Prostate Cancer Risk-Associated Single-Nucleotide Polymorphism Affects Prostate-Specific Antigen Glycosylation and Its Function.
Genetic association studies have reported single-nucleotide polymorphisms (SNPs) at chromosome 19q13.3 to be associated with prostate cancer (PCa) risk. Recently, the rs61752561 SNP (Asp84Asn substitution) in exon 3 of the kallikrein-related peptidase 3 (KLK3) gene encoding prostate-specific antigen (PSA) was reported to be strongly associated with PCa risk (P = 2.3 × 10-8). However, the biological contribution of the rs61752561 SNP to PCa risk has not been elucidated. Recombinant PSA protein variants were generated to assess the SNP-mediated biochemical changes by stability and substrate activity assays. PC3 cell-PSA overexpression models were established to evaluate the effect of the SNP on PCa pathogenesis. Genotype-specific correlation of the SNP with total PSA (tPSA) concentrations and free/total (F/T) PSA ratio were determined from serum samples. Functional analysis showed that the rs61752561 SNP affects PSA stability and structural conformation and creates an extra glycosylation site. This PSA variant had reduced enzymatic activity and the ability to stimulate proliferation and migration of PCa cells. Interestingly, the minor allele is associated with lower tPSA concentrations and high F/T PSA ratio in serum samples, indicating that the amino acid substitution may affect PSA immunoreactivity to the antibodies used in the clinical immunoassays. The rs61752561 SNP appears to have a potential role in PCa pathogenesis by changing the glycosylation, protein stability, and PSA activity and may also affect the clinically measured F/T PSA ratio. Accounting for these effects on tPSA concentration and F/T PSA ratio may help to improve the accuracy of the current PSA test.


Candiduria; a review article with specific data from Iran.
Although, several categories of nosocomial infections are presented during the recent years, urinary tract infections (UTIs) considered as one of the most important systemic infections. The presence of Candida species in the urinary tract system (Candiduria) is seen in only 10-15% of the cases with UTI, however candiduria has been considered as more problematic infection for patients, laboratory workers and physicians. Due to increasing numbers of several predisposing factors, such as antibacterial agents, urinary tract instrumentation, diabetes mellitus, invasive therapies, and prolonged hospital stay, candiduria develops among the hospitalized patients, especially hospitalized in intensive care units (ICUs) and neonatal intensive care units (NICUs). According to the epidemiological studies, Candida albicans is the most common isolated species from candiduric patients. However, during the recent years, due to increasing resistance to antifungal drugs, non-albicans Candida species including, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis have been also implicated. We found that the mean prevalence of candiduria among Iranian patients was lower (16.5%) than worldwide ratio and also males were more frequently affected than females (M:F, 1.2:1). Similar to other countries, C. albicans was most common infectious agent followed by non-albicans Candida species including, C. glabrata, C. tropicalis and C. krusei.


Responsiveness of the coronary circulation to brief vs sustained alpha-adrenergic stimulation.
The effects of brief and sustained pharmacologic alpha-adrenergic stimulation on the coronary arterial circulation were compared in awake pigs. Phenylephrine was administered into the left anterior descending coronary artery (LAD) either as a bolus (eight pigs) or as a 15-minute infusion (eight pigs), with myocardial blood flow measured by the radioactive microsphere technique. Flow in the distribution in the LAD was compared with flow in myocardium perfused by the left circumflex coronary artery (LCF) as the ratio LAD/LCF. This technique corrects for systemic factors capable of modifying oxygen demand, and hence myocardial blood flow, in both zones. After a phenylephrine bolus (50-100 microgram), LAD/LCF fell significantly, whereas no change was observed after the sustained infusion (5-10 and 50-100 microgram/min). Four additional pigs were pretreated with i.v. adenosine to raise myocardial blood flow in excess of demand before sustained stimulation. In this setting LAD/LCF fell significantly during the sustained phenylephrine infusion. Brief alpha-adrenergic stimulation could overcome normal flow regulatory mechanisms and resulted in constriction of coronary resistance vessels. Such changes did not occur after sustained stimulation and suggest an ability of the coronary circulation to offset chronic vasoconstrictive effects. When the myocardium is overperfused, sustained alpha-adrenergic stimulation does not jeopardize myocardial oxygenation and its vasoconstriction potential is unmasked.


Anisotropic Mechanics of Vascular Smooth Muscle Cells Exposed to Dynamic Loads.
Vascular smooth muscle cells (VSMCs) are the most prevalent cells in the arterial wall. In vivo, arteries are exposed to dynamic biaxial loads; thus, when characterizing VSMC mechanics, it is important to determine their anisotropic and time-dependent mechanical properties. In this work, we use cellular microbiaxial stretching to apply complex deformations to single micropatterned VSMCs and measure the resulting changes in cell stress. Previously, cellular microbiaxial stretching has been used to measure VSMC mechanical properties in response to extensional strain. Here, we measure changes in cell stress in response to both extension and compression. Additionally, we measure immediate temporal changes in stress in response to cyclically applied deformations. We find that the VSMCs display clear hysteresis when incrementally stretched and compressed and demonstrate cycle-dependent stress-relaxation when exposed to cyclic step change extension and compression. Finally, we demonstrate that a Hill-type active fiber model is capable of replicating all observed hysteresis and cycle-dependent stress-relaxation, suggesting that the temporal stress-strain behavior of the cell is regulated by acto-myosin contraction and relaxation, rather than passive viscoelasticity. This study improves upon previous studies of cellular mechanical properties by considering cellular architecture and more complex deformations when measuring the time-dependent mechanical properties of VSMCs. These findings have important implications for modeling in mechanobiology as VSMCs are mechanosensitive and actively respond to changes in their mechanical environment to maintain vascular function.


Pharmacologic treatment for prehypertension: to treat or not to treat?
The Seventh Joint National Committee on the Prevention, Detection, Evaluation and Treatment of Hypertension (VII JNC) introduced the term "prehypertension" to designate individuals whose systolic blood pressure (BP) levels are in the range of 120 to 139 mm Hg and diastolic BP between 80 and 89 mm Hg. The decision to establish this new BP category was based on a rate of progression to hypertension, its prevalence and association with other cardiovascular disease (CVD) risk factors, its relationship to the development of CVD, and its therapy. So, the prehypertension term was established to focus attention on a segment of the population who is at higher-than-normal CVD risk and in whom therapeutic approaches to prevent or delay the onset of hypertension would be of value. The VII JNC report has recommended the adoption of healthy lifestyles to achieve BP goals except in prehypertensive subjects with diabetes or chronic renal disease in whom drug treatment is also advocated. The treatment with antihypertensive drugs to prehypertension has been the subject of recent debate. The decision to use antihypertensive drug treatment should be based on global CVD risk rather than on specific levels of BP alone. This review article discusses the background, risk factors, treatment options and some recent patents related to hypertension.


Role of the blood-brain barrier in rabies virus infection and protection.
Rabies is an acute, progressive encephalitis caused by infection with rabies virus (RABV). It is one of the most important zoonotic infections and causes more than 70,000 human deaths annually ( http://www.rabiescontrol.net ). It has long been held that a rabies infection is lethal in humans once the causative RABV reaches the central nervous system (CNS); however, this concept was challenged by the recent recovery of a small number of rabies patients. An analysis of these patients revealed that the bloodbrain barrier (BBB) played a major role in protection against the virus. The main reason for the survival of these patients was enhanced BBB permeability after infection with the causative agent (usually bat-originated RABV showing reduced pathogenicity), which allowed immune cells to enter the tissues of the CNS and clear the infection (Willoughby et al., 2005). These findings have been confirmed in animal infection experiments (Wang et al., 2005; Roy and Hooper, 2007, 2008; Faber et al., 2009). Thus, the BBB has attracted the attention of scientists interested in the pathogenesis of, and therapeutic approaches, for rabies. This paper introduces the role of the BBB in rabies infections and protection of the CNS and provides insight into future treatments for patients with clinical rabies.


Mixture models for single-cell assays with applications to vaccine studies.
Blood and tissue are composed of many functionally distinct cell subsets. In immunological studies, these can be measured accurately only using single-cell assays. The characterization of these small cell subsets is crucial to decipher system-level biological changes. For this reason, an increasing number of studies rely on assays that provide single-cell measurements of multiple genes and proteins from bulk cell samples. A common problem in the analysis of such data is to identify biomarkers (or combinations of biomarkers) that are differentially expressed between two biological conditions (e.g. before/after stimulation), where expression is defined as the proportion of cells expressing that biomarker (or biomarker combination) in the cell subset(s) of interest. Here, we present a Bayesian hierarchical framework based on a beta-binomial mixture model for testing for differential biomarker expression using single-cell assays. Our model allows the inference to be subject specific, as is typically required when assessing vaccine responses, while borrowing strength across subjects through common prior distributions. We propose two approaches for parameter estimation: an empirical-Bayes approach using an Expectation-Maximization algorithm and a fully Bayesian one based on a Markov chain Monte Carlo algorithm. We compare our method against classical approaches for single-cell assays including Fisher's exact test, a likelihood ratio test, and basic log-fold changes. Using several experimental assays measuring proteins or genes at single-cell level and simulations, we show that our method has higher sensitivity and specificity than alternative methods. Additional simulations show that our framework is also robust to model misspecification. Finally, we demonstrate how our approach can be extended to testing multivariate differential expression across multiple biomarker combinations using a Dirichlet-multinomial model and illustrate this approach using single-cell gene expression data and simulations.


Toxicity of nonylphenol diethoxylate in lab-scale anaerobic digesters.
Nonylphenol compounds have high commercial, industrial and domestic uses owing to their surface active properties. In addition to their toxic, carcinogenic and persistent characteristics; they have drawn the attention of scientists lately due to their endocrine disrupting properties. Their widespread use and disposal cause them to enter wastewater treatment systems at high concentrations. Since they are highly persistent and hydrophobic, they accumulate mostly on sludge. In this study using Anaerobic Toxicity Assay (ATA) tests, the toxicity of a model nonylphenol compound, nonylphenol diethoxylate (NP2EO), for anaerobic digestion of sludge was determined. The test bottles were dosed with NP2EO in acetone, with concentrations ranging from 1 mg L(-1) to 30 mg L(-1). During the tests, gas productions and compositions in terms of methane and carbon dioxide were monitored. To be able to judge about the fate, the target compounds were extracted from water and sludge and analyzed using GC/MS. The sludge samples used for assembling the reactors were found to contain NP and NP1EO but no NP2EO. After the assay was completed, all the NP2EO spiked into the live reactors was found to disappear. The increase seen in NP1EO and NP and further accumulation of NP in the system, indicated the conversion of NP2EO to these metabolites. On the other hand, no conversion was observed in abiotic reactors. Inhibition of NP2EO for anaerobic microorganisms was not observed throughout the tests considering the biogas production of the test reactors in comparison to the control reactors.


