AKI with levetiracetam use on the basis of information from case reports. We conducted this study to determine whether new levetiracetam use versus nonuse is associated with a higher risk of AKI. This was a population-based retrospective cohort study of adults with epilepsy in Ontario, Canada. Patients who received a new outpatient prescription for levetiracetam between January 1, 2004 and March 1, 2017 were matched to two nonusers on stage of CKD, recorded seizure in the prior 90 days, and logit of a propensity score for levetiracetam use. The primary outcome was a hospital encounter (emergency department visit or hospitalization) with AKI within 30 days of cohort entry. Secondary outcomes were AKI within 180 days and change in the concentration of serum creatinine. We assessed the primary outcome using health care diagnosis codes. We evaluated the change in the concentration of serum creatinine in a subpopulation with laboratory measurements. We matched 3980 levetiracetam users to 7960 nonusers (mean age 55 years, 51% women). Levetiracetam use was not significantly associated with a higher risk of AKI within 30 days (13 [0.33%] events in levetiracetam users and 21 [0.26%] events in nonusers [odds ratio, 1.24; 95% confidence interval, 0.62 to 2.47]). Similarly, there was no significant association with AKI within 180 days (odds ratio, 0.70; 95% confidence interval, 0.43 to 1.13). The change in the concentration of serum creatinine did not significantly differ between levetiracetam users and nonusers. In this population-based study levetiracetam use was not associated with a higher risk of AKI. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_12_11_Yau_Podcast.mp3.


Comparison study of intraosseous, central intravenous, and peripheral intravenous infusions of emergency drugs.
Intraosseous infusion of emergency drugs is a lifesaving alternative to intravenous administration when intravenous access cannot be rapidly established. We studied the comparative pharmacokinetics of the following six emergency drugs and solutions: epinephrine hydrochloride, 0.01 mg/kg; sodium bicarbonate, 1 mEq/kg; calcium chloride, 10 mg/kg; hydroxyethyl starch, 10 mL/kg; 50% dextrose in water, 250 mg/kg; and lidocaine hydrochloride, 1 mg/kg. Studies were conducted in normotensive, anesthetized dogs, with three animals studied with each of the drugs or solutions and each animal being treated with all three routes of administration (central intravenous, peripheral intravenous, and intraosseous) in randomized sequence. The effects of epinephrine were also assessed in a shock model. The intraosseous route of administration was comparable with the central and peripheral intravenous routes for all of the emergency drugs and solutions studied, with equivalent magnitudes of peak effect or drug level and equal or longer durations of action. Time to placement of the intraosseous needle varied from 15 seconds to 5 minutes, with a mean of 60 seconds. Time to placement of the needle varies with the skill and experience of the individual. With experience, all individuals could place the intraosseous needle in 60 seconds or less. The intraosseous route is comparable in effect to the central and peripheral intravenous routes of drug administration for epinephrine, sodium bicarbonate, hydroxyethyl starch, calcium chloride, 50% dextrose in water, and lidocaine and is a clinically feasible alternative when intravenous access will be critically delayed.


Dementia lifestyle coach pilot program.
This study aimed to conduct a feasibility pilot of the Dementia Lifestyle Coach program; an individual coaching and counselling program for people recently diagnosed with dementia, to help them to adjust to the diagnosis and live well. A randomised controlled pilot trial (n = 11) with wait-list control group was undertaken over 12 months. Intervention group participants received immediate personalised counselling from a registered psychologist and monthly support (face-to-face or by telephone) from a trained peer mentor living with dementia. The wait-listed control group commenced treatment 6 months after baseline. Recruitment and delivery of the Dementia Lifestyle Coach program was highly feasible. The program was acceptable, with nine of the 11 participants describing benefits including informational and emotional support, improving their outlook and mood, and family relationships. The planned program was adapted to participants' individual needs. This small pilot showed that it is feasible to recruit for and deliver a counselling and peer mentoring program for people recently diagnosed with dementia. A larger hybrid implementation randomised control trial should be conducted to evaluate efficacy and effectiveness.


Plasma protein binding by monosodium urate crystals. Analysis by two-dimensional gel electrophoresis.
Using 2-dimensional O'Farrell gel electrophoresis, we have mapped the proteins from undiluted plasma and serum which bind to monosodium urate (MSU) crystals. More than 30 crystal-associated polypeptides were visualized, including anionic and cationic species. Proteins increased on the crystals relative to plasma included C1q, C1-r, C1-s, fibronectin, fibrinogen, and kininogen. Crystal-bound polypeptides derived from IgG, albumin, and transferrin were recovered in decreased amounts relative to plasma. Direct evidence for activation of the complement and coagulation systems in plasma was provided by the identification of crystal-associated activation fragments of C1 and kininogen. Plasmas deficient in selected proteins (e.g., C1q and IgG) were used to define the role of these proteins in such activation events and confirmed activation of C1 in immunoglobulin-deficient plasma by MSU crystals. In summary, we have described a high resolution, semiquantitative approach to analyze protein binding to crystals, have documented the complexity of crystal-plasma protein interaction, and have provided direct evidence for the binding of coagulation system proteins and binding and activation of complement by MSU crystals, in whole plasma and IgG-deficient plasma.


