Evidence for epistasis between SLC6A4 and ITGB3 in autism etiology and in the determination of platelet serotonin levels.
Autism is a neurodevelopmental disorder of unclear etiology. The consistent finding of platelet hyperserotonemia in a proportion of patients and its heritability within affected families suggest that genes involved in the serotonin system play a role in this disorder. The role in autism etiology of seven candidate genes in the serotonin metabolic and neurotransmission pathways and mapping to autism linkage regions (SLC6A4, HTR1A, HTR1D, HTR2A, HTR5A, TPH1 and ITGB3) was analyzed in a sample of 186 nuclear families. The impact of interactions among these genes in autism was assessed using the multifactor-dimensionality reduction (MDR) method in 186 patients and 181 controls. We further evaluated whether the effect of specific gene variants or gene interactions associated with autism etiology might be mediated by their influence on serotonin levels, using the quantitative transmission disequilibrium test (QTDT) and the restricted partition method (RPM), in a sample of 109 autistic children. We report a significant main effect of the HTR5A gene in autism (P = 0.0088), and a significant three-locus model comprising a synergistic interaction between the ITGB3 and SLC6A4 genes with an additive effect of HTR5A (P < 0.0010). In addition to the previously reported contribution of SLC6A4, we found significant associations of ITGB3 haplotypes with serotonin level distribution (P = 0.0163). The most significant models contributing to serotonin distribution were found for interactions between TPH1 rs4537731 and SLC6A4 haplotypes (P = 0.002) and between HTR1D rs6300 and SLC6A4 haplotypes (P = 0.013). In addition to the significant independent effects, evidence for interaction between SLC6A4 and ITGB3 markers was also found. The overall results implicate SLC6A4 and ITGB3 gene interactions in autism etiology and in serotonin level determination, providing evidence for a common underlying genetic mechanism and a molecular explanation for the association of platelet hyperserotonemia with autism.


Remnant left lobe torsion causing hepatic venous outflow obstruction after hepatic right lobectomy for giant hepatocellular carcinoma: report of a case.
We report the case of a 67-year-old man with remnant left liver torsion causing acute hepatic venous outflow obstruction after right hepatectomy for giant hepatocellular carcinoma, which was successfully treated with surgery. After the primary surgery, he developed significant liver dysfunction and renal failure. Doppler ultrasonography disclosed gradual reduction of hepatic perfusion. Abdominal computed tomography revealed that the swollen remnant liver was dislocated in the right subphrenic space. After surgical repositioning of the left lobe into its anatomical position, the hepatic congestion immediately disappeared, and the hemodynamic parameters improved. The falciform and round ligaments were fixed to the anterior abdominal wall to keep the remnant liver in the anatomical position. His postoperative course was uneventful. Doppler ultrasonography was useful to assess hepatic perfusion for screening of acute hepatic venous outflow obstruction and abdominal computed tomography is definitive for diagnosis. Fixation of remnant liver may be effective for preventing hepatic venous outflow obstruction after right hepatectomy, particularly for giant tumor.


Deletion of sigB Causes Increased Sensitivity to para-Aminosalicylic Acid and Sulfamethoxazole in Mycobacterium tuberculosis.
Although the de novo folate biosynthesis pathway has been well studied in bacteria, little is known about its regulation. In the present study, the sigB gene in Mycobacterium tuberculosis was deleted. Subsequent drug susceptibility tests revealed that the M. tuberculosis ΔsigB strain was more sensitive to para-aminosalicylic acid (PAS) and sulfamethoxazole. Comparative transcriptional analysis was performed, and downregulation of pabB was observed in the ΔsigB strain, which was further verified by a quantitative reverse transcription-PCR and Western blot assay. Then, the production levels of para-aminobenzoic acid (pABA) were compared between the sigB deletion mutant and wild-type strain, and the results showed that sigB deletion resulted in decreased production of pABA. In addition, SigB was able to recognize the promoter of pabB in vitro Furthermore, we found that deleting pabC also caused increased susceptibility to PAS. Taken together, our data revealed that, in M. tuberculosis, sigB affects susceptibility to antifolates through multiple ways, primarily by regulating the expression of pabB To our knowledge, this is the first report showing that SigB modulates pABA biosynthesis and thus affecting susceptibility to antifolates, which broadens our understanding of the regulation of bacterial folate metabolism and mechanisms of susceptibility to antifolates.


Novel behavior of heat of micellization of pluronics F68 and F88 in aqueous solutions.
It is well understood that the heat of micellization for surfactants is monotonically decreased along with an increase in temperature. However, this behavior for polymeric surfactants has never been carefully examined. In this study, the heat of micellization of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) (PEO-PPO-PEO) triblock copolymers (Pluronics F68 and F88) in water as a function of temperature is carefully examined by using a high-sensitivity differential scanning calorimeter (HSDSC). The critical micelle temperature (CMT) decreases along with an increase in the concentration of Pluronic F68 (or F88). The heat of micellization decreases along with an increase in the temperature, as expected, when the CMT is higher than 55 and 42 degrees C for Pluronics F68 and F88, respectively. It is interesting to observe that the heat of micellization increases along with the temperature while the temperature is below 55 and 42 degrees C for Pluronics F68 and F88, respectively. The enthalpy-entropy compensation phenomenon for the micellization of Pluronics F68 and F88 in connection with the hydrophobicity is discussed.


Expression of the c-myc oncogene under control of an immunoglobulin enhancer in E mu-myc transgenic mice.
Transgenic mice bearing a cellular myc oncogene coupled to the immunoglobulin heavy-chain enhancer (E mu) exhibit perturbed B-lymphocyte development and succumb to B lymphoid tumors. To investigate how the enhancer has affected myc expression, we analyzed the structure and abundance of myc transcripts in tissues of prelymphomatous mice and in the lymphomas. Expression of the E mu-myc transgene appeared to be confined largely to B lymphoid cells, being dominant in bone marrow, spleen, and lymph nodes, with no detectable expression in T cells or other hematopoietic lineages examined. The myc transcripts initiated very predominantly at the normal myc promoters, although use of the more upstream myc promoter was accentuated and an enhancer-associated promoter may be used infrequently. The level of E mu-myc transcripts in the preneoplastic lymphoid tissues and in the E mu-myc tumors was not markedly higher than myc RNA levels in proliferating normal lymphocytes. Thus, enforced expression of structurally normal myc transcripts at only a modestly elevated level has profound biological consequences. The absence of detectable endogenous c-myc RNA in any tumor, or in preneoplastic bone marrow, supports a negative feedback model for normal c-myc regulation.


Diagnosis of gastric cancer using near-infrared Raman spectroscopy and classification and regression tree techniques.
The purpose of this study is to apply near-infrared (NIR) Raman spectroscopy and classification and regression tree (CART) techniques for identifying molecular changes of tissue associated with cancer transformation. A rapid-acquisition NIR Raman system is utilized for tissue Raman spectroscopic measurements at 785-nm excitation. 73 gastric tissue samples (55 normal, 18 cancer) from 53 patients are measured. The CART technique is introduced to develop effective diagnostic algorithms for classification of Raman spectra of different gastric tissues. 80% of the Raman dataset are randomly selected for spectral learning, while 20% of the dataset are reserved for validation. High-quality Raman spectra in the range of 800 to 1800 cm(-1) are acquired from gastric tissue within 5 s. The diagnostic sensitivity and specificity of the learning dataset are 90.2 and 95.7%; and the predictive sensitivity and specificity of the independent validation dataset are 88.9 and 92.9%, respectively, for separating cancer from normal. The tissue Raman peaks at 875 and 1745 cm(-1) are found to be two of the most significant features to discriminate gastric cancer from normal tissue. NIR Raman spectroscopy in conjunction with the CART technique has the potential to provide an effective and accurate diagnostic means for cancer detection in the gastric system.


Immunotherapeutic Approaches for the Treatment of Glioblastoma Multiforme: Mechanism and Clinical Applications.
Glioma is one of the most aggressive types of primary brain tumor with a high-grade glioma known as glioblastoma multiforme (GBM). Patients diagnosed with GBM usually have an overall survival rate of less than 18 months after conventional therapy. This bleak prognosis underlines the need to consider new therapeutic interventions for GBM treatment to overcome current treatment limitations. By highlighting different immunotherapeutic approaches currently in preclinical and clinical trials, including immune checkpoint inhibitors, chimeric antigen receptors T cells, natural killer cells, vaccines, and combination therapy, this review aims to discuss the mechanisms, benefits, and limitations of immunotherapy in treating GBM patients.


[Studies of red cell deformability and lipid composition of red cell membrane in chronic arterial occlusive diseases].
Red cell deformability (RCD), by a filtration method, was studied on patients with chronic arterial occlusive diseases: Arteriosclerosis obliterans (ASO) and Buerger's disease (TAO). RCD decreased significantly in both ASO and TAO. Furthermore, RCD decreased in patients with gangrene and complications in other organs much more than in those without them in ASO. In ASO positive correlation was observed between RCD and serum HDL-cholesterol level, while negative correlation between RCD and serum lipid peroxide level. The deformability of the red cells resuspended in a standard plasma protein fraction was also studied to assess the influences of plasma factors on RCD. As the result decreased RCD was considered probably due to a change in red cells rather than plasma factors in ASO.


Prevalence of calcific aortic valve disease in the elderly and associated risk factors: a population-based study in a Mediterranean area.
To determine the prevalence of aortic valve sclerosis (ASC) and stenosis (AS) in the elderly in a Mediterranean area and to identify associated clinical factors. Population cross-sectional study in a random sample of 1068 people ≥65 years in a Mediterranean area. ASC was categorized as absent, mild-to-moderate, or moderate-to-severe depending on the severity of thickening and calcification. The relation between the severity of ASC and potential risk factors was assessed by multinomial logistic regression analysis. Some degree of thickening and/or calcification was present in 45.4%, of the sample, 73.5% in >85 years. AS prevalence was 3% for the total cohort and 7.4% in >85 years. Adjusting for gender it was found that age, smoking habit, hypertension, waist circumference, and ankle-brachial index <0.9 were associated with degrees of ASC. Except for waist circumference, there was a gradient between the magnitude of association and the severity of ASC. The OR for age was 1.56 (95% CI 1.39-1.76) for mild-to-moderate ASC and 2.03 (95% CI 1.72-2.4) for moderate-to-severe ASC, and for smoking habit 1.59 (95% CI 1.08-2.34) for mild-to-moderate ASC and 2.13 (95% CI 1.19-3.78) for moderate-to-severe ASC. Diabetes and renal impairment were associated with advanced but not with early stages of ASC. The prevalence of ASC and AS in people ≥65 years is similar to that reported in other regions. The gradient in the association of cardiovascular risk factors with the severity of ASC suggests that they may be causally implied in the pathogenesis of the disease.