Periampullary carcinoma following biliary ascariasis--a case report.
A 42 year old man presented with obstructive jaundice and cholangits. Ultrasonography (USG) revealed dilated intrahepatic biliary radicals and common bile duct (CBD). The bile duct also showed a curvilinear parallel intraluminal structure suggesting biliary ascariasis. The CBD was explored and a dead worm removed but jaundice persisted. Endoscopic retrograde cholangio pancreaticography (ERCP) was done showing a periampullary mass which on biopsy showed a villous adenoma with highly dysplastic changes. A Whipple's pancreaticoduodenectomy was performed and the growth proved to be a well differentiated periampullary adenocarcinoma.


Validation of a semi-quantitative Food Frequency Questionnaire for Argentinean adults.
The Food Frequency Questionnaire (FFQ) is the most commonly used method for ranking individuals based on long term food intake in large epidemiological studies. The validation of an FFQ for specific populations is essential as food consumption is culture dependent. The aim of this study was to develop a Semi-quantitative Food Frequency Questionnaire (SFFQ) and evaluate its validity and reproducibility in estimating nutrient intake in urban and rural areas of Argentina. Overall, 256 participants in the Argentinean arm of the ongoing Prospective Urban and Rural Epidemiological study (PURE) were enrolled for development and validation of the SFFQ. One hundred individuals participated in the SFFQ development. The other 156 individuals completed the SFFQs on two occasions, four 24-hour Dietary Recalls (24DRs) in urban, and three 24DRs in rural areas during a one-year period. Correlation coefficients (r) and de-attenuated correlation coefficients between 24DRs and SFFQ were calculated for macro and micro-nutrients. The level of agreement between the two methods was evaluated using classification into same and extreme quartiles and the Bland-Altman method. The reproducibility of the SFFQ was assessed by Pearson correlation coefficients and Intra-class Correlation Coefficients (ICC). The SFFQ consists of 96 food items. In both urban and rural settings de-attenuated correlations exceeded 0.4 for most of the nutrients. The classification into the same and adjacent quartiles was more than 70% for urban and 60% for rural settings. The Pearson correlation between two SFFQs varied from 0.30-0.56 and 0.32-0.60 in urban and rural settings, respectively. Our results showed that this SFFQ had moderate relative validity and reproducibility for macro and micronutrients in relation to the comparison method and can be used to rank individuals based on habitual nutrient intake.


Postoperative pneumonia in elderly patients: incidence and mortality in comparison with younger patients.
To determine whether elderly patients have an increased incidence of postoperative pneumonia and/or an increased mortality, we conducted a retrospective study of 4,380 patients who underwent thoracic, abdominal or neurosurgery under general anesthesia. Thirty of these patients developed postoperative pneumonia (incidence, 0.68%). The elderly patients aged 65 years or older who underwent thoracic surgery had the highest incidence of pneumonia. Nine of the 30 patients with pneumonia died (mortality, 30%). Elderly patients did not show a higher mortality than the younger patients. The extent of pulmonary infiltrates on chest roentgenogram and the serum bilirubin level, both of which were determined at the onset of pneumonia, independently had a significant association with mortality. Our study suggests that advanced age is a risk factor for postoperative pneumonia in patients who undergo thoracic surgery.


Chronic ulcerations following topical therapy with 5-fluorouracil for vaginal human papillomavirus-associated lesions.
Applied topically to the vagina, 5-fluorouracil (5-FU) cream is an effective therapy for human papillomavirus (HPV)-associated lesions of the vagina including condylomata acuminata and vaginal intraepithelial neoplasia. Although the acute side effects of 5-FU therapy are well recognized, long-term sequelae of intravaginal 5-FU use have not been described in detail in the literature. To assess the incidence and clinical course of 5-FU-related vaginal mucosal alterations, we studied 220 patients who underwent 5-FU therapy for HPV-associated lesions of the vagina. Eighteen women (8.2%) had epithelial ulcers 6 months after completion of the 5-FU treatment. The incidence of ulcers was higher in women who used 5-FU for longer than 10 weeks compared with those who used it for 10 weeks or less (9.6 versus 5.7%; P = .05). All but one of the mucosal defects were in the vaginal fornices and/or the periphery of the ectocervix. The ulcers were mostly singular and measured 0.5-7 cm in greatest diameter. Fourteen patients (77.8%) had symptoms related to the ulcers including a serosanguineous or watery discharge (55.6%), postcoital spotting or bleeding (44.4%), irregular bleeding unrelated to intercourse (16.7%), and pain (5.6%). Spontaneous healing of the ulcers was protracted. Office methods of therapy including estrogen creams and cauterizing agents failed to accelerate healing as compared with untreated patients. Excision of the ulcer and primary closure of the wound was curative in all four cases in which it was used. We conclude that topical 5-FU therapy may lead to troublesome chronic mucosal ulcers that tend to persist despite conservative treatment attempts.


Central complex neurons exhibit behaviorally gated responses to visual motion in Drosophila.
Sensory systems provide abundant information about the environment surrounding an animal, but only a small fraction of that information is relevant for any given task. One example of this requirement for context-dependent filtering of a sensory stream is the role that optic flow plays in guiding locomotion. Flying animals, which do not have access to a direct measure of ground speed, rely on optic flow to regulate their forward velocity. This observation suggests that progressive optic flow, the pattern of front-to-back motion on the retina created by forward motion, should be especially salient to an animal while it is in flight, but less important while it is standing still. We recorded the activity of cells in the central complex of Drosophila melanogaster during quiescence and tethered flight using both calcium imaging and whole cell patch-clamp techniques. We observed a genetically identified set of neurons in the fan-shaped body that are unresponsive to visual motion while the animal is quiescent. During flight their baseline activity increases, and they respond to front-to-back motion with changes relative to this baseline. The results provide an example of how nervous systems selectively respond to complex sensory stimuli depending on the current behavioral state of the animal.


Nomophobia: A Cross-sectional Study to Assess Mobile Phone Usage Among Dental Students.
Mobile phones were originally seen as a gadget for communication but currently, the internet enabled mobile phones have become an integral part of our daily life. Their benefits are incomparable but at the same time, they have some negative effects too. To assess the pattern of usage of mobile phones and its effects on the academic performance of students. A descriptive cross-sectional study was conducted amongst 554 students of D. J. College of Dental Sciences and Research through a self-administered questionnaire to collect the data regarding the usage and associated anxiety with mobile phone. About 39.5% students agreed that they score low marks in professional exams if they spend more time on phone. The number of students who frequently checked their cell phone during their classes or while doing clinical work were 24.7% . A total of 24.12% of the students were found to be nomophobic and at risk of being nomophobes were 40.97%. A statistically significant difference was found among preclinical, clinical, interns and postgraduates regarding the usage and effect of mobile phone on them. The pattern of usage of mobile phone among dental students showed alarming indication that students have been addicted to mobile phone which in turn affect their academic performance in a negative way. It would be useful to advise the students about the controlled as well as proper usage of mobile phone.


Genome-wide analysis of MicroRNA-messenger RNA interactome in ex-vivo gill filaments, Anguilla japonica.
Gills of euryhaline fishes possess great physiological and structural plasticity to adapt to large changes in external osmolality and to participate in ion uptake/excretion, which is essential for the re-establishment of fluid and electrolyte homeostasis. The osmoregulatory plasticity of gills provides an excellent model to study the role of microRNAs (miRs) in adaptive osmotic responses. The present study is to characterize an ex-vivo gill filament culture and using omics approach, to decipher the interaction between tonicity-responsive miRs and gene targets, in orchestrating the osmotic stress-induced responses. Ex-vivo gill filament culture was exposed to Leibovitz's L-15 medium (300 mOsmol l- 1) or the medium with an adjusted osmolality of 600 mOsmol l- 1 for 4, 8 and 24 h. Hypertonic responsive genes, including osmotic stress transcriptional factor, Na+/Cl--taurine transporter, Na+/H+ exchange regulatory cofactor, cystic fibrosis transmembrane regulator, inward rectifying K+ channel, Na+/K+-ATPase, and calcium-transporting ATPase were significantly upregulated, while the hypo-osmotic gene, V-type proton ATPase was downregulated. The data illustrated that the ex-vivo gill filament culture exhibited distinctive responses to hyperosmotic challenge. In the hyperosmotic treatment, four key factors (i.e. drosha RNase III endonuclease, exportin-5, dicer ribonuclease III and argonaute-2) involved in miR biogenesis were dysregulated (P < 0.05). Transcriptome and miR-sequencing of gill filament samples at 4 and 8 h were conducted and two downregulated miRs, miR-29b-3p and miR-200b-3p were identified. An inhibition of miR-29b-3p and miR-200b-3p in primary gill cell culture led to an upregulation of 100 and 93 gene transcripts, respectively. Commonly upregulated gene transcripts from the hyperosmotic experiments and miR-inhibition studies, were overlaid, in which two miR-29b-3p target-genes [Krueppel-like factor 4 (klf4), Homeobox protein Meis2] and one miR-200b-3p target-gene (slc17a5) were identified. Integrated miR-mRNA-omics analysis revealed the specific binding of miR-29b-3p on Klf4 and miR-200b-3p on slc17a5. The target-genes are known to regulate differentiation of gill ionocytes and cellular osmolality. In this study, we have characterized the hypo-osmoregulatory responses and unraveled the modulation of miR-biogenesis factors/the dysregulation of miRs, using ex-vivo gill filament culture. MicroRNA-messenger RNA interactome analysis of miR-29b-3p and miR-200b-3p revealed the gene targets are essential for osmotic stress responses.


