Long-term effects of oral and transdermal hormone replacement therapy on plasma homocysteine levels.
To compare the long-term effects of oral and transdermal hormone replacement therapy (HRT) on serum homocysteine levels in postmenopausal women. An open, prospective, controlled study. Seventy-five healthy postmenopausal women were recruited as eligible for the study. Fifty women seeking HRT were randomized to receive continuous 17beta-estradiol, either by oral (2 mg daily; n = 25) or transdermal (50 microg daily; n = 25) administration, plus 10 mg dydrogesterone daily for 14 days of each 28-day cycle. Twenty-five women unwilling to receive hormone treatment received only calcium supplementation, representing the control group. Fasting blood samples were analyzed at baseline and then after 6, 12, and 24 months to determine plasma homocysteine levels. Fifty-nine women completed the study. After 6 months of therapy, homocysteine concentrations showed a statistically significant reduction in the treated groups versus both baseline and controls, and no further significant variations were found thereafter. The mean reduction in the homocysteine levels throughout the study was 13.6% in the oral and 8.9% in the transdermal group, respectively, without significant difference between the two routes of estradiol administration. Women with the highest baseline levels of homocysteine experienced the greatest reduction. No significant variations in homocysteine concentrations were found in the control group. Oral and transdermal estradiol sequentially combined with dydrogesterone shows comparable effectiveness in reducing plasma homocysteine levels in postmenopausal women. Women with the highest pretreatment concentrations of homocysteine benefit the most by the lowering effect of HRT.


In Situ Detoxification of Venomous Agent X Surrogate Profenofos by Doped Titanium Dioxide Nanoparticles under Illumination at the UV and Visible Ranges.
The photocatalytic activity of titanium dioxide (TiO2) due to the generation of reactive oxygen species (ROS) under UV excitation is often used for the decontamination of toxic hazardous materials and self-cleaning processes. However, the large band gap of TiO2 limits the activity to the UV region. This limitation can be overcome by metal doping, which results in extending TiO2 activity into the visible range (vis). This paper describes the preparation and characterization of several TiO2 forms and their modifications for enhanced photocatalytic activity in the UV/vis range. In order to advance this concept for environmental decontamination, the degradation of the organophosphorus pesticide and chemical warfare agent, profenofos (PF), was tested. Fast and full degradation of PF was achieved using either TiO2 in the near-UV (365 nm) or Ag-doped TiO2 (TiO2-Ag) in the UV and vis ranges (400-550 nm). The degradation products were identified chromatographically using GC/MS and HPLC, while the detoxification effect was determined electrochemically using an acetylcholinesterase biosensor. In view of our results, we suggest that TiO2-Ag may be implemented as an additive in surface coatings to allow in situ green self-cleaning.


Relationship between the optimal cut-off values of anthropometric indices for predicting metabolic syndrome and carotid intima-medial thickness in a Korean population.
Anthropometric measurements are simple and useful methods for predicting metabolic syndrome (MetS) because obesity is a predominant feature of MetS. Although carotid intima-medial thickness (IMT) is generally used to evaluate subclinical atherosclerosis, the relationship between the optimal cut-off anthropometric values for predicting MetS and carotid IMT has not been analyzed in a Korean population.Anthropometric measurements including waist circumference (WC), waist hip ratio (WHR), waist height ratio (WHtR), body mass index (BMI), and carotid IMT were assessed in 2560 Korean subjects without previous history of cardiovascular disease, cerebrovascular disease, neurological abnormalities, or malignancy who participated in baseline health examinations in a self-referral setting in the Seoul area between April 2010 and November 2012. MetS was defined using the National Cholesterol Education Program-Adult Treatment Panel III criteria.In both men and women, the levels of all anthropometric indices were significantly higher in subjects with MetS than in those without MetS. According to the receiver operating characteristic curve, the values of 80.8 cm for WC, 0.87 for WHR, 0.52 for WHtR, and 24.6 kg/m for BMI were the optimal cut-offs for predicting MetS in women. The values of 89.3 cm for WC, 0.90 for WHR, 0.52 for WHtR, and 25.1 kg/m for BMI were the optimal cut-offs for predicting MetS in men. After adjusting for confounding factors, the WC optimal cut-off values for predicting MetS were independently associated with carotid IMT in both women and men (women: β = 0.016, P = .008; men: β = 0.033, P = .009). The optimal BMI cut-off value was independently associated with carotid IMT in men only (β = 0.027, P = .032).Among anthropometric indices including WC, WHR, WHtR, and BMI, the WC optimal cut-off values for MetS were independently associated with an increased carotid IMT in both women and men in a Korean population.


