Properties of four acute phase proteins: C-reactive protein, serum amyloid A protein, alpha 1-acid glycoprotein, and fibrinogen.
Four plasma proteins, referred to as positive acute phase proteins because of increases in concentration following inflammatory stimuli, are reviewed: C-reactive protein (CRP), serum amyloid A protein (SAA), alpha 1-acid glycoprotein (AAG), and fibrinogen. The CRP and SAA may increase in concentration as much as 1000-fold, the AAG and fibrinogen approximately twofold to fourfold. All are synthesized mainly in the liver, but each may be produced in a number of extrahepatic sites. The role of cytokines in induction of the acute phase proteins is discussed, particularly the multiple functional capabilities of interleukin-6 (IL-6). Other cytokines that regulate acute phase gene expression and protein synthesis include IL-1, tumor necrosis factor alpha, interferon gamma, as well as other stimulatory factors and cofactors. The physicochemical characteristics of each protein are reviewed together with the molecular biology. For each protein, the known biological effects are detailed. The following functions for CRP have been described: reaction with cell surface receptors resulting in opsonization, enhanced phagocytosis, and passive protection; activation of the classical complement pathway; scavenger for chromatin fragments; inhibition of growth and/or metastases of tumor cells; modulation of polymorphonuclear function; and a few additional diverse activities. The role of plasma SAA is described as a precursor of protein AA in secondary amyloidosis; other functions are speculative. AAG may play an immunoregulatory role as well as a role in binding a number of diverse drugs. In addition to clot formation, new data are described for binding of fibrinogen and fibrin to complement receptor type 3. Finally, the concentration of each protein is discussed in a wide variety of noninfectious and infectious disease states, particularly in connective tissue diseases. The quantification of the proteins during the course of various acute and chronic inflammatory disorders is useful in diagnosis, therapy, and in some cases, prognosis.


Multiple traversal absorption cell of minimum volume: design.
The design oThe author is with General Electric Company, Valley Forge Space Center, P.O. Box 8555, Philadelphia, Pennsylvania 19101.f a three-mirror absorption cell, first described by White and later improved on by Bernstein and Hertzberg, was analyzed by Edwards to be a unique optical configuration where the only aberration of consequence is astigmatism and associated image curvature. Edwards derived a formula whereby the astigmatic image length could be calculated. This paper relates cell design parameters in a manner that will attain the smallest volume consistent with the design objectives of the objective optics that precede the cell.


Genome-wide expansion and reorganization during grass evolution: from 30 Mb chromosomes in rice and Brachypodium to 550 Mb in Avena.
The BOP (Bambusoideae, Oryzoideae, and Pooideae) clade of the Poaceae has a common ancestor, with similarities to the genomes of rice, Oryza sativa (2n = 24; genome size 389 Mb) and Brachypodium, Brachypodium distachyon (2n = 10; 271 Mb). We exploit chromosome-scale genome assemblies to show the nature of genomic expansion, structural variation, and chromosomal rearrangements from rice and Brachypodium, to diploids in the tribe Aveneae (e.g., Avena longiglumis, 2n = 2x = 14; 3,961 Mb assembled to 3,850 Mb in chromosomes). Most of the Avena chromosome arms show relatively uniform expansion over the 10-fold to 15-fold genome-size increase. Apart from non-coding sequence diversification and accumulation around the centromeres, blocks of genes are not interspersed with blocks of repeats, even in subterminal regions. As in the tribe Triticeae, blocks of conserved synteny are seen between the analyzed species with chromosome fusion, fission, and nesting (insertion) events showing deep evolutionary conservation of chromosome structure during genomic expansion. Unexpectedly, the terminal gene-rich chromosomal segments (representing about 50 Mb) show translocations between chromosomes during speciation, with homogenization of genome-specific repetitive elements within the tribe Aveneae. Newly-formed intergenomic translocations of similar extent are found in the hexaploid A. sativa. The study provides insight into evolutionary mechanisms and speciation in the BOP clade, which is valuable for measurement of biodiversity, development of a clade-wide pangenome, and exploitation of genomic diversity through breeding programs in Poaceae.


Unraveling the substrate-metal binding site of ferrochelatase: an X-ray absorption spectroscopic study.
Ferrochelatase (EC 188.8.131.52), the terminal enzyme of the heme biosynthetic pathway, catalyzes the insertion of ferrous iron into the protoporphyrin IX ring. Ferrochelatases can be arbitrarily divided into two broad categories: those with and those without a [2Fe-2S] center. In this work we have used X-ray absorption spectroscopy to investigate the metal ion binding sites of murine and Saccharomyces cerevisiae (yeast) ferrochelatases, which are representatives of the former and latter categories, respectively. Co(2+) and Zn(2+) complexes of both enzymes were studied, but the Fe(2+) complex was only studied for yeast ferrochelatase because the [2Fe-2S] center of the murine enzyme interferes with the analysis. Co(2+) and Zn(2+) binding to site-directed mutants of the murine enzyme were also studied, in which the highly conserved and potentially metal-coordinating residues H207 and Y220 were substituted by residues that should not coordinate metal (i.e., H207N, H207A, and Y220F). Our experiments indicate four-coordinate zinc with Zn(N/O)(3)(S/Cl)(1) coordination for the yeast and Zn(N/O)(2)(S/Cl)(2) coordination for the wild-type murine enzyme. In contrast to zinc, a six-coordinate site for Co(2+) coordinated with oxygen or nitrogen was present in both the yeast and murine (wild-type and mutated) enzymes, with evidence of two histidine ligands in both. Like Co(2+), Fe(2+) bound to yeast ferrochelatase was coordinated by approximately six oxygen or nitrogen ligands, again with evidence of two histidine ligands. For the murine enzyme, mutation of both H207 and Y220 significantly changed the spectra, indicating a likely role for these residues in metal ion substrate binding. This is in marked disagreement with the conclusions from X-ray crystallographic studies of the human enzyme, and possible reasons for this are discussed.


Rhythmic emission of floral volatiles from Rosa damascena semperflorens cv. 'Quatre Saisons'.
The control of rhythmic emission of floral volatiles emitted from Rosa damascena semperflorens cv. 'Quatre Saisons' throughout floral development under various light regimes was studied. 2-Phenylethanol was the major volatile emitted in addition to monoterpenols, oxidised monoterpenols, monoterpenes and aromatic compounds. All detected volatiles were emitted rhythmically, with maximum peaks coinciding 8-10 h into a 12-h photoperiod. For some compounds a secondary, nocturnal peak was apparent. The primary and secondary maxima both occurred at approximately 24-h intervals. Rhythms appeared to be regulated endogenously: rhythmic emission continued upon exposure to continuous light or continuous darkness, and a phase shift in emission was induced upon inversion of the photoperiod. Additionally, emission continued after flower excision. A similar profile of free volatiles was stored within the floral tissue, together with glycosidic forms of 2-phenylethanol (>99% beta-D-glucoside), benzyl alcohol, citronellol and geraniol. Regression analysis indicated a significant decrease in glycosylated 2-phenylethanol through the photoperiod. These results suggest that glycosylated volatiles stored within petals may be a source of rhythmically emitted volatiles.


Use of computer program for diagnosing jaundice in district hospitals and specialized liver unit.
A computer-assisted model for diagnosing jaundice has been adapted for use on the University of London C.D.C. 7600 computer via an on-line terminal at King's College Hospital to provide a rapid turn-round time. The model was used prospectively in the diagnosis of 219 patients--135 seen in a specialized liver unit and 84 seen in one of four district hospitals in south-east London--with an overall accuracy in distinguishing among 11 different causes of jaundice of 69% and 62% respectively. These figures rose to 77% and 88% respectively when only those patients in whom the final diagnosis reached a "certain" probability were considered. When used to distinguish between a medical and a surgical cause of jaundice the accuracy was 86% in the liver unit and 77% in the district hospitals, rising to 95% in both series for those with a diagnosis of certain probability. The proposed improvements to the model--namely, the use of two deparate data bases and more diagnoses within the matrix--should be improve the accuracy even further. In practice the rapid feedback to the clinicians looking after patients provided help in managing difficult cases.


[New trends in the treatment of liver abscesses].
The authors share their experiences with treatment of 85 patients with abscesses of the liver aged from 17 to 83 years. The size of abscesses was from 2.5 to 23 cm in diameter. For the topical diagnostics the following methods were used: ultrasound scanning, computed tomography, scintigraphy, diagnostic puncture biopsy of the liver, laparoscopy etc. Decision between the methods of operative treatment depended on the concrete clinical situation. Both open and minimally invasive methods were used. Hydropressive technologies and ozone therapy were used for better sanitation of the abscess cavity. A new method of the assisted minimally invasive intervention was developed especially for treatment of patients with large abscesses of the liver. The new technologies allowed to reduce the amount of postoperative complications and to make the time of staying at the hospital substantially shorter.


Effects of omeprazole and famotidine on fibroblast growth factor-2 during artificial gastric ulcer healing in humans.
Endoscopic mucosal resection is a widely accepted technique for the treatment of early gastric cancers, while large ulcers induced by the treatment should be treated promptly. This study aimed to compare the effects of omeprazole and famotidine on ulcer healing and fibroblast growth factor-2 levels in gastric ulcers induced by endoscopic mucosal resection. Sixteen patients indicated for endoscopic mucosal resection were enrolled. They were treated by using either omeprazole (n = 8) or famotidine (n = 8) after endoscopic mucosal resection. Endoscopy was performed on days 4, 7 and 28 during each treatment period. Levels of fibroblast growth factor-2 in biopsy specimens were measured by using an enzyme-linked immunosorbent assay at the time of and after endoscopic mucosal resection. Histological variables were also assessed. Ulcer healing rates under endoscopy were not different between the two treatment groups. In both groups, levels of fibroblast growth factor-2 slightly increased on day 4, but the values were not different at any time point. There were no differences in histological variables on days 4 and 7, but fibromuscular hyperplasia was significantly greater in the omeprazole group than in the famotidine group on day 28 (P < 0.05). Omeprazole and famotidine have an equivalent value for the treatment of ulcers induced by endoscopic mucosal resection. While omeprazole had a more potent effect on fibromuscular hyperplasia than did famotidine, such a difference does not seem to be explained by fibroblast growth factor-2.