Prevalence and characteristics of Shiga toxin-producing Escherichia coli in Swiss raw milk cheeses collected at producer level.
The aim of this study was to describe the prevalence, serotypes, and virulence genes of Shiga toxin-producing Escherichia coli (STEC) isolated from raw milk cheese samples collected at the producer level with the purpose of determining whether raw milk cheeses in Switzerland represent a potential source of STEC pathogenic for humans. Raw milk cheese samples (soft cheese, n = 52; semihard and hard cheese, n = 744; all produced from Swiss cows', goats', and sheep's milk) collected at the producer level throughout Switzerland within the national sampling plan during the period of March 2006 to December 2007 were analyzed. Of the 432 cheese samples obtained in the year 2006 and the 364 samples obtained in the year 2007, 16 (3.7%) and 23 (6.3%), respectively, were found to be stx positive. By colony dot-blot hybridization, non-O157 STEC strains were isolated from 16 samples. Of the 16 strains, 11 were typed into 7 E. coli O groups (O2, O15, O22, O91, O109, O113, O174), whereas 5 strains were nontypeable (ONT). Among the 16 STEC strains analyzed, stx(1) and stx(2) variants were detected in 1 and 15 strains, respectively. Out of the 15 strains with genes encoding for the Stx2 group, 4 strains were positive for stx(2), 6 strains for stx(2d2), 2 strains for stx(2-O118), 1 strain for stx(2-06), 1 strain for stx(2g), 1 strain for stx(2) and stx(2d2), and 1 strain for stx(2) and stx(2g). Furthermore, 3 STEC strains harbored E-hlyA as a further putative virulence factor. None of the strains tested positive for eae (intimin). Results obtained in this work reinforce the suggestion that semihard raw milk cheese may be a potential vehicle for transmission of pathogenic STEC to humans.


Phytochemistry of Verbascum Species Growing in Iraqi Kurdistan and Bioactive Iridoids from the Flowers of Verbascum calvum.
Traditional medicine is still widely practiced in Iraqi Kurdistan, especially by people living in villages on mountainous regions; medicinal plants are also sold in the markets of the large towns, such as at Erbil, the capital of the Kurdistan Autonomous Region. About a dozen of Verbascum species (Scrophulariaceae) are commonly employed in the Kurdish traditional medicine, especially for treating burns and other skin diseases. However, the isolation of bioactive secondary metabolites from these plants has not been the subject of intense scientific investigations in Iraq. Therefore, the information reported in the literature about the species growing in Kurdistan has been summarized in the first part of this paper, although investigations have been performed on vegetable samples collected in neighbouring countries, such as Turkey and Iran. In the second part of the work, we have investigated, for the first time, the contents of a methanol and a hydromethanol extract of V. calvum flowers. The extracts exhibited weak antimicrobial activities, whereas the methanol extract showed significant antiproliferative effects against an A549 lung cancer cell line. Moreover, both extracts exhibited a significant dose-dependent free radical scavenging action against the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, comparable to that of ascorbic acid. In the subsequent phytochemical study, a high phenolic content was determined in both extracts by the Folin-Ciocalteu assay and medium-pressure liquid chromatographic (MPLC) separation led to the isolation of iridoid glucosides ajugol and aucubin from the methanol extract. In conclusion, the high anti-inflammatory effects of aucubin and the remarkable antioxidant (antiradical) properties of the extracts give scientific support to the traditional use of V. calvum flowers for the preparation in Kurdistan of remedies to cure skin burns and inflammations.


Vitelline envelope gps 63 and 75 specifically bind sperm in "in vitro" assays in Discoglossus pictus.
In Xenopus, conflicting data related to sperm-vitelline envelope (VE) binding suggest that further experiments should be performed to study the role of VE glycoproteins in sperm binding. In this article, we studied the VE of Discoglossus pictus, where gp63, the product of the Dp ZP2 gene, has high molecular identity to Xenopus gp69/64 and to mouse ZP2 and only A23187-treated sperm bind to VE. Sperm bind to VE all over the egg, yet a sperm tuft was found only in the animal half of the egg, where the dimple, the site of fertilization, is located and an intense immunostain was detected in VE by an antiserum directed against gp69/64. The same antiserum inhibited sperm binding to VE. Sperm binding to beads coated with gp63, gp40, or gp75 was in the range of 62-70% for gp63-beads, 67-75% for 75 beads, and about 20% for BSA beads and gp40-coated beads. Soluble purified gp63 and gp75 competitively inhibited binding of sperm to gp63-coated beads. Similarly, the same glycoproteins inhibited sperm binding to gp75-coated beads. SDS-polyacrylamide gels (PAGE) of FE and comparison of VE and FE peptide maps showed that gp63 undergoes a minor shift to about 62 kDa in FE. In sperm binding assays with beads coated with FEs gp62, there was no binding. Following fertilization, in the region of the dimple, an F-layer is formed as well as an alteration of the VE structure. Lectin blots of the FE showed that the FE and in particular gp62 acquires a stronger affinity to Maackia amurensis agglutinin (MAA) with respect to VEs gp63. These results indicate that gps 63 and 75 are the sperm binding glycoproteins of D. pictus VE, where major post-fertilization changes occur as in other anuran species.