Unraveling Gene Fusions for Drug Repositioning in High-Risk Neuroblastoma.
High-risk neuroblastoma (NB) remains a significant therapeutic challenge facing current pediatric oncology patients. Structural variants such as gene fusions have shown an initial promise in enhancing mechanistic understanding of NB and improving survival rates. In this study, we performed a comprehensive in silico investigation on the translational ability of gene fusions for patient stratification and treatment development for high-risk NB patients. Specifically, three state-of-the-art gene fusion detection algorithms, including ChimeraScan, SOAPfuse, and TopHat-Fusion, were employed to identify the fusion transcripts in a RNA-seq data set of 498 neuroblastoma patients. Then, the 176 high-risk patients were further stratified into four different subgroups based on gene fusion profiles. Furthermore, Kaplan-Meier survival analysis was performed, and differentially expressed genes (DEGs) for the redefined high-risk group were extracted and functionally analyzed. Finally, repositioning candidates were enriched in each patient subgroup with drug transcriptomic profiles from the LINCS L1000 Connectivity Map. We found the number of identified gene fusions was increased from clinical the low-risk stage to the high-risk stage. Although the technical concordance of fusion detection algorithms was suboptimal, they have a similar biological relevance concerning perturbed pathways and regulated DEGs. The gene fusion profiles could be utilized to redefine high-risk patient subgroups with significant onset age of NB, which yielded the improved survival curves (Log-rank p value ≤ 0.05). Out of 48 enriched repositioning candidates, 45 (93.8%) have antitumor potency, and 24 (50%) were confirmed with either on-going clinical trials or literature reports. The gene fusion profiles have a discrimination power for redefining patient subgroups in high-risk NB and facilitate precision medicine-based drug repositioning implementation.


An evaluation of piroxicam, a new non-steroidal anti-inflammatory agent. A multicentre trial.
A multicentre trial involving 1350 patients evaluated by 310 practitioners throughout South Africa was conducted to determine whether overseas studies relating to the efficacy and toleration of piroxicam (Feldene; Pfizer) would be confirmed in the local environment. Piroxicam, a member of a new class of non-steroidal anti-inflammatory agents, possesses a long plasma half-life permitting a once-a-day dosage regimen in osteo-arthrosis, rheumatoid arthritis, ankylosing spondylitis, acute musculoskeletal disorders and acute gout. In this study it was found to provide significant relief of pain and stiffness and to have a relatively low side-effect profile, confirming that it is a useful addition to current non-steroidal anti-inflammatory drug therapy.


Detection of Borrelia burgdorferi and Borrelia lonestari in birds in Tennessee.
Lyme disease in the United States is caused by the bacterial spirochete Borrelia burgdorferi s.s. (Johnson, Schmid, Hyde, Steigerwalt, and Brenner), which is transmitted by tick vectors Ixodes scapularis (Say) and I. pacificus (Cooley and Kohls). Borrelia lonestari, transmitted by the tick Amblyomma americanum L., may be associated with a related syndrome, southern tick-associated rash illness (STARI). Borrelia lonestari sequences, reported primarily in the southeastern states, have also been detected in ticks in northern states. It has been suggested that migratory birds may have a role in the spread of Lyme disease spirochetes. This study evaluated both migratory waterfowl and nonmigratory wild turkeys (Meleagris gallopavo silvestris, Eastern wild turkey) for B. burgdorferi and B. lonestari DNA sequences. A total of 389 avian blood samples (163 migratory birds representing six species, 125 wild turkeys harvested in habitats shared with migratory birds, 101 wild turkeys residing more distant from migratory flyways) were extracted, amplified, and probed to determine Borrelia presence and species identity. Ninety-one samples were positive for Borrelia spp. Among migratory birds and turkeys collected near migration routes, B. burgdorferi predominated. Among turkeys residing further away from flyways, detection of B. lonestari was more common. All A. americanum ticks collected from these areas were negative for Borrelia DNA; no I. scapularis were found. To our knowledge, this represents the first documentation of B. lonestari among any birds.


Mental pain and pain-proneness in patients with migraine: results from the PAINMIG cohort-study.
Pain has been qualified under four categories: nociception, perception of pain, suffering, and pain behaviors. Most of the literature on migraine has devoted attention to the first two. The aim of the present cohort study was to investigate patients with migraine enrolled at a tertiary care unit to study suffering and mental pain and identify potential risk factors for migraine. An observational cross-sectional study was carried out on patients with chronic migraine (CM) and episodic migraine (EM), and healthy subjects (HS). The three groups were matched for age and sex. A comprehensive assessment of migraine disability, pain, psychiatric disorders, psychosomatic syndromes, depressive and anxious symptoms, euthymia, psychosocial variables, mental pain, and pain-proneness (PP) was performed. Three hundred subjects were enrolled (100 CM, 100 EM, and 100 HS). Based on the multiple regression analyses, those presenting PP (social impairment: odds ratio [OR] = 3.59, 95% confidence interval [CI] = 1.14-11.29; depressive symptoms: OR = 3.82, 95% CI = 1.74-8.41) were more likely to be CM than HS. Those with higher levels of PP (social impairment: OR = 4.04, 95% CI = 1.60-10.22; depressive symptoms: OR = 2.02, 95% CI = 1.26-3.24) were more likely to be EM than HS. Those presenting higher levels of mental pain were more likely to be CM than EM (OR = 1.45, 95% CI = 1.02-2.07). Migraine is an unpleasant sensory and emotional experience associated with psychosocial manifestations that might contribute to the level of suffering of the individuals. Mental pain resulted to be the variable that most differentiated patients with CM from EM.


Mutations of O6-methylguanine-DNA methyltransferase gene in esophageal cancer tissues from Northern China.
Epidemiologic studies have implicated the involvement of environmental factors in the etiology of esophageal cancer (EC). Our previous data have indicated that EC patients and their blood relatives show genomic instability and are deficient in repair of DNA damage induced by N-nitroso-compounds and related genotoxic agents. Thus, exposure to high levels of N-alkylnitrosamines, which are known animal carcinogens and which induce alkyl adducts in DNA, may be causally linked to EC. Among the alkyl adducts, O6-alkylguanine was shown to be the critical one related to carcinogenic lesions; its repair varies widely in a tissue-specific fashion. O6-methylguanine-DNA methyltransferase (MGMT) is responsible for its repair. Hence, inactivating mutations in this protein would impair the efficiency of the repair process. To screen for possible mutations in the MGMT polypeptide in EC patients, we analyzed a highly conserved region of the MGMT gene in 40 EC tissues and lymphocytes of 6 high-risk EC family members from high EC areas of Northern China by polymerase chain reaction single-strand conformation polymorphism and by direct sequencing of PCR products. Ten base substitutions (point mutations) within 8 codons of 7 EC samples were identified. However, no germline mutation was found in the high EC families studied so far. Concurrent study in 30 pairs of fresh EC tissues and their adjacent normal mucosa by Southern blot and Western blot analyses showed deletion of the MGMT gene in 2 samples. Thus, the high frequency of mutations (7/40) and deletions (2/30) of the MGMT gene may be partially responsible for the overall high mutation rate observed in EC tissues.


Defining and validating a short form Montreal Cognitive Assessment (s-MoCA) for use in neurodegenerative disease.
Screening for cognitive deficits is essential in neurodegenerative disease. Screening tests, such as the Montreal Cognitive Assessment (MoCA), are easily administered, correlate with neuropsychological performance and demonstrate diagnostic utility. Yet, administration time is too long for many clinical settings. Item response theory and computerised adaptive testing simulation were employed to establish an abbreviated MoCA in 1850 well-characterised community-dwelling individuals with and without neurodegenerative disease. 8 MoCA items with high item discrimination and appropriate difficulty were identified for use in a short form (s-MoCA). The s-MoCA was highly correlated with the original MoCA, showed robust diagnostic classification and cross-validation procedures substantiated these items. Early detection of cognitive impairment is an important clinical and public health concern, but administration of screening measures is limited by time constraints in demanding clinical settings. Here, we provide as-MoCA that is valid across neurological disorders and can be administered in approximately 5 min.


A multigene locus containing the Manx and bobcat genes is required for development of chordate features in the ascidian tadpole larva.
The Manx gene is required for the development of the tail and other chordate features in the ascidian tadpole larva. To determine the structure of the Manx gene, we isolated and sequenced genomic clones from the tailed ascidian Molgula oculata. The Manx gene contains 9 exons and encodes both major and minor Manx mRNAs, which differ in the length of their 5' untranslated regions. The coding region of the single-copy bobcat gene, which encodes a DEAD-box RNA helicase, is embedded within the first Manx intron. The organization of the bobcat and Manx transcription units was determined by comparing genomic and cDNA clones. The Manx-bobcat gene locus has an unusual organization in which a non-coding first exon is alternatively spliced at the 5' end of two different mRNAs. The bobcat and Manx genes are expressed coordinately during oogenesis and embryogenesis, but not during spermatogenesis, in which bobcat mRNA accumulates independently of Manx mRNA. Similar to Manx, zygotic bobcat transcripts accumulate in the embryonic primordia responsible for generating chordate features, including the dorsal neural tube and notochord, are downregulated during embryogenesis in the tailless species Molgula occulta and are upregulated in M. occulta X M. oculata hybrids, which restore these chordate features. Antisense experiments indicate that zygotic bobcat expression is required for development of the same suite of chordate features as Manx. The results show that the Manx-bobcat gene complex has a role in the development of chordate features in ascidian tadpole larvae.


Lyt-2+ cells. Requirements for concanavalin A-induced proliferation and interleukin 2 production.
The requirements for inducing Lyt-2+ T cell proliferation in response to concanavalin A (Con A) were examined. Purified Lyt-2+ or L3T4+ spleen cells of C57BL/6 origin were stimulated with Con A and syngeneic macrophages (MO) in the presence of monoclonal antibodies to T cell markers or to polymorphic determinants on major histocompatibility complex molecules, and assessed for the ability to proliferate and to produce interleukin (IL) 2. alpha I-Ab failed to inhibit the Con A response of Lyt-2+ cells at dilutions that significantly inhibited the response of L3T4+ cells. In contrast, alphaKb/Db or alpha Lyt-2.2 specifically inhibited the response of Lyt-2+ cells, but not L3T4+ cells. The ability of alpha Kb/Db and of alpha Lyt-2.2 to inhibit the response of Lyt-2+ cells was dependent upon the concentration of Con A. These data demonstrate that optimal triggering of T cell subsets to proliferate and to produce IL-2 in response to Con A requires interactions with the appropriate restricting major histocompatibility complex molecule. The role of accessory cells in Lyt-2+ Con A-induced proliferation and IL-2 production was also investigated. Purified Lyt-2+ cells and purified L3T4+ cells failed to respond to Con A in the absence of MO. IL-1 reconstituted the response when MO were limiting, but failed to restore the response of either Lyt-2+ or L3T4+ cells when T cells were rigorously purified to remove all MO. These results demonstrate that triggering Lyt-2+ T cells, like L3T4+ T cells, requires accessory cells, and that this does not merely reflect a requirement for IL-1 production. Thus, Con A-induced proliferation and IL-2 production by Lyt-2+ T cells requires intimate contact with accessory cells and interactions dependent upon the class I-restricting element.