Characterization of three potato lipoxygenases with distinct enzymatic activities and different organ-specific and wound-regulated expression patterns.
Lipoxygenases are ubiquitous enzymes in eukaryotes. In plants, lipoxygenases are involved in the synthesis of the hormone jasmonic acid that regulates plant responses to wounding and, in addition, is an inducer of tuberization in potato. We have isolated potato lipoxygenase cDNA clones. From their deduced amino acid sequences, three distinct classes are defined (Lox1, Lox2, and Lox3). They are encoded in gene families that display organ-specific expression, lox1 being expressed mostly in tubers and roots, lox2 in leaves, and lox3 in leaves and roots. Consistent with their organ-specific expression pattern, Lox1 expressed in bacteria preferentially uses as substrate linoleic acid, abundant in membrane lipids of tubers, whereas linolenic acid, prevalent in leaves, is the preferred substrate for the other two classes of lipoxygenase. Analyses on reaction products of the enzymes expressed in bacteria reveal that Lox1 primarily produces 9- hydroperoxides. In contrast, the jasmonic acid precursor, 13-hydroperoxylinolenic acid, is the major product of the action of Lox2 and Lox3 on linolenic acid. Upon wounding, the levels of Lox2 and Lox3 transcripts rise markedly in leaves. While Lox3 mRNA accumulation peaks as early as 30 min after wounding, Lox2 shows a steady increase over a 24-h time course, suggesting different roles for these lipoxygenase isoforms in the synthesis of the plant hormone jasmonic acid.


Systemic lupus erythematosus is associated with lower risk of hepatitis B virus infection: A multivariable Mendelian randomization study in East Asian population.
The relationship between systemic lupus erythematosus (SLE) and hepatitis B virus (HBV) infection is still unclear. We conducted a two-sample Mendelian randomization (MR) analysis using summary statistics from genome-wide association studies for SLE and HBV infection in individuals of East Asian ancestry. The inverse-variance weighted (IVW) method, weighted median (WM) method, and MR-Egger method were used to estimate the causal effect of SLE on HBV infection. Additionally, we performed a multivariable MR analysis adjusting for the effects of body mass index and rheumatoid arthritis. This MR study included a total of 225 106 individuals of East Asian ancestry, comprising 5616 cases and 219 490 controls. The IVW method (OR: 0.79, p = 3.34E-08) and the WM method (OR: 0.79, p = 9.09E-06) revealed a causal relationship between genetically predicted SLE and a low risk of HBV infection. The multivariable MR analysis still suggested a low risk of HBV infection associated with SLE (OR: 0.83, p = 2.89E-06). Our MR analysis supports a causal relationship between SLE and a low risk of HBV infection in individuals of East Asian ancestry.


Global surveillance and control of hepatitis C. Report of a WHO Consultation organized in collaboration with the Viral Hepatitis Prevention Board, Antwerp, Belgium.
Hepatitis C is a global health problem caused by infection with the hepatitis C virus. Although representative prevalence data are not available from many countries, available data indicate that approximately 3% of the world's population is infected with HCV. It is estimated that as many as 170 million persons world-wide may be infected with HCV. In many countries, the exact magnitude of the problem and the relative contribution of the various routes of transmission have not been defined with population-based studies. Wherever possible such studies should be performed to enable countries to estimate the burden of hepatitis C disease, to prioritize their preventative measures and to make the most appropriate use of available resources. To assess hepatitis C on a global scale, the World Health Organization (WHO) organized a consultation of international experts, in order to review the public health aspects related to hepatitis C infection and to make recommendations for its prevention and control.


Liver transplantation as a rescue surgery after failure of embolization of a giant hepatic artery pseudoaneurysm.
We present the case of a male diagnosed with a giant hepatic artery aneurysm, which first presented with pain and hemorrhage due to a partial rupture of the aneurysm. After discarding treatment with a stent or surgery due to the wide extension, we chose to embolize the hepatic artery with coils. However, the progress was unfavorable after the procedure, with the appearance of liver failure that was resolved by an urgent liver transplantation. Giant hepatic artery pseudoaneurysms are an infrequent entity and their management is a great challenge. The diagnosis is usually delayed due to non-specific clinical signs and the life of the patient may be threatened in the case of rupture. Thus, endovascular or surgical treatment is recommended. Aneurysm embolization or ligation has been described in the literature as a valid treatment option in cases where revascularization by stent or bypass is not possible, as it preserves the viability of the liver due to the portal flow and collateral arteries. However, in the case of the failure of these treatments, liver transplantation is a rescue option.


Lamotrigine in the maintenance treatment of bipolar disorder.
Bipolar disorder is a chronic mental disorder with repetitive mania/hypomania as well as depressive episodes, which eventually results in marked impairment in overall functioning and health-related quality of life. A worldwide prevalence rate of 2.4% has been reported. The risk of suicide is higher in people with bipolar disorder than those with other mental disorders. Therefore, effective management of bipolar disorder in the maintenance period is warranted to minimize the risk of relapse or recurrence. Although lithium has been the standard treatment of bipolar disorder for many years, it is associated with adverse effects and teratogenicity. Lamotrigine is approved to be expected for prevention of recurrence for the maintenance treatment of bipolar disorder. In addition, lamotrigine is as effective as lithium. Therefore, we performed a systematic review to confirm the efficacy and safety of lamotrigine in the maintenance treatment of bipolar disorder. To assess the efficacy and tolerability of lamotrigine in the maintenance treatment of bipolar disorder. We searched Ovid MEDLINE, Embase, PsycINFO, the Cochrane Common Mental Disorders Group's Specialized Register (CCMDCTR) and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to 21 May 2021. We also searched international trial registries and contacted experts in the field. We included randomized controlled trials enrolling adults with bipolar disorder who were treated with lamotrigine, placebo or lithium. Two reviews authors independently checked the eligibility of studies and extracted data using a standardized form. Data extracted included study characteristics, participant characteristics, intervention details, settings, and outcome measures in the term of efficacy and tolerability. Study information were then entered into RevMan web. We included 11 studies with a total of 2314 participants in this review; 1146 were randomized to lamotrigine, 869 were randomized to placebo and, 299 to lithium. We rated all studies as having an unclear risk of bias in at least one domain of Cochrane's tool for assessing risk of bias, with the most commonly observed weakness being selection bias (random sequence generation and allocation concealment). We judged five studies to be at a high risk of detection bias (blinding of outcome assessment). These potential biases pose as major threat to the validity of the included studies in this review. Outcomes of efficacy showed a possible advantage of lamotrigine over placebo. The estimated risk ratio (RR) for recurrence of manic symptom at one year as measured by the Young Mania Rating Scale (YMRS) was 0.67, (95% confidence interval (CI) 0.51 to 0.87; 3 studies, 663 participants; low-certainty evidence) in favor of lamotrigine. The RR of clinical worsening with the need for additional psychotropic treatment (RR 0.82, 95% CI 0.70 to 0.98; 4 studies, 756 participants) based on moderate-certainty evidence. The possible benefits of lamotrigine were also seen for the outcome of treatment withdrawal due to any reason at 6-12 months after treatment (RR 0.88, 95% CI 0.78 to 0.99; 4 studies, 700 participants; moderate-certainty evidence). Regarding tolerability, our analyses showed that the incidence rates of adverse effects were similar between the lamotrigine group and the placebo group (short-term effect: RR 1.07, 95% CI 0.81 to 1.42; 5 studies, 1138 participants; very low-certainty evidence; long-term effect: RR 0.97, 95% CI 0.77 to 1.23; 4 studies, 756 participants; moderate-certainty evidence). In the comparison between lamotrigine and lithium, efficacy was similar between groups except for recurrence of mania episode at one year. Recurrence of manic symptoms was higher in the lamotrigine group than that of the lithium group (RR 2.13, 95% CI 1.32 to 3.44; 3 studies, 602 participants; moderate-certainty evidence). Analysis of adverse effects at 6-12 months showed that a lower proportion of participants experienced at least one adverse effect when treated with lamotrigine compared to lithium (RR 0.70, 95% CI 0.51 to 0.96; 4 studies, 691 participants; moderate-certainty evidence). Low- to moderate-certainty evidence collectively suggests that lamotrigine may be superior to placebo as a treatment modality for bipolar disorder. In comparison to lithium, people with bipolar disorder seem to tolerate lamotrigine better in the long run; however, the demonstrated efficacy in the maintenance of bipolar disorder was similar between the two groups.


HSV vectors for gene therapy of chronic pain.
Chronic pain is a serious debilitating condition affecting a large number of individuals and with substantial societal impact in terms of quality-of-life and absence from work. Current therapies often exhibit activity at sites other than the nervous system and so are limited by 'off-target' adverse effects. These adverse effects often prevent the administration of an effective therapeutic dose of the approved drug(s). Viral vectors have the potential to deliver and express short-lived, but potent therapeutic peptides in the nervous system. Vector-expressed peptides interrupt or modulate the transmission of nociceptive signals without systemic distribution or off-target effects. This review focuses on the use of non-replicating HSV-based vectors that are introduced into the skin and transduce dorsal root ganglia to express analgesic molecules locally in the spinal cord. Data from preclinical animal models as well as studies that support early phase clinical trials from 2002 to 2008 are described.


Stochastic tunneling and metastable states during the somatic evolution of cancer.
Tumors initiate when a population of proliferating cells accumulates a certain number and type of genetic and/or epigenetic alterations. The population dynamics of such sequential acquisition of (epi)genetic alterations has been the topic of much investigation. The phenomenon of stochastic tunneling, where an intermediate mutant in a sequence does not reach fixation in a population before generating a double mutant, has been studied using a variety of computational and mathematical methods. However, the field still lacks a comprehensive analytical description since theoretical predictions of fixation times are available only for cases in which the second mutant is advantageous. Here, we study stochastic tunneling in a Moran model. Analyzing the deterministic dynamics of large populations we systematically identify the parameter regimes captured by existing approaches. Our analysis also reveals fitness landscapes and mutation rates for which finite populations are found in long-lived metastable states. These are landscapes in which the final mutant is not the most advantageous in the sequence, and resulting metastable states are a consequence of a mutation-selection balance. The escape from these states is driven by intrinsic noise, and their location affects the probability of tunneling. Existing methods no longer apply. In these regimes it is the escape from the metastable states that is the key bottleneck; fixation is no longer limited by the emergence of a successful mutant lineage. We used the so-called Wentzel-Kramers-Brillouin method to compute fixation times in these parameter regimes, successfully validated by stochastic simulations. Our work fills a gap left by previous approaches and provides a more comprehensive description of the acquisition of multiple mutations in populations of somatic cells.