Negative selection systems for transgenic barley (Hordeum vulgare L.): comparison of bacterial codA- and cytochrome P450 gene-mediated selection.
Efficient negative selection systems are increasingly needed for numerous applications in plant biology. In recent years various counter-selectable genes have been tested in six dicotyledonous species, whereas there are no data available for the use of negative selection markers in monocotyledonous species. In this study, we compared the applicability and reliability of two different conditional negative selection systems in transgenic barley. The bacterial codA gene encoding cytosine deaminase, which converts the non-toxic 5-fluorocytosine (5-FC) into the toxic 5-fluorouracil (5-FU), was used for in vitro selection of germinating seedlings. Development of codA-expressing seedlings was strongly inhibited by germinating the seeds in the presence of 5-FC. For selecting plants in the greenhouse, a bacterial cytochrome P450 mono-oxygenase gene, the product of which catalyses the dealkylation of a sulfonylurea compound, R7402, into its cytotoxic metabolite, was used. T1 plants expressing the selectable marker gene showed striking morphological differences from the non-transgenic plants. In experiments with both negative selectable markers, the presence or absence of the transgene, as predicted from the physiological appearance of the plants under selection, was confirmed by PCR analysis. We demonstrate that both marker genes provide tight negative selection; however, the use of the P450 gene is more amenable to large-scale screening under greenhouse or field conditions.


Pentoxifylline reduces coronary leukocyte accumulation early in reperfusion after cold ischemia.
Ischemia/reperfusion injury can complicate recovery in cardiac operations. Ischemia induces endothelial dysfunction, which may contribute to leukocyte accumulation during reperfusion. Leukocyte-mediated injury may then occur. Using intravital microscopy we previously reported increased leukocyte retention in coronary capillaries and venules during early reperfusion during warm ischemia/reperfusion. In this study we investigated whether cold cardioplegic protection would limit leukocyte sequestration in coronary microvessels early in reperfusion. Pentoxifylline (PTX) has antiinflammatory effects and may limit endothelial dysfunction during ischemia/reperfusion. The effect of cardioplegia modification with PTX was also examined. Isolated rat hearts were subjected to 90 minutes of 4 degrees C ischemia after arrest with cardioplegia. Hearts were reperfused with diluted whole blood containing fluorescent-labeled leukocytes. Leukocyte retention in coronary microvessels was observed with intravital microscopy. Three groups were studied, nonischemic control, cold ischemia, and PTX-modified cold ischemia. In coronary capillaries, leukocyte trapping was nearly doubled in unmodified cold ischemia versus control. PTX modification significantly reduced leukocyte accumulation. In coronary venules, greater leukocyte adhesion was observed in unmodified cold ischemia compared to nonischemic controls. PTX modification significantly reduced leukocyte adhesion. Cold cardioplegia did not prevent leukocyte retention in the coronary microcirculation early in reperfusion. PTX modification of cardioplegia significantly reduced leukocyte sequestration in coronary capillaries and venules. Preserving endothelial function during ischemia may limit leukocyte accumulation and ischemia/reperfusion injury after cardiac operation.


Clinical application of varian OBI CBCT system and dose reduction techniques in breast cancer patients setup.
To characterize the standard modes of Varian on board imaging (OBI) v1.4 system and identify techniques to further optimize imaging parameters, in particular, for breast treatment setup. A male anthropomorphic torso phantom was used for image quality assessment and a simpler thorax phantom for dose measurements. Both phantoms had artificial breasts attached. Doses were measured with an ion chamber in seven locations in the thorax and the breast. Evaluation of image quality was performed in terms of contrast-to-noise ratio (CNR) and in combination with the dose-to-contrast-to-noise (CNRD) parameter. The effect of kVp and mAs on the image quality, dose, and CNRD parameter was analyzed. In addition, image geometry with noncentral isocenter location with start and stop imaging angles adjusted for greater sparing of the contralateral breast was evaluated in terms of image quality and dose. The measurements showed doses between 0.02 and 1.6 cGy for the three full-fan modes and 0.6-3.2 cGy for half-fan modes. This is a reduction of over 80% and 30%-50% compared to OBI v.1.3 modes for full-fan and half-fan modes, respectively. The CNRD is the highest for both low dose modes (low dose thorax and low dose head). Optimal ranges for an averaged sized thorax are tube voltages not higher than 100 kVp and current-time products between 100 and 400 mAs. For the contralateral breast and lung, a dose less than 0.03 cGy per scan was measured for the optimized image geometry with the noncentral isocenter location. The OBI v1.4 system allows for imaging with a larger variety of imaging parameters compared to previous OBI v1.3 systems. The largest doses (up to 4 cGy) were measured in a phantom when OBI v1.4 system was used for imaging with half-fan modes. Using full-fan modes resulted in the doses less than 1.6 cGy. Further decrease in dose may be achieved by reducing mAs while preserving acceptable image quality. Organ specific sparing (e.g., contralateral breast) may be achieved by proper selection of the start and stop angles. For thorax imaging, the use of Low Dose Thorax mode is recommended.