Peculiar Structural Phase of a Single-Atom-Thick Layer of Antimony.
Using molecular beam epitaxy, a new structural phase of a single atom thick antimony layer has been synthesized on the W(110) surface. Scanning tunneling microscopy measurements reveal an atomically resolved structure with a perfectly flat surface and unusually large unit cell. The structure forms a well-ordered continuous film with a lateral size in the range of several millimeters, as revealed by low energy electron microscopy and diffraction experiments. The results of density functional theory calculations confirm the formation of a new phase of single-atom-thick antimony film without the buckling characteristic for the known phases of antimonene. The presented results demonstrate a substrate-tuned approach in the preparation of new structural phases of 2D materials.


An update on the use of immunoglobulin for the treatment of immunodeficiency disorders.
For patients with significant antibody deficiencies, immunoglobulin therapy is the mainstay of treatment as it significantly reduces both the frequency and severity of infections. The formulations and delivery methods of immunoglobulin have evolved over time, and continued improvements have allowed for increased access to this effective medication. This review is an update on the current status of immunoglobulin therapy in immunodeficiency disorders, and discusses the mechanisms, forms and dosing, and indications for immunoglobulin replacement.


Lymph distribution of different non-steroidal anti-inflammatory drugs assessed by microsurgical cannulation of the thoracic duct in rat.
The motility of lymphatic vessels is regulated by arachidonate metabolites and, therefore, can be altered by cyclo-oxygenase blockers such as non-steroidal anti-inflammatory drugs (NSAIDs). In order to investigate the lymphotropic properties of different NSAIDs, pharmacokinetics in plasma and lymph following intragastric administration of three model compounds, namely racemic ibuprofen, tenoxicam and nabumetone, were investigated in rats. Microsurgical cannulation of the thoracic duct allowed cumulative sampling of lymph fluid up to 48 hrs (n = 16). Pharmacokinetic parameters in plasma were determined in a control group (n = 12). Concentrations of R-, S-ibuprofen, tenoxicam, nabumetone and the metabolites OH-ibuprofen, COOH-ibuprofen and 6-methoxy-2-naphthyl-acetic acid (6MNA, metabolite of nabumetone) were monitored in lymph and plasma by HPLC. To quantify the lymphotropic properties of the investigated compounds, a "lymphatic clearance" was defined by dividing the amount recovered in lymph fluid by the corresponding area under the plasma concentration-time curve (AUCP). The "lymphatic clearance" substantially differed between the investigated compounds (mean +/- SD: R-ibuprofen 6.71 +/- 3.15 microliters/min, S-ibuprofen 3.24 +/- 1.20 microliters/min, tenoxicam 8.74 +/- 8.11 microliters/min, nabumetone 46.05 +/- 26.08 microliters/min and 6MNA 6.32 +/- 2.96 microliters/min). The overall recovery of the investigated compounds in lymph did not exceed 5% of the doses given. The known fact that lymphatic drainage is regulated by arachidonate metabolites might suggest that NSAIDs differing in their lymphotropic properties could result in different responses of lymphatic vessels to an inflammatory fluid load.


Current concepts in pediatric stroke.
Stroke is a relatively rare but rather significant cause of short- and long-term morbidity and mortality in children. It can be divided into three categories: arterial ischemic stroke (AIS), hemorrhagic stroke (HS) and cerebral sinovenous thrombosis (CSVT). This review focuses on AIS. The etiologies of pediatric AIS are diverse and different from those in adult stroke, chief among these being congenital heart disease, vasculopathies, hematological disorders and prothrombotic states. Additional factors might be related to the age group, ethnicity and geographic factors. Early recognition enables initiation of prompt therapy thereby reducing risk of further recurrence and complications.


Endless Forms: Within-Host Variation in the Structure of the West Nile Virus RNA Genome during Serial Passage in Bird Hosts.
RNA viruses are infamous for their high rates of mutation, which produce swarms of genetic variants within individual hosts. To date, analyses of intrahost genetic diversity have focused on the primary genome sequence. However, virus phenotypes are shaped not only by primary sequence but also by the secondary structures into which this sequence folds. Such structures enable viral replication, translation, and binding of small RNAs, yet within-host variation at the structural level has not been adequately explored. We characterized the structural diversity of the 5' untranslated region (UTR) of populations of West Nile virus (WNV) that had been subject to five serial passages in triplicate in each of three bird species. Viral genomes were sampled from host serum samples at each passage (n = 45 populations) and subjected to next-generation sequencing. For populations derived from passages 1, 3, and 5 (n = 9 populations), we predicted the impact of each mutation occurring at a frequency of ≥1% on the secondary structure of the 5' UTR. As expected, mutations in double-stranded (DS) regions of the 5' UTR stem structures caused structural changes of significantly greater magnitude than did mutations in single-stranded (SS) regions. Despite the greater impact of mutations in DS regions, mutations in DS and SS regions occurred at similar frequencies, with no evidence of enhanced selection against mutation in DS regions. In contrast, mutations in two regions that mediate genome cyclization and thereby regulate replication and translation, the 5' cyclization sequence and the UAR flanking stem (UFS), were suppressed in all three hosts.IMPORTANCE The enzymes that copy RNA genomes lack proofreading, and viruses that possess RNA genomes, such as West Nile virus, rapidly diversify into swarms of mutant lineages within a host. Intrahost variation of the primary genomic sequence of RNA viruses has been studied extensively because the extent of this variation shapes key virus phenotypes. However, RNA genomes also form complex secondary structures based on within-genome nucleotide complementarity, which are critical regulators of the cyclization of the virus genome that is necessary for efficient replication and translation. We sought to characterize variation in these secondary structures within populations of West Nile virus during serial passage in three bird species. Our study indicates that the intrahost population of West Nile virus is a diverse assortment of RNA secondary structures that should be considered in future analyses of intrahost viral diversity, but some regions that are critical for genome cyclization are conserved within hosts. Besides potential impacts on viral replication, structural diversity can influence the efficacy of small RNA antiviral therapies.


Mediation of conformationally controlled photodecarboxylations of chiral and cyclic aryl esters by substrate structure, temperature, pressure, and medium constraints.
An aryl alkanoate, 2,4,6-trimethylphenyl (S)-(+)-2-methylbutyrate, whose ester group has a chiral center alpha to the carbonyl carbon and in which photo-Fries rearrangements are blocked by methyl substituents, undergoes facile photodecarboxylation under a variety of conditions and with complete retention of configuration. In fact, the decarboxylation process has many of the attributes of a symmetry-allowed suprafacial [1,3]sigmatropic rearrangement. The process requires concerted extrusion of carbon dioxide in a spiro-lactonic transition state, which has been investigated using high level DFT and CIS calculations: thermally less stable s-cis conformers in the ground and excited singlet states play an important role in determining the competitive efficiency of the process. Conformational control has also been imposed by substrate structure, solvent interactions, temperature, and applying external pressure, as well as using constraining media such as cyclodextrins and polyethylene films. The results are correlated with steady-state and dynamic fluorescence measurements at various temperatures in order to investigate further degrees to which ground and excited singlet state conformations affect the different photoreactivity channels available to the aryl esters.


How French media have portrayed ADHD to the lay public and to social workers.
Two models of attention deficit hyperactivity disorder (ADHD) coexist: the biomedical and the psychosocial. We identified in nine French newspapers 159 articles giving facts and opinions about ADHD from 1995 to 2015. We classified them according to the model they mainly supported and on the basis of what argument. Two thirds (104/159) mainly supported the biomedical model. The others either defended the psychodynamic understanding of ADHD or voiced both models. Neurological dysfunctions and genetic risk factors were mentioned in support of the biomedical model in only 26 and eight articles, respectively. These biological arguments were less frequent in the most recent years. There were fewer articles mentioning medication other than asserting that medication must be combined with psychosocial interventions (14 versus 57 articles). Only 11/159 articles claimed that medication protects from school failure. These results were compared to those of our two previous studies. Thus, both French newspapers and the specialized press read by social workers mainly defended either the psychodynamic understanding of ADHD or a nuanced version of the biomedical model. In contrast, most French TV programmes described ADHD as an inherited neurological disease whose consequences on school failure can be counteracted by a very effective medication.