[Treatment of hemorrhagic congestive gastropathy with TIPS implantation. Pilot study].
Minimally invasive percutaneous procedures has an important place in internal medicine. In this concept is included a transjugular intrahepatic portosystemic shunts (TIPS). In this pilot study we describe the indication of this therapeutic modality in three cirrhotic patients with hemorrhagic congestive gastropathy unresponsive to infusion of drugs that reduce the portal pressure. All of them were treated by TIPS and control of gastric bleeding occurred in all. One of these showed partial stenosis of the wallstent, treated by prosthesis dilatation. Another developed portosystemic encephalopathy controlled by usual therapeutic measures in the other we implanted two TIPS to obtain a low pressure level of the hepatic-portal gradient. They had no further necessity of blood transfusion, with better hemodynamic conditions and biochemical tests with reduction of the values of the GHP. We conclude that TIPS may be useful to treat hemorrhagic congestive gastropathy acting like a bridge for subsequent elective liver transplantation under good clinical and hemodynamic conditions.


Anatomy and chromosomes of two intersexual dasyurid marsupials.
The intersexual phenotypes of marsupials with XXY and XO chromosome constitutions imply that not all sexual dimorphisms are under the control of testicular hormones and, ultimately, the SRY gene on the Y chromosome. It has been hypothesised that there is a gene on the X chromosome that determines whether either a scrotum will form (one copy of the gene) or a pouch with teats (two copies of the gene). Here, we describe the anatomy and chromosomes of two intersexual dasyurid marsupials. One, a Dasyuroides byrnei, had a pouch, but the reproductive tract was essentially male. The other, a Sminthopsis douglasi, had a hemipouch and a hemiscrotum and the reproductive tract was essentially female. The S. douglasi was a mosaic for cells with an apparently normal 2n = 14, XX female karyotype and cells with 2n = 14 plus (usually) two dot-like supernumerary elements 2n = 14, XX + 2B. The D. byrnei cells examined also had a 2n = 14, XX + 2B karyotype. In fibroblasts from the male and female sides of the S. douglasi, it was possible to assign the 2n = 14, XX karyotype to the male side and the 2n = 14, XX + 2B to the female side.


Personality hardiness: an essential attribute for the ICU nurse?
Staff turnover has been a persistent problem in critical care units, magnified by stress and burn-out in nurses. Researchers studying the concept of personality hardiness over the past 20 years have suggested that it may play a protective role against stress and burn-out. Those who are able to effectively cope with stress and adapt to the uncertain environment of the ICU are less likely to leave it prematurely. The concept of personality hardiness is explored as it relates to adaptation of nurses to the ICU. Suggestions for development of hardiness are based on a review of relevant literature.


Angiopoietin-like protein 2 accelerates carcinogenesis by activating chronic inflammation and oxidative stress.
Chronic inflammation has received much attention as a risk factor for carcinogenesis. We recently reported that Angiopoietin-like protein 2 (Angptl2) facilitates inflammatory carcinogenesis and metastasis in a chemically induced squamous cell carcinoma (SCC) of the skin mouse model. In particular, we demonstrated that Angptl2-induced inflammation enhanced susceptibility of skin tissues to "preneoplastic change" and "malignant conversion" in SCC development; however, mechanisms underlying this activity remain unclear. Using this model, we now report that transgenic mice overexpressing Angptl2 in skin epithelial cells (K14-Angptl2 Tg mice) show enhanced oxidative stress in these tissues. Conversely, in the context of this model, Angptl2 knockout (KO) mice show significantly decreased oxidative stress in skin tissue as well as a lower incidence of SCC compared with wild-type mice. In the chemically induced SCC model, treatment of K14-Angptl2 Tg mice with the antioxidant N-acetyl cysteine (NAC) significantly reduced oxidative stress in skin tissue and the frequency of SCC development. Interestingly, K14-Angptl2 Tg mice in the model also showed significantly decreased expression of mRNA encoding the DNA mismatch repair enzyme Msh2 compared with wild-type mice and increased methylation of the Msh2 promoter in skin tissues. Msh2 expression in skin tissues of Tg mice was significantly increased by NAC treatment, as was Msh2 promoter demethylation. Overall, this study strongly suggests that the inflammatory mediator Angptl2 accelerates chemically induced carcinogenesis through increased oxidative stress and decreased Msh2 expression in skin tissue. Angptl2-induced inflammation increases susceptibility to microenvironmental changes, allowing increased oxidative stress and decreased Msh2 expression; therefore, Angptl2 might be a target to develop new strategies to antagonize these activities in premalignant tissue.


Epidemiology of 21-hydroxylase deficiency in Singapore.
We report the incidence and epidemiology of 21-hydroxylase deficiency in Singapore, based on a retrospective study of all known patients diagnosed with classical 21-hydroxylase deficiency in the past 21 years. The database was obtained from the case registry and questionnaire methodology, with 100% coverage of all practising pediatricians in Singapore. There were 42 patients affected with 21-hydroxylase deficiency in 964,558 live births over 21 years, comprising 64.3% salt wasters and 35.7% simple virilizers, of whom 50.0% were males and 50.0% females. The incidence of classical 21-hydroxylase deficiency is 4.5 per 100,000 live births, with a carrier frequency of 1:76, and a gene frequency of 0.0067. Although retrospective studies have inherent limitations, the gender and phenotype ratios suggest that the data provide a crude incidence level. This study underscores the necessity for prospective neonatal screening, so that the benefits of early diagnosis and treatment can be realized.


Evidence that Mental Contrasting Reduces Health Information Avoidance.
Although learning health information is beneficial for physical well-being, many people opt to avoid learning this information due to its potentially threatening nature. Such avoidance can lead to delays in seeking treatment. This study tested the effectiveness of a self-regulation technique, mental contrasting (MC), specifically MC of a negative future with a positive current reality, in reducing health information avoidance regarding skin cancer (melanoma). We hypothesized that participants who engaged in MC would be more likely to choose to learn about their melanoma risk than those who completed a control, reflection activity. We conducted a randomized controlled trial (N = 354). Participants were assigned to complete a MC or reflection (control) exercise prior to filling out a melanoma risk calculator. Participants were then asked whether they wanted to learn their melanoma risk, and how much information they would like to know. Chi-Square tests revealed that MC decreased melanoma risk information avoidance compared to the reflection activity (12% vs. 23.4%) but did not make participants more likely seek additional information. MC is a brief, engaging, and effective strategy for reducing health information avoidance that could prove useful in medical settings.


Customization of entropy estimation measures for human arterial hypertension records segmentation.
This paper describes a new application of the recently developed Coefficient of Sample Entropy (CosEn) measure. This entropy estimator is specially suited for cases where the length of the time series is extremely short. CosEn has already been used successfully to characterize and detect atrial fibrillation, using as few as 12 heartbeats. We have customized the methodology employed for heartbeat interval series to blood pressure hypertensive (BPHT) human records. Little can be found about BPHT records and its nonlinear regularity analysis. The method described in this paper provides a good segmentation between control and pathologic groups, based on the corresponding labeled BPHT records. The experimental dataset was drawn from the available records at the Hypertension Unit of the University Hospital of Mostoles, in Spain. The hypertension related variables studied were systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MBP). The hypothesis test yielded the following results in each case: acceptance probability of 0 for SBP, 0.005 for DBP and 0 for MBP. The confidence intervals for the three variables were nonoverlapping.


Statistical Approaches to Characterize Functional Connectivity in Brain and Physiologic Networks on a Single-Subject Basis.
The trend toward personalized medicine necessitates drawing conclusions from descriptive indexes of physiopathological states estimated from individual recordings of biomedical signals, using statistical analyses that focus on subject-specific differences between experimental conditions. In this context, the present work introduces an approach to assess functional connectivity in brain and physiologic networks by pairwise information-theoretic measures of coupling between signals, whose significance and variations between conditions are statistically validated on a single-subject basis through the use of surrogate and bootstrap data analyses. The approach is illustrated on single-subject recordings of (i) resting-state functional magnetic resonance imaging (rest-fMRI) signals acquired in a pediatric patient with hepatic encephalography associated to a portosystemic shunt and undergoing liver vascular shunt correction, and of (ii) cardiovascular and cerebrovascular time series acquired at rest and during head-up tilt in a subject suffering from orthostatic intolerance.


Clozapine-induced anemia: A case-report .
Clozapine, an atypical antipsychotic, can cause potentially life-threating side effects such as agranulocytosis. Our case presents a picture of severe anemia without any depression of the white cells or platelet lines. A 36-year-old man with treatment-resistant schizophrenia was admitted to the Psychiatric Unit for therapy assessment. After admission, he was gradually switched to clozapine treatment, 400 mg/d. General laboratory test results were normal, with a hemoglobin (Hb) level of 15.2 g/dL. The Hb level gradually decreased to 7.1 g/dL 10 weeks after switching to clozapine, when the patient underwent blood transfusion and clozapine therapy was stopped. No evidence of bleeding was noted. The reticulocyte count was less than 60.000/µL. Other anemia causes were excluded. Bone marrow aspiration performed at 10 weeks revealed red cell hypocellularity, while myelopoietic and megakaryocytic cell lines were normal. All these findings confirmed the diagnosis of pure red cell aplasia. The Hb level gradually increased to 13.3 g/dL 4 weeks after clozapine discontinuation, and the patient was discharged with olanzapine 5 mg/d. Clozapine has been reported to cause hematological abnormalities. In our patient, the diagnosis of pure red cell aplasia was made on the basis of severe and selective anemia, reticulocytopenia, and erythroid aplasia. The pathogenesis of hematologic abnormalities due to clozapine treatment is not known. Suggested mechanisms include a direct toxic effect of clozapine, or its metabolite, on the erythroid precursor cells, or formation of a drug-antibody complex. These aspects call for further and deeper research and reports of clinical observations.


Maternal and infant hospitalization costs associated with maternal pre-pregnancy body mass index in California, 2007-2011.
In the United States, the number of pregnant women who are overweight or obese is increasing. While such individuals are at increased risk of pregnancy complications, data regarding costs associated with pre-pregnancy body mass index (BMI) and maternal and infant outcomes are lacking. To estimate maternal and infant costs associated with pre-pregnancy BMI in a large cohort of pregnant women. We conducted a retrospective cohort study of women with singleton, non-anomalous births in California from 2007 to 2011. Women with preexisting diabetes mellitus and chronic hypertension were excluded. Hospitalization costs were estimated separately for women and infants using hospital charges adjusted using a cost-to-charge ratio. These costs included hospitalization costs for admission for delivery only. We estimated the differences in median costs between seven categories of pre-pregnancy BMIs, including underweight (BMI <18.5), normal weight (BMI 18.5-24.9), overweight (BMI 25.0-29.9), class I obesity (BMI 30.0-34.9), class II obesity (BMI 35.0-39.9), class III obesity (BMI 40.0-49.9) and obesity with BMI ≥50.0. We also performed stratified analyses by mode of delivery and gestational age at delivery. We examined the length of stay for women and infants and estimated the gestational age at delivery. Analyses were conducted utilizing Kruskal-Wallis equality-of-populations rank tests with a significance cutoff of 0.05. In a California cohort of 1,722,840 women, 787,790 (45.7%) had a pre-pregnancy BMI that was considered overweight or obese. The median maternal and infant costs of each pre-pregnancy BMI strata were significantly different when compared to other strata, with underweight and normal weight women having the lowest median costs ($11,581 and $11,721, respectively) and the most obese category (BMI ≥50) having the highest costs ($15,808). When stratified by mode of delivery and gestational age at delivery, this remained true. Hospitalization costs for women and infants with severe maternal morbidity were also significantly different based on maternal BMI. The hospitalization costs associated with each strata of BMI were significantly different when compared to each other and when stratified by mode of delivery and prematurity. This analysis allows for a greater understanding of the health care costs associated with different maternal pre-pregnancy BMI classes.