Electronic portal imaging devices: a review and historical perspective of contemporary technologies and research.
A review of electronic portal imaging devices (EPIDs) used in external beam, megavoltage radiation therapy is presented. The review consists of a brief introduction to the definition, role and clinical significance of portal imaging, along with a discussion of radiotherapy film systems and the motivations for EPIDs. This is followed by a summary of the challenges and constraints inherent to portal imaging along with a concise, historical review of the technologies that have been explored and developed. The paper then examines, in greater depth, the two first-generation technologies that have found widespread clinical use starting from the late 1980s. This is followed by a broad overview of the physics, operation, properties and advantages of active matrix, flat-panel, megavoltage imagers, presently being commercially introduced to clinical environments or expected to be introduced in the future. Finally, a survey of contemporary research efforts focused on improving portal imaging performance by addressing various weaknesses in existing commercial systems is presented.


The limited usefulness of urine and blood cultures in treating pyelonephritis in pregnancy.
Although urine cultures are performed routinely in managing acute pyelonephritis in pregnancy, little is known about the clinical usefulness of these cultures. The same is true for blood cultures. To evaluate their role in managing patients, we reviewed the records of 156 cases to determine to what extent such cultures influenced treatment. Over 90% of urine isolates were sensitive to the initial antibiotic. Most changes in therapy were based on clinical response; only 3% of pre-treatment urine cultures and 2% of blood cultures led to a change in antibiotics. On a nationwide basis, urine and blood cultures cost $10-20 million each year. Our data suggest that more limited use of cultures will simplify management and save money without compromising patient care.


Eumelanin thin films: solution-processing, growth, and charge transport properties.
Eumelanin pigments show hydration-dependent conductivity, broad-band UV-vis absorption, and chelation of metal ions. Solution-processing of synthetic eumelanins opens new possibilities for the characterization of eumelanin in thin film form and its integration into bioelectronic devices. We investigate the effect of different synthesis routes and processing solvents on the growth, the morphology, and the chemical composition of eumelanin thin films using atomic force microscopy and X-ray photoelectron spectroscopy. We further characterize the films by transient electrical current measurements obtained at 50% to 90% relative humidity, relevant for bioelectronic applications. We show that the use of dimethyl sulfoxide is preferable over ammonia solution as processing solvent, yielding homogeneous films with surface roughnesses below 0.5 nm and a chemical composition in agreement with the eumelanin molecular structure. These eumelanin films grow in a quasi layer-by-layer mode, each layer being composed of nanoaggregates, 1-2 nm high, 10-30 nm large. The transient electrical measurements using a planar two-electrode device suggest that there are two contributions to the current, electronic and ionic, the latter being increasingly dominant at higher hydration, and point to the importance of time-dependent electrical characterization of eumelanin films.


Duration of symptom onset to hospital admission and admission to discharge or death in SARS in mainland China: a descriptive study.
To describe and analyse factors associated with the duration of disease onset to hospital admission, admission to discharge and admission to death for severe acute respiratory syndrome (SARS), using the recently developed comprehensive database covering all regions of mainland China, and compare the results within and outside China. The database included all probable 5327 SARS cases, of whom 343 died. Linear regression (uni- and multivariate analysis) was performed for all three durations to test the impact of the following variables: sex, age, occupation, geographic location and period of the SARS epidemic (time since the first case, i.e. 16 November 2002). The average duration of onset of symptoms to hospital admission was 3.8 days, of admission to discharge for those who survived was 29.7 days, while admission to death for casualties was 17.4 days. Health care workers, patients from Tianjin and patients infected towards the end of the epidemic had the shortest duration of onset to admission. Regarding admission to discharge, particularly young patients and patients from Guangdong had the shortest duration. Older age was the sole factor associated with shorter duration of admission to death. The average duration and pattern (with time of epidemic and age) of onset of symptoms to hospital admission of SARS patients in mainland China were comparable to other affected areas. The duration of hospital admission to discharge was shorter than elsewhere, possibly because of different hospitalisation policies. The duration of hospital admission to death in mainland China, however, appeared to be shorter than in other areas, which is in striking contrast to the much lower case fatality in mainland China.