High dietary selenium and vitamin E supplementation ameliorates the impacts of heat load on oxidative status and acid-base balance in sheep.
The objective of this study was to determine the efficacy of supranutritional dietary selenium and vitamin E (Vit E) to ameliorate the effect of heat stress (HS) on oxidative status and acid-base balance in sheep. Thirty-two Merino × Poll Dorset ewes were acclimated to indoor individual pen feeding of a pelleted control diet (0.24 g Se and 10 IU of Vit E/kg DM) for 1 wk. Sheep were then moved to metabolism cages in climatic chambers and randomly allocated to a 2 × 2 × 2 factorial design with the respective factors being dietary Se (0.24 and 1.20 mg/kg DM as Sel-Plex; Alltech, Australia), Vit E (10 and 100 IU/kg DM), and temperature for 2 wk. After 1 wk of acclimation in metabolic cages, 1 climatic chamber continued on thermoneutral (TN) conditions (18°C to 21°C and 40% to 50% relative humidity [RH]), and the other one was set to HS conditions (28°C to 40°C and 30% to 40% RH) for 1 wk. The sheep were then returned to individual pens and fed the control diet for 1 wk before being returned to the same diet as in the first period but a reversed thermal treatment for a further 2 wk. Physiological parameters were recorded 3 times daily, and blood samples were collected on d 1 and 7 of thermal treatment. Average respiration rate and rectal temperature of sheep were increased (P < 0.001) during HS; however, combined supranutritional supplementation of Se and Vit E reversed the effects of HS. Sheep given the high Se and high Vit E diet had a lower respiration rate (191 vs. 232 breaths/min; P = 0.012) and rectal temperature (40.33°C vs. 40.58°C; P = 0.039) under peak HS (1700 h) compared with those fed the low Se and low Vit E diet. Plasma reactive oxygen metabolites concentrations were reduced (P = 0.048) by 20%, whereas biological antioxidant potential was increased (P = 0.17) by 10% in sheep fed the high Se and high Vit E diet compared with those fed the low Se and low Vit E diet. Blood pH was elevated (P = 0.007) and bicarbonate was reduced (P = 0.049) under HS, and again, these effects were ameliorated by the high Se and high Vit E diet. Both white blood cell glutathione peroxidase gene expression and red blood cell lysate glutathione peroxidase activity were increased in sheep fed the high Se and high Vit E diet. These data suggest that supranutritional dietary Se or Vit E can reduce some of the negative effects of HS. However, the synergism between the 2 antioxidants improves their potential to ameliorate the impacts of HS in sheep.


Appropriate exercise prescription in primary and secondary prevention of cardiovascular disease: why this skill remains to be improved among clinicians and healthcare professionals. A call for action from the EXPERT Network.
In Europe alone, on a yearly basis millions of people need an appropriate exercise prescription to prevent the occurrence or progression of cardiovascular disease (CVD). A general exercise recommendation can be provided to these individuals (at least 150 min of moderate-intensity endurance exercise, spread over 3-5 days/week, complemented by dynamic moderate-intensity resistance exercise 2 days/week). However, recent evidence shows that this one size does not fit all and that individual adjustments should be made according to the patient's underlying disease(s), risk profile and individual needs, to maximise clinical benefits of exercise. In this paper, we 1. argue that this general exercise prescription simply provided to all patients with CVD, or elevated risk for CVD, is insufficient for optimal CVD prevention, and 2. show that clinicians and healthcare professionals perform heterogeneously when asked to adjust exercise characteristics (e.g. intensity, volume and type) according to the patient's condition, hereby leading to suboptimal CVD risk factor control. Since exercise training is a class 1A intervention in the primary and secondary prevention of CVD, the awareness of the need to improve exercise prescription has to be raised among clinicians and healthcare professionals, if optimized prevention of CVD is ambitioned.


A fine tuning of metallaborane to bridged-boryl complex, [(Cp*Ru)2(μ-H)(μ-CO)(μ-Bcat)] (cat = 1,2-O2C6H4; Cp* = η5-C5Me5).
Room temperature photolysis of [(Cp*RuCO)2BH4(Bcat)], 3, generated from the reaction of arachno-[(Cp*RuCO)2B2H6], 1, with HBcat (cat = 1,2-O2C6H4), yielded a rare homodinuclear bridged-boryl complex, [(Cp*Ru)2(μ-H)(μ-CO)(μ-Bcat)], 4, confirmed by X-ray diffraction.


Laboratory pain reactivity and gender: relationship to school nurse visits and school absences.
Currently, there are no clear methods for identifying children vulnerable to frequent school absences. Our study examined relationships between gender and laboratory pain reactivity to the cold-pressor task (CPT), and parent-involved school absences and self-initiated school nurse visits in 57 children (36 female; ages 8-10 years). Using multiple regression analyses, CPT pain ratings, tolerance, and gender were analyzed in relation to nurse visits and absences collected prospectively across 2 years. We found that higher pain ratings and female gender predicted more absences; female gender also predicted increased nurse visits for acute complaints with documented physical findings. Our results suggest that laboratory pain reactivity is a potentially useful indicator of vulnerability to parent-involved functional impairment, as indexed by school absences, and that girls are more likely than boys to miss school and visit the nurse for acute illnesses. Limitations and pathways for further study are discussed.


Development and validation of a liquid chromatographic method for monitoring of process-related synthetic organic impurities of profenofos in technical products.
A simple and rapid reversed-phase high-performance liquid chromatographic method for the monitoring of process-related synthetic organic impurities of profenofos (PFS) is developed. Impurities are separated and determined on a reversed-phase Hypersil C(18) column using gradient elution of 50 mM ammonium formate buffer-acetonitrile as a mobile phase and detection at 230 nm at ambient temperature. The method is validated with respect to accuracy, precision, linearity, and limits of detection and quantitation. The method is found to be suitable not only for monitoring the reactions involved in the process development of PFS, but also quality assurance, as it can detect impurities at the level of 1.5 x 10(-8) g.


Foot orthoses.
This review article describes shoe inserts and provides information to assist physical therapists to identify patients who may benefit from foot orthoses. The article discusses goals for and types of shoe inserts, in addition to the materials and methods that can be used in fabricating appliances. Clinical considerations for the use of shoe inserts and application to specific patient populations are presented.


Physical activity can reduce the prevalence of gallstone disease among males: An observational study.
Several previous studies have reported that physical activity (PA) levels can independently affect the prevalence of gallstone disease (GD) in Western countries. However, this association has not been reported in Eastern countries. Therefore, this study aimed to determine whether PA is an independent determinant of GD prevalence in a Korean population, according to the World Health Organizations Global Recommendations on PA for Health.A total of 8908 subjects who completed a questionnaire underwent medical examination and ultrasound scanning at the Health Promotion Center of the Jeju National University Hospital between January 2009 and December 2018. GD and fatty liver disease were diagnosed by abdominal ultrasound. Biochemical parameters and body mass index were determined, and metabolic syndrome status, age, and PA levels were extracted from medical records. Univariate and multivariate analyses were performed to identify independent factors affecting GD.The estimated rates of PA and GD among male subjects were 23.7% and 4.6%, whereas the rates among females were 18.4% and 4.2%, respectively. Multivariate analysis suggested that no PA, old age, and higher aspartate aminotransferase level in males and nonalcoholic fatty liver disease status in females were independent factors affecting GD.In our study, PA was associated with a reduction in GD among males but not females.


[Volar transcaphocapitate perilunate disclocation of the carpus: a new variety, a new approach].
On the one hand, surgical treatment of dorsal perilunate fracture-dislocation is now well codified. The posterior approach is preferred by the majority of the authors. On the other hand, surgical schedule for volar perilunate dislocation is not well establish in the literature. The anterior approach is the most frequently recommended. In case of Fenton's syndrome (scaphocapitate fracture), the head of the capitatum is described with a rotation of 180 degrees. The authors reports a case of a volar transcaphocapitate perilunate fracture-dislocation of the carpus in a polytrauma. The head of the capitatum was in place onto the neck. By a posterior approach, a primary repair of all the elements has been performed including open reduction and internal fixation of the carpal scaphoid fracture in addition with a bone graft. The capitatum were fixed by wiring. At two years follow-up, the result were good. The patient did return at the same work. Clinically, there was a range of motion of 70 degrees in flexion-extension. Radiologically, all the fractures healed and there were no intracarpal desaxation. Volar perilunate fracture-dislocation of the carpus and Fenton's fracture (scaphocapitate fracture) are two exceptional entities in the literature. Association of both lesions has been found only twice in the literature. No similar case with a head of the capitatum in place has been already described.


Effect of pH, temperature and media on acid and alkaline phosphatase activity in "clinical" and "nonclinical" isolates of Bordetella bronchiseptica.
Twenty-two isolates of Bordetella bronchiseptica were studied to determine the effects of pH, incubation temperature and type of media on peak acid and alkaline phosphatase activity. The pH optimum for alkaline phosphatase activity was 9.0 for all of the isolates tested. The pH optimum for acid phosphatase activity was 5.8 for 67% of the isolates and 4.8 for 33%. All of the isolates showed peak phosphatase activity at 37 degrees C. No preference was shown in 35% of the isolates between the types of media tested; however, 40% preferred tryptose broth, 20% preferred nutrient broth and 5% preferred brain-heart infusion broth. No relationship was shown between phosphatase activity and the mouse lethality of the isolates.


Treatment-Induced Mutagenesis and Selective Pressures Sculpt Cancer Evolution.
Despite the great progress in our understanding of the molecular basis of human cancer, the heterogeneity of individual tumors and the evolutionary pressures imposed by therapy have hampered our ability to effectively eradicate and control this disease. How, therefore, do cancers evolve under the selective pressures of cancer therapy? Recent studies have linked both primary (or de novo) and acquired treatment resistance to intratumor heterogeneity and clonal evolution. Resistance to targeted therapies often includes mutation of the drug target itself and aberrations of pathways upstream of, downstream from, or parallel to the drug target. For systemic chemotherapies, discrete and recurrent resistance-conferring genetic aberrations have eluded the community, due in part to their wide-ranging mutagenic effects. In this review, we discuss different patterns of clonal evolution during treatment-specific selective pressures and focus on the genetic mechanisms of treatment resistance that have emerged to both targeted therapies and chemotherapies.