Short communication: Effect of cross ventilation with or without evaporative pads on core body temperature and resting time of lactating cows.
A trial was performed to assess the effect of evaporative pads on core body temperature (CBT) and lying behavior of lactating Holstein cows housed in cross-ventilated freestall facilities in a humid environment. This trial was undertaken in 2 barns equipped with (EP) or without (NP) evaporative pads. Each facility had 4 pens, 1 baffle/pen, and a nominal width of 122 m. Stocking density was higher (123.4 vs. 113.1%) and freestalls were slightly shorter (2.3 vs. 2.4 m) and narrower (1.16 vs. 1.21 m) in EP compared with NP barns. In each pen, lying behavior of 20 cows was monitored using electronic data loggers that recorded at 1-min intervals. A subset (n=14) of these cows within each pen were also fitted with temperature loggers attached to blank controlled intravaginal drug release devices to determine CBT every 5 min. Ambient conditions were collected every 15 min. Individual cow lying duration and lying bouts were assessed for each cow, as well as time spent standing and CBT within the following categories: CBT <38.6°C, and CBT >38.6, >38.9, >39.2, >39.4, and >39.7°C. These variables were analyzed using pen as the experimental unit, with cow and day as additional random effects. The average maximum ambient conditions over the 9 d were 25°C and 78.74% relative humidity. No differences were observed in lying duration and number of lying bouts over the 9-d period, with overall means of 696±31 min/d and 12.6±0.5 bouts/d. The EP cows spent 170 min/d longer with a CBT <38.6°C and 107 min/d less with CBT >39.2°C than did NP cows. Cooling with evaporative pads tended to increase time spent lying with a CBT >8.6°C and lying bouts/d for EP cows versus NP cows. Results from this trial show that even under mild heat stress, evaporative cooling in cross-ventilated facilities can decrease CBT and tended to increase lying time.


Genetic reconstruction of a bullfrog invasion to elucidate vectors of introduction and secondary spread.
Reconstructing historical colonization pathways of an invasive species is critical for uncovering factors that determine invasion success and for designing management strategies. The American bullfrog (Lithobates catesbeianus) is endemic to eastern North America, but now has a global distribution and is considered to be one of the worst invaders in the world. In Montana, several introduced populations have been reported, but little is known of their sources and vectors of introduction and secondary spread. We evaluated the genetic composition of introduced populations at local (Yellowstone River floodplain) and regional (Montana and Wyoming) scales in contrast to native range populations. Our objectives were to (1) estimate the number of introductions, (2) identify probable native sources, (3) evaluate genetic variation relative to sources, and (4) characterize properties of local- and regional-scale spread. We sequenced 937 bp of the mitochondrial cytochrome b locus in 395 tadpoles collected along 100 km of the Yellowstone River, from three additional sites in MT and a proximate site in WY. Pairwise ΦST revealed high divergence among nonnative populations, suggesting at least four independent introductions into MT from diverse sources. Three cyt b haplotypes were identical to native haplotypes distributed across the Midwest and Great Lakes regions, and AMOVA confirmed the western native region as a likely source. While haplotype (H d = 0.69) and nucleotide diversity (π = 0.005) were low in introduced bullfrogs, the levels of diversity did not differ significantly from source populations. In the Yellowstone, two identified haplotypes implied few introduction vectors and a significant relationship between genetic and river distance was found. Evidence for multiple invasions and lack of subsequent regional spread emphasizes the importance of enforcing legislation prohibiting bullfrog importation and the need for continuing public education to prevent transport of bullfrogs in MT. More broadly, this study demonstrates how genetic approaches can reveal key properties of a biological invasion to inform management strategies.


Trabecular bone microdamage and microstructural stresses under uniaxial compression.
The balance between local remodeling and accumulation of trabecular bone microdamage is believed to play an important role in the maintenance of skeletal integrity. However, the local mechanical parameters associated with microdamage initiation are not well understood. Using histological damage labeling, micro-CT imaging, and image-based finite element analysis, regions of trabecular bone microdamage were detected and registered to estimated microstructural von Mises effective stresses and strains, maximum principal stresses and strains, and strain energy density (SED). Bovine tibial trabecular bone cores underwent a stepwise uniaxial compression routine in which specimens were micro-CT imaged following each compression step. The results indicate that the mode of trabecular failure observed by micro-CT imaging agreed well with the polarity and distribution of stresses within an individual trabecula. Analysis of on-axis subsections within specimens provided significant positive relationships between microdamage and each estimated tissue stress, strain and SED parameter. In a more localized analysis, individual microdamaged and undamaged trabeculae were extracted from specimens loaded within the elastic region and to the apparent yield point. As expected, damaged trabeculae in both groups possessed significantly higher local stresses and strains than undamaged trabeculae. The results also indicated that microdamage initiation occurred prior to apparent yield at local principal stresses in the range of 88-121 MPa for compression and 35-43 MPa for tension and local principal strains of 0.46-0.63% in compression and 0.18-0.24% in tension. These data provide an important step towards understanding factors contributing to microdamage initiation and establishing local failure criteria for normal and diseased trabecular bone.


[Gut-heart axis : How gut bacteria influence cardiovascular diseases].
The view of humans as holobionts consisting of eukaryotic host cells and associated prokaryotic organisms, has opened up a new perspective on cardiovascular pathophysiology. In particular, intestinal bacteria influence the cell and organ functions of the host. Intestinal bacteria represent a metabolically active community whose composition and function can influence cardiovascular health and disease. The interaction between the intestinal microbiota and the heart occurs via metabolites of bacterial origin, which are resorbed in the intestine and distributed via the circulation. Bacterial metabolites are produced from food components, which in turn emphasizes the importance of nutrition. Some of these metabolites, such as trimethylamine N‑oxide (TMAO), can exacerbate cardiovascular pathologies. Short-chain fatty acids (SCFA) in turn are considered to be protective metabolites. The host's immune system is an important target for these metabolites and explains much of their effects. In the future, the targeted manipulation of intestinal bacteria could help to prevent the development and progression of cardiovascular diseases.


Degradation of endothelial glycocalyx in Tanzanian children with falciparum malaria.
A layer of glycocalyx covers the vascular endothelium serving important protective and homeostatic functions. The objective of this study was to determine if breakdown of the endothelial glycocalyx (eGC) occurs during malaria infection in children. Measures of eGC integrity, endothelial activation, and microvascular reactivity were prospectively evaluated in 146 children: 44 with moderately severe malaria (MSM), 42 with severe malaria (SM), and 60 healthy controls (HC). Biochemical measures of eGC integrity included plasma syndecan-1 and total urinary glycosaminoglycans (GAG). Side-stream dark field imaging was used to quantitatively assess integrity of eGC. Plasma angiopoietin-2 (Ang-2) was measured as a marker of endothelial activation and also as a possible mediator of eGC breakdown. Our results show that urinary GAG, syndecan-1, and Ang-2 were elevated in patients with MSM and SM compared with HC. Syndecan-1 and GAG levels correlated significantly with each other and with plasma Ang-2. The eGC breakdown products also inversely correlated significantly with hemoglobin and platelet count. In the MSM group, imaging results provided further evidence for eGC degradation. Although not correlated with markers of eGC degradation, vascular function (assessed by non-invasive near infrared spectroscopy [NIRS]) demonstrated reduced microvascular reactivity, particularly affecting the SM group. Our findings provide further evidence for breakdown of eGC in falciparum malaria that may contribute to endothelial activation and adhesion of parasitized red blood cells, with reduced nitric oxide formation, and vascular dysfunction.


Use of sleep hygiene in the treatment of insomnia.
Sleep hygiene (SH) refers to a list of behaviors, environmental conditions, and other sleep-related factors that can be adjusted as a stand-alone treatment or component of multimodal treatment for patients with insomnia. This paper presents a review of SH, how this concept has been applied and often modified over the past 24 years, and how it relates to the modern sleep disorder nosology, particularly Inadequate Sleep Hygiene. Although a recognized and commonly utilized treatment option, there is no absolute consensus about which steps must be included to constitute SH treatment, and there is much overlap between SH and other cognitive-behavioral treatments for insomnia such as Stimulus Control Procedures and Sleep Restriction Therapy. The literature on the effects of manipulations of individual components of SH under experimental conditions (e.g. effects of presleep alcohol or caffeine intake) in normal sleepers show mixed results. Empirical data demonstrating the role of poor SH as a contributor to insomnia, or showing that good SH improves sleep in patients with insomnia, is not available. Instead of evaluating the impact of a comprehensive list of SH recommendations, a focus on guidelines for use of individual rules is needed.