Unmet need and psychological distress predict emergency department visits in community-dwelling elderly women: a prospective cohort study.
Unmet need to perform activities of daily living (ADL) is associated with increased use of urgent health services by the elderly. However, the reported associations may be confounded by psychological distress. We examine the independent effects of unmet need and psychological distress upon emergency department (ED) visits. We conducted a prospective study of randomly selected community-dwelling adults aged ≥ 75. We report here the results for women only (n = 530). In-person interviews collected data on self-reported unmet need and the 14-item l'Indice de détresse psychologique de Santé Québec psychological distress scale. ED visits were identified from an administrative database. Multivariable logistic regression was used to identify predictors of any ED visit in the 6 months following the baseline interview. In multivariable analysis, unmet need in instrumental ADL was associated with subsequent ED visits (odds ratio = 1.57, 95% confidence interval = 1.02-2.41), as was psychological distress (odds rate = 1.30, 95% confidence interval = 1.02-1.67). The magnitude of the association between unmet need and ED visits was overestimated in statistical models that did not adjust for psychological distress. Both unmet need and psychological distress were independent predictors of ED visits. Future investigations of unmet need and health services utilization should include psychological distress to control for confounding and improve the internal validity of statistical models.


The effect of pulsatile cardiopulmonary bypass on lung function in elderly patients.
Cardiopulmonary bypass is still a major cause of lung injury and delay in pulmonary recovery after cardiac surgery. Although it has been shown that pulsatile flow induced by intra-aortic balloon pumping is beneficial for preserving lung function, it is not clear if the same beneficial effect can be accomplished with pulsatile flow generated in the extracorporeal circuit. Therefore, we investigated the effect of pulsatile flow, produced by a centrifugal pump, on lung function in elderly patients. Serial measurements of lung biomarkers Clara cell 16 kD protein, surfactant protein D, and elastase were performed on blood samples from 37 elderly patients (≥75 years) who underwent elective aortic valve replacement surgery with CPB, either with pulsatile perfusion or continuous perfusion. Pulmonary function was assessed by postoperative ventilation time, the arterial blood oxygenation (PaO2/FiO2), the alveolar-arterial oxygen gradient (Aa-O2 gradient) and the pulmonary vascular resistance indexed by body surface area (PVRi). There was no difference in lung function between both groups, as assessed by the postoperative ventilation time, the PaO2/FiO2 ratio, and the Aa-O2 gradient. The PVRi, however, was significantly lower in the pulsatile perfusion group 15 mins after the administration of protamine (p<0.05). The plasma concentrations of the lung biomarkers increased during surgery and peaked at 1 h ICU, there were however no differences between groups. Pulsatile flow does not seem beneficial to postoperative lung function in elderly patients. Moreover, pulsatile flow does not affect lung function on a subclinical level as assessed by lung biomarkers.


Randomized, international study of cyclosporine microemulsion absorption profiling in renal transplantation with basiliximab immunoprophylaxis.
Increasing information suggests that absorption profiling may be superior to trough level monitoring for optimal concentration control of cyclosporine microemulsion (Neoral) therapy, and that CsA exposure early post-transplant may correlate significantly with reduced risk of acute graft rejection. This randomized, prospective, multicenter international concentration-controlled study was conducted in 21 renal transplant centers in 8 countries to test and compare the clinical feasibility, functionality, accuracy, precision and prediction of rejection by cyclosporine microemulsion absorption profiling to conventional trough-level drug monitoring. Primary or second renal allograft recipients treated with basiliximab, cyclosporine microemulsion and prednisone immunosuppression were randomized to two study groups in which cyclosporine microemulsion therapy was monitored using a multipointalgorithm or by trough levels. The two study arms were comparable in terms of baseline characteristics, treatment and clinical outcomes. Treatment failure, consisting of acute rejection, graft loss or death, occurred with equal incidence in the two groups (30% and 33%, respectively). Diagnostic feasibility, measured as the proportion of samples obtained within the designated time window, was marginally lower in area under the time-concentration curve (AUC) than in trough groups, but the therapeutic accuracy and precision were comparable or superior in the AUC group. Cox regression analysis performed across study groups showed a highly significant correlation between the predicted probability of acute rejection and cyclosporine (CsA) exposure measured by AUC over the entire 12-h dosage interval (AUC[0-12]) (p = 0.0068), AUC over the first 4 h of the 12-h dosage interval (AUC[0-4]) (p = 0.0014) or 2h post-dose (C2) CsA level (p = 0.0027). Day 3 dose- and weight-corrected C2 values (EMIT equivalent) separated patients into low (< 200 microg/L/mg/kg dose), intermediate (200-350 microg/L/mg/kg dose) and high absorber categories (> 350 microg/L/mg/kg dose), defining those at greatest risk. Within these categories, C2 values above approximately 1500 microg/L by day 3 post-transplant were associated with the lowest predicted probability of rejection. Comparable analysis by Cox regression using C0 levels did notreach statistical significance. Absorption profiling is a feasible, accurate and precise method for monitoring cyclosporine microemulsion therapy in clinical practice and, as shown in the companion article, may be simplified by the use of single-point C2 concentrations which accurately predict individual AUC[0-4] exposure levels. Both cyclosporine microemulsion relative absorption (i.e. dose- and weight-corrected exposure) and CsA exposure (measured by predicted AUC or C2 levels) are closely correlated with the risk of rejection, and define patients at high and low risk of acute graft rejection. Trough (C0) levels are not closely correlated with either CsA exposure or rejection risk, and should not be considered reliable for monitoring cyclosporine microemulsion therapy.


Factors Associated with Turnover Intention Among Healthcare Workers During the Coronavirus Disease 2019 (COVID-19) Pandemic in China.
This study assessed the prevalence of turnover intention and explored associated factors on turnover intention among healthcare workers during the COVID-19 pandemic in China. An institutional-based cross-sectional study was conducted from July to February 13th to 20th, 2020, in 31 provinces of mainland China. A total of 1403 healthcare workers were recruited. Hierarchical logistic regressions were used to identify potential factors associated with turnover intention among Chinese health care workers. The prevalence of turnover intention among healthcare workers was 10.1% during the COVID-19 pandemic in China. Results of hierarchical regression revealed that working in Grade II hospital (OR = 1.78), technician (OR = 0.30), daily working hours over 12 h (OR = 2.92), frequency of mask replacement between 4 and 8 h (OR = 3.51), refuse volunteer to frontline (OR = 1.68), patient-physician relation unchanged (OR = 1.73), depression (OR = 2.21) and lower social support (OR = 1.75) were significantly associated with the risk of turnover intention. Additionally, healthcare worker's psychosocial syndemic (OR = 6.13) was positively associated with turnover intention. Turnover intention is relatively prevalent among healthcare workers during the COVID-19 pandemic in China, and the factors contributing to turnover intention were complex and varied. Early screening of high-risk groups for turnover intention among healthcare workers and more psychosocial health care and physical protection are needed during the COVID-19 pandemic in China.


Relationship between literacy, knowledge, self-care behaviors, and heart failure-related quality of life among patients with heart failure.
We sought to examine the relationship between literacy and heart failure-related quality of life (HFQOL), and to explore whether literacy-related differences in knowledge, self-efficacy and/or self-care behavior explained the relationship. We recruited patients with symptomatic heart failure (HF) from four academic medical centers. Patients completed the short version of the Test of Functional Health Literacy in Adults (TOFHLA) and questions on HF-related knowledge, HF-related self-efficacy, and self-care behaviors. We assessed HFQOL with the Heart Failure Symptom Scale (HFSS) (range 0-100), with higher scores denoting better quality of life. We used bivariate (t-tests and chi-square) and multivariate linear regression analyses to estimate the associations between literacy and HF knowledge, self-efficacy, self-care behaviors, and HFQOL, controlling for demographic characteristics. Structural equation modeling was conducted to assess whether general HF knowledge, salt knowledge, self-care behaviors, and self-efficacy mediated the relationship between literacy and HFQOL. We enrolled 605 patients with mean age of 60.7 years; 52% were male; 38% were African-American and 16% Latino; 26% had less than a high school education; and 67% had annual incomes under $25,000. Overall, 37% had low literacy (marginal or inadequate on TOFHLA). Patients with adequate literacy had higher general HF knowledge than those with low literacy (mean 6.6 vs. 5.5, adjusted difference 0.63, p < 0.01), higher self-efficacy (5.0 vs. 4.1, adjusted difference 0.99, p < 0.01), and higher prevalence of key self-care behaviors (p < 0.001). Those with adequate literacy had better HFQOL scores compared to those with low literacy (63.9 vs. 55.4, adjusted difference 7.20, p < 0.01), but differences in knowledge, self-efficacy, and self-care did not mediate this difference in HFQOL. Low literacy was associated with worse HFQOL and lower HF-related knowledge, self-efficacy, and self-care behaviors, but differences in knowledge, self-efficacy and self-care did not explain the relationship between low literacy and worse HFQOL.


[Optimization of numerical measurement parameters for ECG-triggered MRI snapshot-FLASH myocardial perfusion studies].
In MR examinations of myocardial perfusion by the use of Snapshot-FLASH sequences it is of major importance that the achievable signal difference between pre- and normal postcontrast myocardium be maximized. In ECG-triggered Snapshot-FLASH sequences the signal intensity of the myocardium depends on the flip angle alpha, the inversion time TI and the trigger delay TD (both depending on the cardiac frequency f) for unchanged slice thickness (SL), matrix size (MA), repetition time (TR) and echo time (TE). Therefore a simulation of the signal behavior of pre- and postcontrast myocardium based on Bloch's equations was performed by varying the flip angle alpha, TI and TD for different cardiac frequencies in order to determine an optimized combination of the measurement parameters. In normal heart rates (50-70 beats/min) maximal signal differences between pre- and normal postcontrast myocardium can be reached for inversion times TI = 170-200 ms and a flip angle alpha = 11 degrees. For higher heart rates again alpha = 11 degrees and TI = 200-220 ms with shortened TD (TD = 0 for f > 90 beats/min) were found to be optimal. The calculated values were semiquantitatively confirmed in phantom and volunteer measurements. The described method allows cardiac frequency dependent optimization of the Snapshot-FLASH measurement parameters alpha, TI and TD in order to reach a maximum in signal contrast between normal and malperfused myocardium.