The impact of early RPE cell junction loss on VEGF, Ang-2, and TIMP secretion in vitro.
The retinal pigment epithelium (RPE) is an important tissue for maintaining a healthy retina. Retinal pigment epithelial cells help regulate nutrient transport to photoreceptors and are heavily pigmented to prevent light scattering. These cells also have junction proteins to form monolayers. Monolayers are key players in pathologies such as age-related macular degeneration (AMD), a leading cause of vision loss in older adults. During AMD, RPE cell detachment can occur, resulting in a loss of junctions. Losing junctions can increase the expression of pro-angiogenic vascular endothelial growth factor (VEGF). This overexpression can cause abnormal blood vessel growth or angiogenesis in the retina. Age-related macular degeneration treatments target VEGF to slow angiogenesis progression. However, other proteins, such as angiopoietin-2 (Ang-2) and the tissue inhibitor of metalloproteinase-1 (TIMP-1), may also play important roles, making them potential targets for treatment. Controlling RPE junction formation will help elucidate the relationship between RPE cell detachment and additional angiogenic factor secretion, lead to more therapeutics, and increase the efficacy of current treatments. Micropatterning was used to control the spatial arrangement of primary porcine RPE cells using polydimethylsiloxane (PDMS) stencils. Patterns were formed into PDMS stencils to mimic 10%, 25%, and 50% overall detachment of the RPE monolayer. Zonula-occludens-1 (ZO-1), Ang-2, and VEGF were visualized using immunocytochemical (ICC) staining. An enzyme-linked immunosorbent assay (ELISA) was used to quantify extracellular Ang-2, VEGF, TIMP-1, and TIMP-2 levels. A rod outer segment (OS) phagocytosis assay was performed to determine how RPE junction loss directly affects photoreceptor support. The growth of primary porcine RPE cells was successfully controlled using stencils. Morphological changes and a decrease in pigmentation were observed, showing a decline in barrier and light absorption functions as degeneration increased. One day after stencil removal, junction proteins were delocalized, and angiogenic factor secretions were correlated with increased levels of detachment. Secretion levels of Ang-2 and TIMP-1 were significantly increased, whereas VEGF and TIMP-2 concentrations were not as affected by varying levels of detachment. OS phagocytosis appeared lower in RPE cells when ZO-1 was affected. These results suggest a correlation between loss of junctions, abnormal angiogenic protein secretion, and reduced OS phagocytosis. Furthermore, Ang-2 and TIMP-1 proteins might be beneficial targets for AMD treatments, and their roles in retinal diseases deserve further investigation.


Systematic oral hydration with water is similar to parenteral hydration for prevention of contrast-induced nephropathy: an updated meta-analysis of randomised clinical data.
Contrast-induced nephropathy (CIN) is the third most common cause of hospital-acquired kidney injury and is related to increased long-term morbidity and mortality. Adequate intravenous (IV) hydration has been demonstrated to lessen its occurrence. Oral (PO) hydration with water is inexpensive and readily available but its role for CIN prevention is yet to be determined. PubMed, EMBASE and the Cochrane Central register of controlled trials (CENTRAL) databases were searched until April 2015 and studies were selected using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. All randomised clinical trials with head-to-head comparison between PO and IV hydration were included. A total of 5 studies with 477 patients were included in the analysis, 255 of those receiving PO water. The incidence of CIN was statistically similar in the IV and PO arms (7.7% and 8.2%, respectively; relative risk 0.97; 95% CI 0.36 to 2.94; p=0.95). The incidence of CIN was statistically similar in the IV and PO arms in patients with chronic kidney disease and with normal renal function. Rise in creatinine at 48-72 h was lower in the PO hydration group compared with IV hydration (pooled standard mean difference 0.04; 95% CI 0.03 to 0.06; p<0.001; I(2)=62%). Our meta-analysis shows that systematic PO hydration with water is at least as effective as IV hydration with saline to prevent CIN. PO hydration is cheaper and more easily administered than IV hydration, thus making it more attractive and just as effective.


Strategies for ascertaining the interference of phase II metabolites co-eluting with parent compounds using LC-MS/MS.
LC-MS/MS is currently the most selective and efficient tool for the quantitative analysis of drugs and metabolites in the pharmaceutical industry and in clinical assays. However, phase II metabolites sometimes negatively affect the selectivity and efficiency of the LC-MS/MS method, especially for the metabolites that possess similar physicochemical characteristics and generate the same precursor ions as their parent compounds due to the in-source collision-induced dissociation during the ionization process. This paper proposes some strategies for examining co-eluting metabolites existing in real samples, and further assuring whether these metabolites could affect the selectivity and accuracy of the analytical methods. Strategies using precursor-ion scans and product-ion scans were applied in this study. An example drug, namely, caffeic acid phenethyl ester, which can generate many endogenous phase II metabolites, was selected to conduct this work. These metabolites, generated during the in vivo metabolic processes, can be in-source-dissociated to the precursor ions of their parent compounds. If these metabolites are not separated from their parent compounds, the quantification of the target analytes (parent compounds) would be influenced. Some metabolites were eluted closely to caffeic acid phenethyl ester on LC columns, although long columns and relatively long elution programs were used. The strategies can be utilized in quantitative methodologies that apply LC-MS/MS to assure the performance of selectivity, thus enhancing the reliability of the experimental data.


Autonomous replicating sequences from intron of human ras gene in a simian virus 40 T antigen dependent system.
Of the several DNA fragments present in the human lung cancer gene, 1.1 and 2.0 kilobase (kb) fragments corresponding to the intron of this gene were hybridized to a half part of the 27 nucleotides perfect palindrome present in the initiation part of replication in simian virus 40 (SV40) DNA. These two fragments cloned in pBR322 had good template activity, and the initiation of DNA replication started from the region of these fragments in an in vitro system, in which the initiation of DNA replication occurs on cloned DNA containing SV40 origin of DNA replication as described previously. Furthermore, these two clones could replicate autonomously in nuclei of SV40 transformed Cos cells, producing SV40 T antigen constitutively when the clones were transfected into Cos cells. These results show that functional SV40 origin-like sequences are present in human genomes, and they can replicate autonomously within the cells which are producing SV40 T antigen.


Circles reshaping the RNA world: from waste to treasure.
A new type of RNAs was identified from genes traditionally thought to express messenger or linear ncRNA (noncoding RNA) only. They were subsequently named as circRNAs (circular RNAs) due to the covalently closed structure. Accumulating studies were performed to explore the expression profile of circRNAs in different cell types and diseases, the outcomes totally changed our view of ncRNAs, which was thought to be junk by-products in the process of gene transcription, and enriched our poor understanding of its underlying functions. The expression profile of circRNAs is tissue-specific and alters across various stages of cell differentiation. The biological function of circRNAs is multi-faceted, involving five main features (sponge effect, post-transcriptional regulation, rolling circle translation, circRNA-derived pseudogenes and splicing interference) and varying differently from the locations, binding sites and acting modes of circRNAs. The regulating role of circRNAs is not isolated but through an enormous complicated network involving mRNAs, miRNAs and proteins. Although most of the potential functions still remain unclear, circRNAs have been proved to be ubiquitous and critical in regulating cellular processes and diseases, especially in cancers, from the laboratory to the clinic. Herein, we review circRNAs' classification, biogenesis and metabolism, their well-studied and anticipated functions, the current understanding of the potential implications of circRNAs in tumorigenesis and cancer targeted therapy.


The patient experience.
The impact of improved treatments for the management of hormone-sensitive breast cancer extends beyond clinical responses. Thanks to appropriate literature and access to the internet, patient awareness of treatment options has grown and patients are now, in many cases, able to engage their oncologists in informed conversations regarding treatment and what to expect in terms of efficacy and safety. Indeed, patients realize that although there is no cure for metastatic disease, treatment can greatly reduce the risk of progression and in the adjuvant setting, where treatment is administered with a curative intent, current treatment options reduce the risk of relapse. The approval of letrozole throughout the breast cancer continuum has provided patients with many reassuring options. The improvement in outcome with letrozole is achieved without a detrimental effect on overall quality of life. Adverse events such as hot flushes, arthralgia, vaginal dryness, and potential osteoporosis are most significant from the patient's perspective, and it is important that caregivers pay attention to patients experiencing these events, as they can impact compliance unless effectively explained and managed. The major benefits of letrozole are to improve prospects for long-term survivorship in the adjuvant setting and to delay progression and the need for chemotherapy in the metastatic setting.


Demand and Signing of General Practitioner Contract Service among the Urban Elderly: A Population-Based Analysis in Zhejiang Province, China.
This study aims to examine whether the urban elderly in the Zhejiang Province of China signed contracts with their general practitioner (GP) based on their health service needs, and to further identify the determinants of their demand and signing decisions. A community-based cross-sectional study was conducted in 16 community health service (CHS) institutions in Zhejiang Province, China. The urban elderly over 60 years of age were enrolled when visiting the sampled CHS. Baseline characteristics were compared between participants using Chi-Square tests for categorical variables. Univariate and multivariable logistic regression analyses were used to identify determinants of the GP contract service demand and signing decisions, respectively. Among the 1440 urban elderly, 56.67% had signed contracts with their GP, and 55.35% had a demand of the GP contract service. The influencing factors of demand were a history of diabetes or cardiovascular disease (OR = 1.33, 95% CI, 1.05-1.68); urban resident basic medical insurance (URBMI) vs. urban employee basic medical insurance (UEBMI) (OR = 1.96, 95% CI, 1.46-2.61); and middle-income vs. low-income (OR = 0.67, 95% CI, 0.50-0.90 for RMB 1001-3000; OR = 0.59, 95% CI, 0.39-0.90 for RMB 3001-5000). Having a demand for the GP contract service was the strongest determinant of signing decisions (OR = 13.20, 95% CI, 10.09-17.27). Other factors also contributed to these decisions, including gender, caregiver, and income. The urban elderly who had signed contracts with GPs were mainly based on their health care needs. Elderly people with a history of diabetes or cardiovascular disease, as well as those with URBMI, were found to have stronger needs of a GP contract service. It is believed that the high-income elderly should be given equal priority to those of low-income.


