Investigation of the role of postnatal testosterone in the expression of sex differences in behavior in infant rhesus macaques (Macaca mulatta).
In several primate species, males have been shown to exhibit a surge in circulating testosterone during the early postnatal period. This surge has been postulated to play a role in the development of sex differences in behavior. In this study, the role of postnatal testosterone in infant behavioral development was investigated in socially living rhesus macaques. Seven male infants were treated with a GnRH agonist, avorelin, from the first week of life onwards. Ten female infants were exposed to testosterone by implantation of capsules containing testosterone. The behavioral development of these and control infants was recorded from birth to 6 months of age. The sexually dimorphic patterns of play and mounting were not affected by manipulation of postnatal testosterone in either male or female infants. Similarly, most mother-infant interactions were not affected by the hormonal manipulation of infants. Mothers of testosterone-treated females were found to take more responsibility for moving into and out of arm's reach of their infants than mothers of some other groups of infants; however, this measure did not normally differ between mothers of male and female infants. Manipulation of the postnatal testosterone surge does significantly affect penile growth and development, but does not affect the expression of infant sex differences in behavior nor greatly affect the development of the mother-infant relationship in rhesus macaques.


Phenotype Analysis of Early Risk Factors from Electronic Medical Records Improves Image-Derived Diagnostic Classifiers for Optic Nerve Pathology.
We examine imaging and electronic medical records (EMR) of 588 subjects over five major disease groups that affect optic nerve function. An objective evaluation of the role of imaging and EMR data in diagnosis of these conditions would improve understanding of these diseases and help in early intervention. We developed an automated image-processing pipeline that identifies the orbital structures within the human eyes from computed tomography (CT) scans, calculates structural size, and performs volume measurements. We customized the EMR-based phenome-wide association study (PheWAS) to derive diagnostic EMR phenotypes that occur at least two years prior to the onset of the conditions of interest from a separate cohort of 28,411 ophthalmology patients. We used random forest classifiers to evaluate the predictive power of image-derived markers, EMR phenotypes, and clinical visual assessments in identifying disease cohorts from a control group of 763 patients without optic nerve disease. Image-derived markers showed more predictive power than clinical visual assessments or EMR phenotypes. However, the addition of EMR phenotypes to the imaging markers improves the classification accuracy against controls: the AUC improved from 0.67 to 0.88 for glaucoma, 0.73 to 0.78 for intrinsic optic nerve disease, 0.72 to 0.76 for optic nerve edema, 0.72 to 0.77 for orbital inflammation, and 0.81 to 0.85 for thyroid eye disease. This study illustrates the importance of diagnostic context for interpretation of image-derived markers and the proposed PheWAS technique provides a flexible approach for learning salient features of patient history and incorporating these data into traditional machine learning analyses.


Comparison of the lactate minimum speed and the maximal lactate steady state to determine aerobic capacity in purebred Arabian horses.
To compare five different protocols for estimating the lactate minimum speed (LMS) with that for estimating the maximal lactate steady state (MLSS) in Arabian horses, in order to obtain a more rapid method for monitoring aerobic capacity and prescribing training schedules. Eight purebred Arabian horses were conditioned to exercise on a treadmill for 12 days then submitted to three to five exercise sessions to determine the MLSS. Blood samples were collected from a jugular catheter at specific intervals for measurement of lactate concentrations. The MLSS was the velocity maintained during the last 20 minutes of constant submaximal exercise, at which the concentration of lactate increased by no more than 1.0 mmol/L. The LMS test protocols (P1 - P5) included a warm-up period followed by a high-intensity gallop. The speed was then reduced to 4 m/s, and the incremental portion of the test was initiated. In P1, P2, and P3, the velocity increment was 0.5 m/s, and the duration of each incremental stage was three, five and seven minutes, respectively. In P4 and P5, the velocity increments were 1.0 and 1.5 m/s, respectively, and the duration of the stages was fixed at five minutes each. A second-degree polynomial function was fitted to the lactate-velocity curve, and the velocity corresponding to the lowest concentration of lactate was the LMS. Only the mean LMS determined by P1 and P2 did not differ from the velocity determined by the MLSS test (p > 0.1). There was a strong correlation (r >0.6) between P1 and the MLSS velocity. A limits of agreement plot revealed that the best agreement occurred between the MLSS test and P1 (mean bias = 0.14 m/s), followed by P2 (bias = -0.22 m/s). The lactate concentrations associated with the various LMS protocols did not differ. This study shows the variation between protocols of the LMS test for determining the onset of blood lactate accumulation but also reveals that, at least for Arabian horses, the P1 protocol of the LMS has good agreement with the MLSS.


An Applied Anatomic Guide to Anterior Temporal Lobectomy and Amygdalohippocampectomy: Laboratory Cranial and White Matter Dissections to Inform Surgical Practice.
Anterior temporal lobectomy and amygdalohippocampectomy is a challenging procedure because of the deep surgical trajectory and complex regional neurovascular anatomy. A thorough knowledge of the involved anatomic structures is crucial for a safe and effective procedure. Our objective is to explore the white matter pathways in or around the operative corridor and to illuminate the 3-dimensional relationships of the pertinent operative parenchymal and skull base anatomy, aiming to inform and simplify surgical practice. Four normal, adult, cadaveric, formalin-fixed cerebral hemispheres (2 left and 2 right) treated with the Klinger's technique and 2 formalin-fixed and colored-latex-injected cadaveric heads (4 sides) were used. Focused white matter and cadaveric dissections were used to study the relevant anatomy implicated during an anterior temporal lobectomy. Four illustrative cases were also included. Digital photographs from every dissection step were obtained. Major white matter pathways that are inevitably traversed during the approach are the inferior longitudinal fasciculus, uncinate fasciculus, and inferior arm of the cingulum. Tracts that can be potentially injured, should the dissection plane tilt inadvertently superiorly or posteriorly, are the inferior fronto-occipital fasciculus, Meyer's loop, superior longitudinal fasciculus/arcuate fasciculus complex, and basal ganglia. Consistent cranial and parenchymal landmarks that can act as a roadmap during the procedure are recorded and paired with their intraoperative equivalent to provide a thorough, yet simple, stepwise guide for the surgeon. White matter dissections, cadaveric cranial dissections, and intraoperative images are put together to provide a simplified stepwise surgical manual for anterior temporal lobectomy. Laboratory investigations that focus on the intricate 3-dimensional relationships of the pertinent operative anatomy from the surgeon's eye may enrich anatomic knowledge and push surgical boundaries, to minimize complication rates and ultimately improve patient outcomes.


Peptides of myelin basic protein are encephalitogenic in rats without the aid of emulsions.
Immunization with peptides is usually done with the aid of Freund's adjuvant. Using peptides derived from myelin basic protein, we show that aqueous solutions can be antigenic (encephalitogenic in this instance) in Lewis rats. The first procedure involved multiple doses of aqueous peptide, increased absorption into the lymphatic system from the peritoneal cavity in the postinflammatory state, and the use of pertussis vaccine. Three different peptides containing the major encephalitogenic site were active in this system, with the activity somewhat proportional to the size of the fragment. The second procedure, the direct delivery of peptide to lymph nodes by percutaneous inoculation, was equally successful and did not require the use of pertussis vaccine.


Family History of Alzheimer's Disease is Associated with Impaired Perceptual Discrimination of Novel Objects.
Early detection may be the key to developing therapies that will combat Alzheimer's disease (AD). It has been consistently demonstrated that one of the main pathologies of AD, tau, is present in the brain decades before a clinical diagnosis. Tau pathology follows a stereotypical route through the medial temporal lobe beginning in the entorhinal and perirhinal cortices. If early pathology leads to very subtle changes in behavior, it may be possible to detect these changes in subjects years before a clinical diagnosis can currently be made. We aimed to discover if cognitively normal middle-aged adults (40-60 years old) at increased risk for AD due to family history would have impaired performance on a cognitive task known to challenge the perirhinal cortex. Using an oddity detection task, we found that subjects with a family history of AD had lowered accuracy without demonstrating differences in rate of acquisition. There were no differences between subjects' medial temporal lobe volume or cortical thickness, indicating that the changes in behavior were not due to significant atrophy. These results demonstrate that subtle changes in perceptual processing are detectable years before a typical diagnosis even when there are no differences detectable in structural imaging data. Anatomically-targeted cognitive testing may be useful in identifying subjects in the earliest stages of AD.


Subacute stent thrombosis in a patient with type 2 diabetes and clopidogrel resistance: A case report .
Clopidogrel has become the mainstay oral antiplatelet regimen for recurrent ischemic event prophylaxis after acute coronary syndromes or stent placement. Stent thrombosis is considered a multifactorial problem that mostly occurs due to clopidogrel resistance. We report a case of subacute stent thrombosis in a CYP2C19*2 reduced-function allele carrier. A 56-year-old Chinese male diabetic patient suffered from acute myocardial infarction and underwent successful percutaneous coronary intervention (PCI) of the left anterior descending coronary artery (LAD) with two drug eluting stents (DESs). He was treated with a loading dose of aspirin 300 mg and ticagrelor 180 mg before stent placement. Ticagrelor was switched to clopidogrel of 75 mg maintenance dose, after emergency PCI. Stent thrombosis appeared 8 days after stent placement. The patient was found to be a CYP2C19*2 reduced-function allele carrier with type 2 diabetes. After intravenous administration of tirofiban, balloon angioplasty was performed, resulting in thrombolysis in myocardial infarction (TIMI) III antegrade flow. The present case demonstrates that both diabetes mellitus and carriage of CYP2C19*2 allele are associated with a reduced response to clopidogrel in the setting of this standard dose of clopidogrel and a high risk of stent thrombosis. CYP2C19 genetic testing seems to be helpful for identifying patients-at-risk, and optimal antiplatelet regimen should be considered in these fragile populations.


Effects of mitogens for mouse B lymphocytes on chicken lymphoid cells.
Lipopolysaccharide from E. coli (LPS) and purified protein derivative from tuberculin (PPD) increased the [3H]thymidine incorporation of chicken spleen cells in culture. No such stimulation was observed with dextran sulphate. Thymus and bursa lymphocytes were not stimulated by any of these compounds. Spleen cells from chickens chemically bursectomized with cyclophosphamide treatment showed decreased responses to LPS and PPD, but responded normally to the T-cell mitogen concanavalin A. None of the tested mitogens induced polyclonal antibody synthesis or directly enhanced the primary antibody response to sheep erythrocytes (SRBC) in spleen cell cultures. LPS-coated SRBC, however, enhanced the in vitro antibody response to SRBC. The results suggest a moderate proliferative response of chicken lymphocytes to LPS and PPD, possibly involving B cells, but not further effects comparable to those on mouse B lymphocytes.