Phase separation of a Lennard-Jones fluid interacting with a long, condensed polymer chain: implications for the nuclear body formation near chromosomes.
Phase separation in a biological cell nucleus occurs in a heterogeneous environment filled with a high density of chromatins and thus it is inevitably influenced by interactions with chromatins. As a model system of nuclear body formation in a cell nucleus filled with chromatins, we simulate the phase separation of a low-density Lennard-Jones (LJ) fluid interacting with a long, condensed polymer chain. The influence of the density variation of LJ particles above and below the phase boundary and the role of attractive interactions between LJ particles and polymer segments are investigated at a fixed value of strong self-interaction between LJ particles. For a density of LJ particles above the phase boundary, phase separation occurs and a dense domain of LJ particles forms irrespective of interactions with the condensed polymer chain whereas its localization relative to the polymer chain is determined by the LJ-polymer attraction strength. Especially, in the case of moderately weak attractions, the domain forms separately from the polymer chain and subsequently associates with the polymer chain. When the density is below the phase boundary, however, the formation of a dense domain is possible only when the LJ-polymer attraction is strong enough, for which the domain grows in direct contact with the interacting polymer chain. In this work, different growth behaviors of LJ particles result from the differences in the density of LJ particles and in the LJ-polymer interaction, and this work suggests that the distinct formation of activity-dependent and activity-independent nuclear bodies (NBs) in a cell nucleus may originate from the differences in the concentrations of body-specific NB components and in their interaction with chromatins.


Prevalence of mental incapacity in medical inpatients and associated risk factors: cross-sectional study.
Although mental incapacity is becoming increasingly important in clinical practice, little information is available on its frequency in medical inpatients. We aimed to estimate the prevalence of mental incapacity in acutely admitted medical inpatients; to determine the frequency that medical teams recognised patients who did not have mental capacity; and to identify factors associated with mental incapacity. Over an 18-month period, we recruited 302 consecutive acute medical inpatients. Participants were assessed with the MacArthur competence tool for treatment and by clinical interview. Cognitive impairment was measured by the mini-mental state examination. 72 (24%) patients were severely cognitively impaired, unconscious, or unable to express a choice and were automatically assigned to the incapacity group. 71 (24%) refused to participate or could not speak English. Thus, 159 patients were interviewed. Of these, 31% (95% CI 24-38) were judged not to have mental capacity. For the total sample (n=302), we estimated that at least 40% did not have mental capacity. Clinical teams rarely identified patients who did not have mental capacity: of 50 patients interviewed, 12 (24%) were rated as lacking capacity. Factors associated with mental incapacity were increasing age and cognitive impairment. Mental incapacity is common in acutely ill medical inpatients, and clinicians tend not to recognise it. Screening methods for cognitive impairment could be useful in detecting those with doubtful capacity to consent.


Eliminating Delocalization Error to Improve Heterogeneous Catalysis Predictions with Molecular DFT + U.
Approximate semilocal density functional theory (DFT) is known to underestimate surface formation energies yet paradoxically overbind adsorbates on catalytic transition-metal oxide surfaces due to delocalization error. The low-cost DFT + U approach only improves surface formation energies for early transition-metal oxides or adsorption energies for late transition-metal oxides. In this work, we demonstrate that this inefficacy arises due to the conventional usage of metal-centered atomic orbitals as projectors within DFT + U. We analyze electron density rearrangement during surface formation and O atom adsorption on rutile transition-metal oxides to highlight that a standard DFT + U correction fails to tune properties when the corresponding density rearrangement is highly delocalized across both metal and oxygen sites. To improve both surface properties simultaneously while retaining the simplicity of a single-site DFT + U correction, we systematically construct multi-atom-centered molecular-orbital-like projectors for DFT + U. We demonstrate this molecular DFT + U approach for tuning adsorption energies and surface formation energies of minimal two-dimensional models of representative early (i.e., TiO2) and late (i.e., PtO2) transition-metal oxides. Molecular DFT + U simultaneously corrects adsorption energies and surface formation energies of multilayer models of rutile TiO2(110) and PtO2(110) to resolve the paradoxical description of surface stability and surface reactivity of semilocal DFT.


Clinical course of ICU patients with severe pandemic 2009 influenza A (H1N1) pneumonia: single center experience with proning and pressure release ventilation.
A number of different modalities have been employed in addition to conventional ventilation to improve oxygenation in patients with severe 2009 pandemic influenza A (H1N1) pneumonia. Outcomes with ventilatory and rescue therapies for H1N1 influenza-related acute respiratory distress syndrome (ARDS) have been varied. A single intensive care unit (ICU) experience with management of laboratory-confirmed 2009 pandemic influenza A (H1N1) ARDS with a combination of proning and airway pressure release ventilation (APRV) is described. A retrospective review of medical records of ICU patients seen at Utah Valley Regional Medical Center during the first and second waves of the H1N1 influenza pandemic was done. Fourteen ICU patients were managed with invasive ventilation for 2009 pandemic influenza A (H1N1)-related ARDS. Hypoxemia refractory to conventional ventilation was noted in 11 of 14 patients despite application of APRV. Following proning in patients on APRV, improvement of hypoxemia and hemodynamic status was achieved. Only 2 of 11 patients on APRV and proning required continuous dialysis. Mortality in intubated patients receiving a combination of proning and APRV was 27.3% (3/11) with 2 of these dying during the first wave of the H1N1 influenza pandemic. In all, 3 of 11 patients on proning and APRV underwent tracheostomy, with 2 of these undergoing tube thoracostomy. ARDSnet fluid-conservative protocol was safely tolerated in 8 of 11 of the intubated patients following initiation of proning and APRV. Proning in combination with APRV provides improvement of hypoxemia with limitation of end-organ dysfunction and thereby facilitates recovery from severe 2009 pandemic influenza A (H1N1).