Changes in intracellular Ca2+ concentration produced by the alteration of intracellular pH in rat parotid acinar cells.
The effects of intracellular pH (pH(i)) on intracellular Ca2+ concentration ([Ca2+]i) vary in different cells, and mechanisms underlying these effects are still not clear. In the experiments reported here, the effects of changes in pH(i) produced by ammonium chloride and butyric acid were studied in enzymatically dispersed acinar cells of rat parotid glands. The changes in pH(i) and [Ca2+]i were estimated using the fluorescent dyes biscarboxyethyl-5,6-carboxyfluorescein (BCECF) and fura-2, respectively. pH(i) was altered using NH4Cl, butyric acid, or propionic acid while keeping the external pH constant at 7.4. NH4Cl (20 mM) applied for 4-5 min increased pH(i) from 7.18 to 7.79 (a decrease of proton concentration, [H+]i, from 66 to 16 nM) and produced a transient [Ca2+]i increase followed by a small sustained decrease. On the other hand, butyric acid (20 mM) decreased pH(i) from 7.16 to 6.81 (an increase of [H+]i from 69 to 155 nM) and produced a small sustained increase in [Ca2+]i. Washing out the butyric acid 4 min after application induced the recovery of pH(i) from 6.93 to 7.43 (a decrease of [H+]i from 118 to 37 nM) and a further transient increase in [Ca2+]i. The removal of external Ca2+ had little effect on changes in pH(i) produced by NH4Cl or butyric acid, but markedly reduced both the sustained and transient components of [Ca2+]i response. Cyclopiazonic acid (0.3 microM), an inhibitor of Ca2+ pump in intracellular stores, abolished the transient [Ca2+]i increase produced by the application of NH4Cl or withdrawal of butyric acid. These results suggest that a decrease in [H+]i, not the absolute level of [H+]i may release Ca2+ from intracellular stores.


[Toxic shock-like syndrome caused by streptococci--treated with clindamycin].
The number of invasive group A streptococcal infections have been increasing in the last years. Toxic Shock-like Syndrome due to infections with streptococci (TSLS) is a serious condition still associated with a mortality rate of 30% despite proper treatment. Early diagnosis is difficult and early treatment is important. A typical case of TSLS in a previously healthy 33 year-old woman treated with clindamycin is reported. Penicillin is still the drug of choice for most Group A streptococcal infections, but in fulminant infections failure has been described. Clindamycin is a good choice in complicated infections.


Vertical-cavity semiconductor devices for fluorescence spectroscopy in biochips and microfluidic platforms.
This paper describes the properties of vertical-cavity semiconductor devices designed to emit light when driven in forward bias mode and detect optical radiation at wavelengths longer than that of emission when driven in reverse bias mode. The study of this type of devices is motivated by the miniaturization and integration into a single unit of the three functions that a microfluorimeter has to perform, optical pumping, optical detection, and optical filtering of weak light sources. The devices produced can generate fluorescence with a low output power since their emission wavelength can be tuned with that of maximum absorption of the fluorescent dye. We demonstrate also that they can detect low power fluorescence generated in a small volume of concentrated solution of a commercial dye. These devices can find useful application in microanalytical systems such as microfluidic devices or optical biochips.


An Innovative Anchoring Technique for Anterior Transfer of the Tibialis Posterior Tendon.
Favorable results have been reported for tibialis posterior tendon transfers, which can effectively restore the dorsiflexion of the ankle and normal heel-to-toe gait. However, the commonly used methods for anchoring the transplanted tendon have some drawbacks. Therefore, we developed a new tendon-anchoring method to improve fixation of the transferred tendon and reduce the related complications. The new method entails tying the anchoring suture to the navicular bone instead of the button on the plantar foot to avoid wound complications. It requires no additional skin incisions or special equipment. We retrospectively evaluated 24 feet of 19 pediatric patients (13 [68.4%] females and 6 [31.6%] males) who had undergone anterior transfer of the tibialis posterior tendon with our new method from 2000 to 2013. All patients were clinically followed up. At the final follow-up visit, they were evaluated while standing and walking, and the range of motion of the foot was evaluated. The mean age at surgery was 7.8 (range 2 to 16) years. At the longest follow-up point, all the patients exhibited improved gait, except for 1 patient who required a secondary procedure. All the transferred tibialis posterior tendons could be palpated with certainty during active dorsiflexion or withdrawal of the foot. No tendon displacements, wound infections, or postoperative complications were observed. Fixation of a transferred tibialis posterior tendon by tying the suture to the navicular bone is simple and reliable. This technique can efficiently prevent the plantar ulcers that can develop with the traditional pull-out button method and provides a solution when appropriate-size bioabsorbable interference screws are unavailable.


Expression of steroid and xenobiotic receptor in uterine carcinosarcoma, leiomyosarcoma and endometrial stromal sarcoma.
We analyzed the expression of the steroid and xenobiotic receptor (SXR) in human uterine sarcomas and evaluated its clinical significance. Forty-seven cases with archival specimens were examined for SXR expression using immunohistochemistry. All cases were scored using a semi-quantitative histological scoring (HSCORE) method. Specimens with a HSCORE >40 were regarded as SXR-positive. Various clinicopathological variables, including the expression status of estrogen receptor (ER)-α, progesterone receptor (PR) and Ki67 (MIB-1) were examined. The mean SXR HSCOREs of carcinosarcoma (CS) and leiomyosarcoma (LMS) were 9.13 and 23.6, respectively, and SXR-positive rates were 3 out of 24 (12.5%) and 4 out of 17 (23.5%), respectively. SXR was not detected in endometrial stromal sarcoma (ESS). In CS cases, significant differences were detected between the expression of SXR and age and disease stages. There was no significant correlation between SXR-positive status and either disease-free survival or overall survival. Our results support an association between SXR and malignant behavior. Our results show that overexpression of SXR may represent a useful marker to identify patients with advanced-stage CS. In addition, our results showed that SXR may aid in the diagnosis of uterine sarcomas.


Unrecognized laceration of main bronchus caused by fracture of the T6 vertebra.
We report on an extremely rare case of a 58-year-old male polytraumatized patient who sustained a bursting fracture of the T6 vertebral body associated with laceration of the posterior wall of the right main bronchus from the spiculae of the vertebral body fragments. The patient was on admission asymptomatic until he underwent an endotracheal anesthesia for stabilization of associated fractures of the extremities, when he developed acute respiratory disturbances. The opening of the bronchus was repaired via a thoracotomy, while the spine was successfully supported with a custom-made brace for 3 months. In the 3-year follow-up evaluation, the patient did well and suffered no complaints of the spine or lungs. Spine surgeons should be aware of this rare complication, which may accompany bursting fractures in the midthoracic spine. Laceration of the bronchus should be suspected when fragments of the vertebral body are dislocated far anteriorly.


Identification of 13- and 14-coordinated structures of first hydrated shell of [AuCl4](-) acid aqueous solution by combination of MD and XANES.
Molecular dynamics simulations combined with multiple scatting X-ray absorption spectral calculations have been employed to study the local geometry of an [AuCl4](-) cluster in acid aqueous solution. It is found that the previously assumed simple octahedral structure with two H atoms located in the axial position of the [AuCl4](-) plane fails to correctly reproduce the experimental X-ray absorption spectra. Molecular dynamics simulations have revealed a very complicated first hydrated water shell that mainly consists of 13 or 14 ligand water molecules. In general, the first hydrated water molecules are located in two orthogonal quasi-elliptic surfaces around [AuCl4](-) cluster. The water molecules' configuration in the first hydrated shell is further confirmed by the X-ray absorption spectral analysis, which gives a good agreement with the experiment when the 13-hydrated and 14-hydrated complexes are evenly mixed. It shows the power of the combined molecular dynamics simulations and spectra calculations in determining the local structure of molecular ligands around the metal center.


Consecutive en-bloc liver (30%)-pancreas-duodenum-spleen-stomach transplant in Lewis rats.
It is well-known that 30% of the remaining liver mass, following partial hepatectomy, regenerates to full original mass within 2 weeks in rats. In order to carry the transplanted rat liver to repeated transplantation, a technique of combining 30% of the liver with the pancreaticoduodenum and spleen transplantation is performed in this consecutive organ transplantation study. Our laboratory observed several 37-month-old transplanted rats by carrying through 2-3 generations, and histological disclosure were made. Because the partial liver transplants did not regenerate after the transplantation with other splanchnic organs, this technique is not so difficult though subsequent surgical maneuvers are needed and the liver histology proved entirely normal in every aspect when followed beyond the rat's life span of 24 months.


Ultrasonography-guided endovascular management of femoral artery pseudoaneurysm after unintended dialysis catheterization with suture-mediated vascular closure devices.
Although iatrogenic pseudoaneurysm is an infrequent complication, it can be life threatening if ruptured. There are several treatment methods for managing this complication. This case report demonstrates a technique using ultrasonography-guided suture-mediated vascular closure devices without angiography to successfully treat iatrogenic superficial femoral pseudoaneurysm following an unintended hemodialysis catheter insertion. In particular, when it is difficult to use a contrast due to a patient's condition as in this case, suture-mediated vascular closure device with ultrasonography guidance can be used as a therapeutic method.


[Subcutaneous rupture of hydatid cyst of liver: dealing with a rare observation].
Hydatid cyst of liver is a parasitosis of endemic proportions in Tunisia. The purpose of this report is to describe a case involving subcutaneous rupture of a hydatid cyst of liver in a 41-year-old patient. Diagnosis was established by ultrasonography and CT-scan. The patient underwent surgical treatment and recovered uneventfully. Subcutaneous rupture remains an uncommon complication. This is only the second case reported in the literature up to now.


New evidence on the structure of potassium salts of 12-tungstophosphoric acid, KxH3-xPW12O40.
Physicochemical properties and compositions of KxH(3-x)PW12O40 salts, where 2 < or = x < or = 3, have been investigated. It has been found that freshly prepared K2HPW12O40 salt (drying at 313 K) contains particles of heteropolyacid and particles of the neutral potassium salt, the sample being in 78.6% amorphous. On aging at room temperature, the heteropolyacid spreads to form a surface layer covering the neutral potassium salt particles K3PW12O40. Heat treatment of KxH(3-x)PW12O40 salts, where 2 < or = x < 3, from 313 K to higher temperatures induces the transformation of the heteropolyacid-covering K(3) core into a well-dispersed, amorphous surface layer. On further heating of the acidic potassium salts, the surface layer decomposes between 855 and 915 K with the formation of a PW8O26-type bronze as a new phase, the K3PW12O40 salt remaining unchanged. The latter starts to decompose at 1093 K, and in the case of all samples, the process is completed at about 1183 K. Rietveld structure refinement, XPS, and 31P NMR measurements of acidic potassium salts indicate that the core of these salts is always formed by the K3PW12O40 salt, which is covered by a heteropolyacid. Comparison of lattice parameters of the K3 salt and HPW leads to the conclusion that the layer is composed of partially or completely dehydrated heteropolyacid molecules. The coverage of the core by HPW in the K2 sample was estimated to be equal to one monolayer.