Comparative Study between Pentoxifylline and Pioglitazone in the Treatment of Non-Alcoholic Fatty Liver Disease among Newly Detected Glucose Intolerant Patients.
This quasi experimental study was carried out to compare the efficacy of Pentoxifylline versus Pioglitazone in non-alcoholic fatty liver disease (NAFLD) among newly detected glucose intolerant patients attended at GHPD, BIRDEM, Dhaka, Bangladesh from March 2011 to May 2012. Sixty patients with newly detected abnormal glucose tolerance, naive to any antidiabetic drugs were randomly selected, with the findings of USG changes of fatty liver and raised ALT. Patients were divided into Group A (51.7%; mean age - 44.45±7.34 years, BMI - 26.76±3.65kg/m(2)) receiving Pioglitazone 30mg/day and Group B (48.3%; mean age - 43.97±10.13 years, BMI - 27.52±4.44kg/m(2)) receiving Pentoxifylline 1200mg/day along with dietary and lifestyle modification. Baseline, follow up 1 & follow up 2: Serum AST in Group A (66.58±40.78U/L, 45.00±19.43U/L and 33.25±9.92U/L) respectively and in Group B (54.13±20.11U/L, 38.31±12.90U/L and 30.62±9.63U/L) respectively. Serum ALT in Group A (113.48±61.38U/L, 61.16±19.45U/L and 42.45±13.84U/L) respectively & in Group B (99.13±37.95U/L, 50.27±15.95U/L and 37.24±9.51U/L) respectively. No patient with normal USG finding was included in the study. Baseline USG finding: Grade I - Group A (35.5%), Group B (27.6%); Grade II - Group A (54.8%), Group B (48.3%); Grade III - Group A (9.7%), Group B (24.1%). Final Follow up: Normal - Group A (16.1%), Group B (10.3%); Grade I - Group A (38.7%), Group B (34.5%); Grade II - Group A (41.9%), Group B (44.8%); Grade III - Group A (3.2%), Group B (10.3%). Within groups findings were statistically significant (P<0.001) but between groups not significant (P>0.001). Biochemical and USG grading were improved in follow ups in both the groups. Such findings were observed due to synergistic effect of both therapeutic intervention along with supplementary dietary and lifestyle modification. Both Pioglitazone and Pentoxifylline have similar therapeutic outcome combined with supplementary dietary and lifestyle modification.


Combined use of root conditioning, fibrin-fibronectin system and a collagen membrane to treat a localized gingival recession: a 10-case report.
The purpose of this research was to evaluate the effectiveness of combined root surface conditioning with tetracycline HCI, fibrin sealing system, guided tissue regeneration procedure and coronal sliding flap application in the treatment of localized gingival recessions. The present study was conducted on 10 patients with localized facial recessions of at least 3mm. A trapezium-shaped flap was elevated apically to the margin of the bone dehiscence and the root surface was thoroughly scaled by hand instruments and burs. Tetracycline HCI (pH 1.9) solution was then topically applied for 5 minutes and the root surface thoroughly rinsed with sterile saline. A collagen membrane was trimmed and shaped to cover the entire root surface and later removed and a fibrin sealing system injected onto the root surface. Immediately membrane was placed again on the root surface without applying any pressure. The flap was sutured in the coronal position to completely cover the root surface and membrane. Control group patients were treated with only coronal sliding flap operation. Sutures were removed 10 days after surgery. Patients were clinically reevaluated 6 months postoperatively. The mean amount of root surface coverage obtained was similar in the test and control groups (test = 71.7%; control = 68.55%) but the clinical attachment gain (test = 4.21mm; control = 2.86mm) and pocket depth variations (test = 1.14mm reduction; control = 0.07mm reduction) differed significantly (P < 0.001). This study found promising healing of localized gingival recessions to result from a combined use of tetracycline HCI root demineralization, fibrin sealing system application, guided tissue regeneration procedure and coronal sliding flap operation.


Current update on IVC leiomyosarcoma.
Primary leiomyosarcoma of the inferior vena cava (IVC) is a rare soft tissue sarcoma associated with poor prognosis. Patients are often asymptomatic or present with nonspecific abdominal symptoms, which delays initial diagnosis and contributes to poor oncologic outcome. Key imaging modalities include ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI). Characteristic imaging features include imperceptible caval lumen, dilation of the IVC, heterogeneous enhancement of the tumor, and development of extensive collateral circulation. Surgical resection is the mainstay of treatment, while chemotherapy and/or radiation may serve as therapy adjuncts. This article reviews the pathology, clinical findings, imaging features and management of IVC leiomyosarcoma.


Torque teno virus in liver diseases: On the way towards unity of view.
The review presents the data accumulated for more than 20 years of research of torque teno virus (TTV). Its molecular genetic structure, immunobiology, epidemiology, diagnostic methods, possible replication sites, and pathogenicity factors are described. TTV is a virus that is frequently detectable in patients with different viral hepatitides, in cases of hepatitis without an obvious viral agent, as well as in a healthy population. There is evidence suggesting that biochemical and histological changes occur in liver tissue and bile duct epithelium in TTV monoinfection. There are sufficient histological signs of liver damage, which confirm that the virus can undergo a replicative cycle in hepatocytes. Along with this, cytological hybridization in TTV-infected cells has shown no substantial cytopathic (cell-damaging) effects that are characteristic of pathogenic hepatotropic viruses. Studying TTV has led to the evolution of views on its role in the development of human pathology. The first ideas about the hepatotropism of the virus were gradually reformed as new data became available on the prevalence of the virus and its co-infection with other viruses, including the viruses of the known types of hepatitides. The high prevalence of TTV in the human population indicates its persistence in the body as a virome and a non-pathogenic virus. It has recently been proposed that the level of TTV DNA in the blood of patients undergoing organ transplantation should be used as an endogenous marker of the body's immune status. The available data show the polytropism of the virus and deny the fact that TTV can be assigned exclusively to hepatitis viruses. Fortunately, the rare detection of the damaging effect of TTV on hepatic and bile duct epithelial cells may be indirect evidence of its conditionally pathogenic properties. The ubiquity of the virus and the variability of its existence in humans cannot put an end to its study.


Analytical characterisation of Negroamaro red wines by "Aroma Wheels".
In this work we characterised Negroamaro red wines, made by an autochthonous cultivar of Southern Italy, by linking volatile composition to aroma properties. This linking was carried out by picturing "Aroma Wheels", built by Odour Activity Values (OAVs) of all the identified volatile compounds grouped in "aromatic series" belonging to 13 classes of sensory descriptors. The 18 most active odorants with OAV>1 were mainly alcohols, fatty acids and their ethyl esters. The "OAVs' Aroma Wheels" showed that the classes of sensory descriptors are first fruity and floral, next fatty and pungent and minor nutty and caramelised notes. Principal Component Analysis displayed correlations between sensory descriptors and wine samples; the main 7-fruity and 5-floral sensory features of Negroamaro wines have negative values of PC1 and they are negatively correlated with the second main sensory feature, i.e. 13-fatty, falling at positive value of PC1; this fit the aroma perception of this varietal.


New polycyclic diamine scaffolds from dimerization of 3-alkyl-1,4-dihydropyridines in acidic medium.
[reaction: see text] 3-Alkyl-1,4-dihydropyridines dimerize in acidic medium, at low temperature, to give polycyclic imminium salts derivatives that were reduced to afford new polycyclic diamine scaffolds. The reaction can be extended to enantiopure series starting from R-(+)- or S-(-)-1-phenylethylamine. Long exposure of the polycyclic imminium salt intermediates to air moisture at 20 degrees C resulted in formation of new amide derivatives. This is probably due to the addition of water followed by an intramolecular oxido-reduction process.


Eplerenone: a review of its use in patients with chronic systolic heart failure and mild symptoms.
Eplerenone (Inspra®) is a selective mineralocorticoid receptor antagonist (MRA). In the EU, it is approved for use (in addition to standard optimal therapy) to reduce the risk of cardiovascular (CV) mortality and morbidity in adult patients with chronic systolic heart failure (HF) and mild symptoms. This article reviews the efficacy and tolerability of eplerenone in this indication and briefly summarizes its pharmacology. In the EMPHASIS-HF study, relative to placebo, the addition of eplerenone to optimal background therapy significantly reduced the risk of death from CV causes or hospitalization for HF in patients with chronic systolic HF and mild symptoms. Benefits of eplerenone therapy over placebo were also observed in several secondary outcomes, including: death from any cause or hospitalization for HF; death from any cause; hospitalization for any reason; or hospitalization for HF. Eplerenone was generally well tolerated in this study, with the most frequent adverse event being hyperkalaemia, which is a known adverse event of the drug class. Sexual adverse events (e.g. gynecomastia) occurred in <1 % of eplerenone recipients, reflecting the selectivity of eplerenone for mineralocorticoid receptors. Based on these results, European guidelines have been updated and recommend the use of an MRA to reduce the risk of HF hospitalization and premature death in all patients with persisting symptoms (New York Heart Association class II-IV) and a left-ventricular ejection fraction of ≤35 %, despite treatment with ACE inhibitor (or an angiotensin receptor blocker if an ACE inhibitor is not tolerated) and a β-blocker.


Actinomycotic osteomyelitis of the cranial vault presenting with headache: an unusual presentation.
A case of left parietal calvarial actinomycotic osteomyelitis in a young woman is described. She had no predisposing illnesses. She had delivered a live child at term and presented in the puerperal period. No extracranial focus of infection was identified. She responded well to a combination of surgery and medical therapy and had an excellent outcome. The authors emphasise the importance of establishing a histopathological diagnosis since radiological signs are non-specific and unreliable.