Overstatements in abstract conclusions claiming effectiveness of interventions in psychiatry: a study protocol for a meta-epidemiological investigation.
Abstracts are the major and often the most important source of information for readers of the medical literature. However, there is mounting criticism that abstracts often exaggerate the positive findings and emphasise the beneficial effects of intervention beyond the actual findings mentioned in the corresponding full texts. In order to examine the magnitude of this problem, we will introduce a systematic approach to detect overstated abstracts and to quantify the extent of their prevalence in published randomised controlled trials (RCTs) in the field of psychiatry. We will source RCTs published in 2014 from the Cochrane Register of Controlled Trials (CENTRAL) that claim effectiveness of any intervention for mental disorders. The abstract conclusions will be categorised into three types: superior (only stating significant superiority of intervention to control), limited (suggesting that intervention has limited superiority to control) and equal (claiming equal effectiveness of intervention as control). The full texts will also be classified as one of the following based on the primary outcome results: significant (all primary outcomes were statistically significant in favour of the intervention), mixed (primary outcomes included both significant and non-significant results) or all non-significant results. By comparing the abstract conclusion classification and that of the corresponding full text, we will assess whether each study exhibited overstatements in its abstract conclusion. This trial requires no ethical approval. We will publish our findings in a peer-reviewed journal. UMIN000018668; Pre-results.


Efficacy of a Short-term Six-food Elimination Diet and Reintroduction Therapy in Pediatric Eosinophilic Gastroenteritis.
A 13-year-old boy presented to the hospital with a 3-month history of repeated vomiting and abdominal pain. Results of esophagogastroduodenoscopy revealed a diagnosis of eosinophilic gastroenteritis (EGE). We initiated a short-term six-food elimination diet (SFED) and reintroduction therapy over five days. On the third day of SFED, the patient's abdominal symptoms completely disappeared. However, he experienced unbearable abdominal pain six hours after the reintroduction of milk and peanuts. His symptoms remain completely controlled at present after eliminating milk and peanut products. The SFED and reintroduction therapy for EGE may be effective even for short-term treatments over a five-day period.


Birth weight among women of different ethnic groups.
Differences in mean birth weight and low birth weight (less than 2.5 kg) are analyzed among Asians, blacks, Hispanics, and whites who were enrolled in the Northern California Kaiser-Permanente Birth Defects Study, a prospective study of 29,415 pregnancy outcomes. Large differences in birth weight among babies of different ethnic groups persist after controlling for the joint effects of maternal smoking and alcohol use during pregnancy, sex of child, parity, length of prenatal care, and maternal weight-for-height percentile. Compared with whites, the relative mean differences in birth weight are estimated as -246 g for blacks, -210 g for Asians, -105 g for Hispanics, and -140 g for others. The low-birth-weight rates and crude odds ratios are 7.70% (2.17) for blacks; 5.57% (1.57) for Asians; 5.52% (1.55) for others; 4.00% (1.13) for Hispanics; and 3.55% (1.00) for whites. After controlling for the effects of 22 factors, the odds ratios for a low-birth-weight infant are 2.41 for blacks, 1.37 for Asians, 1.93 for others, and 1.25 for Hispanics. It is concluded that factors currently used to control for ethnic differences in birth weight are insufficient to explain the observed differences.