Gender Differences in Awareness of Preconception Care and Pregnancy.
This study was conducted to identify awareness levels in regard to preconception care and gender differences targeting single undergraduate students in their 20s. The study participants were 867 single undergraduate students aged 20~29 (523 women, 344 men). This was a descriptive research, in which awareness levels of preconception care and pregnancy were identified the through questionnaire surveys. Gender differences in the awareness of reproductive care before conception were found. Generally, women's awareness of issues related to preconception care and pregnancy was higher than that of men. Women recognized risk factors in pregnancy (chi2=22.85, p<.001) and positive behaviors (chi2=10.91, p = .012) better than men. Women's awareness of preconception care was significantly higher than that of men (t=8.37, p<.001). The awareness levels of the students who completed a reproduction related class (t=3.16, p = .002) and the students who knew about folic acid (t=-10.78, p<.001) in preconception care were statistically significantly higher. The results indicate that the ways to educate and alert students to major risk factors before pregnancy and other reproductive care content before conception is to provide education both single women and single men.


The potential of mesothelial cells in tissue engineering and regenerative medicine applications.
Injury to the serosa through injurious agents such as radiation, surgery, infection and disease results in the loss of the protective surface mesothelium and often leads to fibrous adhesion formation. Mechanisms that increase the rate of mesothialisation are therefore actively being investigated in order to reduce the formation of adhesions. These include intraperitoneal delivery of cultured mesothelial cells as well as administration of factors that are known to increase mesothelial proliferation and migration. An exciting alternative that has only recently received attention, is the possible role of mesothelial progenitor cells in the repair and regeneration of denuded serosal areas. Accumulating evidence suggests that such a population exists and under certain conditions is able to form a number of defined cell types indicating a degree of plasticity. Such properties may explain the extensive use of mesothelial cells in various tissue engineering applications including the development of vascular conduits and peripheral nerve replacements. It is likely that with the rapid explosion in the fields of tissue engineering and regenerative medicine, a greater understanding of the potential of mesothelial progenitor cells to repair, replace and possibly regenerate damaged or defective tissue will be uncovered.


Vancomycin population pharmacokinetics in neonates.
Recently the value of vancomycin therapeutic drug monitoring, as well as the required therapeutic range, has been subject of debate, resulting in new recommendations. This study was performed to incorporate these new insights in an up-to-date dosing scheme for neonates of various gestational ages. In this retrospective study with prospective validation, 108 newborns with suspected central line-related septicemia during the first month of life received 30 mg/kg/day vancomycin divided into two doses regardless of gestational or postconceptional age. Trough and peak vancomycin serum concentrations were determined before and after the third dose. Vancomycin data were analyzed according to a one-compartment open model with use of NONMEM population pharmacokinetic software. Model parameters were evaluated and then used to simulate vancomycin dosing for different dose and dose interval combinations. Targets were a trough concentration between 5 and 15 mg/L and a peak below 40 mg/L. In the prospective study, the optimal scheme was tested in 22 patients. Of the 108 patients, 34.3% of measured trough concentrations and 17.6% of peak concentrations were outside the desired therapeutic range. The model that best fitted the data included clearance and volume per kilogram and was independent of gestational age. Simulation of various dosing schemes showed that a dosing schedule of 30 mg/kg/day, irrespective of gestational age, in three doses was optimal, and this scheme was prospectively tested. Mean trough concentrations before the second dose were 8.2 +/- 2.2 mg/L versus a predicted trough of 8.9 +/- 2.5 mg/L. No peak levels higher than 40 mg/L were found. The use of the proposed schedule leads to adequate vancomycin trough serum concentrations, and there is no need for routine monitoring of peak serum concentrations.


The rDNA transcription machinery is assembled during mitosis in active NORs and absent in inactive NORs.
In cycling cells, the rDNAs are expressed from telophase to the end of G2 phase. The early resumption of rDNA transcription at telophase raises the question of the fate of the rDNA transcription machinery during mitosis. At the beginning of mitosis, rDNA transcription is arrested, and the rDNAs are clustered in specific chromosomal sites, the nucleolar organizer regions (NOR). In human cells, we demonstrate that the rDNA transcription machinery, as defined in vitro, is colocalized in some NORs and absent from others whatever the mitotic phase: RNA polymerase I and the RNA polymerase I transcription factors, upstream binding factor and promoter selectivity factor (as verified for TATA-binding protein and TATA-binding protein-associated factor for RNA polymerase I [110]), were colocalized in the same NORs. The RNA polymerase I complex was localized using two different antibodies recognizing the two largest subunits or only the third largest subunit, respectively. These two antibodies immunoprecipitated the RNA polymerase I complex in interphase cells as well as in mitotic cells. These results clearly indicated that the RNA polymerase I complex remained assembled during mitosis. In addition, RNA polymerase I and the transcription factors varied in the same proportions in the positive NORs, suggesting stoichiometric association of these components. The fact that the rDNA transcription machinery is not equally distributed among NORs most likely reflects the implication of the different NORs during the subsequent interphase. Indeed, we demonstrate that only positive NORs exhibit transcription activity at telophase and that the level of transcription activity is related to the amount of rDNA transcription machinery present in the NOR. We propose that assembly of rDNA transcription machinery preceding mitosis determines expression of the rDNAs at the beginning of the next cell cycle. Consequently, the association of rDNAs with the rDNA transcription machinery defines the "active" NORs and the level of activity at the transition telophase/interphase.