3-D electrode designs for flow-through dielectrophoretic systems.
Traditional methods of dielectrophoretic separation using planar microelectrodes have a common problem: the dielectrophoretic force, which is proportional to nabla|E|2, rapidly decays as the distance from the electrodes increases. Recent advances in carbon microelectromechanical systems have allowed researchers to create carbon 3-D structures with relative ease. These developments have opened up new possibilities in the fabrication of complex 3-D shapes. In this paper, the use of 3-D electrode designs for high-throughput dielectrophoretic separation/concentration/filtration systems is investigated. 3-D electrode designs are beneficial because (i) they provide a method of extending the electric field within the fluid. (ii) The 3-D electrodes can be designed so that the velocity field coincides with the electric field distribution. (iii) Novel electrode designs, not based on planar electrodes designs, can be developed and used. The electric field distribution and velocity fields of 3-D electrode designs that are simple extensions of 2-D designs are presented, and two novel electrode designs that are not based on 2-D electrode designs are introduced. Finally, a proof-of-concept experimental device for extraction of nanofibrous carbon from canola oil is demonstrated.


The commonly used eye-specific sev-GAL4 and GMR-GAL4 drivers in Drosophila melanogaster are expressed in tissues other than eyes also.
The binary GAL4-UAS system of conditional gene expression is widely used by Drosophila geneticists to target expression of the desired transgene in tissue of interest. In many studies, a preferred target tissue is the Drosophila eye, for which the sev-GAL4 and GMR-GAL4 drivers are most widely used since they are believed to be expressed exclusively in the developing eye cells. However, several reports have noted lethality following expression of certain transgenes under these GAL4 drivers notwithstanding the fact that eye is not essential for survival of the fly. Therefore, to explore the possibility that these drivers may also be active in tissues other than eye, we examined the expression of UAS-GFP reporter driven by the sev-GAL4 or GMR-GAL4 drivers. We found that both these drivers are indeed expressed in additional tissues, including a common set of specific neuronal cells in larval and pupal ventral and cerebral ganglia. Neither sev nor glass gene has so far been reported to be expressed in these neuronal cells. Expression pattern of sev-GAL4 driver parallels that of the endogenous Sevenless protein. In addition to cells in which sev-GAL4 is expressed, the GMR-GAL4 is expressed in several other larval cell types also. Further, two different GMR-GAL4 lines also show some specific differences in their expression domains outside the eye discs. These findings emphasize the need for a careful confirmation of the expression domains of a GAL4 driver being used in a given study, rather than relying only on the empirically claimed expression domains.


MicroRNA-608 acts as a prognostic marker and inhibits the cell proliferation in hepatocellular carcinoma by macrophage migration inhibitory factor.
Human hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in the world. Research on HCC has recently focused on microRNAs (miRNAs) that play crucial roles in cancer development and progression of HCC. In this study, we aimed to analyze the expression and function of a metastasis-associated microRNA-608 (miR-608) in HCC. Samples of human HCC and matched adjacent normal tissues were surgically removed, and miR-608 expression and the pathological characteristics of HCC were investigated. In this study, we found that miR-608 expression was significantly reduced in HCC and its expression levels were highly associated with tumor size, differentiation, clinical stage, and overall and disease-free survival of HCC. Overexpression of miR-608 in HCC cell lines HepG2 and SK-Hep-1 inhibited cell proliferation by G1 arrest. Macrophage migration inhibitory factor (MIF), a potential target gene of miR-608, was inversely correlated with miR-608 expression in HCC tissues and cell lines. Furthermore, we demonstrated that MIF was directly regulated by miR-608 and the restoration of MIF expression reversed the inhibitory effects of miR-608 on HCC cell proliferation. Taken together, these findings collectively demonstrate that miR-608 exerts its anti-cancer function by directly targeting MIF in HCC, indicating a potential novel prognostic biomarker and therapeutic target for HCC.


Is routine neck dissection warranted at salvage laryngectomy?
There is controversy regarding management of the neck at salvage laryngectomy. The aim of this study was to perform an analysis to determine the incidence of occult node positivity in this group and analyse factors affecting it. A retrospective analysis of 171 patients who underwent salvage total laryngectomy between 2000 and 2015 for recurrent or residual disease following definitive non-surgical treatment and were clinico-radiologically node negative at the time salvage laryngectomy was carried out. A total of 171 patients with laryngeal or hypopharyngeal cancers underwent concurrent neck dissection at laryngectomy. There were 162 patients (94.7 per cent) who underwent bilateral neck dissection, and 9 patients (5.3 per cent) who underwent ipsilateral neck dissection. The occult lateral nodal metastasis rate was 10.5 per cent. Of various factors, initial node positive disease was the only factor predicting occult metastasis on univariable and multivariable analysis (p = 0.001). Risk of occult metastasis is high in patients who have node positive disease before starting radiotherapy. This group should be offered elective neck dissection.


[Cinema-based interventions implemented at the Day Hospital of Sapienza University of Rome - Policlinico Umberto I Hospital: group therapy, projective evaluation, psychoeducation and treatment]
Cinema has been extensively used in psychiatric care. In the present article the cinema-based interventions implemented at the Day Hospital of Sapienza University of Rome - Policlinico Umberto I Hospital with various modalities and aims (e.g. rehabilitation, group therapies, projective evaluations, psychoeducation) will be discussed.


Altered auditory processing in acutely psychotic never-medicated first-episode patients.
Individuals with psychosis fail to differentiate external impulses and suffer from distortions of reality testing. Schizophrenia group illnesses are also associated with deficits in working memory and perception. We examined the manifestations of a very early phase of psychotic illness to automatic auditory deviance detection to clarify the basic mechanisms underlying misinterpretations of perception. Twenty-five never-medicated patients admitted for hospital evaluation of acute psychosis were studied. Fifty-eight EEG channels were recorded during an auditory oddball paradigm. Event-related potentials (ERPs) time-locked to non-attended deviant auditory stimuli were studied in patients and compared with healthy controls. Auditory processing was examined both at the level of the measured biosignals (standard and deviant responses) and with subtraction waveforms. Topographical differences were characterized using global field power (GFP) and minimum norm estimates. The maximum GFP amplitudes and mean amplitudes of the 58 channels within the time windows corresponding to the previously known 'N2b', 'P3a' and 'P3b' components were clearly reduced in patients when compared to healthy controls. However, the groups did not differ during attention-independent automatic processing corresponding to the 'N1' and 'MMN' components, or with respect to the peak latencies of the GFP maxima. Impairment of the processing of a deviance in simple auditory input in acutely ill drug-naive first-episode psychotic patients only appears in attention-dependent processing after about 250 ms. The alterations in auditory processing differed between stimulus types, suggesting at least two mechanisms underlying the auditory discrimination impairments in acute psychosis. After 250 ms there was a linear and gradually increasing difference in magnitude between the groups in their responses to deviant stimuli, probably related to arousal. In addition, however, there was a striking difference between the groups in the processing of standard stimuli. The early processing was similar in patients and controls, but the striking difference appeared in later processing. The sensory memory deficits associated with psychosis may be explained by an abnormality in sensory model formation rather than by impaired deviant detection.


Fabrication of functional bioinorganic nanoconstructs by polymer-silica wrapping of individual myoglobin molecules.
Discrete core-shell hybrid nanoparticles comprising individual met-myoglobin (met-Mb) molecules incarcerated within an ultrathin polymer/silica shell were prepared without loss of biofunctionality by a facile self-assembly procedure. Solubilisation of met-Mb in cyclohexane in the near-absence of water was achieved by wrapping individual protein molecules in the amphiphilic triblock copolymer poly(ethylene-oxide)19-poly(propylene-oxide)69-poly(ethylene-oxide)19 (EO19-PO69-EO19, P123). Addition of tetramethoxysilane to the met-Mb/P123 conjugates in cyclohexane produced discrete nanoparticles that contained protein, polymer and silica, and which were 3-5.5 nm in size, consistent with the entrapment of single molecules of met-Mb. The hybrid nanoconstructs were isolated and re-dispersed in water without loss of secondary structure, and remained functionally active with respect to redox reactions and CO and O2 ligand binding at the porphyrin metallocentre. The incarcerated met-Mb biomolecules showed enhanced thermal stability up to a temperature of around 85 °C. These properties, along with the high biocompatibility of silica and P123, suggest that the silicified protein-polymer constructs could be utilised as functional nanoscale components in bionanotechnology.


Selective isolation and analysis of glycoprotein fractions and their glycomes from hepatocellular carcinoma sera.
As one of the most important post-translational modifications, the discovery, isolation, and identification of glycoproteins are becoming increasingly important. In this study, a Con A-magnetic particle conjugate-based method was utilized to selectively isolate the glycoproteins and their glycomes from the healthy donor and hepatocellular carcinoma (HCC) case sera. The isolated glycoproteins and their N-linked glycans were identified by LC-ESI-MS/MS and MALDI-TOF/TOF-MS, respectively. A total of 93 glycoproteins from the healthy donors and 85 glycoproteins from the HCC cases were identified. There were 34 different glycoproteins shown between the healthy donors (21/34) and the HCC cases (13/34). Twenty-eight glycans from the healthy donors and 30 glycans from the HCC cases were detected and there were 22 different glycans shown between the healthy donors (10/22) and HCC cases (12/22). Among these glycoproteins, 50 were known to be N-linked glycoproteins and three novel glycopeptides from two predicted potential glycoproteins were discovered. Moreover, lectin blotting, Western blotting and lectin/glyco-antibody microarrays were applied to definitely elucidate the change of selective protein expressions and their glycosylation levels, the results indicated that the differences of the identified glycoproteins between the healthy donors and HCC cases were caused by the change of both protein expression and their glycosylation levels.