Microbial influence on triggering and treatment of host cancer: An intestinal barrier perspective.
Inflammatory bowel disease (IBD) is associated with complex complications that may lead to tumors. However, research on the mechanisms underlying susceptibility to chronic immune diseases and cancer pathogenesis triggered by the inflammatory environment remains limited. An imbalance in the host gut microbiota often accompanies intestinal inflammation. The delayed recovery of the dysregulated intestinal microbiota may exacerbate systemic inflammatory responses, multiorgan pathology, and metabolic disorders. This delay may also facilitate bacterial translocation. This review examined the relationship between gut barrier disruption and unbalanced microbial translocation and their impact on the brain, liver, and lungs. We also explored their potential roles in tumor initiation. Notably, the role of the intestinal microbiota in the development of inflammation is linked to the immune surveillance function of the small intestine and the repair status of the intestinal barrier. Moreover, adherence to a partially anti-inflammatory diet can aid in preventing the malignant transformation of inflammation by repairing the intestinal barrier and significantly reducing inflammation. In conclusion, enhancing intestinal barrier function may be a novel strategy for preventing and treating chronic malignancies in the intestine and other body areas.


Analysis of Cardiac Myocyte Maturation Using CASAAV, a Platform for Rapid Dissection of Cardiac Myocyte Gene Function In Vivo.
Loss-of-function studies in cardiac myocytes (CMs) are currently limited by the need for appropriate conditional knockout alleles. The factors that regulate CM maturation are poorly understood. Previous studies on CM maturation have been confounded by heart dysfunction caused by whole organ gene inactivation. To develop a new technical platform to rapidly characterize cell-autonomous gene function in postnatal murine CMs and apply it to identify genes that regulate transverse tubules (T-tubules), a hallmark of mature CMs. We developed CRISPR/Cas9/AAV9-based somatic mutagenesis, a platform in which AAV9 delivers tandem guide RNAs targeting a gene of interest and cardiac troponin-T promoter-driven Cre to RosaCas9GFP/Cas9GFP neonatal mice. When directed against junctophilin-2 (Jph2), a gene previously implicated in T-tubule maturation, we achieved efficient, rapid, and CM-specific JPH2 depletion. High-dose AAV9 ablated JPH2 in 64% CMs and caused lethal heart failure, whereas low-dose AAV9 ablated JPH2 in 22% CMs and preserved normal heart function. In the context of preserved heart function, CMs lacking JPH2 developed T-tubules that were nearly morphologically normal, indicating that JPH2 does not have a major, cell-autonomous role in T-tubule maturation. However, in hearts with severe dysfunction, both adeno-associated virus-transduced and nontransduced CMs exhibited T-tubule disruption, which was more severe in the transduced subset. These data indicate that cardiac dysfunction disrupts T-tubule structure and that JPH2 protects T-tubules in this context. We then used CRISPR/Cas9/AAV9-based somatic mutagenesis to screen 8 additional genes for required, cell-autonomous roles in T-tubule formation. We identified RYR2 (Ryanodine Receptor-2) as a novel, cell-autonomously required T-tubule maturation factor. CRISPR/Cas9/AAV9-based somatic mutagenesis is a powerful tool to study cell-autonomous gene functions. Genetic mosaics are invaluable to accurately define cell-autonomous gene function. JPH2 has a minor role in normal T-tubule maturation but is required to stabilize T-tubules in the failing heart. RYR2 is a novel T-tubule maturation factor.