Muscle-derived fibro-adipogenic progenitor cells for production of cultured bovine adipose tissue.
Cultured meat is an emergent technology with the potential for significant environmental and animal welfare benefits. Accurate mimicry of traditional meat requires fat tissue; a key contributor to both the flavour and texture of meat. Here, we show that fibro-adipogenic progenitor cells (FAPs) are present in bovine muscle, and are transcriptionally and immunophenotypically distinct from satellite cells. These two cell types can be purified from a single muscle sample using a simple fluorescence-activated cell sorting (FACS) strategy. FAPs demonstrate high levels of adipogenic potential, as measured by gene expression changes and lipid accumulation, and can be proliferated for a large number of population doublings, demonstrating their suitability for a scalable cultured meat production process. Crucially, FAPs reach a mature level of adipogenic differentiation in three-dimensional, edible hydrogels. The resultant tissue accurately mimics traditional beef fat in terms of lipid profile and taste, and FAPs thus represent a promising candidate cell type for the production of cultured fat.


Source patterns of potentially toxic elements (PTEs) and mining activity contamination level in soils of Taltal city (northern Chile).
Mining activities are among the main sources of potentially toxic elements (PTEs) in the environment which constitute a real concern worldwide, especially in developing countries. These activities have been carried out for more than a century in Chile, South America, where, as evidence of incorrect waste disposal practices, several abandoned mining waste deposits were left behind. This study aimed to understand multi-elements geochemistry, source patterns and mobility of PTEs in soils of the Taltal urban area (northern Chile). Topsoil samples (n = 125) were collected in the urban area of Taltal city (6 km2) where physicochemical properties (redox potential, electric conductivity and pH) as well as chemical concentrations for 35 elements were determined by inductively coupled plasma optical emission spectrometer. Data were treated following a robust workflow, which included factor analysis (based on ilr-transformed data), a new robust compositional contamination index (RCCI), and fractal/multi-fractal interpolation in GIS environment. This approach allowed to generate significant elemental associations, identifying pool of elements related either to the geological background, pedogenic processes accompanying soil formation or to anthropogenic activities. In particular, the study eventually focused on a pool of 6 PTEs (As, Cd, Cr, Cu, Pb, and Zn), their spatial distribution in the Taltal city, and the potential sources and mechanisms controlling their concentrations. Results showed generally low baseline values of PTEs in most sites of the surveyed area. On a smaller number of sites, however, higher values concentrations of As, Cd, Cu, Zn and Pb were found. These corresponded to very high RCCI contamination level and were correlated to potential anthropogenic sources, such as the abandoned mining waste deposits in the north-eastern part of the Taltal city. This study highlighted new and significant insight on the contamination levels of Taltal city, and its links with anthropogenic activities. Further research is considered to be crucial to extend this assessment to the entire region. This would provide a comprehensive overview and vital information for the development of intervention limits and guide environmental legislation for these pollutants in Chilean soils.


Isotopic ratio outlier analysis global metabolomics of Caenorhabditis elegans.
We demonstrate the global metabolic analysis of Caenorhabditis elegans stress responses using a mass-spectrometry-based technique called isotopic ratio outlier analysis (IROA). In an IROA protocol, control and experimental samples are isotopically labeled with 95 and 5% (13)C, and the two sample populations are mixed together for uniform extraction, sample preparation, and LC-MS analysis. This labeling strategy provides several advantages over conventional approaches: (1) compounds arising from biosynthesis are easily distinguished from artifacts, (2) errors from sample extraction and preparation are minimized because the control and experiment are combined into a single sample, (3) measurement of both the molecular weight and the exact number of carbon atoms in each molecule provides extremely accurate molecular formulas, and (4) relative concentrations of all metabolites are easily determined. A heat-shock perturbation was conducted on C. elegans to demonstrate this approach. We identified many compounds that significantly changed upon heat shock, including several from the purine metabolism pathway. The metabolomic response information by IROA may be interpreted in the context of a wealth of genetic and proteomic information available for C. elegans . Furthermore, the IROA protocol can be applied to any organism that can be isotopically labeled, making it a powerful new tool in a global metabolomics pipeline.


Evaluating clinical decision support systems: monitoring CPOE order check override rates in the Department of Veterans Affairs' Computerized Patient Record System.
To measure critical order check override rates in VA Puget Sound Health Care System's computerized practitioner order entry (CPOE) system and to compare 2006 results to a similar 2001 study. Analysis of ordering and order check data gathered by a post-hoc logging program. Use of Pearson's chi-square contingency table test comparing results from this study and the earlier study. Factors measured were total number of orders, frequency of order check types, frequency of order check overrides by order check type and comparisons of these results with previous results. A total of 37,040 orders generated 908 (2.5%) critical order checks. Drug-drug critical alert override rate was 74/85 (87%) in 2006 compared to 95/108 (88%) in 2001 (X ( 2 )=0.04, df=1, p=0.85). The drug-allergy override rate was 341/420 (81%) compared to 72/105 (69%) in 2001 (X ( 2 )=7.97, df=1, p=0.005). In 2001, 0.25% (105/42,621) orders generated a drug-allergy order check compared to 1.13% (420/37,040) in 2006 (X ( 2 )=238.45, df=1, p<0.0001). Override rates of critical drug-drug and drug-allergy order checks remain high at VA Puget Sound Health Care System including significant increases in drug-allergy order checks. We recommend that monitoring override rates be regular practice in clinical computing systems and conclude that qualitative research should be carried out to better understand how physicians interact with decision support at the point of ordering.