Polygonal tundra geomorphological change in response to warming alters future CO2 and CH4 flux on the Barrow Peninsula.
The landscape of the Barrow Peninsula in northern Alaska is thought to have formed over centuries to millennia, and is now dominated by ice-wedge polygonal tundra that spans drained thaw-lake basins and interstitial tundra. In nearby tundra regions, studies have identified a rapid increase in thermokarst formation (i.e., pits) over recent decades in response to climate warming, facilitating changes in polygonal tundra geomorphology. We assessed the future impact of 100 years of tundra geomorphic change on peak growing season carbon exchange in response to: (i) landscape succession associated with the thaw-lake cycle; and (ii) low, moderate, and extreme scenarios of thermokarst pit formation (10%, 30%, and 50%) reported for Alaskan arctic tundra sites. We developed a 30 × 30 m resolution tundra geomorphology map (overall accuracy:75%; Kappa:0.69) for our ~1800 km² study area composed of ten classes; drained slope, high center polygon, flat-center polygon, low center polygon, coalescent low center polygon, polygon trough, meadow, ponds, rivers, and lakes, to determine their spatial distribution across the Barrow Peninsula. Land-atmosphere CO2 and CH4 flux data were collected for the summers of 2006-2010 at eighty-two sites near Barrow, across the mapped classes. The developed geomorphic map was used for the regional assessment of carbon flux. Results indicate (i) at present during peak growing season on the Barrow Peninsula, CO2 uptake occurs at -902.3 10(6) gC-CO2 day(-1) (uncertainty using 95% CI is between -438.3 and -1366 10(6) gC-CO2 day(-1)) and CH4 flux at 28.9 10(6) gC-CH4 day(-1) (uncertainty using 95% CI is between 12.9 and 44.9 10(6) gC-CH4 day(-1)), (ii) one century of future landscape change associated with the thaw-lake cycle only slightly alter CO2 and CH4 exchange, while (iii) moderate increases in thermokarst pits would strengthen both CO2 uptake (-166.9 10(6) gC-CO2 day(-1)) and CH4 flux (2.8 10(6) gC-CH4 day(-1)) with geomorphic change from low to high center polygons, cumulatively resulting in an estimated negative feedback to warming during peak growing season.


The human endosomal sorting complex required for transport (ESCRT-I) and its role in HIV-1 budding.
Efficient human immunodeficiency virus type 1 (HIV-1) budding requires an interaction between the PTAP late domain in the viral p6(Gag) protein and the cellular protein TSG101. In yeast, Vps23p/TSG101 binds both Vps28p and Vps37p to form the soluble ESCRT-I complex, which functions in sorting ubiquitylated protein cargoes into multivesicular bodies. Human cells also contain ESCRT-I, but the VPS37 component(s) have not been identified. Bioinformatics and yeast two-hybrid screening methods were therefore used to identify four novel human proteins (VPS37A-D) that share weak but significant sequence similarity with yeast Vps37p and to demonstrate that VPS37A and VPS37B bind TSG101. Detailed studies produced four lines of evidence that human VPS37B is a Vps37p ortholog. 1) TSG101 bound to several different sites on VPS37B, including a putative coiled-coil region and a PTAP motif. 2) TSG101 and VPS28 co-immunoprecipitated with VPS37B-FLAG, and the three proteins comigrated together in soluble complexes of the correct size for human ESCRT-I ( approximately 350 kDa). 3) Like TGS101, VPS37B became trapped on aberrant endosomal compartments in the presence of VPS4A proteins lacking ATPase activity. 4) Finally, VPS37B could recruit TSG101/ESCRT-I activity and thereby rescue the budding of both mutant Gag particles and HIV-1 viruses lacking native late domains. Further studies of ESCRT-I revealed that TSG101 mutations that inhibited PTAP or VPS28 binding blocked HIV-1 budding. Taken together, these experiments define new components of the human ESCRT-I complex and characterize several TSG101 protein/protein interactions required for HIV-1 budding and infectivity.


Perceptions of risk in motorcyclists: unrealistic optimism, relative realism and predictions of behaviour.
In the first phase of a prospective investigation, a national sample of motorcyclists completed a postal questionnaire about their perceptions of risk, their behaviour on the roads and their history of accidents and spills. In the second phase a year later, they reported on their accident history and behaviour over the preceding 12 months. A total of 723 respondents completed both questionnaires. Four sets of findings are reported. First, the group as a whole showed unrealistic optimism: on average, respondents believed themselves to be less at risk than other motorcyclists of an accident needing hospital treatment in the next year. Second, optimism was tempered by 'relative realism', in that respondents who were young and inexperienced saw themselves as more at risk than other motorcyclists, as did riders who reported risky behaviours on the road. Third, there was some evidence of debiasing by personal history, in that having a friend or a relative who had been killed or injured on the roads was associated with perceptions of absolute risk of injury or death--though there were no effects on comparative risk and no effects on any of the judgments of a history of accidents of one's own. Finally, there was good evidence that perceptions of risk predicted subsequent behaviour, though generally in the direction not of precaution adoption but of precaution abandonment: the greater the perceived risk at time 1, the more frequent the risky behaviour at time 2. The implications of the findings are discussed, and possible interpretations are suggested.


Axons of olfactory receptor cells of transsexually grafted antennae induce development of sexually dimorphic glomeruli in Manduca sexta.
The influence of olfactory receptor cell (ORC) axons from transsexually grafted antennae on the development of glomeruli in the antennal lobes (ALs), the primary olfactory centers, was studied in the moth Manduca sexta. Normally during metamorphic adult development, the pheromone-specific macroglomerular complex (MGC) forms only in the ALs of males, whereas two lateral female-specific glomeruli (LFGs) develop exclusively in females. A female AL innervated by ORC axons from a grafted male antenna developed an MGC with three glomeruli, like the MGC of a normal male AL. Conversely, a male AL innervated by ORC axons from a grafted female antenna lacked the MGC but exhibited LFGs. ORC axons from grafted male antenna terminated in the MGC-specific target area, even in cases when the antennal nerve (AN) entered the AL via an abnormal route. Within ectopic neuromas formed by ANs that had become misrouted and failed to enter the brain, male-specific axons were not organized and formed terminal branches in many areas. The results suggest the presence of guidance cues within the AL for male-specific ORC axons. Depending on the sex of the antennal innervation, glial borders formed in a pattern characteristic of the MGC or LFGs. The sex-specific number of projection neurons (PNs) in the medial group of AL neurons remained unaffected by the antennal graft, but significant changes occurred in the organization of PN arborizations. In gynandromorphic females, LFG-specific PNs extended processes into the induced MGC, whereas in gynandromorphic males, PNs became restricted to the LFGs. The results indicate that male-and female-specific ORC axons play important roles in determining the position, anatomical features, and innervation of sexually dimorphic glomeruli.


Adult development of the hippocampal-serotonin system of C57BL/6N mice; analysis of high-affinity uptake of (3)H-5HT in slices and synaptosomes.
The saturable and specific high-affinity uptake of [(3)H]serotonin ([(3)H]5HT) (5 x 10(?8) M) was studied in slices from the hippocampus, parietal cortex, septum-preoptic area, and hypothalamus of male 2, 6, 12 and 24-32 month old C57BL/6N mice. Hippocampal [(3)H]5-HT uptake showed a significant biphasic relationship to age, with lower values in the 2 and 24-32 month old mice compared to 6 month old mice. No significant age effects were seen in the other regions, or in [(3)H]norepinephrine high-affinity uptake in the hippocampus. Studies of the high-affinity uptake mechanism in synaptosomal preparations were made in a subgroup of 12 and 24 month old mice. A micro-assay using a tissue-harvester measured high-affinity uptake on 8-30 ?l of the P(2) suspension (crude-synaptosomal preparation). The high-affinity uptake was linear for 4 min at 37 degrees C and inhibited in both the adult and aged tissue by 10(?5) M cold 5-HT (83 and 78% respectively), 10(?5) M fluoxetine (85 and 82% respectively) and 10(?3) M NaCN (57 and 57% respectively). Kinetic analysis of the [(3)H]5HT high-affinity uptake in the hippocampus (3 min, 37 degrees C) revealed the same apparent K(m) for serotonin at both ages (6.7 x 10(?8) M), but a 44% decrease in V(max) in the aged hippocampal synaptosomal high-affinity uptake compared to adults (120 vs 215 pmol of 5-HT/g-tissue/3 min). These results are discussed in relationship to the reported age effects on the intrinsic neurons of the hippocampus.


Intrusion in implant-tooth-supported fixed prosthesis: an in vitro photoelastic stress analysis.
Intrusion of natural teeth is a very common and interesting problem associated with implant-assisted fixed partial prostheses. Various theories have been put forth to explain this phenomenon, most of which revolve around the philosophy of exertion of excessive forces onto the natural tooth in a combination fixed partial denture. This photoelastic study examines the current theories revolving around intrusion and evaluates whether natural tooth intrusion is a definite possibility in an implant-tooth-connected fixed partial prosthesis. A two-dimensional photoelastic method was employed for testing and analysis. Two sets of photoelastic models were fabricated, one depicting a totally tooth-supported situation and the other an implant-tooth-supported situation. A rigid type and non-rigid type of connection were also incorporated into the fixed partial denture used in the both the situations in the study. Loads were applied on the anterior and posterior abutments and the pontic regions in both sets of models and the fringe patterns were photographically recorded for analysis. The forces were proportionately consistent with the increase in applied loads in both the situations. The use of a non-rigid connection did not show any major significance but in fact may be erroneous. The forces were considerably higher in the implant-tooth-connected situation. The results indicated that the differences in the forces exerted were not light and continuous and may not cause tooth intrusion. Natural tooth intrusion may be caused by reasons other than excessive forces and needs further investigation.


[Changes in the sodium current under the action of etmozin and lidocaine inside and outside the membrane of single rat myocardial cells].
The voltage clamp experiments were carried out on single internally perfused rat myocardial cells. The effect of ethmozine (8 x 10(-5) g/ml) and lidocain (8 x 10(-6) g/ml) on the fast maximum inward sodium current (INa) was studied. The drugs were tested inside and outside the cell. INa was inhibited insignificantly when ethmozine was added inside the cell. After 5 min of ethmozine action outside the cell INa dropped on the average to 43 +/- 6% of its initial value. Under these conditions the reactivation constrant of INa did not change significantly. Lidocain depressed INa both when added outside and inside the cell. However, when lidocain was added outside the cell a longer period was needed to depress INa. Comparison of lidocain and ethmozine action outside and inside the myocardial cell has shown that the sites of action of these antiarrhythmic drugs on the cellular membrane are different.


Characterization of a Porcine Model for Von Willebrand Disease Type 1 and 3 Regarding Expression of Angiogenic Mediators in the Nonpregnant Female Reproductive Tract.
Von Willebrand disease (VWD), a blood coagulation disorder, is also known to cause angiodysplasia. Hitherto, no animal model has been found with angiodysplasia that can be studied in vivo. In addition, VWD patients tend to have a higher incidence of miscarriages for reasons unknown. Thus, we aimed to examine the influence of von Willebrand factor (VWF) on the female reproductive tract histology and the expression and distribution of angiogenic factors in a porcine model for VWD types 1 and 3. The disease-causing tandem duplication within the VWF gene occurred naturally in these pigs, making them a rare and valuable model. Reproductive organs of 6 animals (2 of each mutant genotype and 2 wildtype (WT) animals) were harvested. Genotype plus phenotype were confirmed. Several angiogenic factors were chosen for possible connections to VWF and analyzed alongside VWF by immunohistochemistry and quantitative gene expression studies. VWD type 3 animals showed angiodysplasia in the uterus and shifting of integrin αVβ₃ from the apical membrane of uterine epithelium to the cytoplasm accompanied by increased vascular endothelial growth factor (VEGF) expression. Varying staining patterns for angiopoietin (Ang)-2 were observed among the genotypes. As compared with WT, the ovaries of the VWD type 3 animals showed decreased gene expression of ANG2 and increased gene expression of TIE (tyrosine kinase with immunoglobulin and epidermal growth factor homology domains) 2, with some differences in the ANG/TIE-system among the mutant genotypes. In conclusion, severely reduced VWF seems to evoke angiodysplasia in the porcine uterus. Varying distribution and expression of angiogenic factors suggest that this large animal model is promising for investigation of influence of VWF on angiogenesis in larger groups.