Comprehensive analysis of cuproptosis genes and cuproptosis-related genes as prognosis factors in esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) is a common invasive and pernicious cancer with a low five-year survival rate. To identify potential therapeutic targets, we first investigated the characteristics of cuproptosis genes (CUGs) in ESCC. The expression patterns of 10 CUGs (FDX1, LIPT1, LIAS, DLAT, DLD, PDHA1, PDHB, GLS, MTF1, and CDKN2A) were analyzed to identify ESCC-relevant targets. Weighted correlation network analysis (WGCNA) was performed to obtain CUG-related genes (CRGs). A total of seven differentially expressed genes were identified (FDX1, DLAT, LIAS, PDHB, MTF1, GLS, and CDKN2A). DLAT was upregulated in stage III, and LIPT1 was upregulated in N0 + N1 cancers. The high expression of CDKN2A, and PDHA1, was related to better overall survival, whereas the low expression of LIAS was related to better clinical outcomes. WGCNA was performed to get CUG-related genes (CRGs) and showed three key modules that related to FDX1, DLAT, and LIPT1. Moreover, CRGs (BTLA, CT47A1, and PRRX1) were selected to construct a risk score model in order to predict the survival and prognosis of patients with ESCC. Additionally, the cuproptosis score based on CUGs and a nomogram constructed based on it helped accurately predict the prognosis of patients with ESCC; thus, maybe it can be used for the clinical diagnosis of ESCC. The results also showed that milciclib might inhibit the proliferation and migration of KYSE150 and KYSE510 cells by targeting CDKN2A. In conclusion, the abovementioned CUGs and CRGs play a crucial role in tumorigenesis and cancer progression in ESCC, indicating their potential as therapeutic targets.


Phylogeny of lobose amoebae based on actin and small-subunit ribosomal RNA genes.
Lobose amoebae are abundant free-living protists and important pathogenic agents, yet their evolutionary history and position in the universal tree of life are poorly known. Molecular data for lobose amoebae are limited to a few species, and all phylogenetic studies published so far lacked representatives of many of their taxonomic groups. Here we analyze actin and small-subunit ribosomal RNA (SSU rRNA) gene sequences of a broad taxon sampling of naked, lobose amoebae. Our results support the existence of a monophyletic Amoebozoa clade, which comprises all lobose amoebae examined so far, the amitochondriate pelobionts and entamoebids, and the slime molds. Both actin and SSU rRNA phylogenies distinguish two well-defined clades of amoebae, the "Gymnamoebia sensu stricto" and the Archamoebae (pelobionts + entamoebids), and one weakly supported and ill-resolved group comprising some naked, lobose amoebae and the Mycetozoa.


Heteroglycoclusters With Dual Nanomolar Affinities for the Lectins LecA and LecB From Pseudomonas aeruginosa.
Multivalent structures displaying different instead of similar sugar units, namely heteroglycoclusters (hGCs), are stimulating the efforts of glycochemists for developing compounds with new biological properties. Here we report a four-step strategy to synthesize hexadecavalent hGCs displaying eight copies of αFuc and βGal. These compounds were tested for the binding to lectins LecA and LecB from Pseudomonas aeruginosa. While parent fucosylated (19) and galactosylated (20) homoclusters present nanomolar affinity with LecB and LecA, respectively, we observed that hGCs combining these sugars (11 and 13) maintain their binding potency with both lectins despite the presence of an unspecific sugar. The added multivalency is therefore not a barrier for efficient recognition by bacterial receptors and it opens the route for adding different sugars that can be selected for their immunomodulatory properties.


[Experimental transmission of Crimean-Congo hemorrhagic fever virus by Rhipicephalus evertsi evertsi (Acarina:Ixodidae)].
We have conducted experiments to assess the ability of Rhipicephalus evertsi evertsi tick to transmit the Crimean-Congo haemorrhagic fever (CCHF) and determine their reproductive cycle. The Rh. e. evertsi was infected by intracoelomic (transparietal and intra-anal) inoculation during the imaginal stases and by oral feeding on an infected viremic goat during imaginal and nymphal stases. The infection rate, transovarial and trans-stasial CCHF virus transmission were monitored for virus reisolation after suckling mice inoculation and the virus identified by ELISA and IFA for antigen detection. After intracoelomic inoculation, unfed adults had viral titers ranging from 0.67 to 2.9 log DL50/0.02 ml and had transmitted the virus to their vertebrate hosts by blood feeding. After 8 to 10 days of blood feeding duration, infection rates were respectively 36% and 100% for male and female ticks. In two instances out of seven transovarial transmission was observed and the virus reisolated from larvae of first generation. However, the virus was not detected after nymphal metamorphosis. After blood feeding on viremic goats, 71% of the nymphae were infected. After metamorphoses 22% of the males and 42% of the females had a low virus titer. Rh. e. evertsi appears to have a limited efficacy in transmitting and replicating the CCHF virus but must be not neglected as a potential vector during an epizootic manifestation.