Emotional numbing in posttraumatic stress disorder: current and future research directions.
Despite being understudied and poorly understood relative to the chronic fear, anxiety and other aversive emotional states that occur in the immediate aftermath of trauma, emotional numbing has become a core defining feature of posttraumatic stress disorder (PTSD). This paper seeks to briefly review the literature bearing on these seemingly disparate emotional responses to trauma as well as theoretical accounts of emotional numbing that have been proffered to date. We then offer an alternative theory of post-traumatic emotional functioning and review empirical support for this model. The experience of trauma produces very intense emotions such as overwhelming fear, horror, and anxiety, and these reactions can linger for a lifetime. Many trauma survivors also report restrictions in their emotional experience - a phenomenon most commonly referred to as emotional numbing. In contrast to previous accounts of posttraumatic emotional functioning our model posits that individuals with PTSD have difficulty expressing positive emotions as a result of re-experiencing states. We further argue that patients with PTSD are capable of experiencing and expressing the full range of emotions that were available pretraumatically. Our model holds that individuals with PTSD are not, in fact, 'emotionally numb' as a result of traumatic experience. Rather, PTSD is associated with hyperresponsivity to negatively valenced emotional stimuli. Consequently, patients with PTSD require more intense positive stimulation to access the full complement of appetitive or pleasant emotional behaviour.


Strontium-doped lanthanum iron nickelate oxide as highly efficient electrocatalysts for oxygen evolution reaction.
Pursuing efficient and low-cost catalysts for the sluggish oxygen evolution reaction (OER) is imperative for the large-scale deployment of promising electrochemical technologies such as water splitting and CO2 electrochemical reduction. The earth-abundant perovskite catalysts based on LaNiO3-δ show promise in OER catalysis because of their relatively low cost and their optimal electronic structure but suffer from low electrode-area normalized activity. In this work, we partially substituted La with Sr and Ni with Fe to enable a remarkably high OER activity with an ultra-low overpotential of 374 ± 3 mV vs RHE at a current density of 10 mA cm-2 normalized by electrode geometric area. This performance even surpasses the performance of benchmark RuO2. Our results show that Sr could promote OER-active sites including Ni(III), O2-2/O-, and optimal Ni/Fe ratios, which significantly improve the surface intrinsic activity at the perovskite surface. Therefore, this work not only developed a highly efficient earth-abundant catalyst towards OER, but also demonstrated the effective modulation of catalyst surface interactions through A-site doping for perovskite oxides for key applications such as water splitting, CO2 electrochemical reduction and N2 electrochemical fixations.


The Gaps between Knowing and Doing in Hearing Aid Fitting Management.
Evidence based practice has become an important aspect in many healthcare provisions to improve patient outcomes. Investigating the gaps between knowing and doing in audiology practice will provide future directions for successful service delivery. The purpose of this study was to explore "know-do" gaps related to professional awareness and attitude in hearing aid fitting management (HAFM) by analyzing data of a questionnaire. It consisted of 22 questions focusing on 11 HAFM components. Each component had two sub-questions involving levels of the importance and practice for HAFM. Respondents answered each question based on subjective judgments for their own hearing aid fitting services with a Visual Analogue Scale. A total of 51 responses from hearing care professionals were collected and the scores for knowing and doing were compared. The results showed overall high scores in doing and knowing responses; however, there were significant "know-do" gaps demonstrating higher knowing scores than doing scores across all HAFM components. The largest "know-do" gaps were observed in three components mostly implemented during follow-up sessions which indicate the need to improve their corresponding services and practical guidelines emphasizing the follow-up services.


Increased survival of skin flaps by scavengers of superoxide radical.
Elevation of rat abdominal skin flaps, followed by ligation and division of the left inferior neurovascular pedicle, resulted in only a 40% survival of the area normally perfused by the ligated artery and vein. Superoxide dismutase (SOD) (EC 22.214.171.124) administered i.v. (20,000 U/kg) 30 min before flap elevation increased survival to 52%. SOD derivatized with polyethylene glycol, which increases circulating half-life, was more effective, increasing survival to 80%. This protective effect resulted from the catalytic activity of the derivatized enzyme because inactivation by treatment with H2O2 eliminated its effect on skin flap survival. An equimolar mixture of Desferal and MnCl2, which catalyzes the dismutation of O2- in vitro, improved survival to 72%. Desferal-Fe3+, which lacks in vitro SOD activity, or Mn2+ alone did not affect the survival of skin flaps, but Desferal alone was nearly as effective as the Desferal-Mn2+ mixture. This effect of Desferal may result from acquisition of and subsequent removal of iron in vivo. These results support the view that the superoxide radical or a product derived from it plays a role in limiting the survival of island skin flaps.


Specificity of mutation by UV light and delayed photoreversal in umuC-defective Escherichia coli K-12: a targeting intermediate at pyrimidine dimers.
Prototrophic mutants produced by UV light in Escherichia coli K-12 strains with argE3(Oc) and hisG4(Oc) defects are distinguished as backmutations and specific nonsense suppressor mutations. In strains carrying a umuC defect, mutants are not produced unless irradiated cells are incubated and then exposed to photoreversing light (delayed photoreversal mutagenesis). The mutants thus produced are found to be specifically suppressor mutations and not backmutations. The suppressor mutations are primarily glutamine tRNA ochre suppressor mutations, which have been attributed previously to mutation targeted at T = C pyrimidine dimers. In a lexA51 recA441 strain, where the SOS mutagenesis functions are constitutive, targeting at dimers is confirmed by demonstrating that the induction of glutamine tRNA suppressor mutations is susceptible to photoreversal. In the same strain induction of backmutations is not susceptible to photoreversal. Thus delayed photoreversal mutagenesis produces suppressor mutations that can be targeted at pyrimidine dimers and does not produce backmutations that are not targeted at pyrimidine dimers. This correlation supports the idea that delayed photoreversal mutagenesis in umuC defective cells reflects a mutation process arrested at a targeting pyrimidine dimer photoproduct, which is the immediate cause of both the alteration in DNA sequence and the obstruction (unless repaired) to mutation fixation and ultimate expression.


The Key Role of the RPS14 Gene in Neoplasms and Solid Tumors.
The ribosomal protein S14 (RPS14) gene located at 5q33 codes for a protein involved in ribosomal biogenesis. The RPS14 gene has a length of 5.9 kb of DNA comprising 5 exons and 4 introns. It is possible that RPS14 is involved in the formation of pre-RNA 18s, an intermediate RNA that serves for the formation of the 40S small subunit of the ribosome. RPS14 haploinsufficiency (HI) produces alterations in intermediate RNA levels (pre-RNA 30S/18SE/18S), which are found in del(5q) MDS. In addition, RPS14 haploinsufficiency results in the formation of the MDM2 (double minute mouse E3 ubiquitin ligase)-RP (ribosomal protein) complex that prevents the MDM2-p53 interaction, generating an accumulation of p53 levels. This accumulation produces cell cycle arrest, impaired DNA repair, senescence, and apoptosis. RPS14 haploinsufficiency has been seen in MDS. Altered expression levels of RPS14 have also been reported in glioma, colorectal cancer, hepatocellular carcinoma, breast cancer, renal cell carcinoma, and primary myelofibrosis.


Psychometric properties of three medication adherence scales in patients with rheumatoid arthritis.
Patient adherence to their health care protocols is important to encourage the best health outcomes in rheumatoid arthritis (RA); however, little attention has been given to assessing the psychometric properties of adherence measures in this patient population. The purpose of this study was to evaluate the psychometric properties of three existing self-report measures of medication adherence in a sample of patients with RA--the compliance-questionnaire-rheumatology (CQR), the Medication Adherence Report Scale (MARS), and the medication adherence scale (MAS). A cross-sectional study of 108 clinic patients with rheumatoid arthritis was conducted to evaluate the reliability and validity of the measures. Cronbach's alpha was .77 for both the CQR and a modified version of the MARS. For the MAS, the Kuder-Richardson 20 reliability was .25. Although not strong, test-retest reliability was adequate for all measures. Factor analysis indicated that both the MARS and the CQR measure two factors. All three instruments were moderately correlated with each other, with correlations ranging between .48 and .56. Although these scales were significantly correlated, moderate correlations among the scales indicate that they may not measure the same aspects of adherence. Among the three adherence measures, the modified MARS demonstrated the best evidence of reliability and validity and ease of administration in this sample of persons with RA.


Genetic modifications of Mecr reveal a role for mitochondrial 2-enoyl-CoA/ACP reductase in placental development in mice.
Mitochondrial fatty acid synthesis (mtFAS) is an underappreciated but highly conserved metabolic process, indispensable for mitochondrial respiration. It was recently reported that dysfunction of mtFAS causes childhood onset of dystonia and optic atrophy in humans (MEPAN). To study the role of mtFAS in mammals, we generated three different mouse lines with modifications of the Mecr gene, encoding mitochondrial enoyl-CoA/ACP reductase (Mecr). A knock-out-first type mutation, relying on insertion of a strong transcriptional terminator between the first two exons of Mecr, displayed embryonic lethality over a broad window of time and due to a variety of causes. Complete removal of exon 2 or replacing endogenous Mecr by its functional prokaryotic analogue fabI (Mecrtm(fabI)) led to more consistent lethality phenotypes and revealed a hypoplastic placenta. Analyses of several mitochondrial parameters indicate that mitochondrial capacity for aerobic metabolism is reduced upon disrupting mtFAS function. Further analysis of the synthetic Mecrtm(fabI) models disclosed defects in development of placental trophoblasts consistent with disturbed peroxisome proliferator-activated receptor signalling. We conclude that disrupted mtFAS leads to deficiency in mitochondrial respiration, which lies at the root of the observed pantropic effects on embryonic and placental development in these mouse models.


Lack of association between hepatitis B birth immunization and neonatal death: a population-based study from the vaccine safety datalink project.
There have been no population-based studies of the potential association between neonatal death and newborn immunization with hepatitis B vaccine (HBV). As part of the Vaccine Safety Datalink Project, we defined a birth cohort at Southern and Northern California Kaiser Permanente Health Plans of more than 350,000 live births from 1993 to 1998 and ascertained all deaths occurring under 29 days of age. We compared the proportions of deaths among birth HBV-vaccinated and unvaccinated newborns and reviewed the causes and circumstances of their deaths. We performed detailed clinical reviews of all HBV-vaccinated neonates who died and a sample of unvaccinated neonates who died and who were matched to vaccinated deaths for days of life, sex, birth year and site of care. To avoid confounding, we categorized the causes of death as either "expected" or "unexpected" and performed a stratified analysis to compare mortality with immunization status. There were 1363 neonatal deaths during the study period. Whereas 67% of the entire birth cohort received HBV at birth, only 72 (5%) of the neonates who died were HBV-vaccinated at birth (P < 0.01). We found no significant difference in the proportion of HBV-vaccinated (31%) and unvaccinated (35%) neonates dying of unexpected causes (P = 0.6). Further we could not identify a plausible causal or temporal relationship between HBV administration and death for the 22 vaccinated neonates who died unexpectedly. A relationship between HBV and neonatal death was not identified.