Identification and functional prediction of mitochondrial complex III and IV mutations associated with glioblastoma.
Glioblastoma (GBM) is the most common primary brain tumor in adults, with a dismal prognosis. Treatment is hampered by GBM's unique biology, including differential cell response to therapy. Although several mitochondrial abnormalities have been identified, how mitochondrial DNA (mtDNA) mutations contribute to GBM biology and therapeutic response remains poorly described. We sought to determine the spectrum of functional complex III and IV mtDNA mutations in GBM. The complete mitochondrial genomes of 10 GBM cell lines were obtained using next-generation sequencing and combined with another set obtained from 32 GBM tissues. Three-dimensional structural mapping and analysis of all the nonsynonymous mutations identified in complex III and IV proteins was then performed to investigate functional importance. Over 200 mutations were identified in the mtDNAs, including a significant proportion with very low mutational loads. Twenty-five were nonsynonymous mutations in complex III and IV, 9 of which were predicted to be functional and affect mitochondrial respiratory chain activity. Most of the functional candidates were GBM specific and not found in the general population, and 2 were present in the germ-line. Patient-specific maps reveal that 43% of tumors carry at least one functional candidate. We reveal that the spectrum of GBM-associated mtDNA mutations is wider than previously thought, as well as novel structural-functional links between specific mtDNA mutations, abnormal mitochondria, and the biology of GBM. These results could provide tangible new prognostic indicators as well as targets with which to guide the development of patient-specific mitochondrially mediated chemotherapeutic approaches.


Evaluation of Student Performance through a Multidimensional Finite Mixture IRT Model.
In the Italian academic system, a student can enroll for an exam immediately after the end of the teaching period or can postpone it; in this second case the exam result is missing. We propose an approach for the evaluation of a student performance throughout the course of study, accounting also for nonattempted exams. The approach is based on an item response theory model that includes two discrete latent variables representing student performance and priority in selecting the exams to take. We explicitly account for nonignorable missing observations as the indicators of attempted exams also contribute to measure the performance (within-item multidimensionality). The model also allows for individual covariates in its structural part.


Impaired fasting glucose, type 2 diabetes mellitus, and lifetime risk of cardiovascular disease among women and men: the Rotterdam Study.
Data on sex-specific lifetime risk of cardiovascular disease (CVD) across the glycemic spectrum, in particular in impaired fasting glucose (IFG) state, are scarce. Whether overweight/obesity modifies the CVD burden also remains unclear. Using a prospective population-based Rotterdam Study, normoglycemia, IFG, and type 2 diabetes mellitus (T2D) were defined. First incident cases of coronary heart disease, heart failure, and stroke during a follow-up time until January 1, 2015 were identified and formed the composite CVD end point. The remaining lifetime risks of CVD were estimated in each glucose category at 55, 65, 75, and 85 years of age, using a modified version of survival analysis adjusted for the competing risk of death. Among 5698 women and 3803 men free of CVD at baseline, the mean age was 64.5 years (SD 9.6) and 60.0% of participants were women. At age 55 years, the remaining lifetime risk of any CVD event among women was 55.1% (95% CI 48.3 to 61.9) for IFG, compared with 52.7% (95% CI 49.5 to 55.9) for normoglycemia and 61.5% (95% CI 54.7 to 68.3) for T2D. For men, the remaining lifetime risk of any CVD event was 62.1% (95% CI 55.2 to 69.1) for IFG, compared with 59.1% (95% CI 55.5 to 62.7) for normoglycemia and 60.3% (95% CI 53.1 to 67.5) for T2D. At age 55 years, the lifetime risk for incident CVD was higher, although not statistically significant, among women and men with IFG who were overweight or had obesity compared with normal-weight women and men. IFG carried a large lifetime risk for incident CVD among both women and men compared with normoglycemia. In particular among men, the risk was comparable to that of T2D. Overweight/Obesity modifies the risk and conferred a larger burden of lifetime CVD risk among women and men with IFG.


Synthesis and Cytotoxic Evaluation of Kojic Acid Derivatives with Inhibitory Activity on Melanogenesis in Human Melanoma Cells.
Malignant melanoma is an agressive tumour related to the overproduction of melanin, which provides colors of skin, eyes and hair. In addition contributing to the risk of malignant melanoma, abnormal production of melanin has many drawbacks, including hyperpigmentation, post-inflammatory pigmentation, melasma and skin aging. Kojic acid is currently employed in order to lighten skin pigmentation and provide depigmentation. Mannich bases of kojic acid with the structure of 2-substituted-3-hydroxy-6-hyroxymethyl/chloromethyl/ methyl/morpholinomethyl/piperidinylmethyl/pyrrolidinylmethyl-4H-pyran-4-one (compounds 1-23) were synthesized by the reaction of kojic acid/chlorokojic acid/allomaltol and substituted benzylpiperazine derivatives in the presence of formaline. To obtain the cyclic amine (morpholine, piperidine and pyrrolidine) derivatives, nucleophilic substitutions were carried out. Cytotoxic effects on A375 human malignant melanoma, HGF-1 human gingival fibroblasts, and MRC-5 human lung cell lines were investigated by sulphorhodamine B assay. Control agents were vemurafenib, dacarbazine, temozolomide, and lenalidomide, which are the commercially available drugs for the treatment of malignant melanoma. Cytotoxic action against melanoma cells was significantly more efficacious (IC50: 11.26-68.58 μM) than the FDA-approved drugs except for vemurafenib. Fourteen of the compounds were proven to have higher IC50 values for the non-cancerous cell lines, HGF-1, and MRC-5 cells. Melanogenesis inhibition assay was performed to observe the ability of the drugs to inhibit melanin production and certain compounds were shown to be capable of actively inhibiting melanin production in melanoma cells. Mannich bases of kojic acid derivatives may be promising therapeutic agents, since some have more potent effects on melanoma cells than previously FDA-approved drugs for the treatment of malignant melanoma.


Gynecologic cancer patients' psychosocial needs and their views on the physician's role in meeting those needs.
The aim of this study was to identify the psychosocial needs of patients after treatment for gynecological malignancies and their views concerning the role physicians should take in meeting those needs. Self-administered questionnaires were answered by 95 patients at least 6 months after completion of therapy. Topic areas included emotional needs, spiritual concerns, patient-family communication, patient participation in decision making, and advance directives. In addition, all participants completed the Functional Assessment of Cancer Therapy (FACT-G, version 4) quality of life questionnaire. Fifty-seven percent of respondents stated that they had needed help dealing with emotional problems, and 73% wanted the physician to ask whether help is needed. The most common emotional concerns were feeling nervous (40% of subjects), being worried (34%), fear (25%), needing someone to talk to (24%), sadness (21%), and loss of control (17%). Fifty-nine percent stated that physicians should ask whether help is needed in discussing spiritual matters. Sixty-one percent stated that physicians should ask patients whether they want help starting conversations with their families about difficult-to-raise topics such as the possibility of dying. Forty-six of 86 respondents (53%) stated that discussions about advance directives such as living wills should take place soon after the cancer diagnosis has been established. Most patients surveyed want physicians to take an active role in dealing with psychosocial needs.


18S ribosomal DNA typing and tracking of Acanthamoeba species isolates from corneal scrape specimens, contact lenses, lens cases, and home water supplies of Acanthamoeba keratitis patients in Hong Kong.
We examined partial 18S ribosomal DNA (Rns) sequences of Acanthamoeba isolates cultured in a study of microbial keratitis in Hong Kong. Sequence differences were sufficient to distinguish closely related strains and were used to examine links between strains obtained from corneal scrape specimens, contact lenses, lens cases, lens case solutions, and home water-supply faucets of patients with Acanthamoeba. We also looked for evidence of mixed infections. Identification of Acanthamoeba Rns genotypes was based on sequences of approximately 113 bp within the genus-specific amplicon ASA.S1. This permitted genotype identification by using nonaxenic cultures. Of 13 specimens obtained from corneal scrapes, contact lenses, lens cases, or lens case solutions, 12 were Rns genotype T4 and the remaining one was Rns genotype T3. The sequences of corneal scrape specimens of two patients also were the same as those obtained from their contact lenses or lens case specimens. A possible triple-strain infection was indicated by three different T4 sequences in cultures from one patient's lenses. Although faucet water used by patients to clean their lenses is a possible source of infections, specimens isolated from the faucets at two Acanthamoeba keratitis patients' homes differed from their corneal scrape or lens specimens. The overall results demonstrate the potential of this Rns region for tracking Acanthamoeba keratitis strains in infections and for distinguishing single-strain and closely related multiple-strain infections even when other microorganisms might be present with the cultured specimens. They also confirm the predominance of Rns genotype T4 strains in Acanthamoeba keratitis infections.


Prevalence of ototoxicity in University of Benin Teaching Hospital, Benin city: a 5-year review.
Ototoxicity refers to damage of the cochlea and/or vestibular apparatus from exposure to chemical substances, resulting in hearing impairment and or disequilibrium. An earlier study carried out at University of Benin Teaching Hospital (UBTH) in 2000 implicated chloramphenicol as the commonest ototoxic drug, followed by antimalarials (Quinine). To identify the commonly implicated drugs in patients diagnosed with ototoxicity in Ear, Nose and Throat (ENT) Clinic of UBTH. One-hundred and three patients' case notes, diagnosed as having ototoxicity, between June 2005 and July 2010 at the ENT Clinic of UBTH were reviewed. Seventy-nine cases met the criteria for diagnosis of ototoxicity in this study. Intravenous quinine (19.0%) was the commonest implicated drug, followed by oral chloroquine (6.3%), antihypertensive drugs (nifedipine, moduretics, artenolol [6.3%]), native herbal medicine (13.9%), chloramphenicol (1.3%), and unidentifiable drugs accounted for 53.2%. Most patients had severe to profound hearing loss at 4000 Hz and at 8000 Hz. Tinnitus was found in 84.8% of the patients. Quinine is still the commonest implicated ototoxic drug in this part of the country.