Hepatitis C virus detection by single-round PCR specific for the terminal 3' noncoding region.
A single-round PCR method with primers specific for the 3' noncoding region (NCR) of hepatitis C virus (HCV) has been developed. Using a double RNAzol-B extraction, a high-temperature reverse-transcription step with SuperScript II reverse transcriptase, and a 40-cycle two-temperature PCR with a TaqStart antibody hot-start procedure, we were able to detect a 92-nucleotide fragment of the recently discovered 98-nucleotide highly conserved sequence at the 3' terminus of the HCV genome. Direct sequencing of the PCR products confirmed the specificity of the PCR and demonstrated conservation in this region. Only one nucleotide change in 14 specimens was found. End point dilution titration of sera with known viral RNA titers showed the sensitivity of the single-round 3' NCR PCR to be comparable to those of the established nested 5' NCR assays (fewer than 25 HCV genome equivalents). To evaluate specificity and sensitivity, a panel of 116 serum samples characterized by nested 5'-end PCR, genotyping, and quantitative assays was tested. A high degree of concordance (96%) between the 3' NCR and 5' NCR PCR results was found. The sequence conservation at the 3' end of the HCV genome among common genotypes and the savings in time, labor, and reagents from a single-round PCR make this assay a useful addition to the detection systems available to identify and monitor HCV infection.


Late luteal phase dysphoric disorder and the thyroid axis revisited.
Late luteal phase dysphoric disorder (LLPDD), also known as premenstrual dysphoria, has been etiologically linked to both depression and thyroid disease. We examined baseline and TRH-stimulated thyroid function in 45 otherwise healthy women with prospectively confirmed LLPDD during the follicular and luteal phases of their menstrual cycles. The means of all thyroid variables were normal. Three (6.8%) subjects had elevated baseline TSH (mild hypothyroidism), and 6 (13.3%) had an exaggerated TSH response (delta max TSH) to TRH (subclinical hypothyroidism). A blunted delta max TSH (< 5 mU/L) was found in only 4.4% of the subjects. History of a past major psychiatric diagnosis (mostly depression) or a current personality disorder correlated with a lower delta max TSH. As baseline TSH, using the new ultrasensitive radioimmunometric assay, correlated strongly with delta max TSH, the utility of the TRH challenge is questioned. Our findings suggest that LLPDD is not related to depression on the basis of this marker and that hypothyroidism is not the cause of LLPDD.


Treatment of skewfoot by multiple lesser tarsal osteotomies and calcaneal osteotomy.
A 9-year-old male with bilateral skewfoot deformity underwent corrective surgery consisting of multiple abductory, lesser tarsal osteotomies, and medial displacement L-shaped calcaneal osteotomy. The author prefers this surgical approach because it minimizes shortening of the lateral column without limiting the amount of transverse plane correction. The calcaneal osteotomy offers excellent stability in the sagittal plane without limiting frontal or transverse plane correction.


Immediate Inferior Alveolar Nerve Reconstruction With Ablative Mandibular Resection Results in Functional Sensory Recovery.
Ablative mandibular resection with sacrifice of the inferior alveolar nerve (IAN) results in loss of sensation and decreased quality of life. The purpose of this study is to evaluate functional sensory recovery (FSR) of immediate IAN allograft reconstruction performed during ablative mandibular resection at 1 year following surgery. This is a single-center retrospective cohort study that included consecutive subjects who underwent mandibular resection with IAN discontinuity and used a nerve allograft of ≥40 mm. The primary predictor variable is the use of an immediate nerve allograft in mandibular reconstruction. The main outcome variable is FSR at 1 year using the Medical Research Council Scale. Covariates include subject age, sex, specific pathology, nerve gap length, and development of neuropathic pain. Statistical analysis of comparison of neurosensory outcomes was measured by bivariate statistics, weighted values, repeated measures, analysis of variance, and McNemar test. The study sample was composed of 164 subjects, of whom 55 (33.5%) underwent nerve allograft reconstruction and 30 (18.3%) did not have nerve reconstruction. Seventy-nine subjects (48.2%) did not meet the inclusion criteria. In the entire nerve allograft group of 55 subjects, FSR was achieved in 80% at 1 year; however, in benign disease alone, 31 of 33 (94%) achieved FSR at 1 year. In the nonallograft group (all benign disease), only 2 of 30 (7%) achieved FSR at 1 year. The significant covariates were age and pathology. Benign pathologic resections were 5.2 times more likely to achieve FSR than malignancies, and all subjects ≤ 18 years of age achieved FSR. After adjusting for age, sex, pathology, nerve gap length, nerve allograft was significantly associated with achieving FSR at 1 year (adjusted odds ratio = 5.52, 95% confidence interval = (1.03, 29.51), P value = .045 < .05). Immediate long-span IAN allograft reconstruction is effective in restoration of sensation with an overall 80% of subjects achieving FSR at 1 year, while benign disease resulted in 94% FSR at 1 year. Immediate IAN reconstruction should be considered with mandibular resection involving the IAN, especially for children and benign disease.


ATF6α Activation Enhances Survival against Chemotherapy and Serves as a Prognostic Indicator in Osteosarcoma.
Patients with metastatic or relapsed/refractory osteosarcoma (OS) have a 5-year survival rate of <30%. This has remained unchanged over several decades. One of the factors contributing to lack of improvement in survival is the development of chemoresistance. Hence, elucidating and targeting the mechanisms that promote survival against chemotherapy and lead to chemoresistance is pivotal to improving outcomes for these patients. We identified that endoplasmic reticulum (ER) stress-activated transcription factor, ATF6α, is essential for the survival of OS cells against chemotherapy induced cell death. ATF6α cleavage and activity were enhanced in OS cells compared to normal osteoblasts and knockdown of ATF6α expression enhanced sensitivity of OS cells against chemotherapy induced cell death. This was in part due to increased Bax activation. Pharmacologic inhibition or knock-down of downstream targets of ATF6α, protein disulfide isomerases (PDI) and ERO1β, a thiol oxidase that is involved in the re-oxidation of PDIs also independently induced pronounced killing of OS cells following chemotherapy. Analysis of primary tumors from OS patients reveals that patients with high levels of nuclear ATF6α: (1) also had increased expression of its downstream targets the chaperone BiP and enzyme PDI, (2) had a significant likelihood of developing metastasis at diagnosis, (3) had significantly poorer overall and progression free survival, and (4) had poorer response to chemotherapy. These findings suggest that targeting survival signaling by the ATF6α pathway in OS cells may favor eradication of refractory OS tumor cells and ATF6α could be a useful predictor for chemo-responsiveness and prognosis.


Development of a multiplex PCR assay for identification of Klebsiella pneumoniae hypervirulent clones of capsular serotype K2.
Hypervirulent Klebsiella pneumoniae isolates of capsular serotype K2 (hvKP-K2) that cause community-acquired invasive infections represent several unrelated clones, which all belong to phylogenetic group KpI. These clones can be recognized using multilocus sequence typing and genomic analyses, but no rapid method currently exists to differentiate them. In this work, a multiplex PCR assay was developed to identify three hvKP-K2 groups: (i) sequence type (ST)86; (ii) ST380 and ST679 (i.e. clonal group 380); and (iii) ST65 and ST375. A specific genetic marker, Kp50233, allowing K. pneumoniae sensu stricto (corresponding to phylogroup KpI) to be distinguished from closely related species, was included in the assay. This PCR assay will be useful in better defining the epidemiology and clinical features of emerging virulent K. pneumoniae clones.


Long-term respiratory support in children with giant omphalocele.
Omphalocele is one of the most common fetal abdominal wall defects. When this defect is of giant size, significant respiratory compromise may occur and impact on prognosis. We present three infants with giant omphalocele, highlighting the potential need for ongoing ventilatory support after the neonatal period in children born with this condition. The three cases had very different outcomes but all had significant ventilatory insufficiency and required substantial respiratory support at least into the second year of life. The possibility of a requirement for long-term ventilatory support should be discussed with families at antenatal diagnosis. A conservative surgical approach, together with early monitoring for hypoventilation and screening for the development of pulmonary hypertension is indicated for these children to limit morbidity. We suggest early tertiary respiratory input and advocate for a specific case manager to oversee the regional care of these children.


Demonstration of dose and scatter reductions for interior computed tomography.
With continuing developments in computed tomography (CT) technology and its increasing use of CT imaging, the ionizing radiation dose from CT is becoming a major public concern particularly for high-dose applications such as cardiac imaging. We recently proposed a novel interior tomography approach for x-ray dose reduction that is very different from all the previously proposed methods. Our method only uses the projection data for the rays passing through the desired region of interest. This method not only reduces x-ray dose but scatter as well. In this paper, we quantify the reduction in the amount of x-ray dose and scattered radiation that could be achieved using this method. Results indicate that interior tomography may reduce the x-ray dose by 18% to 58% and scatter to the detectors by 19% to 59% as the FOV is reduced from 50 to 8.6 cm.


Focal nodular hyperplasia with major sinusoidal dilatation: a misleading entity.
Focal nodular hyperplasia (FNH) is a benign liver lesion thought to be a non-specific response to locally increased blood flow. Although the diagnosis of FNH and hepatocellular adenoma (HCA) has made great progress over the last few years using modern imaging techniques, there are still in daily practice some difficulties concerning some atypical nodules. Here, the authors report the case of a 47-year-old woman with a single liver lesion thought to be, by imaging, an inflammatory HCA with major sinusoidal congestion. This nodule was revealed to be, at the microscopical level and after specific immunostaining and molecular analysis, an FNH with sinusoidal dilatation (so-called telangiectatic focal nodular hyperplasia).