An educational partnership to enhance evidence-based wound care.
This article describes an educational initiative that aimed to raise the knowledge and practice of nurses at one hospital where staff had become deskilled in wound care. An audit questionnaire was used to determine nurses' knowledge before and 4 months after an educational workshop, part of which considered pain issues. Following the educational initiative, nurses within the Trust were knowledgeable about when to take a wound swab and could recognize the signs of wound infection, but there were still issues around the clinical practice of taking a wound swab. Conversely, their use of descriptors of tissue type to justify dressing choice was improved. Analgesia was commonly given to address previous uncomfortable dressing changes, but there was no mention of pain assessment. When a product had adhered to the wound bed, many nurses advocated soaking to aid removal. This has limited efficacy, but few nurses advocated using an alternative dressing on subsequent occasions. These results suggest that 4 months may be too short a time to fully evaluate whether a single educational workshop is sufficient to sustain change in an organization. An ongoing competency-based programme has been implemented.


[Chemical toxicants and preconception health: the role of nurses].
The influence of chemical toxicants on human reproduction is often overlooked. However, couples previously exposed to toxicants face a higher risk of birth defects in their children. Through preconception care, nurses can provide prevention education to men and women of childbearing age and play a positive role in reducing rates of infertility and fetal harm due to chemical toxicity. This paper introduces chemical toxicants prevalent in the community, workplace, and home and also the impact of exposure to such on conception and fetal development. Working on primary prevention, secondary prevention, and sexual history collection, professional nurses can assess, counsel, educate, and provide relevant services to help prevent environmental exposure damage to reproductive functions and promote reproductive health.


A Machine Learning Framework Identifies Plastid-Encoded Proteins Harboring C3 and C4 Distinguishing Sequence Information.
C4 photosynthesis is known to have at least 61 independent origins across plant lineages making it one of the most notable examples of convergent evolution. Of the >60 independent origins, a predicted 22-24 origins, encompassing greater than 50% of all known C4 species, exist within the Panicoideae, Arundinoideae, Chloridoideae, Micrairoideae, Aristidoideae, and Danthonioideae (PACMAD) clade of the Poaceae family. This clade is therefore primed with species ideal for the study of genomic changes associated with the acquisition of the C4 photosynthetic trait. In this study, we take advantage of the growing availability of sequenced plastid genomes and employ a machine learning (ML) approach to screen for plastid genes harboring C3 and C4 distinguishing information in PACMAD species. We demonstrate that certain plastid-encoded protein sequences possess distinguishing and informative sequence information that allows them to train accurate ML C3/C4 classification models. Our RbcL-trained model, for example, informs a C3/C4 classifier with greater than 99% accuracy. Accurate prediction of photosynthetic type from individual sequences suggests biologically relevant, and potentially differing roles of these sequence products in C3 versus C4 metabolism. With this ML framework, we have identified several key sequences and sites that are most predictive of C3/C4 status, including RbcL, subunits of the NAD(P)H dehydrogenase complex, and specific residues within, further highlighting their potential significance in the evolution and/or maintenance of C4 photosynthetic machinery. This general approach can be applied to uncover intricate associations between other similar genotype-phenotype relationships.


Imaging in alpha-1 antitrypsin deficiency: a window into the disease.
Imaging modalities such as plain chest radiograph and computed tomography (CT) are important tools in the assessment of patients with chronic obstructive pulmonary disease (COPD) of any etiology. These methods facilitate differential diagnoses and the assessment of individual lung pathologies, such as the presence of emphysema, bullae, or fibrosis. However, as emphysema is the core pathological consequence in the lungs of patients with alpha-1 antitrypsin deficiency (AATD), and because AATD is associated with the development of other lung pathologies such as bronchiectasis, there is a greater need for patients with AATD than those with non-AATD-related COPD to undergo more detailed assessment using CT. In the field of AATD, CT provides essential information regarding the presence, distribution, and morphology of emphysema. In addition, it offers the option to quantify the extent of emphysema. These data have implications for treatment decisions such as initiation of alpha-1 antitrypsin (AAT) therapy, or suitability for surgical or endoscopic interventions for reducing lung volume. Furthermore, CT has provided vital insight regarding the natural history of emphysema progression in AATD, and CT densitometry has underpinned research into the efficacy of AAT therapy. Moving forward, hyperpolarized xenon gas (129Xe) lung magnetic resonance imaging (MRI) is emerging as a promising complement to CT by adding comprehensive measures of regional lung function. It also avoids the main disadvantage of CT: the associated radiation. This chapter provides an overview of technological aspects of imaging in AATD, as well as its role in the management of patients and clinical research. In addition, perspectives on the future potential role of lung MRI in AATD are outlined.


Effect of a micronutrient-rich snack taken preconceptionally and throughout pregnancy on ultrasound measures of fetal growth: The Mumbai Maternal Nutrition Project (MMNP).
Improving micronutrient intakes of under-nourished mothers in low- and middle-income countries increases birth weight, but there is little data on the nature and timing during gestation of any effects on fetal growth. Ultrasound measures of fetal size were used to determine whether and when a food-based supplement affected fetal growth. Non-pregnant women living in Mumbai slums, India (N = 6,513), were randomly assigned to receive either a daily micronutrient-rich snack containing green leafy vegetables, fruit, and milk (treatment) or a snack made from lower-micronutrient vegetables (control) in addition to their usual diet from before pregnancy until delivery. From 2,291 pregnancies, the analysis sample comprised 1,677 fetuses (1,335 fetuses of women supplemented for ≥3 months before conception). First-trimester (median: 10 weeks, interquartile range: 9-12 weeks) fetal crown-rump length was measured. Fetal head circumference, biparietal diameter, femur length, and abdominal circumference were measured during the second (19, 19-20 weeks) and third trimesters (29, 28-30 weeks). The intervention had no effect on fetal size or growth at any stage of pregnancy. In the second trimester, there were interactions between parity and allocation group for biparietal diameter (p = .02) and femur length (p = .04) with both being smaller among fetuses of primiparous women and larger among those of multiparous women, in the treatment group compared with the controls. Overall, a micronutrient-rich supplement did not increase standard ultrasound measures of fetal size and growth at any stage of pregnancy. Additional ultrasound measures of fetal soft tissues (fat and muscle) may be informative.


Computer-assisted robotic antireflux surgery.
Antireflux surgery has evolved significantly since its inception 50 years ago. The current standard is laparoscopic fundoplication. The computer-assisted telemanipulator, a new device recently approved for use in laparoscopy, reduces some of the shortcomings of the laparoscopic approach. This review specifically discusses the role of this novel surgical tool in antireflux surgery.


Fe Site Order and Magnetic Properties of Fe1/4NbS2.
Transition-metal dichalcogenides (TMDs) have long been attractive to researchers for their diverse properties and high degree of tunability. Most recently, interest in magnetically intercalated TMDs has resurged due to their potential applications in spintronic devices. While certain compositions featuring the absence of inversion symmetry such as Fe1/3NbS2 and Cr1/3NbS2 have garnered the most attention, the diverse compositional space afforded through the host matrix composition as well as intercalant identity and concentration is large and remains relatively underexplored. Here, we report the magnetic ground state of Fe1/4NbS2 that was determined from low-temperature neutron powder diffraction as an A-type antiferromagnet. Despite the presence of overall inversion symmetry, the pristine compound manifests spin polarization induced by the antiferromagnetic order at generic k points, based on density functional theory band-structure calculations. Furthermore, by combining synchrotron diffraction, pair distribution function, and magnetic susceptibility measurements, we find that the magnetic properties of Fe1/4NbS2 are sensitive to the Fe site order, which can be tuned via electrochemical lithiation and thermal history.


Sound preference test in animal models of addicts and phobias.
Biased or too strong preference for a particular object is often problematic, resulting in addiction and phobia. In animal models, alternative forced-choice tasks have been routinely used, but such preference test is far from daily situations that addicts or phobic are facing. In the present study, we developed a behavioral assay to evaluate the preference of sounds in rodents. In the assay, several sounds were presented according to the position of free-moving rats, and quantified the sound preference based on the behavior. A particular tone was paired with microstimulation to the ventral tegmental area (VTA), which plays central roles in reward processing, to increase sound preference. The behaviors of rats were logged during the classical conditioning for six days. Consequently, some behavioral indices suggest that rats search for the conditioned sound. Thus, our data demonstrated that quantitative evaluation of preference in the behavioral assay is feasible.


Insulin resistance in polycystic ovarian disease.
The classic polycystic ovarian syndrome (PCOS) was originally described by Stein and Leventhal as the association of amenorrhea with polycystic ovaries and, variably, hirsutism and/or obesity. It is estimated that 5 to 10% of women of reproductive age have PCOS. Although insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS can not be denied. PCOS is associated with insulin resistance, independent of total or fat-free body mass. Postreceptor defects in the action of insulin have been described in PCOS that are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin, and thiazolidinediones (TZDs) improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that women who have PCOS have higher circulating levels of inflammatory mediators such as C-reactive protein, tumor necrosis factor, tissue plasminogen activator, and plasminogen activator inhibitor-1 (PAI-1). It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.


Sex and Management of Rheumatoid Arthritis.
Rheumatoid arthritis (RA) is a chronic and progressive autoimmune disease more common in women than men (3:1). Although sex-based differences may play a complex role in promoting an autoimmune dysfunction, to date the comprehensive knowledge of the link between sex and RA is still partially lacking. Furthermore, males and females have been demonstrated to differently deal with their chronic pathologies, modifying the perceived sex-based burden of disease. Gender medicine is a newly approach focusing on the impact of gender differences on human physiology, pathophysiology, and clinical features of diseases, analyzing the complex interrelation and integration of sex and psychological and cultural behavior. A better comprehension of possible factors influencing sexual dimorphism in RA susceptibility, pattern of presentation, disease activity, and outcome could contribute to a tailored approach, in order to limit the morbidity of the disease. RA disease activity seems to be higher in women, whereas the response rate to synthetic and biologic disease-modifying therapies appears to be better in males. Moreover, the common strategies for RA management may be affected by concomitant pregnancy or childbearing desire, with particular regard to treatments with potential teratogenic effects or impact on fertility. Finally, comorbidities, such as fibromyalgia, major depression, and osteoporosis, are more frequent in females, while the impact of sex on cardiovascular risk is still controversial. Moving from the role of sex in influencing RA pathogenesis, epidemiology, and disease characteristics, this review explores the evidence on how sex can have an impact on strategies for managing patients with RA.