A sensitive, versatile microfluidic assay for bacterial chemotaxis.
We have developed a microfluidic assay for bacterial chemotaxis in which a gradient of chemoeffectors is established inside a microchannel via diffusion between parallel streams of liquid in laminar flow. The random motility and chemotactic responses to L-aspartate, L-serine, L-leucine, and Ni(2+) of WT and chemotactic-mutant strains of Escherichia coli were measured. Migration of the cells was quantified by counting the cells accumulating in each of 22 outlet ports. The sensitivity of the assay is attested to by the significant response of WT cells to 3.2 nM L-aspartate, a concentration three orders of magnitude lower than the detection limit in the standard capillary assay. The response to repellents was as robust and easily recorded as the attractant response. A surprising discovery was that L-leucine is sensed by Tar as an attractant at low concentrations and by Tsr as a repellent at higher concentrations. This assay offers superior performance and convenience relative to the existing assays to measure bacterial tactic responses, and it is flexible enough to be used in a wide range of different applications.


Proposed Update to the Taxonomy of Pestiviruses: Eight Additional Species within the Genus Pestivirus, Family Flaviviridae.
Pestiviruses are plus-stranded RNA viruses belonging to the family Flaviviridae. They comprise several important pathogens like classical swine fever virus and bovine viral diarrhea virus that induce economically important animal diseases. In 2017, the last update of pestivirus taxonomy resulted in demarcation of 11 species designated Pestivirus A through Pestivirus K. Since then, multiple new pestiviruses have been reported including pathogens associated with disease in pigs or small ruminants. In addition, pestivirus sequences have been found during metagenomics analysis of different non-ungulate hosts (bats, rodents, whale, and pangolin), but the consequences of this pestivirus diversity for animal health still need to be established. To provide a systematic classification of the newly discovered viruses, we analyzed the genetic relationship based on complete coding sequences (cds) and deduced polyprotein sequences and calculated pairwise distances that allow species demarcation. In addition, phylogenetic analysis was performed based on a highly conserved region within the non-structural protein NS5B. Taking into account the genetic relationships observed together with available information about antigenic properties, host origin, and characteristics of disease, we propose to expand the number of pestivirus species to 19 by adding eight additional species designated Pestivirus L through Pestivirus S.


Metabolic biotinylation of secreted and cell surface proteins from mammalian cells.
Due to its strength and specificity, the interaction between avidin and biotin has been used in a variety of medical and scientific applications ranging from drug targeting to immunohistochemistry. To maximize the application of this technology in mammalian systems, we recently demonstrated the ability to metabolically biotinylate tagged proteins in mammalian cells using the endogenous biotin ligase enzymes of the mammalian cell. This technology allows site-specific biotinylation without any exogenous reagents and eliminates possible inactivation of the protein of interest by nonspecific biotinylation. Here, we report further expansion of the mammalian metabolic biotinylation technology to enable biotinylation of proteins secreted from mammalian cells and expressed on their cell surface by cosecretion with BirA, the biotin ligase of E. coli. This technique can be used to biotinylate secreted proteins for purification or targeting and also for biotinylating the surfaces of mammalian cells to facilitate their labeling and purification from other nontagged cells.


Random start ovarian stimulation before gonadotoxic therapies in women with cancer: a systematic review and meta-analysis.
The aim of this systematic review and meta-analysis was to quantify the effect of random start ovarian stimulation (RSOS) compared with conventional start ovarian stimulation (CSOS) in cancer patients before gonadotoxic treatment. The final analytical cohort encompassed 688 RSOS and 1076 CSOS cycles of cancer patients before gonadotoxic treatment. Eleven studies were identified by database searches of MEDLINE, Cochrane Library and cited references. The primary outcomes of interest were the number of oocytes and mature oocytes collected, the number of embryos cryopreserved and the metaphase II (MII)-antral follicle count (AFC) ratio. The studies were rated from medium to high quality (from 6 to 9) according to the Newcastle-Ottawa Quality Assessment Scale. The two protocols resulted in similar numbers of oocytes collected, MII oocytes, embryos available for cryopreservation and comparable MII-AFC and fertilization rates. The duration of ovarian stimulation was longer (standardized mean difference [SMD] 0.35, 95% CI 0.09 to 0.61; P = 0.009) and gonadotrophin consumption was higher (SMD 0.23, 95% CI 0.06 to 0.40; P = 0.009) in RSOS compared with CSOS. This systematic review and meta-analysis show that the duration of stimulation is longer, and the total gonadotrophin consumption is higher in cancer patients undergoing RSOS compared with those undergoing CSOS, with no significant effect on mature oocyte yield.


Age dependent variations in choline and ethanolamine phosphorylating activities of rodents.
The substrate concentration-velocity relationship as influenced by age of animal was determined. At all stages of growth of rat and mouse ethanolamine kinase activity responded with a hyperbolic pattern to substrate concentration. Choline kinase on the other hand, underwent "enzyme differentiation". In rat liver up to 4 days of age of animal, in mouse liver up to 7 days and in mouse kidney up to 15 days, choline kinase activity responded with a hyperbolic pattern; but from then onwards the response to substrate concentration was sigmoid. The results obtained pointed to the regulatory nature of choline kinase and a possible distinction between the proteins catalyzing the phosphorylation of the two bases.


Opposing central and peripheral actions of brain-gut peptides: a basis for regulation of gastric function.
The existence of an increasing number of peptides in both the gut and the brain provides the basis for the concept of a brain-gut axis. However, to date, no unifying hypothesis has been put forward to explain the physiologic significance of this remarkable phenomenon. The present study examines the central and peripheral actions on gastric function of cholecystokinin octapeptide (CCK-8), somatostatin, and bombesin, all of which exist in both the gut and brain. Intravenous infusion of CCK-8, in doses of 50, 100, and 200 pmol X kg-1 X hr-1, caused 28%, 38%, and 52% inhibition, respectively, of the rate of gastric emptying of a liquid meal in dogs. By contrast, the injection of 32, 64, and 128 pmol X kg-1 into the lateral cerebral ventricle of these dogs accelerated gastric emptying by 6%, 26%, and 32%, respectively. Bombesin, which stimulated gastric acid secretion in a dose-dependent manner but which had no effect on the submaximal acid response to pentagastrin when administered peripherally, inhibited in a dose-dependent manner the submaximal response to pentagastrin when given centrally, with a maximal inhibition of 66% +/- 5%, at a dose of bombesin of 180 pmol X kg-1. Similarly, somatostatin-14 caused graded inhibition of pentagastrin-stimulated acid secretion when it was administered peripherally but caused dose-dependent augmentation of the acid response when it was given centrally. Maximal inhibition of 51% of the pentagastrin response occurred with a peripheral dose of somatostatin of 800 pmol X kg-1 X hr-1. By contrast, maximal augmentation of the pentagastrin response of 78% occurred when a dose of 400 pmol X kg-1 of the peptide was injected into the lateral ventricle. We conclude that CCK-8, bombesin, and somatostatin have opposing actions on gastric function when administered centrally and peripherally. We propose that this phenomenon may be common to all neuropeptides of the brain-gut axis and may provide a basis for central regulation of gut function.


Assessment of the proarrhythmic effects of repurposed antimalarials for COVID-19 treatment using a comprehensive in vitro proarrhythmia assay (CiPA).
Due to the outbreak of the SARS-CoV-2 virus, drug repurposing and Emergency Use Authorization have been proposed to treat the coronavirus disease 2019 (COVID-19) during the pandemic. While the efficiency of the drugs has been discussed, it was identified that certain compounds, such as chloroquine and hydroxychloroquine, cause QT interval prolongation and potential cardiotoxic effects. Drug-induced cardiotoxicity and QT prolongation may lead to life-threatening arrhythmias such as torsades de pointes (TdP), a potentially fatal arrhythmic symptom. Here, we evaluated the risk of repurposed pyronaridine or artesunate-mediated cardiac arrhythmias alone and in combination for COVID-19 treatment through in vitro and in silico investigations using the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. The potential effects of each drug or in combinations on cardiac action potential (AP) and ion channels were explored using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and Chinese hamster ovary (CHO) cells transiently expressing cardiac ion channels (Nav1.5, Cav1.2, and hERG). We also performed in silico computer simulation using the optimized O'Hara-Rudy human ventricular myocyte model (ORd model) to classify TdP risk. Artesunate and dihydroartemisinin (DHA), the active metabolite of artesunate, are classified as a low risk of inducing TdP based on the torsade metric score (TMS). Moreover, artesunate does not significantly affect the cardiac APs of hiPSC-CMs even at concentrations up to 100 times the maximum serum concentration (Cmax). DHA modestly prolonged at APD90 (10.16%) at 100 times the Cmax. When considering Cmax, pyronaridine, and the combination of both drugs (pyronaridine and artesunate) are classified as having an intermediate risk of inducing TdP. However, when considering the unbound concentration (the free fraction not bound to carrier proteins or other tissues inducing pharmacological activity), both drugs are classified as having a low risk of inducing TdP. In summary, pyronaridine, artesunate, and a combination of both drugs have been confirmed to pose a low proarrhythmogenic risk at therapeutic and supratherapeutic (up to 4 times) free Cmax. Additionally, the CiPA initiative may be suitable for regulatory use and provide novel insights for evaluating drug-induced cardiotoxicity.


The use of CT for selectron patients.
Radiation-induced bladder and rectal complications are recognized complications of intracavitary therapy. In clinical studies the correlation between dose calculated and complications seen are inconsistent. The inconsistency is also present when utilizing the reference points recommended by the ICRU. We attempted to illustrate this inconsistency when looking at the bladder or rectum in intracavitary treatments. If reference points are inconsistent with maximum doses (which directly affect morbidity), their application is dubious.