Percolation theory as a conceptual framework to explain spontaneous atrial fibrillation termination: a pilot study.
Atrial fibrillation (AF) strikingly possesses the ability to abruptly transition into more organized electrical activity and spontaneously terminate, even after persisting for long periods. Despite being central to the clinical behavior and treatment of AF, these phenomena remain incompletely understood. In this paper, we hypothesized that the spontaneous termination of AF may represent a type of percolation phase transition, which is more likely to occur when a domain spanning cluster of refractory sites in the atrium are connected (called a 'percolation cluster'). This was assessed in n=50 computational simulations of AF developed using the Aliev-Panfilov (APV) 2-dimensional cell model. In self-terminating simulations of AF, it was found that the average refractory cluster size, χ(p) (median: 647.7), and the largest refractory cluster size, M1 (median: 1702.3), abruptly increased just prior to AF spontaneously terminating, indicating the onset of the formation of a domain spanning percolation cluster. In contrast, simulations of sustained AF did not demonstrate an increase in χ(p) (median: 463.0) and M1 (median: 1448.2). Self-terminating AF simulations also demonstrated hallmark properties characteristic of a percolation phase transition, such as an abrupt increase in χ(p) at the critical occupation probability pc. The cluster size distribution was also shown to obey a power law for various occupation probabilities p, also indicative of a percolation phase transition. Collectively, these properties suggests that the spontaneous termination of AF could be a form of percolation phase transition, which could provide new insights for AF treatment.


[Afobasol efficacy in a model of vagotonic atrial fibrillation].
The new anxiolytic agent afobasol (Russia) was introduced into clinical practice by V. V. Zakusov Research Institute of Pharmacology. When administered to cats with vagotonic atrial fibrillation afobasol (7.5 mg/kg v/v) exhibited anti-arrhythmic activity at least as high as that of class 1 and III anti-arrhythmic agents (etacisin and cardiocyclide respectively) (Vaughan Williams classification). However, duration of its action was much smaller. These experimental findings were confirmed in clinical studies involving patients with severe psychosomatic pathology associated with paroxysmal flutter. It is supposed that afobasol activates cytosolic sigma-1 receptors in cardiomyocytes and may be used to manage psychoasthenic conditions accompanied by cardioneuroses and/or cardiophobias with disturbed rhythmic activity of the heart.


The crystal structure of apo-FtsH reveals domain movements necessary for substrate unfolding and translocation.
The hexameric membrane-spanning ATP-dependent metalloprotease FtsH is universally conserved in eubacteria, mitochondria, and chloroplasts, where it fulfills key functions in quality control and signaling. As a member of the self-compartmentalizing ATPases associated with various cellular activities (AAA+ proteases), FtsH converts the chemical energy stored in ATP via conformational rearrangements into a mechanical force that is used for substrate unfolding and translocation into the proteolytic chamber. The crystal structure of the ADP state of Thermotoga maritima FtsH showed a hexameric assembly consisting of a 6-fold symmetric protease disk and a 2-fold symmetric AAA ring. The 2.6 A resolution structure of the cytosolic region of apo-FtsH presented here reveals a new arrangement where the ATPase ring shows perfect 6-fold symmetry with the crucial pore residues lining an open circular entrance. Triggered by this conformational change, a substrate-binding edge beta strand appears within the proteolytic domain. Comparison of the apo- and ADP-bound structure visualizes an inward movement of the aromatic pore residues and generates a model of substrate translocation by AAA+ proteases. Furthermore, we demonstrate that mutation of a conserved glycine in the linker region inactivates FtsH.


Electron microscopy in pathology articles: a retrospective appraisal.
Electron microscopy (EM) is a valuable standard tool in basic research and teaching. However, its use in diagnosis is limited, either for strategic reasons or budgetary constraints. This means that its many potential applications are more often neglected, either as an ancillary tool, quality control method, or gold standard, to complement, support, or confirm results of pathological studies. To evaluate the use of EM in this setting, the authors analyzed all articles (n = 2,531) in the three top indexed diagnostic pathology journals for a period of 60 months from July 1993 to June 1998. A total of 448 articles in which the use of EM was indicated, according to standard surgical pathology textbooks, were selected. Both the actual and the potential EM content of each article were scored, as follows: zero, illustrative, supportive, gold standard (for confirmation of research results), extensive, and predominant. Of the total number of articles in which EM was indicated, 77% made use of the technique. EM support was lacking most frequently in articles on serosal neoplasms and on new diagnostic strategies (p < .00005). There was no definite trend toward an increase or decrease in the use of EM during the period analyzed. The authors conclude that EM is used in most reports on diagnostic pathology, when it is indicated. However, a small but non-negligible percentage of articles (23%) could benefit from including EM as an ancillary, control, or gold standard method to complement, support, or confirm their results.


Structure-function relationships of the RNA-dependent RNA polymerase from poliovirus (3Dpol). A surface of the primary oligomerization domain functions in capsid precursor processing and VPg uridylylation.
The primary oligomerization domain of poliovirus polymerase, 3Dpol, is stabilized by the interaction of the back of the thumb subdomain of one molecule with the back of the palm subdomain of a second molecule, thus permitting the head-to-tail assembly of 3Dpol monomers into long fibers. The interaction of Arg-455 and Arg-456 of the thumb with Asp-339, Ser-341, and Asp-349 of the palm is key to the stability of this interface. We show that mutations predicted to completely disrupt this interface do not produce equivalent growth phenotypes. Virus encoding a polymerase with changes of both residues of the thumb to alanine is not viable; however, virus encoding a polymerase with changes of all three residues of the palm to alanine is viable. Biochemical analysis of 3Dpol derivatives containing the thumb or palm substitutions revealed that these derivatives are both incapable of forming long fibers, suggesting that polymerase fibers are not essential for virus viability. The RNA binding activity, polymerase activity, and thermal stability of these derivatives were equivalent to that of the wild-type enzyme. The two significant differences observed for the thumb mutant were a modest reduction in the ability of the altered 3CD proteinase to process the VP0/VP3 capsid precursor and a substantial reduction in the ability of the altered 3Dpol to catalyze oriI-templated uridylylation of VPg. The defect to uridylylation was a result of the inability of 3CD to stimulate this reaction. Because 3C alone can substitute for 3CD in this reaction, we conclude that the lethal replication phenotype associated with the thumb mutant is caused, in part, by the disruption of an interaction between the back of the thumb of 3Dpol and some undefined domain of 3C. We speculate that this interaction may also be critical for assembly of other complexes required for poliovirus genome replication.


Social class, gay men and AIDS prevention.
The relationship between sexuality, gay communities and class is potentially a very large problem for AIDS prevention. Class is a historical process which interacts with sexuality in ways still little understood. The complexities of modern class structures need full acknowledgement; labour market groupings are internally divided, and cultural privilege and exclusion are important. A community survey in New South Wales of men who have sex with men shows the class selectiveness usual in such research. An exploration of correlates of labour market position, income and education finds few relationships with attachment to milieu except for involvement with gay organisations, and minor differences in broad measures of sexuality but some class differences in HIV risk-taking and some differences in exposure to information and in attitude. An exploration of several cases from a life-history study of working-class gay men shows the impact of class circumstance on the formation of sexual relationships and points to the accessibility of unlabelled homosexual activity in working-class milieux. Research on working-class education points to the importance of curriculum change in overcoming class exclusion, and is moving towards empowerment models of great relevance in AIDS education.


Classification of major newborn birth injuries.
A classification system of various forms of major newborn birth injuries is clearly lacking in the literature. Currently, no scales exist for distinguishing degrees, extent, or distinctions of major birth injuries. The purpose of this study was to use published and online literature to explore the timing, prediction, and outcomes of major newborn birth injuries. Potential antecedents and causes were used in depicting what were reported to be major birth injuries. The outcome of this literature search was the development of a classification table synthesizing the most frequently reported (n = 20) major newborn birth injuries. This classification was developed according to (1) types of tissue involved in the primary injury, (2) how and when the injury occurred, and (3) the relationship of the injury to birth outcomes. A classification scheme is critically needed as the first step to achieving preventive interventions and plans for long-term recovery from birth injuries. Because major birth trauma contributes to increased neonatal morbidity and mortality, its occurrence requires careful study and preventive efforts to better promote newborn health.


Community engagement in biomedical research in an African setting: the Kintampo Health Research Centre experience.
Community engagement (CE) is becoming relevant in health research activities; however, models for CE in health research are limited in developing countries. The Kintampo Health Research Centre (KHRC) conducts research to influence health policy locally and also internationally. Since its establishment in 1994 with the mandate of conducting relevant public health studies in the middle part of Ghana, KHRC has embarked on a series of clinical and operational studies involving community members. In these studies, community members have been engaged through community durbars before, during and also after all study implementations. Lessons learnt from these activities suggested the need to embark on further CE processes that could serve as a model for emerging research institutions based in African communities. Interactive community durbars, workshops, in-depth discussions, focus group discussions and radio interactions were used as the main methods in the CE process. Community members outlined areas of research that they perceived as being of interest to them. Though community members expressed continual interest in our traditional areas of research in communicable, maternal, neonatal and child health, they were interested in new areas such as non- communicable diseases such as diabetes and hypertension. Misconceptions about KHRC and its research activities were identified and clarified. This research provided KHRC the opportunity to improve communication guidelines with the community and these are being used in engaging the community at various stages of our research, thus improving on the design and implementation of research. KHRC has developed a culturally appropriate CE model based on mutual understanding with community members. The experience obtained in the CE process has contributed to building CE capacity in KHRC. Other health research institutions in developing countries could consider the experiences gained.


Controlled formation of mono- and dihydroxy-resolvins from EPA and DHA using soybean 15-lipoxygenase.
Resolvins and protectins are important anti-inflammatory and pro-resolution compounds derived from the enzymatic oxidation of omega-3 fatty acids all-cis-5,8,11,14,17-eicosapentaenoic acid (EPA) and all-cis-4,7,10,13,16,19-docosahexaenoic acid (DHA). We have developed a simple, controlled method to synthesize an array of resolvin and protectin analogs from fatty acid starting materials using soybean 15-lipoxygenase. The conditions were optimized for the production of both mono- and dihydroxy derivatives, with enzyme concentration and pH found to have a significant effect on the reaction products. The methods were applied to five biologically important omega-3 and omega-6 fatty acid substrates. Mono- and dihydroxy compounds were successfully synthesized from all substrates and the products were characterized by normal phase (NP) HPLC, GC-MS, TOF-MS, UV-visible (UV-vis) spectroscopy, and NMR spectroscopy. The methods could be further applied to any polyunsaturated fatty acids containing the cis-1,4,7,10-undecatetraene moiety to produce a range of novel compounds with potential biological activity.