Synthesis and novel fluorescence phenomenon of terbium complex with a new Schiff base ligand derived from condensation of triaminotriethylamine and 3-indolemethanal.
A new Schiff base ligand with tripodal structure, N,N',N''-tri-(3-indolemethanal)-triaminotriethylamine (L), and its complex with terbium was synthesized. The complex was characterized by element analysis, IR spectra, mass spectra, thermal analysis and molar conductivity. The terbium ion was found to coordinate to the Schiff base nitrogen atoms and the bridgehead nitrogen atom. The fluorescence properties of the complex in aqueous solutions were studied. Under the excitation of UV light, the complex exhibits characteristic fluorescence of terbium ion. H(+) concentration could strongly enhance the luminescence of terbium complex with L in aqueous solutions. This phenomenon will make the new complex favorable to be used in the fluorescence switches and sensors. The mechanism of the fluorescence enhancement by protonation of the indole nitrogen atoms is due to the suppressed photoinduced electron transfer (PIET) fluorescence quenching when adding acid.


Exploring and exploiting the synergy of non-covalent interactions on the surface of gold nanoparticles for fluorescent turn-on sensing of bacterial lipopolysaccharide.
The sensing of lipopolysaccharide (LPS) relies on the synergy of multiple electrostatic and hydrophobic interactions between LPS and the sensor. However, how non-covalent interactions are coordinated to impel the recognition process still remains elusive, and the exploration of which would promote the development of LPS sensors with higher specificity and sensitivity. In this work, we hypothesize that Au NPs would provide a straightforward and flexible platform for studying the synergy of non-covalent interactions. The detailed mechanism of interactions between the designed fluorescent probes and Au NPs with two distinct surface properties was systematically explored. We demonstrated that only when the electrostatic attraction and hydrophobic stacking are both present, the binding of fluorescent probes onto Au NPs can be not only highly efficient, but also positively cooperative. After that, hybrid systems that consist of Au NPs and surface-assembled fluorescent probes were exploited for fluorescent turn-on sensing of LPS. The results show that the sensitivity and selectivity to LPS relies strongly on the binding affinity between fluorescent probes and Au NPs. Fluorescent probes assembled Au NPs thus provide an attractive platform for further optimization of the sensitivity/selectivity of LPS sensing.


Experimental micropolycystic ovarian disease. I. Measurement of body weight, ovarian weight and histochemical activity of 17 beta-hydroxysteroid dehydrogenase.
The effects of administration of 1.25 mg testosterone propionate between the 2nd and 5th day of life on body weight, ovarian weight, food and water consumption, and the histochemical activity of 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) were studied in female Wistar rats during the evolution of experimental micropolycystic ovaries. Biometric studies showed a 9.9 day delay of vaginal opening for the treated animals and that the increased body weight of the animals during the disease was not related to food intake and thus presumably due to the induced metabolic disorder. Reduced histochemical activity of the 17 beta-HSD of testosterone-treated rats was detected at ages 30, 60 and 90 days before the onset of morphological alterations of the ovaries. The possible participation of 17 beta-HSD in the disequilibrium between androstenedione and testosterone and in the genesis of the disease is discussed.


Assessment of Sperm Deoxyribose Nucleic Acid Fragmentation Using Sperm Chromatin Dispersion Assay.
The integrity of sperm deoxyribose nucleic acid (DNA) is one of the determinants that ensure normal fertilization, implantation, pregnancy, and the generation of a healthy progeny. Assessment of sperm DNA fragmentation has gained importance as a tool to provide significant information regarding sperm quality, and it can independently predict sperm fertilizing potential. The sperm chromatin dispersion (SCD) assay is one of the available techniques to detect sperm DNA damage with results comparable to the gold standard - Sperm Chromatin Structure Assay. We present here a detailed methodology of an alkaline modification of SCD that can be carried out with minimal laboratory equipment. The SCD assay is a modified halo assay that utilizes chemical methods to demonstrate sperm DNA fragmentation. It involves the embedding of sperms in an agarose medium followed by exposure to alkaline denaturation and deproteinization. The results are interpreted under a light microscope. A visual scoring system is utilized to differentiate the sperms with possible DNA fragmentation from those without fragmented DNA and to determine the sperm DNA fragmentation index (SDFI) % for each semen sample. The SDFI % is directly proportional to the quality of sperm. The SCD assay is a simple, cost-effective, and reliable technique that can detect sperm DNA fragmentation, thus providing information regarding sperm functional quality and reproductive capacity. It is of significance in clinical and research areas of andrology and reproductive medicine, toxicology, and pharmacotherapeutics.


Phosphorylation and inactivation of rat hepatocyte glycogen synthase by phorbol esters and mezerein.
Incubation of rat hepatocytes with active phorbol esters and mezerein provoked a decrease in glycogen synthase activity. After the incubation of [3 2 P] phosphate-labeled cells with these tumor promoters, an increase in the amount of 3 2 P bound to the immunoprecipitated enzyme was observed. The decrease in activity highly correlated with the phosphorylation in the smaller CNBr fragment (CB-1) and only at high concentration of the phorbol ester the increase in the phosphorylation of the larger CNBr fragment (CB-2) became significative. Tryptic degradation of CB-1 showed two phosphopeptides after isoelectro focusing analysis (pI 3.9 and pI 3.4) and only one of them (pI 3.9) increased its phosphorylation state after treatment of the cells. These results indicate that the decrease in activity of glycogen synthase by phorbol esters and mezerein is a result of the phosphorylation of the enzyme and that a single site located in CB-1 is preferentially phosphorylated by these agents.


Functional polymorphism of detoxification gene NQO1 predicts intensity of empirical treatment of childhood asthma.
The management of moderate to severe childhood asthma remains empirical. Genotypic variation has been proposed as a way to tailor specific pharmaceutical regimens to individual patients. The objective of this study was to determine the factors associated with asthma treatment progression, including functional polymorphisms of phase II detoxification enzymes, demographics, and environmental factors. In a study of 120 asthmatic children cared for in a single pediatric pulmonary practice, intensity of medical treatment over the year prior was modeled as a function of null mutations of glutathione S transferase (GST) M1 and T1, ile105val variant of GSTP1, and pro187ser variant of NAD(P)H:quinone oxidoreductase 1 (NQO1). The model included demographics, medical information, and environmental factors obtained via questionnaire analyzed with multivariate logistic regression and artificial neural networks. Multivariate logistic regression with bootstrapped validation identified a polymorphic variant of NQO1 as significantly contributing to increasing the odds of receiving more aggressive medical therapy (odds ratio, 11.56; p=0.0001). Parent income and education inversely correlated with medical treatment (odds ratio, 1.50; p=0.001 and odds ratio, 0.375; p=0.002, respectively). Age and reporting restricted physical activity due to asthma also impacted medical treatment (odds ratio, 0.63; p=0.0001 and odds ratio, 5.90; p=0.004, respectively). The optimism-adjusted discriminative ability (c-index) of the model was 0.881 (close to Bayes optimum of 0.902) with 80% overall classification accuracy. Our study supports the role of NQO1 polymorphism as an important factor determining the intensity of medical therapy in asthmatic children after adjusting for significance relating to parental income and education level, age, and restricted physical activity. Asthmatic children with a functional polymorphism of NQO1 may require more intensive pharmaceutical treatment to effectively control their asthma.


Instrument specific brain activation in sensorimotor and auditory representation in musicians.
Musicians show a remarkable ability to interconnect motor patterns and sensory processing in the somatosensory and auditory domains. Many of these processes are specific for the instrument used. We were interested in the cerebral and cerebellar representations of these instrument-specific changes and therefore applied functional magnetic resonance imaging (fMRI) in two groups of instrumentalists with different instrumental training for comparable periods (approximately 15 years). The first group (trumpet players) uses tight finger and lip interaction; the second (pianists as control group) uses only the extremities for performance. fMRI tasks were balanced for instructions (piano and trumpet notes), sensory feedback (keypad and trumpet), and hand-lip interaction on the trumpet. During fMRI, both groups switched between different devices (trumpet or keypad) and performance was combined with or without auditory feedback. Playing the trumpet without any tone emission or using the mouthpiece showed an instrument training-specific activation increase in trumpet players. This was evident for the posterior-superior cerebellar hemisphere, the dominant primary sensorimotor cortex, and the left Heschl's gyrus. Additionally, trumpet players showed increased activity in the bilateral Heschl's gyrus during actual trumpet playing, although they showed significantly decreased loudness while playing with the mouthpiece in the scanner compared to pianists.


The influence of partial-match cues on event-based prospective memory.
In event-based prospective memory tasks people form an intention to respond when an environmental cue signals that conditions are appropriate to fulfil an intended activity. In the ongoing activity the authors embedded partial-match cues that only partially, but not completely, satisfied the conditions required to make a prospective response. The consequence of encountering these partial-match cues was to increase responses to appropriate prospective memory cues encountered later. This outcome occurred both with semantic and orthographic cues, but only the former led to longer processing latencies of the partial-match cues. This asymmetry suggests that partial-match cues may not need to be processed consciously in order to benefit event-based prospective memory. A parametric manipulation of the number of partial-match cues resulted in numerically but not statistically better prospective memory. Consequently, partial-match cues may function as overt reminders of the intention to respond or they may serve to engage participants in self-initiated remindings of the intention.