Long-term pediatric skin eruption-related hospitalizations in offspring conceived via fertility treatment.
Although concerns have been raised regarding the long-term health risks of offspring conceived following fertility treatments, limited information is available regarding their health status beyond the neonatal period. We aimed to evaluate the risk of long-term eruptive dermatological morbidity among children born following fertility treatments as compared to those conceived spontaneously. A population-based cohort study was conducted, including all singleton deliveries occurring between the years 1991 and 2014 at a single tertiary medical center. Fetuses with congenital malformations and multiple gestations were excluded. Children delivered following fertility treatment pregnancies and spontaneous pregnancies were compared. Hospitalizations of the offspring up to the age of 18 years involving cutaneous eruptions were evaluated. A Kaplan-Meier survival curve was used to compare cumulative morbidity incidence and a Cox regression model to control for confounders. During the study period, 242,187 singleton deliveries met the inclusion criteria, 1.8% of which were following fertility treatments (n = 4324). Eruptive dermatological morbidity of the offspring up to the age of 18 years was significantly more common in the fertility treatment group (1.5%) as compared to spontaneous pregnancies (1.1%; P = 0.023). The Kaplan-Meier survival curve demonstrated a significantly higher cumulative incidence of eruptive dermatological morbidity following fertility treatments (log-rank P = 0.007). Using the Cox regression model, while controlling for multiple confounders, fertility treatment was noted as an independent risk factor for long-term pediatric eruptive dermatological morbidity (adjusted HR = 1.43, CI 1.12-1.83, P = 0.004). Singletons conceived via fertility treatments appear to be at an increased risk for long-term eruptive dermatological morbidity.


Pronounced inter- and intrachromosomal variation in linkage disequilibrium across the zebra finch genome.
The extent of nonrandom association of alleles at two or more loci, termed linkage disequilibrium (LD), can reveal much about population demography, selection, and recombination rate, and is a key consideration when designing association mapping studies. Here, we describe a genome-wide analysis of LD in the zebra finch (Taeniopygia guttata) using 838 single nucleotide polymorphisms and present LD maps for all assembled chromosomes. We found that LD declined with physical distance approximately five times faster on the microchromosomes compared to macrochromosomes. The distribution of LD across individual macrochromosomes also varied in a distinct pattern. In the center of the macrochromosomes there were large blocks of markers, sometimes spanning tens of mega bases, in strong LD whereas on the ends of macrochromosomes LD declined more rapidly. Regions of high LD were not simply the result of suppressed recombination around the centromere and this pattern has not been observed previously in other taxa. We also found evidence that this pattern of LD has remained stable across many generations. The variability in LD between and within chromosomes has important implications for genome wide association studies in birds and for our understanding of the distribution of recombination events and the processes that govern them.


[Echographic aspects of cerebral sulci in the ante- and perinatal period].
70 fetuses (10 to 37 weeks) and 30 full term infants were examined by ultrasound (U.S.). Anatomic correlations were made with frontal, axial and sagittal sections of 43 fetal and 3 neonatal brains. At 12 weeks gestational age (w.g.a.) only the inter hemispheric fissure is seen by U.S. The sylvian fissure (21 w.g.a.), the callosal sulcus (21 w.g.a.), the parieto-occipital sulcus (25 w.g.a.), the calcarine fissure (25 w.g.a.), the cingulate sulcus (26 w.g.a.) and the collateral sulcus (25-27 w.g.a.) are visualized rather late with in-utero U.S. The other sulci are more difficult to see. The peripheral location of these sulci contributes to the difficulty encountered in their visualization. The morphology of the sylvian fissure is quite characteristic on U.S. imaging and can be used to estimate the gestational age of the fetus. Compared to the embryological development there is a 2-4 weeks delay between the first infolding of the brain and the visualization of a sulcus by U.S. Abnormal sulcal patterns can be recognized based on the normal appearance for each gestational age. Sulcal anomalies are quite specific in holoprosencephaly, lissencephaly, micropolygyry, schizencephaly, agenesis of the corpus callosum. Silhouetting of the sulci may occur if the parenchymal echogenicity is sufficiently increased that the sulci no longer stand out (ischemia, tumors, encephalitis). Thickening of the sulci occurs in subdural hematomas, external hydrocephalus, meningitis and toxoplasmosis.


Multipotent peripheral glial cells generate neuroendocrine cells of the adrenal medulla.
Adrenaline is a fundamental circulating hormone for bodily responses to internal and external stressors. Chromaffin cells of the adrenal medulla (AM) represent the main neuroendocrine adrenergic component and are believed to differentiate from neural crest cells. We demonstrate that large numbers of chromaffin cells arise from peripheral glial stem cells, termed Schwann cell precursors (SCPs). SCPs migrate along the visceral motor nerve to the vicinity of the forming adrenal gland, where they detach from the nerve and form postsynaptic neuroendocrine chromaffin cells. An intricate molecular logic drives two sequential phases of gene expression, one unique for a distinct transient cellular state and another for cell type specification. Subsequently, these programs down-regulate SCP-gene and up-regulate chromaffin cell-gene networks. The AM forms through limited cell expansion and requires the recruitment of numerous SCPs. Thus, peripheral nerves serve as a stem cell niche for neuroendocrine system development.


[4-Tesla 1H MR spectroscopy in patients with temporal lobe epilepsy].
7 patients with drug-resistant temporal lobe epilepsy (TLE) and localized EEG-focus were investigated with a 4 Tesla whole body MR-scanner. Proton (1H) magnetic resonance (MR) spectra were analyzed quantitatively and compared to the healthy side. MRS allowed the differentiation of the following metabolites in 5 patients: N-acetyl-aspartate (NAA), creatine and phosphocreatine, phosphorylcholine and glycerophosphorylcholine, beta- and gamma-glutamate (GLU). To compare the results with those of an already evaluated normal population, these metabolites were measured also in parietal region. The standard deviation was 42-46% in the patients. Unfortunately, in the temporal region, the field homogeneity was worse than parietal and thus the spectral analysis less distinct especially for GLU with a standard deviation of 45% for NAA and 66% for GLU on the healthy side. Thus, no significant findings were seen on focus side. There was only a tendency to an elevation of glutamate and a reduction of N-acetyl-aspartate.


2023 GEIS Guidelines for gastrointestinal stromal tumors.
Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.


Distinct functional levels of human voice processing in the auditory cortex.
Voice signaling is integral to human communication, and a cortical voice area seemed to support the discrimination of voices from other auditory objects. This large cortical voice area in the auditory cortex (AC) was suggested to process voices selectively, but its functional differentiation remained elusive. We used neuroimaging while humans processed voices and nonvoice sounds, and artificial sounds that mimicked certain voice sound features. First and surprisingly, specific auditory cortical voice processing beyond basic acoustic sound analyses is only supported by a very small portion of the originally described voice area in higher-order AC located centrally in superior Te3. Second, besides this core voice processing area, large parts of the remaining voice area in low- and higher-order AC only accessorily process voices and might primarily pick up nonspecific psychoacoustic differences between voices and nonvoices. Third, a specific subfield of low-order AC seems to specifically decode acoustic sound features that are relevant but not exclusive for voice detection. Taken together, the previously defined voice area might have been overestimated since cortical support for human voice processing seems rather restricted. Cortical voice processing also seems to be functionally more diverse and embedded in broader functional principles of the human auditory system.


Evidence-based medicine and headache patient management by general practitioners in Italy.
The study explores the awareness of technical terms used in evidence-based medicine (EBM) and manner of treating patients with migraine among a random sample of 500 general practitioners (GPs). A mailed questionnaire included questions on GPs' demographics and practice characteristics; awareness of EBM; sources of information about migraine and EBM; and patient's treatment behaviour. Only 27.2% of GPs agreed that clinical trials are needed to evaluate the efficacy of treatments and this awareness was higher in those who learned about migraine from scientific journals or continuing education courses and who attended courses on EBM. For two-thirds of GPs, disability is equivalent to illness diagnosis, and this behaviour was more prevalent in those who agreed that clinical trials are needed to evaluate the efficacy of preventive or curative treatments of migraine and that the clinical approach to migraine required an evaluation of clinical effectiveness, in those who treated a lower number of headache patients, who were older, and in those who did not use guidelines. The majority (93.1%) of GPs indicated that it is important to integrate clinical practice and the best available evidence, and this behaviour was significantly more frequent in those who agreed that the clinical approach to migraine required a clinical effectiveness evaluation, that clinical trials are needed to evaluate the efficacy of preventive or curative treatments of migraine, and in those who attended courses on EBM. Training and continuing educational programmes on EBM and guidelines on treatments of headache for GPs are strongly needed.


The T cell as a bridge between innate and adaptive immune systems: implications for the kidney.
The T cell as a bridge between innate and adaptive immune systems: Implications for the kidney. The immune system is classically divided into innate and adaptive components with distinct roles and functions. T cells are major components of the adaptive immune system. T cells are firmly established to mediate various immune-mediated kidney diseases and are current targets for therapy. Ischemic acute renal failure, a major cause of native kidney and allograft dysfunction, is mediated in part by inflammatory components of the innate immune system. However, recent data from experimental models in kidney as well as liver, intestine, brain and heart implicate T cells as important mediators of ischemia reperfusion injury. These data reveal new insights into the pathogenesis of ischemic acute renal failure, as well as identify novel and feasible therapeutic approaches. Furthermore, the identification of T cells as a mediator of early alloantigen-independent tissue injury demonstrates that the functional capacity of T cells spreads beyond adaptive immunity into the realm of the innate immune response.