State of the science on controversial topics: missing maxillary lateral incisors--a report of the Angle Society of Europe 2012 meeting.
The optimal long-term management of the congenitally missing maxillary lateral incisor continues to cause controversy within the specialty. The Angle Society of Europe meeting 2012 dedicated a day to address some of the current controversies relating to the management of these missing lateral incisors. The format of the day consisted of morning presentations and afternoon breakout sessions to discuss a variety of questions related to the management of missing lateral incisors. The consensus viewpoint from this day was that the care of patients with congenitally missing lateral incisors is best achieved through a multi-disciplinary approach. The current evidence base is weak, and further well-designed, prospective trials are needed.


Acid-Base Interactions of Polystyrene Sulfonic Acid in Amorphous Solid Dispersions Using a Combined UV/FTIR/XPS/ssNMR Study.
This study investigates the potential drug-excipient interactions of polystyrene sulfonic acid (PSSA) and two weakly basic anticancer drugs, lapatinib (LB) and gefitinib (GB), in amorphous solid dispersions. Based on the strong acidity of the sulfonic acid functional group, PSSA was hypothesized to exhibit specific intermolecular acid-base interactions with both model basic drugs. Ultraviolet (UV) spectroscopy identified red shifts, which correlated well with the color change observed in lapatinib-PSSA solutions. Fourier transform infrared (FTIR) spectra suggest the protonation of the quinazoline nitrogen atom in both model compounds, which agrees well with data from the crystalline ditosylate salt of lapatinib. X-ray photoelectron spectroscopy (XPS) detected increases in binding energy of the basic nitrogen atoms in both lapatinib and gefitinib, strongly indicating protonation of these nitrogen atoms. (15)N solid-state NMR spectroscopy provided direct spectroscopic evidence for protonation of the quinazoline nitrogen atoms in both LB and GB, as well as the secondary amine nitrogen atom in LB and the tertiary amine nitrogen atom in GB. The observed chemical shifts in the LB-PSSA (15)N spectrum also agree very well with the lapatinib ditosylate salt where proton transfer is known. Additionally, the dissolution and physical stability behaviors of both amorphous solid dispersions were examined. PSSA was found to significantly improve the dissolution of LB and GB and effectively inhibit the crystallization of LB and GB under accelerated storage conditions due to the beneficial strong intermolecular acid-base interaction between the sulfonic acid groups and basic nitrogen centers.


Circulating Cell-Free DNA and DNA Integrity as Molecular Diagnostic Tools in Hepatocellular Carcinoma.
We assessed the ability to use circulating cell-free DNA (cfDNA) and the DNA integrity index (DNAII) to detect the transition from liver cirrhosis (LC) to hepatocellular carcinoma (HCC). Circulating cfDNA and DNAII were measured in 50 patients with advanced LC and 50 patients with HCC who were followed for 1 month after transarterial chemoembolization (TACE). Fifty healthy participants served as a control group. Real-time quantitative polymerase chain reaction (PCR) was used to measure circulating cfDNA concentration, and Alu-PCR was used to measure the concentration of Alu repeats, both short fragments (115 base pairs [bp]) and long fragments (247 bp). We compared liquid biopsy results with the relevant traditional markers. The HCC group showed significantly higher circulating cfDNA concentrations and DNAII values compared with the LC and control groups. No significant differences were found in circulating cfDNA concentrations and DNAII values between the LC and control groups. Circulating cfDNA concentrations decreased significantly after treatment (TACE); areas under the curve of circulating cfDNA concentration and DNAII values were significantly better than those of ɑ-fetoprotein and vascular endothelial growth factor in discriminating between LC and HCC. The combined use of DNAII with proteins induced by vitamin K absence or antagonist showed better diagnostic performance in HCC. Circulating cfDNA could have a potential role in monitoring HCC treatment.


ECT in the Postpartum Period: A Retrospective Case Series from a Tertiary Health Care Center in India.
To evaluate the clinical profile and effectiveness of ECT in females with postpartum onset psychiatric syndromes or worsening of psychiatric disorder during the postpartum period. A retrospective chart review was carried out to identify females who had received ECT during their postpartum period from January2004 to April 2017. During the study period, 13 females in their postpartum period received ECT, which accounted for 2.24% of the total females (n = 578) who had received ECT and 1% of total patients who were administered ECT during this period. The most common clinical diagnosis was postpartum depression (n = 7; 53.86%). Three (23.1%) patients were diagnosed with bipolar disorder and had experienced a relapse during the postpartum period. Two (15.4%) patients were diagnosed with schizophrenia and 1 (7.7%) patient was diagnosed with postpartum psychosis/acute and transient psychotic disorder. ECT was considered as a treatment of choice in 9 (69.2%) patients. All the patients with depression or mania achieved clinical remission, and patients with psychotic disorders also had significant reduction in their symptoms. Cognitive complaints were reported by 4 (30.8%) patients, and aches and pains after ECT were reported by 7 (53.8%). ECT is a safe and effective treatment option in postpartum onset psychiatric syndromes or patients experiencing relapse or exacerbation of severe mental disorders during the postpartum period and is associated with a very good response rate with minimal or no complications.