Hypoxia mediates mitochondrial biogenesis in hepatocellular carcinoma to promote tumor growth through HMGB1 and TLR9 interaction.
The ability of cancer cells to survive and grow under hypoxic conditions has been known for decades, but the mechanisms remain poorly understood. Under certain conditions, cancer cells undergo changes in their bioenergetic profile to favor mitochondrial respiration by activating the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) and up-regulating mitochondrial biogenesis. In this study, we hypothesized that augmented mitochondrial biogenesis plays a critical role for cancer cells to survive hypoxia. Consistent with this hypothesis, both hypoxic human hepatocellular carcinoma (HCC) tumors and HCC cell lines subjected to hypoxia increase mitochondrial biogenesis. Silencing of PGC-1α in hypoxic HCC cell lines halts their proliferation. Mechanistic investigations in vitro indicated that intracellular high mobility group box 1 (HMGB1) protein, a nuclear protein overexpressed in HCC, is essential for the process. Silencing of HMGB1 in hypoxic HCC cell lines resulted in a significant decrease in PGC-1α activation and mitochondrial biogenesis. Without HMGB1, hypoxic HCC cells had significantly reduced adenosine triphosphate production, decreased cellular proliferation, and increased apoptosis. In a diethylnitrosamine-induced murine model of HCC, genetic blocking of HMGB1 in hypoxic tumors resulted in a significant decrease in tumor growth. Tumors lacking HMGB1 had a significant reduction in mitochondrial biogenesis and a significant increase in mitochondrial dysfunction. Further in vitro mechanistic experiments indicated that during hypoxia HMGB1 translocates from the nucleus to the cytoplasm and binds to cytoplasmic Toll-like receptor-9. This binding leads to activation of p38 and subsequent phosphorylation of PGC-1α, with resultant up-regulation of mitochondrial biogenesis. Taken together, our findings suggest that during hypoxia HMGB1 up-regulates mitochondrial biogenesis in HCC cancer cells, promoting tumor survival and proliferation. (Hepatology 2017;66:182-197).


Profiling N-glycans of the egg jelly coat of the sea urchin Paracentrotus lividus by MALDI-TOF mass spectrometry and capillary liquid chromatography electrospray ionization-ion trap tandem mass spectrometry systems.
Sea urchin eggs are surrounded by a carbohydrate-rich layer, termed the jelly coat, that consists of polysaccharides and glycoproteins. In the present study, we describe two mass spectrometric strategies to characterize the N-glycosylation of the Paracentrotus lividus egg jelly coat, which has an alecithal-type extracellular matrix like mammalian eggs. Egg jelly was isolated, lyophilized, and dialyzed, followed by peptide N-glycosidase F (PNGase-F) treatment to release N-glycans from their protein chain. These N-glycans were then derivatized by permethylation reaction, and analyzed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and capillary liquid chromatography electrospray ionization-ion trap tandem mass spectroscopy (CapLC ESI-Ion trap-MS/MS). N-glycans in the egg jelly coat glycoproteins were indicated by sodiated molecules at m/z 1579.8, 1783.9, 1988.0, 2192.0, and 2397.1 for permethylated oligosaccharides on MALDI-TOF MS. Fragmentation and structural characterization of these oligosaccharides were performed by ESI-Ion trap MS/MS. Then, MALDI-TOF-MS and ESI-Ion trap-MS/MS spectra were interpreted using the GlycoWorkbench software suite, a tool for building, displaying, and profiling glycan masses, to identify the original oligosaccharide structures. The oligosaccharides of the isolated egg jelly coat were mainly of the high mannose type.


Activity and recovery cycles and skill involvements of successful and unsuccessful elite rugby league teams: A longitudinal analysis of evolutionary changes in National Rugby League match-play.
We investigated changes in activity and recovery cycles and skill involvements: (1) during National Rugby league (NRL) match-play from 2004 to 2014 and (2) among successful and unsuccessful teams over the same period. Teams were divided into 4 tiers according to final ladder position: (A) 1st-4th, (B) 5th-8th, (C) 9th-12th and (D) 13th-16th. Total, mean and maximum ball-in-play time decreased, while recovery time increased from 2004 to 2014. Offensive and defensive skill involvements changed differentially over time with moderate to large reductions in the number of play-the-balls, offloads and missed tackles, and moderate to large increases in the number of passes, tackles made and ineffective tackles. The gap between Tier A and Tier D decreased for mean activity time and the proportion of short (<45 s) ball-in-play periods. Conversely, the gap between Tier A and Tier D increased for skill involvements, with Tier A completing more play-the-balls, and Tier D performing a greater number of offloads, and total, missed and ineffective tackles. Our results demonstrate the decreasing ball-in-play demands of NRL competition over 11 seasons. However, our data also highlight the narrowing gap in ball-in-play demands, and increasing gap in skill involvements between the top tier and bottom tier teams.


Species identification and comparative molecular and physiological analysis of Candida zemplinina and Candida stellata.
Strains of the recently described yeast species Candida zemplinina have been identified in botrytized grapes and musts in geographically distant areas. C. zemplinina is almost indistinguishable from C. stellata, another yeast common in fermenting botrytized wines. In this work a specific PCR-RFLP method is described for the differentiation of the two species. It is also shown that both species have three chromosomes, display chromosomal length polymorphism, and C. zemplinina has a smaller genome. C. zemplinina is acidogenic, highly osmotolerant, grows much better than C. stellata in the presence of ethanol and at low temperatures.


Characterization of multiple mRNA species of simian immunodeficiency virus from macaques in a CD4+ lymphoid cell line.
Cytoplasmic poly(A)+ RNA was isolated from CEMX721.174 cells 5 to 10 days after infection with molecularly cloned simian immunodeficiency virus SIVmac239. Expression of SIV RNA was analyzed by Northern (RNA) blot hybridization and by sequencing of cDNA clones. As expected, a splice donor site was demonstrated in the untranslated leader sequence outside the left long terminal repeat. The region between pol and env was found to contain at least two splice donor and six splice acceptor sites. Splice acceptor and donor sites in the intergenic region were suitably positioned for expression of vpx, vpr, tat, and rev. Splice acceptor sites at nucleotides 8802 and 8805 were demonstrated in singly and doubly spliced RNAs with the potential of expressing nef and the second exons of tat and rev. Our results demonstrate a complex pattern of alternative splicing of SIV mRNAs. The results are very similar to what has been observed in human immunodeficiency virus type 1-infected cells, suggesting that both human and simian immunodeficiency viruses are subject to multiple levels of regulation.


Nano vanadium dioxide films deposited on biomedical titanium: a novel approach for simultaneously enhanced osteogenic and antibacterial effects.
Vanadium is a trace element in the human body, and vanadium compounds have a promising future in biological and medical applications due to their various biological activities and low toxicity. Herein, a novel pure vanadium dioxide (VO2) nanofilm was deposited on a substrate of biomedical titanium by magnetron sputtering. The antibacterial effect of VO2 against the methicillin-resistant Staphylococcus aureus (MRSA) was validated in vitro and in vivo. Moreover, the biocompatibility of VO2 and its osteogenic effects were systematically illustrated. A possible osteogenic mechanism involving the amelioration of highly reactive oxygen species (ROS) levels were investigated. According to the results of our present and previous studies, the simultaneous antibacterial and osteogenic effects of VO2 are attributed to its differential regulation of ROS levels in rat bone marrow mesenchymal stem cells (rBMSCs) and bacteria. This study is the first to report the simultaneous effects of VO2 on bactericidal and osteogenic activities through its differential modification of ROS activity in eukaryotic (rBMSCs) and prokaryotic (MRSA) cells. The findings in this work may yield a deeper understanding of the biological activities of vanadium compounds while also paving the way for the further investigation and application of VO2 in biological and medical materials.


Psychometric evaluation of the Korean version of the Diabetes Self-efficacy Scale among South Korean older adults with type 2 diabetes.
To evaluate the psychometric properties (reliability and validity) of the Korean version of the Diabetes Self-efficacy Scale among South Korean older adults with type 2 diabetes mellitus. Self-efficacy has been reported to be a key component of enhancing diabetes self-management, and many healthcare providers have paid attention to the instruments to accurately measure self-efficacy as related to diabetes self-management. A psychometric test of an instrument measuring self-efficacy as related to diabetes self-management. A total of 278 Korean older adults with type 2 diabetes were recruited in one senior centre in Seoul, South Korea. The instrument included the Diabetes Self-efficacy Scale and the summary of the Diabetes Self-care Activities. Item analyses, reliability including internal consistency and stability, and validity including exploratory factor analysis, confirmatory factor analysis, and hypothesised relationships test were used to examine the psychometric properties of the Korean version of the Diabetes Self-efficacy Scale. The item-total correlation coefficients of all items were >0·30 and ranged from 0·47-0·73. The coefficient alpha for the internal consistency was 0·89, and the intraclass correlation coefficient for the stability was 0·90. Two factors were extracted from the exploratory factor analysis (factor 1, self-efficacy for diet-related self-management behaviours; factor 2, self-efficacy for diabetes self-management behaviours except diet), and the two-factor model for the confirmatory factor analysis had good fitness indices. The diabetes self-efficacy scores were positively correlated with the level of diabetes self-management. The findings supported that the Korean version of the Diabetes Self-efficacy Scale was reliable and valid in measuring self-efficacy as related to diabetes self-management in Korean older adults with type 2 diabetes. The Korean version of the Diabetes Self-efficacy Scale can allow healthcare providers to effectively measure self-efficacy related to diabetes self-management so that they can provide the appropriate and adequate nursing care to Korean older adults with type 2 diabetes.


CRISPR to the Rescue: Advances in Gene Editing for the FMR1 Gene.
Gene-editing using Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) is promising as a potential therapeutic strategy for many genetic disorders. CRISPR-based therapies are already being assessed in clinical trials, and evaluation of this technology in Fragile X syndrome has been performed by a number of groups. The findings from these studies and the advancement of CRISPR-based technologies are insightful as the field continues towards treatments and cures of Fragile X-Associated Disorders (FXADs). In this review, we summarize reports using CRISPR-editing strategies to target Fragile X syndrome (FXS) molecular dysregulation, and highlight how differences in FXS and Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) might alter treatment strategies for each syndrome. We discuss the various modifications and evolutions of the CRISPR toolkit that expand its therapeutic potential, and other considerations for moving these strategies from bench to bedside. The rapidly growing field of CRISPR therapeutics is providing a myriad of approaches to target a gene, pathway, or transcript for modification. As cures for FXADs have remained elusive, CRISPR opens new avenues to pursue.


In silico estimation of basic activity-relevant parameters for a set of drug absorption promoters.
Finding a balance between a desired drug's potency and its physicochemical properties that are important for its molecule pharmacokinetic or pharmacodynamics profile is still a challenging issue in rational drug discovery. Quantitative assessment of the lipophilic characteristics of potential drug molecules is indispensable for efficient development of Absorption, Distribution, Metabolism, Excretion, Toxicity-tailored structure-activity models; therefore reliable procedures for deriving log P from molecular structure are desirable. In the current work a range of various software log P predictors for estimation of the numerical lipophilic values for a set of cholic acid derivatives were employed and subsequently cross-compared with the experimental parameters. Thus, the empirical lipophilicity (RM) was compared with the corresponding log P characteristics calculated using alternative methods for deducing the lipophilic features. The mean values of the selected molecular descriptors that were averaged over the chosen calculation methods (consensus clog P) were subsequently correlated with the RM parameter. As an additional experiment, the iterative variable elimination partial least squares (IVE-PLS) methodology for an ensemble of descriptors retrieved from Dragon 6.0 software was applied for a set of drug transporters. To investigate the variations within the ensemble of cholic acid derivatives principal component analysis (PCA) and self-organizing neural network (SOM) procedures were used to visualize the major differences in the performance of drug promoters with respect to their lipophilic profile.