Acute chagas disease: new global challenges for an old neglected disease.
Chagas disease is caused by infection with the protozoan Trypanosoma cruzi, and although over 100 years have passed since the discovery of Chagas disease, it still presents an increasing problem for global public health. A plethora of information concerning the chronic phase of human Chagas disease, particularly the severe cardiac form, is available in the literature. However, information concerning events during the acute phase of the disease is scarce. In this review, we will discuss (1) the current status of acute Chagas disease cases globally, (2) the immunological findings related to the acute phase and their possible influence in disease outcome, and (3) reactivation of Chagas disease in immunocompromised individuals, a key point for transplantation and HIV infection management.


Contributing factors to performance of a medicine ball explosive power test: a comparison between jump and nonjump athletes.
The present study examined the factors contributing to performance of a backward overhead medicine ball throw (B-MBT) across 2 types of athletes. Twenty male volleyball players (jump athletes) and 20 wrestlers (nonjump athletes) were evaluated on 4 measures of power, including B-MBT, chest medicine ball throw (C-MBT), countermovement vertical jump (CMJ), and power index (PI). The athletes also completed 3 measures of strength: a 1-repetition-maximum (1RM) bench press (BP), a 1RM leg press (LP), and combined BP + LP strength. Jump athletes demonstrated greater absolute scores for CMJ, C-MBT, and B-MBT (p < 0.05), whereas nonjump athletes demonstrated greater strength scores for BP and for BP + LP (p < 0.05). When performances were examined on a relative basis, jump athletes achieved superior scores for C-MBT (p < 0.05), whereas nonjump athletes had greater scores for BP, LP, and BP + LP (p < 0.05). For both groups, B-MBT had strong correlations with PI (r = 0.817 [jump] and 0.917 [nonjump]), whereas for C-MBT, only nonjump athletes demonstrated a strong correlation (r = 0.842). When expressed in relative terms, B-MBT was strongly correlated with C-MBT (r = 0.762 [jump] and 0.835 [nonjump]) and CMJ (r = 0.899 [jump] and 0.945 [nonjump]). Only nonjump athletes demonstrated strong correlations with strength for absolute LP (r = 0.801) and BP + LP (r = 0.810) strength. The interaction of upper- and lower-body strength and power in the performance of a B-MBT appears complex, with the contributing factors differing for athletes with divergent skill sets and performance demands.


Fistula in Cleft Lip and Palate Patients-A Systematic Scoping Review.
(1) Assess the level of available evidence regarding fistula occurrence in cleft lip and palate patients, (2) identify main research areas in the original studies, (3) evaluate the quality of original studies, and (4) summarize the evidence. Two independent researchers searched the Cochrane Database of Systematic Reviews, Medline, Web of Knowledge, Web of Science and EMBASE, the Grey literature, and the reference lists of main references. The level of evidence was assessed based on study design and according to the Hierarchy of Evidence. The quality assessment was done using the adapted Consolidated Standards of Reporting Trials and Strengthening the Reporting of Observational Studies in Epidemiology checklists and a validity scoring system. Main findings were summarized, and fistula rates were compared between early and more recent articles, also between high-quality and low-quality studies. The systematic search and relevance assessment identified a total of 127 sources of evidence. The overall level of evidence was weak because it was dominated by small studies (<30 subjects), retrospective cohort studies, and case series. Main research areas were either: (1) focused on surgeries or (2) focused on risk determinants associated with fistula occurrence. Recent reports were of higher quality than the older ones, but the overall quality in the majority of reports was low. Knowledge synthesis demonstrated a wide range of rates for primary fistula (0-78%). No significant difference was found in the fistula rates of older studies compared with more recent studies or among different quality studies. Multiple risk determinants were studied and age at surgery, surgeon's experience, type and severity of cleft were the most frequently examined risk determinants. However, findings concerning different risk determinants and fistula occurrence were not consistent. The research mainly focused on surgeries and fistula-related risk determinants. The available evidence was low level and of poor quality. No consistent pattern between fistula occurrence and any of the risk determinants could be detected. Reported fistula rates did not differ significantly when comparing older studies with more recent studies or when high-quality studies were compared with low-quality studies.


Online attentional bias modification training targeting anxiety and depression in unselected adolescents: Short- and long-term effects of a randomized controlled trial.
Based on information processing models of anxiety and depression, we investigated the efficacy of multiple sessions of online attentional bias modification training to reduce attentional bias and symptoms of anxiety and depression, and to increase emotional resilience in youth. Unselected adolescents (N = 340, age: 11-18 years) were randomly allocated to eight sessions of a dot-probe, or a visual search-based attentional training, or one of two corresponding placebo control conditions. Cognitive and emotional measures were assessed pre- and post-training; emotional outcome measures also at three, six and twelve months follow-up. Only visual search training enhanced attention for positive information, and this effect was stronger for participants who completed more training sessions. Symptoms of anxiety and depression reduced, whereas emotional resilience improved. However, these effects were not especially pronounced in the active conditions. Thus, this large-scale randomized controlled study provided no support for the efficacy of the current online attentional bias modification training as a preventive intervention to reduce symptoms of anxiety or depression or to increase emotional resilience in unselected adolescents. However, the absence of biased attention related to symptomatology at baseline, and the large drop-out rates at follow-up preclude strong conclusions.


The effect of acute autologous blood transfusion on coagulation dysfunction after cardiopulmonary bypass.
To evaluate the influence of acute autologous blood transfusion on postcardiopulmonary bypass coagulation disturbances evaluated by thromboelastography (TEG) as a point-of-care test. This prospective randomized controlled study included consecutive patients who underwent elective cardiac surgery with cardiopulmonary bypass. The patients in group A underwent acute autologous blood transfusion with acute normovolemic haemodilution and those in group H received homologous blood, if needed, and served as controls. A total of 62 patients, from 68 enrolled, completed the study: 27 in group A and 35 in group H. Both groups had similar prolongation of prothrombin time and partial thromboplastin time, decreased platelets count and changes in postoperative thromboelastographic variables. There were no differences between them for postoperative bleeding, blood transfusions or haemoglobin values. There was significant prolongation of the R value of TEG (without heparinase) in both groups at 4 h after surgery compared with the immediate postoperative values: from 11.3 +/- 4.2 to 12.3 +/- 5.5 mm, P < 0.05 for group A and from 9.9 +/- 3.7 to 12.5 +/- 5.4 mm, P < 0.01 for group H. The R values of TEG with and without heparinase differed significantly (P < 0.05) at 4 h postoperatively. Autologous blood transfusion of 15% estimated blood volume did not affect postcardiopulmonary bypass coagulopathy, nor did it decrease blood loss or homologous blood and its products transfusion in the early postoperative period. TEG is a valuable measure for detecting coagulation dysfunction with a potential role in the postoperative management of cardiac patients.


Self-service computerized bibliographic retrieval: a comparison of Colleague and PaperChase, programs that search the MEDLINE data base.
Colleague and PaperChase are the two most widely used computer systems designed specifically for clinicians and scientists who wish to search the National Library of Medicine's MEDLINE data base of references to the biomedical literature. The present study compares the performance of these two systems. Two matched groups of second-year medical students each received 3 hr of instruction, one group in Colleague, the other in PaperChase. Each student then attempted 10 test searches. The next day the groups were reversed, and each student attempted 5 additional searches. During 3 1/2 hr allocated for searching, users of Colleague attempted 64 test searches and retrieved 326 target references; users of PaperChase attempted 78 searches and retrieved 496. Users of Colleague took a mean of 2.2 min and spent a mean of $1.20 to find each target reference; users of PaperChase took 1.6 min and spent $0.92. We conclude that after limited training, medical students find more references faster and at lower cost with PaperChase than with Colleague.


Managed care liability and ERISA preemption.
Patients enrolled in managed care organizations (MCOs) are concerned about quality of care and restrictions imposed. There is concern about being harmed due to the negligence of MCOs. Meanwhile, MCOs are protected by the federal Employment Retirement Income Security Act (ERISA) of 1974, which preempts state law claims and results in eliminating many of the recoveries otherwise available to a harmed beneficiary in non-MCOs. This article reviews the ERISA exemption and legal theories for patient redress.


Purine alkaloids in Paullinia.
Among the few purine alkaloid-containing genera consumed as stimulants, Paullinia is the least investigated with respect to both chemotaxonomy and within-the-plant allocation of caffeine and its allies. Since purine alkaloids (PuA) have been proved to be valuable marker compounds in chemotaxonomy, 34 species of Paullinia and related genera were screened for them, but only one, P. pachycarpa, was positive in addition to the already known P. cupana and P. yoco. The PuA allocation in P. pachycarpa was examined and found to be restricted to theobromine in the stem, leaves and flowers. Moreover, the theobromine concentration in the stem cortex increased significantly towards the base of the plant. Since the stem cortex of P. yoco is traditionally used by the natives of Colombia and Ecuador to prepare a caffeine-rich beverage, we suspected that within the genus Paullinia the PuA are preferentially allocated to the older parts of the stem and not to young shoots like e.g., in the coffee plant (Coffea spp.). Indeed, the axis (greenhouse) of P. cupana (guaraná), known for its caffeine-rich seeds, exhibited a basipetal PuA gradient (0.005-0.145%). Moreover, the analysis of young cortex samples (herbarium) and of one piece of old stem (museum collection) revealed the same for P. yoco, even though we found much less (0.5 vs 2.5%) caffeine in the old cortex as compared to the only two analyses in 1926 of similar material. However, this discrepancy may be explained by the high variability of the PuA pattern we detected among yoco, the diversity of which the Indians take advantage.


The accuracy of intra-oral scanners in full arch implant rehabilitation: a narrative review.
This narrative review aims to study the accuracy of different intra-oral scanner (IOS) devices already available on the market. The accuracy emerged during in vitro, in vivo and ex vivo studies made with IOS devices during the scan of a full arch implant rehabilitation that have been analysed to evaluate which device may be the most suitable in this clinical situation. The literature review was performed by searching topics and keywords using the PubMed and Medline databases, for example, 'digital workflow', 'full arch', 'full arch implant rehabilitation' and 'accuracy of IOS'. Inclusion and exclusion criteria for studies were: correct IMRAD (introduction, methods, results and discussion) structure; article with clear and detailed objectives; consistency of the articles with the purpose of the review; two-year range from the year of publication of the article; reproducible materials and methods; and correct follow-up. Most of the intra-oral scanners employed in vitro provided acceptable accuracy (below a threshold of 150 μm). The main parameters identified for their influence on precision were interim plant distance, body scan design, scanning pattern and operator experience. Even though literature is limited, significant differences emerged between the different models of intra-oral scanners evaluated in the studies considered within this review.