Insulin binding and sensitivity in rat skeletal muscle: effect of starvation.
In contrast to adipose tissue and heart, the in vitro sensitivity of skeletal muscle to insulin is enhanced by starvation. To determine the basis for this, insulin binding and its ability to stimulate glucose metabolism were examined in the incubated rat soleus. In solei from 50-g rats, starvation for 48 h enhanced insulin binding by 50-100% at concentrations of 100 ng/ml or less. Starvation also resulted in higher basal and insulin-stimulated rates of glycogen synthesis, glycolysis, and glucose uptake. The enhanced effect of insulin only occurred at concentrations less than 50-75 ng/ml, in keeping with the increased binding of insulin in this concentration range. On the other hand, under conditions in which binding at equilibrium was the same, glucose uptake was still higher in the starved group, suggesting that some postreceptor event may have been more sensitive to insulin. These studies confirm that the in vitro sensitivity of rat skeletal muscle to insulin is enhanced by 48 h of starvation. They suggest that this is due at least partially to an increase in insulin binding at physiological concentrations.


Alcohol consumption in relation to cardiovascular diseases and mortality: a systematic review of Mendelian randomization studies.
The causal effects of alcohol-in-moderation on cardiometabolic health are continuously debated. Mendelian randomization (MR) is an established method to address causal questions in observational studies. We performed a systematic review of the current evidence from MR studies on the association between alcohol consumption and cardiometabolic diseases, all-cause mortality and cardiovascular risk factors. We performed a systematic search of the literature, including search terms on type of design and exposure. We assessed methodological quality based on key elements of the MR design: use of a full instrumental variable analysis and validation of the three key MR assumptions. We additionally looked at exploration of non-linearity. We reported the direction of the studied associations. Our search yielded 24 studies that were eligible for inclusion. A full instrumental variable analysis was performed in 17 studies (71%) and 13 out of 24 studies (54%) validated all three key assumptions. Five studies (21%) assessed potential non-linearity. In general, null associations were reported for genetically predicted alcohol consumption with the primary outcomes cardiovascular disease (67%) and diabetes (75%), while the only study on all-cause mortality reported a detrimental association. Considering the heterogeneity in methodological quality of the included MR studies, it is not yet possible to draw conclusions on the causal role of moderate alcohol consumption on cardiometabolic health. As MR is a rapidly evolving field, we expect that future MR studies, especially with recent developments regarding instrument selection and non-linearity methodology, will further substantiate this discussion.


Induction of DNA damage and caspase-independent programmed cell death by vitamin E.
Vitamin E comprises 8 functionally unique isoforms and may be a suitable candidate for the adjuvant treatment of prostate cancer. In this study, we examined the ability of 2 vitamin E isoforms [α-tocotrienol (γ-TT) and δ-tocotrienol (δ-TT)] and 4 synthetic derivatives [γ- and δ-tocotrienol succinate (γ-TS, δ-TS), α-tocopheryl polyethylene glycol succinate (TPGS), and α-tocopheryl polyethylene glycol ether (TPGS-e)] of vitamin E to induce cell death in AR- (DU145 and PC-3) and AR+ (LNCaP) prostate cancer cell lines. Our results show that δ-TT and TPGS-e are the most effective isoform and synthetic derivative, respectively, of all compounds examined. Overall, the results of our study suggest that isoforms and synthetic derivatives of vitamin E have the potency to trigger both caspase-dependent and -independent DNA damage and dominant caspase-independent programmed cell death. The capacity of vitamin E to trigger caspase-independent programmed cell death suggests that it may be useful in the chemotherapy of prostate cancer since it may prevent the tumor resistance commonly associated with the use of classical chemotherapeutic agents that trigger caspase-dependent programmed cell death.


Mechanism of alpha-adrenergic excitation in bovine lymphatic smooth muscle.
Measurements were made, using the double sucrose-gap technique, of electrical and mechanical responses of bovine lymphatic smooth muscle to constant current pulses. After beta-blockade with 10(-6) M propranolol, stimulation of the alpha-receptors with norepinephrine (5 X 10(-6) M) depolarized the membrane and decreased membrane conductance. The depolarization and decrease in membrane conductance persisted in Li+- and choline-substituted low-Na+ solution, in methanesulfonate-substituted low-Cl- solution, and in Ca2+- free solution containing 1 mM ethyleneglycol-bis(beta-aminoethylether)-N, N'-tetraacetic acid. Tetraethylammonium (10 mM) did not itself affect membrane resistance nor did it block the increase in resistance due to norepinephrine. In contrast, cesium (10 mM) increased membrane resistance and prevented norepinephrine from increasing this further. As well as these effects on membrane resistance, norepinephrine (5 X 10(-6) M) increased the duration of the action potential, and this was accompanied by an increased force of contraction. Tetraethylammonium prolonged the action-potential plateau and potentiated norepinephrine's effect. These results suggest that norepinephrine is likely to increase the efficiency of lymphatic pumping due to both its positive inotropic effect and the improved safety margin for propagation resulting from the increase in membrane resistance. The latter effect may be due to the suppression of an outward K+ current.