In vitro evaluation of the effects of tobramycin and parathyroid hormone on mesenchymal stem cells.
Approximately 7.9 million bone fractures occur every year in the United States, with an estimated cost of $70 billion. It is estimated that 5-10 percent of patients will develop infections or delayed healing following orthopedic surgery. The probability of osteomyelitis is related to the severity of trauma and infection is most frequent after high velocity, open injuries with skin loss. Complications with bone healing and antibiotic drug-resistance increases morbidity and costs associated with osteomyelitis are estimated at $15,000-$30,000 per incident. Traditional osteomyelitis treatment often requires additional surgery and systemic antibiotics that are harmful, burdensome, and costly. There is limited evidence in the literature examining the effects pharmacological agents tobramycin (TOB) and parathyroid hormone (PTH) have on the mesenchymal stem cells (MSCs) that differentiate into many cell types. The purpose of this investigation was to evaluate the in vitro dose-dependent effects of TOB and PTH on mesenchymal stem cells. MSCs were treated for periods of 24, 48 and 72 hours in the presence of TOB and PTH. Following incubation, MSCs were examined for cellular morphology, viability, proliferation, and damage. Our results show an increase in morphological changes following treatments with both PTH and TOB which are confirmed by decreases in cellular protein concentration. Are results also indicate PTH acts as an essential factor in mesenchymal development and may control differentiation into osteogenic or chondrogenic lineage. Development of targeted delivery of PTH and TOB to a fracture may be effective at treating both infection and bone loss.


A multiblob approach to colloidal hydrodynamics with inherent lubrication.
This work presents an intermediate resolution model of the hydrodynamics of colloidal particles based on a mixed Eulerian-Lagrangian formulation. The particle is constructed with a small set of overlapping Peskin's Immersed Boundary kernels (blobs) which are held together by springs to build up a particle impenetrable core. Here, we used 12 blobs placed in the vertexes of an icosahedron with an extra one in its center. Although the particle surface is not explicitly resolved, we show that the short-distance hydrodynamic responses (flow profiles, translational and rotational mobilities) agree with spherical colloids and provide consistent effective radii. A remarkable property of the present multiblob model is that it naturally provides zero relative mobility at some finite inter-particle distance. In terms of mutual friction, this divergent force accurately represents the "soft" lubrication regime of spherical colloids and permits to resolve the increase of the solution viscosity up to moderately dense systems with volume fraction up to about 0.50. This intermediate resolution model is able to recover highly non-trivial (many-body) hydrodynamics using small particles whose radii are similar to the grid size h (in the range [1.6 - 3.2] h). Considering that the cost of the embedding fluid phase scales such as the cube of the particle radius, this result brings about a significant computational speed-up. Our code Fluam works in Graphics Processor Units and uses Fast Fourier Transform for the Poisson solver, which further improves its efficiency.


Brain regions involved in moxibustion-induced analgesia in irritable bowel syndrome with diarrhea: a functional magnetic resonance imaging study.
Moxibustion is one of the most commonly used therapies in acupuncture practice, and is demonstrated to be beneficial for patients with diarrhea from irritable bowel syndrome (D-IBS). But its mechanism remains unclear. Because visceral hypersensitivity in IBS patients has been documented by evaluation of perceived stimulations through functional magnetic resonance imaging (fMRI) studies, we focused on observing brain imaging changes in D-IBS patients during rectal balloon distention before and after moxibustion in order to reveal its possible central mechanism and further evaluate its effect. This clinical trial is registered under the number: ChiCTR-TRC-10000887. Eighty D-IBS patients were randomly divided into a moxibustion and sham moxibustion group (control group) for a 4-week treatment. Fifteen patients in moxibustion group and thirteen patients in control group completed two fMRI scans during a 50 and 100 ml rectal balloon distention before and after treatment. Rectal pain were obtained with a scan test. Birmingham IBS Symptom Scale and IBS Quality of Life (QOL) Scale were used to evaluate therapeutic effect. After treatment, the decrease in Birmingham IBS Symptom Scale and IBS QOL Scale scores in moxibustion group was significantly greater than that of control group (P < 0.01). The defecation urge threshold and the pain perception threshold of moxibustion group was also significantly higher after treatment than that of control group (P < 0.01). The decrease in pain score during the 100 ml rectal balloon distention in moxibustion group was significantly greater than that of control group (P < 0.05). There was no definite activated center during the 50 ml rectal distention in either group before treatment. After treatment, the prefrontal cortex (PFC) was affected in moxibustion group, while the PFC and the anterior cingulated cortex (ACC) were affected in control group. During the 100 ml distention before treatment in both groups, the PFC and ACC were activated. After treatment, they disappeared in moxibustion group but remained in control group. Moxibustion can improve symptoms and quality of life in D-IBS patients. It can also decrease rectal sensitivity. The activation of PFC and ACC during a 100 ml rectal distention disappeared after moxibustion treatment.


Ram spermatozoa migrating through artificial mucus in vitro have reduced mitochondrial membrane potential but retain their viability.
Sperm motility in vitro is one of the most common predictors of fertility in male screening. We propose that a mucus-penetration assay can isolate a cellular subpopulation critical to reproductive success. To this end, a device was designed with three modules (sample, test and collection) and its conditions of use evaluated (length of mucus, incubation time, mucus medium, sperm concentration and position in relation to the horizontal). The number of spermatozoa migrating and the viability and acrosomal status of the spermatozoa not migrating were calculated. The second objective was to evaluate the qualitative parameters of the spermatozoa migrating in 1.6% polyacrylamide for 30min. The number of spermatozoa migrating and the sperm motility, viability and the acrosomal and mitochondrial status of three sperm populations (fresh, not migrating and migrating) were determined. A higher number of migrating spermatozoa were observed after 60min of incubation, but this situation adversely affected sperm quality. The methylcellulose-based test showed a significantly lower number of migrating spermatozoa than the polyacrylamide test. The position at an angle of 45° resulted in a higher number of migrating spermatozoa in the polyacrylamide-based test. The sperm counts for three consecutive assays indicated an acceptable repeatability of the method. The viability and acrosomal status of the migrating spermatozoa showed no significant changes with regard to the control when the device was placed at 45°, whereas these parameters showed lower values at 0°. The percentage of high mitochondrial membrane potential spermatozoa was significantly reduced in the population of migrating spermatozoa.


(3)He-MRI in follow-up of lung transplant recipients.
The aim of this study was to evaluate the possible contribution of (3)He-MRI to detect obliterative bronchiolitis (OB) in the follow-up of lung transplant recipients. Nine single- and double-lung transplanted patients were studied by an initial and a follow-up (3)He-MRI study. Images were evaluated subjectively by estimation of ventilation defect area and quantitatively by individually adapted threshold segmentation and subsequent calculation of ventilated lung volume. Bronchiolitis obliterans syndrome (BOS) was diagnosed using pulmonary function tests. At (3)He-MRI, OB was suspected if ventilated lung volume had decreased by 10% or more at the follow-up MRI study compared with the initial study. General accordance between pulmonary function testing and (3)He-MRI was good, although subjective evaluation of (3)He-MRI underestimated improvement in ventilation as obtained by pulmonary function tests. The (3)He-MRI indicated OB in 6 cases. According to pulmonary function tests, BOS was diagnosed in 5 cases. All diagnoses of BOS were also detected by (3)He-MRI. In 2 of these 5 cases, (3)He-MRI indicated OB earlier than pulmonary function tests. The results support the hypothesis that (3)He-MRI may be sensitive for early detection of OB and emphasize the need for larger prospective follow-up studies.


Big guns take aim at RN crunch.
Johnson & Johnson leads the way as major organizations pump money and expertise into trying to alleviate a nurse shortage that experts say may never completely go away. One strategy: enhance the image of the field so it becomes a profession of choice among men and young people, including those from ethnic minorities.


The influences of reappraisal and suppression instructions on memory for neutral words in negative background.
Previous studies have investigated the influences of emotion regulation on memory for emotional stimuli. However, whether and how emotion regulation impacts recognition memory for neutral items in negative background is still unclear. Thus, the present study used event-related potentials and the study-recognition memory task to examine the effects of the two commonly used emotion regulation strategies, cognitive reappraisal and expressive suppression, on recognition memory of neutral words centrally presented on negative pictures. The behavior results showed that, compared with suppression, the reappraisal strategy enhanced the neutral words memory. Moreover, the event-related potential data demonstrated larger FN400 old/new effect indexing familiarity and late positive component old/new effect presenting episodic information recollection for the reappraisal condition relative to view and suppression conditions. These might be due to significant elaboration encouraged by this strategy.


Identification and proteome analysis of the two-component VirR/VirS system in epidemic Streptococcus suis serotype 2.
Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen that infects pigs and sporadically causes serious infections in humans. Two recent large-scale outbreaks of human streptococcal toxic-shock-like syndrome with high mortality occurred in China, posing new challenges for global public health. However, the global regulation of the virulence of epidemic SS2 isolates lacks a systematic understanding. In this study, we performed a mutational and functional analysis of an SS2 two-component system that is orthologous to the VirR/VirS regulatory system of Clostridium perfringens. An isogenic knockout mutant of VirR/VirS (ΔvirRS) was found to exhibit marked phenotypic changes, including the formation of shorter chains and thinner capsular walls, more easily cleared in whole blood, and decreased oxidative stress tolerance. Furthermore, the ΔvirRS mutant was greatly attenuated in a mouse model. Comparative proteome analysis of the expression profiles of the wild-type strain with the ΔvirRS mutant allowed us to identify 72 proteins that are differentially expressed in the absence of the VirR/VirS system and that are directly responsible for the pleiotropic phenotype of the ΔvirRS mutant.