A novel peptide-based encoding system for "one-bead one-compound" peptidomimetic and small molecule combinatorial libraries.
The "one-bead one-compound" (OBOC) combinatorial library method is highly efficient, especially when used with well-established on-bead binding or functional assays. Literally, millions of compounds can be screened concurrently within 1 to 2 days. However, structure determination of peptidomimetic and small molecule compounds on one single bead is not trivial. A novel, highly efficient, and robust peptide-based encoding system has been developed for OBOC peptidomimetic and small molecule combinatorial libraries. In this system, topologically segregated bifunctional beads, which are made by a simple biphasic solvent strategy, are employed for the preparation and screening of an OBOC combinatorial peptidomimetic and small molecule libraries. Testing molecules are on the outer layer, and the coding tags in the interior of the bead do not interfere with screening. The coding tag is a peptide containing a large number of unnatural alpha-amino acids derived from different building blocks used for generating the peptidomimetic or small molecule. By coupling common building blocks simultaneously to the scaffold of the testing compound and to the side chains of the alpha-amino acids on the coding peptide, extra synthetic steps are eliminated and the amount of undesirable side products is minimized. Positive bead decoding is easy and straightforward as there is no need for cleavage and retrieval of the coding tag, and positive beads can be sequenced directly with Edman degradation. To demonstrate the efficiency and simplicity of our encoding system, an encoded 158 400-member model peptidomimetic library has been generated and screened for ligands that bind to streptavidin. Potent and novel ligands with clear motifs have been identified.


A fluorescent probe for simultaneously sensing NTR and hNQO1 and distinguishing cancer cells.
Identifying cancer at the cellular level during an early stage offers the hope of greatly improved outcomes for cancer patients. As potential cancer biomarkers, nitroreductase (NTR) and human quinine oxidoreductase 1 (hNQO1) are overexpressed in many type of cancer cells. Simultaneous detection of these two biomarkers would benefit diagnostic precision in related cancers without yielding false positive results. Herein, based on a dye generated in situ strategy, a dual-enzyme-responsive probe, CNN, was rationally designed and synthesized by installing p-nitrobenzene and trimethyl-locked quinone propionic acid groups, which are specific for NTR and hNQO1, respectively, into a single fluorophore. This probe is only activated in the presence of both NTR and hNQO1 and produces a large fluorescence response, enabling the detection of both endogenous NTR and hNQO1 activity in living cells. The imaging results indicate that the CNN probe differentiates cancer cells (HeLa, MDA-MB-231 and HepG2 cells) from normal liver HL-7702 cells owing to the existence of relatively high endogenous levels of both biomarkers in these cancer cells.


Cognitive Reappraisal and Expressive Suppression Evoke Distinct Neural Connections during Interpersonal Emotion Regulation.
Interpersonal emotion regulation is the dynamic process where the regulator aims to change the target's emotional state, which is presumed to engage three neural systems: cognitive control (i.e., dorsal and ventral lateral PFC, etc.), empathy/social cognition (i.e., dorsal premotor regions, temporal-parietal junction, etc.), and affective response (i.e., insula, amygdala, etc.). This study aimed to identify the underlying neural correlate (especially the interpersonal one), of interpersonal emotion regulation based on two typical strategies (cognitive appraisal, expressive suppression). Thirty-four female dyads (friends) were randomly assigned into two strategy groups, with one assigned as the target and the other as the regulator to downregulate the target's negative emotions using two strategies. A functional near-infrared spectroscopy system was used to simultaneously measure participants' neural activity. Results showed that these two strategies could successfully downregulate the targets' negative emotions. Both strategies evoked intrapersonal and interpersonal neural couplings between the cognitive control, social cognition, and mirror neuron systems (e.g., PFC, temporal-parietal junction, premotor cortex, etc.), whereas cognitive reappraisal (vs expressive suppression) evoked a broader pattern. Further, cognitive reappraisal involved increased interpersonal brain synchronization between the prefrontal and temporal areas at the sharing stage, whereas expressive suppression evoked increased interpersonal brain synchronization associated with the PFC at the regulation stage. These findings indicate that intrapersonal and interpersonal neural couplings associated with regions within the abovementioned systems, possibly involving mental processes, such as cognitive control, mentalizing, and observing, underlie interpersonal emotion regulation based on cognitive reappraisal or expressive suppression.SIGNIFICANCE STATEMENT As significant as intrapersonal emotion regulation, interpersonal emotion regulation subserves parent-child, couple, and leader-follower relationships. Despite enormous growth in research on intrapersonal emotion regulation, the field lacks insight into the neural correlates underpinning interpersonal emotion regulation. This study aimed to probe the underlying neural correlates of interpersonal emotion regulation using a multibrain neuroimaging (i.e., hyperscanning) based on functional near-infrared spectroscopy. Results showed that both cognitive reappraisal and expressive suppression strategies successfully downregulated the target's negative emotions. More importantly, they evoked intrapersonal and interpersonal neural couplings associated with regions within the cognitive control, social cognition, and mirror neuron systems, possibly involving mental processes, such as cognitive control, mentalizing, and observing. These findings deepen our understanding of the neural correlates underpinning interpersonal emotion regulation.


Antioxidant vitamins and lysophospholipids are critical for inducing mouse spermatogenesis under organ culture conditions.
In vitro mouse spermatogenesis using a classical organ culture method became possible by supplementing basal culture medium with only the product of bovine serum albumin purified by chromatography (AlbuMAX), which indicated that AlbuMAX contained every chemical factor necessary for mouse spermatogenesis. However, since the identity of these factors was unclear, improvements in culture media and our understanding of the nutritional and signal substances required for spermatogenesis were hindered. In the present study, chemically defined media (CDM) without AlbuMAX was used to evaluate each supplementary factor and their combinations for the induction of spermatogenesis. Similar to in vivo conditions, retinoic acid, triiodothyronine (T3 ), and testosterone (T) were needed. Based on differences in spermatogenic competence between AlbuMAX, fetal bovine serum, and adult bovine serum, we identified α-tocopherol, which strongly promoted spermatogenesis when combined with ascorbic acid and glutathione. Differences were also observed in the abilities of lipids extracted from AlbuMAX using two different methods to induce spermatogenesis. This led to the identification of lysophospholipids, particularly lysophosphatidylcholine, lysophosphatidic acid, and lysophosphatidylserine, as important molecules for spermatogenesis. New CDM formulated based on these results induced and promoted spermatogenesis as efficiently as AlbuMAX-containing medium. In vitro spermatogenesis with CDM may provide a unique experimental system for research on spermatogenesis that cannot be performed in in vivo experiments.


Hepatoma-derived growth factor induces tumorigenesis in vivo through both direct angiogenic activity and induction of vascular endothelial growth factor.
Hepatoma-derived growth factor (HDGF) is highly expressed in tumor cells, and stimulates their proliferation. In the present study, we investigated the role of HDGF in tumorigenesis and elucidated the mechanism of action. Stable transfectants of NIH3T3 cells overexpressing HDGF did not show significant anchorage-independent growth in soft agar assay. However, these stable transfectants overexpressing HDGF generated sarcomatous tumors in nude mice. These tumors were red-colored macroscopically, and histologically showed a rich vascularity. Immunohistochemical analysis using CD31 antibody showed new vessel formation. Recombinant HDGF stimulated proliferation of human umbilical vein endothelial cells in a dose-dependent manner, and stimulated tubule formation. Furthermore, vascular endothelial growth factor (VEGF) was detected immunohistochemically in the tumor tissues. Transient expression of HDGF induced both VEGF gene and protein expression as demonstrated by a reporter assay using VEGF gene promoter. The administration of anti-VEGF neutralizing antibody significantly suppressed, but did not block, the tumor growth of HDGF-overexpressing cells in nude mice. Thus, these findings suggested that HDGF-induced tumor formation in vivo involves induction of VEGF as well as direct angiogenic activity.


A Placebo Controlled Trial on Add-on Modafinil on the Anti-psychotic Treatment Emergent Hyperglycemia and Hyperlipidemia.
Modafinil is non stimulant drug which is marketed for mainly Narcolepsy and daytime drowsiness. The clinical experience and Summary of Product Characteristics (SPC) of the drug also mentions Anorexia as one of the side effects. Anorexia can have a direct impact on the carbohydrate and fat intake, which may, in turn, regulate antipsychotic induced dyslipidemia and Hyperglycaemia. To compare the effects of Modafinil- ADDON with Placebo add on with olanzapine, Clozapine and Risperidone in drug naive subjects and people who were started on the drugs within 15days of assessment. Randomized, Double blind, Placebo controlled study, which was conducted at two centres, one at department of Psychiatry, S.V Medical College, Tirupati and the other at Asha hospitals, Hyderabad. Seventy two patient were randomised, sixty three patients have completed the total study period of three months. The dose of Modafinil was 200 mgs constantly as Flexible doses of Olanzapine, Clozapine and Risperidone as per clinical need was given. A baseline, three week and twelve week assessments of Fasting blood Glucose and fasting Serum cholesterol were made and the groups were compared on these parameters. From baseline to week 3 there was a significant raise in Fasting serum cholesterol followed by a fall from week 3 to week 12 in the Modafinil addon group, though it could not be considered a drug for hypercholesteremia like Statins in controlling hyperlipidaemia. The implications of these findings were discussed.


Optic nerve trauma with unilateral edema as a result of head injury.
We encountered a patient who suffered a head injury that translated to the optic nerves, leading to dramatic unilateral right optic nerve edema. The decedent was a 20-year-old unsecured passenger in a convertible. The car collided with a pickup truck. The patient survived for 8 h. At autopsy, a comminuted skull fracture involving the right frontal bone including the right orbital plate was found. The right optic nerve measured 1.2 cm in diameter, compared to only 0.4 cm for the left optic nerve. Microscopically, the right optic nerve was markedly edematous, but the nerve fibers and nuclei were viable and intact. The dramatic difference in size between the right and left optic nerves can be attributed to several mechanisms. The survival interval was essential for the asymmetrical swelling to take place. Optic nerve trauma is relatively rare in head injuries, reported to be present in 0.5% of automobile accidents and assaults. Other causes of optic nerve trauma and edema include tumors, osteopetrosis, or reaction to a peripheral hemodialysis shunt.