Non-redundant function of dystroglycan and β1 integrins in radial sorting of axons.
Radial sorting allows the segregation of axons by a single Schwann cell (SC) and is a prerequisite for myelination during peripheral nerve development. Radial sorting is impaired in models of human diseases, congenital muscular dystrophy (MDC) 1A, MDC1D and Fukuyama, owing to loss-of-function mutations in the genes coding for laminin α2, Large or fukutin glycosyltransferases, respectively. It is not clear which receptor(s) are activated by laminin 211, or glycosylated by Large and fukutin during sorting. Candidates are αβ1 integrins, because their absence phenocopies laminin and glycosyltransferase deficiency, but the topography of the phenotypes is different and β1 integrins are not substrates for Large and fukutin. By contrast, deletion of the Large and fukutin substrate dystroglycan does not result in radial sorting defects. Here, we show that absence of dystroglycan in a specific genetic background causes sorting defects with topography identical to that of laminin 211 mutants, and recapitulating the MDC1A, MDC1D and Fukuyama phenotypes. By epistasis studies in mice lacking one or both receptors in SCs, we show that only absence of β1 integrins impairs proliferation and survival, and arrests radial sorting at early stages, that β1 integrins and dystroglycan activate different pathways, and that the absence of both molecules is synergistic. Thus, the function of dystroglycan and β1 integrins is not redundant, but is sequential. These data identify dystroglycan as a functional laminin 211 receptor during axonal sorting and the key substrate relevant to the pathogenesis of glycosyltransferase congenital muscular dystrophies.


Nutritional considerations to counteract gastrointestinal permeability during exertional heat stress.
Intestinal barrier integrity and function are compromised during exertional heat stress (EHS) potentially leading to consequences that range from minor gastrointestinal (GI) disturbances to fatal outcomes in exertional heat stroke or septic shock. This mini-review provides a concise discussion of nutritional interventions that may protect against intestinal permeability during EHS and suggests physiological mechanisms responsible for this protection. Although diverse nutritional interventions have been suggested to be protective against EHS-induced GI permeability, the ingestion of certain amino acids, carbohydrates, and fluid per se is potentially effective strategy, whereas evidence for various polyphenols and pre/probiotics is developing. Plausible physiological mechanisms of protection include increased blood flow, epithelial cell proliferation, upregulation of intracellular heat shock proteins, modulation of inflammatory signaling, alteration of the GI microbiota, and increased expression of tight junction (TJ) proteins. Further clinical research is needed to propose specific nutritional candidates and recommendations for their application to prevent intestinal barrier disruption and elucidate mechanisms during EHS.


Tunable Schottky and Ohmic contacts in graphene and tellurene van der Waals heterostructures.
We systematically investigate the effects of external electric field and interlayer coupling on the electronic structures and contact characteristics of hybrid graphene and tellurene (G/Te) van der Waals heterostructures (vdWHs) based on first-principles calculations. Our results show that the G/α-Te interface is formed by an n-type Schottky contact with a negligible Schottky barrier height (SBH), while the G/β-Te interface is formed by a p-type Schottky contact with a SBH of 0.51 eV. By applying external electric fields perpendicular to the G/Te interfaces or changing the interlayer distance between the graphene and tellurene monolayers, both Schottky barriers and contact types (n-type Schottky, p-type Schottky, and Ohmic) at the G/Te interfaces can be effectively modulated. The changes in charge transfer, as well as the corresponding interface dipole and potential step with the external electric field and interlayer coupling, are revealed to account for the reason for tunable Schottky and Ohmic contacts at the G/Te interfaces. Therefore, the G/Te vdWHs show tunable Schottky and Ohmic contacts with promising applications of graphene-based field-effect transistors in future experiments.


When less is more: Psychometric properties of Norwegian short-forms of the Ambivalent Sexism Scales (ASI and AMI) and the Illinois Rape Myth Acceptance (IRMA) Scale.
This paper reports on the development and the psychometric properties of short forms of Ambivalent Sexism Scales toward women (ASI; Glick & Fiske, 1996) and men (AMI; Glick & Fiske, 1999), and a scale measuring rape stereotypes (IRMA; McMahon & Farmer, 2011). The short form AMI/ASI were applied for examining gender and educational differences in university students (N = 512) and in high school students (N = 1381), and for predicting individual differences in rape stereotypes in the latter. The short forms demonstrated good to excellent psychometric properties across samples of emerging adults. Relative to female students, male students reported markedly more hostility toward women and more stereotypical beliefs about rape. Despite sampling from a highly gender egalitarian and secular culture, these gender differences are on a par with those reported internationally. Rape stereotypes were predicted by sexism in high school students. Additional predictors were educational program, relationship status, and acceptance of derogatory sexual slurs. The paper questions the validity of separate constructs for benevolent sexism toward women versus men. The short form versions of the scales may substitute the original versions in future research, and help prevent attrition while measuring the same constructs.


Age independently affects myelin integrity as detected by magnetization transfer magnetic resonance imaging in multiple sclerosis.
Multiple sclerosis (MS) is a heterogeneous disorder with a progressive course that is difficult to predict on a case-by-case basis. Natural history studies of MS have demonstrated that age influences clinical progression independent of disease duration. To determine whether age would be associated with greater CNS injury as detected by magnetization transfer MRI. Forty MS patients were recruited from out-patient clinics into two groups stratified by age but with similar clinical disease duration as well as thirteen controls age-matched to the older MS group. Images were segmented by automated programs and blinded readers into normal appearing white matter (NAWM), normal appearing gray matter (NAGM), and white matter lesions (WMLs) and gray matter lesions (GMLs) in the MS groups. WML and GML were delineated on T2-weighted 3D fluid-attenuated inversion recovery (FLAIR) and T1 weighted MRI volumes. Mean magnetization transfer ratio (MTR), region volume, as well as MTR histogram skew and kurtosis were calculated for each region. All MTR measures in NAGM and MTR histogram metrics in NAWM differed between MS subjects and controls, as expected and previously reported by several studies, but not between MS groups. However, MTR measures in the WML did significantly differ between the MS groups, in spite of no significant differences in lesion counts and volumes. Despite matching for clinical disease duration and recording no significant WML volume difference, we demonstrated strong MTR differences in WMLs between younger and older MS patients. These data suggest that aging-related processes modify the tissue response to inflammatory injury and its clinical outcome correlates in MS.


Limitations of dose tolerance studies on predictability for phase III.
Phases I, II and III of the development of a new drug are briefly described. The limitations of dose tolerance studies in Phase I are considered in relation to their predictive value for Phase III. Limitations on predictability may arise because of differences between Phase I and Phase III in both study population and study design. The study population in Phase I, in contrast with Phase III, is usually numerically small, male, young, of average size, healthy, asymptomatic and free from other medication. The Phase III population may be of different nationality or race. Phase I studies are always of short duration. Drug administration is usually in the morning and may be accompanied by more restrictions on diet, smoking and alcohol intake than in Phase III trials. The implications of these differences in study population and design are discussed. The predictive value of dose tolerance studies for Phase III can be substantial, provided that the results are interpreted sensibly. However, the tolerance studies should perhaps be regarded mainly as an essential preliminary to single and multiple dose kinetic, dynamic and interaction studies; the combined experience of these trials should have much greater predictive power for Phase III than dose tolerance studies alone.


Optimization of extraction of novel pectinase enzyme discovered in red pitaya (Hylocereus polyrhizus) peel.
Plant peels could be a potential source of novel pectinases for use in various industrial applications due to their broad substrate specificity with high stability under extreme conditions. Therefore, the extraction conditions of a novel pectinase enzyme from pitaya peel was optimized in this study. The effect of extraction variables, namely buffer to sample ratio (2:1 to 8:1, X₁), extraction temperature (-15 to +25 °C, X₂) and buffer pH (4.0 to 12.0, X₃) on specific activity, temperature stability, storage stability and surfactant agent stability of pectinase from pitaya peel was investigated. The study demonstrated that the optimum conditions for the extraction of pectinase from pitaya sources could improve the enzymatic characteristics of the enzyme and protect its activity and stability during the extraction procedure. The optimum extraction conditions cause the pectinase to achieve high specific activity (15.31 U/mg), temperature stability (78%), storage stability (88%) and surfactant agent stability (83%). The most desirable conditions to achieve the highest activity and stability of pectinase enzyme from pitaya peel were the use of 5:1 buffer to sample ratio at 5 °C and pH 8.0.


IMP regulates Kuzbanian to control the timing of Notch signalling in Drosophila follicle cells.
The timing of Drosophila egg chamber development is controlled by a germline Delta signal that activates Notch in the follicle cells to induce them to cease proliferation and differentiate. Here, we report that follicle cells lacking the RNA-binding protein IMP go through one extra division owing to a delay in the Delta-dependent S2 cleavage of Notch. The timing of Notch activation has previously been shown to be controlled by cis-inhibition by Delta in the follicle cells, which is relieved when the miRNA pathway represses Delta expression. imp mutants are epistatic to Delta mutants and give an additive phenotype with belle and Dicer-1 mutants, indicating that IMP functions independently of both cis-inhibition and the miRNA pathway. We find that the imp phenotype is rescued by overexpression of Kuzbanian, the metalloprotease that mediates the Notch S2 cleavage. Furthermore, Kuzbanian is not enriched at the apical membrane in imp mutants, accumulating instead in late endosomes. Thus, IMP regulates Notch signalling by controlling the localisation of Kuzbanian to the apical domain, where Notch cleavage occurs, revealing a novel regulatory step in the Notch pathway.


IgG and complement-mediated tissue damage in the absence of C2: evidence of a functionally active C2-bypass pathway in a guinea pig model.
In vitro complement-mediated lysis of heavily sensitized sheep erythrocytes by C4-deficient (C4D) guinea pig and C2-deficient (C2D) human sera was demonstrated some years ago. It was postulated that these "complement-bypass" pathways resulted from activation of C1 and components of the alternative pathway. We used normal, C2D, and C4D guinea pigs in a Forssman shock model to test the in vivo relevance of the C2- and C4-bypass pathways of complement activation. High concentrations of both anti-Forssman Ab and C2D or C4D guinea pig serum induced efficient lysis of sheep erythrocytes in vitro. The most efficient lysis was observed when IgG Ab and C2D guinea pig serum were used. Blocking either the classical pathway (treatments with EGTA-Mg2+ or soluble recombinant complement receptor type 1 (sCR1)) or the alternative pathway (treatment with heating at 50 degrees C, sCR1, or soluble recombinant CR1 lacking the first of the four long homologous repeat sequences (sCR1[desLHR-A])) inhibited lysis; both pathways were required for lysis of sheep erythrocytes by C2D and C4D guinea pig sera. i.v. injection of anti-Forssman Ab in normal guinea pigs resulted in rapid death from pulmonary shock, whereas C4D guinea pigs had no adverse effect. Surprisingly, C2D guinea pigs either died in a delayed fashion or had a sublethal reaction. sCR1 treatment prevented Forssman shock in both normal and C2D guinea pigs, whereas sCR1[desLHR-A] prevented Forssman shock only in C2D animals. Our results suggest that the C2-bypass pathway occurs in vivo to produce tissue damage. Activation of complement in the absence of C2 appears to be far more efficient than in the absence of C4.