N-syndecan (syndecan 3) from neonatal rat brain binds basic fibroblast growth factor.
The cell surface proteoglycan N-syndecan (syndecan 3) was isolated from neonatal rat brain. Purified brain N-syndecan had biochemical properties very similar to N-syndecan previously identified in Schwann cells: it contained mainly, if not exclusively, heparan sulfate glycosaminoglycan chains and had a core protein with an apparent molecular mass of 120 kDa by sodium dodecyl sulfate-gel electrophoresis. We examined the interactions between purified N-syndecan and extracellular ligands using a solid phase binding assay. It was found that among all proteins tested, including a variety growth factors and extracellular matrix molecules, only basic fibroblast growth factor (bFGF) exhibited significant N-syndecan binding. N-syndecan binding to bFGF was saturable and exhibited a KD = 0.5 nM. Soluble bFGF effectively competed with immobilized bFGF for binding to N-syndecan, indicating that these two proteins also interact in solution. Heparin and heparan sulfate, but not chondroitin sulfate, inhibited N-syndecan-bFGF binding. Isolated N-syndecan core protein did not exhibit significant binding to bFGF. Thus, the heparan sulfate chains of N-syndecan, rather than its core protein, appear to be responsible for binding to bFGF. Interestingly, acidic fibroblast growth factor, which is structurally similar to bFGF, did not exhibit significant N-syndecan binding. N-syndecan also did not bind to several other heparin-binding proteins used in this study, indicating a high degree of specificity for the N-syndecan-bFGF interaction. Both N-syndecan and bFGF are abundant in neonatal brain, suggesting that N-syndecan may function as a co-receptor for bFGF during nerve tissue development.


Emergence of antimicrobial resistance in gram-negative bacilli causing bacteremia during therapy.
Treatment of serious infections caused by gram-negative bacilli with beta-lactam antimicrobial agents can induce Class I beta-lactamase production. This phenomenon can result in resistant microorganisms, and has been postulated to be a cause of therapeutic failure. The charts of patients bacteremic with Pseudomonas aeruginosa, Serratia marcescens, Enterobacter cloacae, Citrobacter freundii, Proteus vulgaris, and Providencia species (n = 120) during a 3-year period were reviewed to determine how common the emergence of resistance was, and to determine if in vitro susceptibility testing was a reliable therapeutic guide. Emergence of resistance was believed to occur when a subsequent bacteremic isolate showed at least a fourfold increase in minimum inhibitory concentration accompanied by a change of interpretive susceptibility category. In the group of patients who survived at least 48 hours that received beta-lactam therapy (n = 76), one case of emergence of resistance was identified (1.3%). Emergence of resistance to beta-lactam antimicrobial agents did not commonly cause therapeutic failure at our institution, and susceptibility testing of gram-negative bacilli by usual methods was a reliable guide to antimicrobial therapy.


Plain radiography and computed tomography of invasive thymomas: clinico-radiologic-pathologic correlation.
Fifteen computed tomography (CT) scans in nine patients with invasive thymoma are presented. The CT findings were an anterior mediastinal mass (89%), pleural deposits (78%), local infiltration of the mediastinum (100]), invasion of the cardiovascular structures (22%), lung invasion (11%) and diaphragmatic or subdiaphragmatic deposits (33%). Radiologic-pathologic correlation available in six patients showed a sensitivity of 89.5%, specificity of 87.5% and accuracy of 88.6% for CT. We conclude that CT is superior to plain radiography in the diagnosis of invasive thymoma. It provides an accurate pre-operative assessment by better demonstration of the full extent of abnormalities, and is useful in surgical planning, monitoring of therapeutic response and detecting recurrence.


[Pregnancy and the respiratory function].
The respiratory function of pregnant women is changed for more than one reason. There is a mechanical effect due to the increase in the uterine volume and the elevation of the diaphragm. However, there are only modest functional consequences, because the pulmonary volumes are only little changed, with the exception of a reduction in the functional residual capacity. Bronchial permeability is unaltered due to the balancing of constrictors (mechanical, hypocapnia) and dilators (hormonal influences). As regards pulmonary haemodynamics, the hypovolaemia of the pregnant woman has no repercussions on pulmonary vascular pressure. Gas exchange and alveolar-capillary diffusion are normal or even improved as a consequence of chronic hyperventilation. The latter is the most important functional change, sometimes expressed as a sensation of dyspnoea. The origin of this hyperventilation relates to the diminution of the threshold of sensibility in the respiratory centres to CO2 due to the effect of raised progesterone levels.


Immunohistochemical and histomorphological analysis of rat mammary tumors after simvastatin treatment.
The results of experimental studies have indicated the pleiotropic effects of statins in organism, e.g. the influence on cell cycle, apoptosis or angiogenesis. In this study, the effects of simvastatin on selected parameters of apoptosis and proliferation in chemocarcinogen-induced mammary tumorigenesis in female rats were determined. Simvastatin was administered dietary at a dose of 18 mg/kg and highly effective dose of 180 mg/kg the entire experiment (18 weeks). At autopsy mammary tumors were removed and prepared for immunohistochemical and histomorphological analysis. In treated animals (simvastatin 180 mg/kg), significant decrease by 12% in Bcl-2 protein expression and non-significant decrease by 27% of Ki67 protein expression in tumor cells compared to tumor cells in control animals were observed after semiquantitative evaluation. Morphometrical analysis has shown significant proapototic shift in Bcl-2/Bax ratio in tumor cells. In high grade control carcinoma cells, the expression of Ki67 increased by 37% (non-significantly) in comparison with control low grade carcinomas. A histomorphological analysis of malignant tumors has revealed a shift from high grade to low grade carcinomas after simvastatin treatment. The noticeable decrease of mammary tumor frequency and incidence in rats after simvastatin treatment was accompanied with antiapoptotic Blc-2 protein decrease and proapoptotic Bax protein increase in this experiment.


Autologous cell based therapy for treating chronic infarct myocardium.
Recent experimental and clinical studies have shown that autologous cell based therapy using skeletal myoblasts or bone marrow-derived stem cells might have beneficial effects in chronic ischemic heart disease. The underlying concept is based on the repopulation of necrotic tissue by either readily contractile myoblasts or by bone marrow-derived stem cells. However, there is a need to resolve a number of issues for determining the better way to perform these treatments and, moreover, for assessing the real beneficial functional effect of each of these cell therapies. In this mini-review, we will discuss (i) the issues of the selection of chronic infarct animal to truly determine the impact of cell therapy on cardiac function recovery, and (ii) the evaluation of the bio-availability and the bio-distribution of transplanted cells. Some new investigational methodologies based on clinical end-points are also proposed.


Study of nanocrystalline BiMnO3-PbTiO3: synthesis, structural elucidation, and magnetic characterization of the whole solid solution.
In the last ten years, the study and the search for new multiferroic materials have been a major challenge due to their potential applications in electronic technology. In this way, bismuth-containing perovskites (BiMO(3)), and particularly those in which the metal M position is occupied by a magnetically active cation, have been extensively investigated as possible multiferroic materials. From the point of view of synthesis, only a few of the possible bismuth-containing perovskites can be prepared by conventional methods but at high pressures. Herein, the preparation of one of these potential multiferroic systems, the solid solution xBiMnO(3)-(1-x)PbTiO(3) by mechanosynthesis is reported. Note that this synthetic method allows the oxides with high x values, and more particularly the BiMnO(3) phase, to be obtained as nanocrystalline phases, in a single step and at room temperature without the application of external pressure. These results confirm that, in the case of Bi perovskites, mechanosynthesis is a good alternative to high-pressure synthesis. These materials have been studied from the point of view of their structural characteristics by precession electron diffraction and magnetic property measurements.


The swollen neck. Cervical lymphadenitis, parotitis, thyroiditis, and infected cysts.
Swelling of the neck can result from a variety of causes, both infectious and noninfectious. This article describes the major causes of neck swelling from the more common infectious processes in the neck--cervical lymphadenitis, parotitis, thyroiditis, and infected cysts. The etiology and pathogenetic considerations, clinical manifestations, differential diagnosis, therapy, and prevention are discussed for each of these conditions.


The right gastroepiploic artery in coronary artery bypass grafting.
The right gastroepiploic artery (RGEA) has been used as a conduit in coronary artery bypass grafting. Although some reports presenting good results justify its use in clinical settings, there is still much concern about using the RGEA in bypass surgery. The RGEA demonstrates different behaviors from the internal thoracic artery (ITA) in bypass surgery due to its histological characteristics and anatomical difference, which might contribute to the long-term outcome. Now that left ITA (LITA) to left anterior descending artery (LAD) is the gold standard, other grafts are expected to cover the rest of the coronary arteries. It should be elucidated how we can use other grafts and what we can expect from them. RGEA, as an arterial graft, can be used as an in situ graft or a free graft. The RGEA is mainly used to graft to the right coronary artery (RCA) because of its anatomical position, and its patency is not inferior to that of the saphenous vein (SVG). The RGEA can cover the lateral walls when its length is long enough or by making a composite graft with other grafts. However, when used to graft to the LAD, its mid-term patency is not favorable.


Agonist versus antagonist muscle fatigue effects on thigh muscle activity and vertical ground reaction during drop landing.
Agonist and antagonist co-activation plays an important role for stabilizing the knee joint, especially after fatigue. However, whether selective fatigue of agonists or antagonist muscles would cause different changes in muscle activation patterns is unknown. Knee extension fatigue would have a higher influence on landing biomechanics compared with a knee flexion protocol. Repeated-measures design. Twenty healthy subjects (10 males and 10 females) performed two sets of repeated maximal isokinetic concentric efforts of the knee extensors (KE) at 120 degrees s(-1) until they could no longer consistently produce 30% of maximum torque. On a separate day, a similar knee flexion (KF) fatigue protocol was also performed. Single leg landings from 30cm drop height were performed before, in the middle and after the end of the fatigue test. The mean normalized electromyographic (EMG) signal of the vastus medialis (VM), vastus lateralis (VL), biceps femoris (BF) and gastrocnemius (GAS) at selected landing phases were determined before, during and after fatigue. Quadriceps:hamstrings (Q:H) EMG ratio as well as sagittal hip and knee angles and vertical ground reaction force (GRF) were also recorded. Two-way analysis of variance designs showed that KE fatigue resulted in significantly lower GRF and higher knee flexion angles at initial contact while maximum hip and knee flexion also increased (p<0.05). This was accompanied by a significant decline of BF EMG, unaltered EMG of vastii and GAS muscles and increased Q:H ratio. In contrast, KF fatigue had no effects on vGRFs but it was accompanied by increased activation of VM, BF and GAS while the Q:H increased during before landing and decreased after impact. Fatigue responses during landing are highly dependent on the muscle which is fatigued.


Nonparametric Dimension Reduction via Maximizing Pairwise Separation Probability.
In this brief, we propose a novel nonparametric supervised linear dimension reduction (SLDR) algorithm that extracts the features by maximizing the pairwise separation probability. The separation probability, as a new class separability measure, describes the generalization accuracy when we use the obtained features to train a linear classifier. Obtaining high-quality features, the proposed method avoids the overlaps between classes that are close to each other in the input space and improves the subsequent classification performance. Experiments on benchmark data sets show the superiority of the proposed algorithm over some other state-of-the-art SLDR methods.


[Drug delivery system for infectious diseases].
Various types of antimicrobial agents have been evolved to inhibit growth of or to kill different microorganisms. In recent years, encapsulation of antimicrobial agents in lipid formulations has been a popular practice in research work related to drug delivery system, although most of the studies are based primary on animal models. The recent developments of lipid formulations of anti-infectious drug (antibiotics, antifungals, and antiviral agents) with longer half-life opens new therapeutic avenues in treating infections. The passive targeting of liposomes to the sites of infection is of great value with respect to clinical application. Liposome entrapment can exchange their pharmacokinetics and, hence reduce their toxicity.


Treatment options for the occlusal surface of first permanent molars.
Restorative dentistry has been increasingly concerned with preservation of the dental structure. For that reason, ultraconservative cavity preparations have been performed with air abrasion systems. The aim of this study was to present treatment options for the occlusal surface of first permanent molars with employment of the conventional method and the air abrasion system for accomplishment of the cavity preparation and a composite occlusal matrix for an accurate reproduction of the tooth surface.


Low-energy quasi-circular electron correlations with charge order wavelength in Bi2Sr2CaCu2O8+δ.
Most resonant inelastic x-ray scattering (RIXS) studies of dynamic charge order correlations in the cuprates have focused on the high-symmetry directions of the copper oxide plane. However, scattering along other in-plane directions should not be ignored as it may help understand, for example, the origin of charge order correlations or the isotropic scattering resulting in strange metal behavior. Our RIXS experiments reveal dynamic charge correlations over the qx-qy scattering plane in underdoped Bi2Sr2CaCu2O8+δ. Tracking the softening of the RIXS-measured bond-stretching phonon, we show that these dynamic correlations exist at energies below approximately 70 meV and are centered around a quasi-circular manifold in the qx-qy scattering plane with radius equal to the magnitude of the charge order wave vector, qCO. This phonon-tracking procedure also allows us to rule out fluctuations of short-range directional charge order (i.e., centered around [qx = ±qCO, qy = 0] and [qx = 0, qy = ±qCO]) as the origin of the observed correlations.


Dimer-dependent intrinsic/basal activity of the class B G protein-coupled receptor PAC1 promotes cellular anti-apoptotic activity through Wnt/β-catenin pathways that are associated with dimer endocytosis.
The high expression of PACAP (pituitary adenylate cyclase-activating polypeptide)-preferring receptor PAC1 is associated with nerve injury and tumors. Our previous report (Yu R, et al. PLoS One 2012; 7: e51811) confirmed the dimerization of PAC1 and found that the M-PAC1 mutation in the N-terminal first Cys/Ala lost the ability to form dimers. In this study, Chinese hamster ovary (CHO-K1) cells overexpressing wild-type PAC1 (PAC1-CHO) had significantly higher anti-apoptotic activities against serum withdrawal-induced apoptosis associated with a lower caspase 3 activity and a higher Bcl-2 level in a ligand-independent manner than those of CHO cells overexpressing the mutant M-PAC1 (M-PAC1-CHO). PAC1-CHO had significantly higher β-catenin, cyclin D1 and c-myc levels corresponding to the Wnt/β-catenin signal than did M-PAC1-CHO. In addition, the Wnt/β-catenin pathway inhibitor XAV939 significantly inhibited the anti-apoptotic activities of PAC1-CHO. Top-flash assays demonstrated that PAC1-CHO had a significantly stronger Wnt/β-catenin signal than did M-PAC1-CHO. Acetylcysteine (NAC) as an inhibitor of the dimerization of PAC1 inhibited the anti-apoptotic activities that were endowed by PAC1 and decreased the Wnt/β-catenin signal in Top-flash assays. In the PAC1 Tet (tetracycline)-on inducible gene expression system by doxycycline (Dox), higher expression levels of PAC1 resulted in higher anti-apoptotic activities that were associated with a stronger Wnt/β-catenin signal. A similar correlation was also found with the down-regulation of PAC1 in the Neuro2a neuroblastoma cell. BiFC combined with fluorescence confocal imaging indicated that during serum-withdrawal-induced apoptosis, PAC1 dimers displayed significant endocytosis. These findings indicate that PAC1 has ligand-independent and dimer-dependent intrinsic/basal activity, conferring cells with anti-apoptotic activities against serum withdrawal, which is involved in the Wnt/β-catenin signal and is associated with the endocytosis of PAC1 dimers. The discovery and study of the dimer-dependent basal activity of PAC1 not only help us understand the physiological and pathological role of PAC1 but also promote the development of drugs targeting PAC1.


Wnt signaling promotes androgen-independent prostate cancer cell proliferation through up-regulation of the hippo pathway effector YAP.
Aberrant up-regulation of Wnt/β-catenin signaling is associated with the development and progression of prostate cancer, but the underlying mechanism is unclear. Here we show that in the absence of androgens, the Wnt/β-catenin pathway activates AR-mediated transcription through up-regulation of the Hippo pathway effector Yes-associated protein (YAP). Wnt3a-conditioned medium (Wnt3a-CM) promotes the growth of LNCaP cells and increases AR and YAP protein levels. Moreover, Wnt3a-CM induces the nuclear translocation of YAP and the AR, but not β-catenin, thereby activating the expression of AR- and YAP-dependent genes, in an androgen-independent manner. In addition, depletion of YAP with small interfering RNA (siRNA) prevented Wnt3a-CM-mediated up-regulation of AR-dependent gene expression. Thus, our findings provide mechanistic insight into the proposed cross-talk between the Wnt/β-catenin and Hippo pathways in androgen-independent prostate cancer development.


Repellency of the Origanum onites L. essential oil and constituents to the lone star tick and yellow fever mosquito.
The oregano, Origanum onites L., essential oil (EO) was tested in laboratory behavioural bioassays for repellent activity against Amblyomma americanum (L.) and Aedes aegypti (L.). The O. onites EO was characterised using GC-FID and GC-MS. Carvacrol (75.70%), linalool (9.0%), p-cymene (4.33%) and thymol (1.9%) were the most abundant compounds. At a concentration of 0.413 mg oil/cm2 of filter paper, O. onites EO repelled 100% of the ticks tested and at 0.103 mg oil/cm2 of filter paper, 66.7% of the ticks were repelled. At 0.075 mg oil/cm2 filter paper, thymol repelled 66.7% of the ticks compared to 28.7% by carvacrol at that same concentration. Against Ae. aegypti, O. onites EO was repellent at the minimum effective dosage (MED) of 0.011 (±0.00) mg/cm2 in the cloth patch assay compared to the reference control, N,N-dimethyl-3-methylbenzamide (DEET) with a MED = 0.007 ± (0.003) mg/cm2.


Symptom severity and lifetime and prospective health service use among military veterans evaluated for PTSD.
We used structural equation modeling with 174 treatment-seeking military trauma survivors evaluated for posttraumatic stress disorder (PTSD) at a VA Medical Center PTSD clinic to examine relationships among lifetime mental health service use, PTSD symptom severity and medical problems (from self-report), as well as prospective (1-year) mental health and medical care use visit counts extracted from medical records. We discovered an adequate statistical fit to a hypothesized model of previous and prospective health service use, and current PTSD severity and health-related problems. Previous inpatient mental health treatment was significantly related to PTSD severity and prospective outpatient mental health use. However, PTSD severity was unrelated to prospective use of mental health or medical services. Health problems were related to prospective medical service use. Clinical and administrative implications in predicting health care use among trauma survivors are discussed.


The state of immunization 2013: we are the world.
Most vaccine-preventable diseases in the U.S. are at record low levels, and immunization coverage among toddlers and teenagers is high or increasing. However, importations of measles virus from other countries, resurgences of pertussis and mumps, and the 2009 pandemic of influenza A H1N1 are reminders that Americans remain vulnerable to vaccine-preventable diseases and that sustained support for public health and clinician efforts is needed. Geographic areas with high rates of exemptions from vaccinations required for school attendance place communities at risk for disease outbreaks. There has been much progress internationally in reducing the toll of vaccine-preventable diseases, through public-private partnerships like the Global Alliance for Vaccines and Immunizations (GAVI). Paralytic poliomyelitis is on the verge of eradication, with wild virus transmission continuing in only three countries - Nigeria, Afghanistan and Pakistan. Intensified efforts in those countries are critical. The Decade of Vaccines Collaboration offers an opportunity to strengthen immunization in every community and country.


Developing Criteria for Lumbar Spine Magnetic Resonance Imaging (MRI) Using RAND Appropriateness Method (RAM).
Studies show that a large proportion of healthcare offered may be inappropriate or unnecessary. Magnetic resonance imaging (MRI) is a new and expensive diagnostic technology which has been increasingly used all over the world. Moreover, this trend has been more rapidly increasing in Iran. Low back pain is a common disorder all over the world and MRI technique is one of the several ways to assess its cause. The present study aims to develop scenarios for lumbar spine MRI. In the present study, the RAND Appropriateness Method (RAM) was used in order to reach consensus regarding developing scenarios for lumbar spine MRI. We generated scenarios from valid clinical guidelines as well as the experts' opinion. The panel members included nine specialists from various medical specialties that had scored scenarios in two rounds, the first of which was without interaction, while the second one was with interaction. We extracted 97 scenarios for the lumbar spine MRI in the scenario extracting phase of the study and the panel members added 18 scenarios. After implementation of two rounds, the scenarios were categorized into three ranges. Sixty seven (58%) of the scenarios were considered as appropriate, 45 (39%) as uncertain, and three (2.6%) as inappropriate. RAM is useful for identifying stakeholder views in settings with limited resources. Since RAM has precise instructions for consensus developing, a large number of scenarios were considered as uncertain. Therefore, more research has to be conducted on the issue.