CircDYM attenuates microglial apoptosis via CEBPB/ZC3H4 axis in LPS-induced mouse model of depression.
Major depressive disorder (MDD) is a highly prevalent condition and one of the most common psychiatric disorders worldwide. Circular RNA (circRNA) has been increasingly implicated in MDD. However, a comprehensive understanding of circRNA and microglial apoptosis in depression is incomplete. Here, we show that circDYM inhibits microglial apoptosis induced by LPS via CEBPB/ZC3H4 axis. CircDYM prevents the translocation of CEBPB from cytoplasm to the nucleus by binding with CEBPB. Moreover, LPS-induced CEBPB nuclear entry downregulates the expression of ZC3H4, in which promotes autophagy and apoptosis in microglia. Taken together, our findings provide new insights into the relationship between circDYM and microglial apoptosis and shed new light on the function of this novel mechanism in depression-associated complex changes in the brain.


A Penicillin Derivative Exerts an Anti-Metastatic Activity in Melanoma Cells Through the Downregulation of Integrin αvβ3 and Wnt/β-Catenin Pathway.
The synthetic triazolylpeptidyl penicillin derivative, named TAP7f, has been previously characterized as an effective antitumor agent in vitro and in vivo against B16-F0 melanoma cells. In this study, we investigated the anti-metastatic potential of this compound on highly metastatic murine B16-F10 and human A375 melanoma cells. We found that TAP7f inhibited cell adhesion, migration and invasion in a dose-dependent manner. Additionally, we demonstrated that TAP7f downregulated integrin αvβ3 expression and Wnt/β-catenin pathway, a signaling cascade commonly related to tumor invasion and metastasis. Thus, TAP7f reduced both the enzymatic activity and the expression levels of matrix-metalloproteinases-2 and -9 in a time dependent manner. Moreover, TAP7f inhibited the expression of the transcription factor Snail and the mesenchymal markers vimentin, and N-cadherin, and up-regulated the expression of the epithelial marker E-cadherin, suggesting that the penicillin derivative affects epithelial-mesenchymal transition. Results obtained in vitro were supported by those obtained in a B16-F10-bearing mice metastatic model, that showed a significant TAP7f inhibition of lung metastasis. These findings suggest the potential of TAP7f as a chemotherapeutic agent for the treatment of metastatic melanoma.


Analysis of blink dynamics in patients with blepharoptosis.
Owing to the rapid movements of the human upper eyelid, a high-speed camera was used to record and characterize voluntary blinking and the blink dynamics of blepharoptosis patients were compared to a control group. Twenty-six blepharoptosis patients prior to surgery and 45 control subjects were studied and the vertical height of the palpebral aperture (PA) was measured manually at 2 ms intervals during each blink cycle. The PA and blinking speed were plotted with respect to time and a predictive model was generated. The blink dynamic was analysed in closing and opening phases, and revealed a reduced speed of the initial opening phase in ptotic patients, suggesting intrinsic muscle function change in ptosis pathogenesis. The PA versus time curve for each subject was reconstructed using custom-built parameters; however, there were significant differences between the two groups. Those parameters used included the rate of closure, the delay between opening and closing, rate of initial opening, rate of slow opening (nonlinear function) and the 'switch point' between those two rates of opening. The model was tested against a new group of subjects and was able to discriminate ptosis patients from controls with 80% accuracy.


Tachycardia recognition algorithms for implantable systems.
The detection algorithm of current antitachycardia pacing systems incorporates derivatives of heart rate as the only objective parameter used for recognition. Present pacing systems use one or more rate-related parameters: (1) rate cutoff, (2) sudden onset, (3) rate stability, and (4) sustained high rate. Recently, the development of antitachycardia systems has focused on combining the four detection criteria to form multiple recognition algorithms. Nevertheless, inability to differentiate between supraventricular and ventricular tachycardias at compatible rates remains a limitation. Incorporating atrial sensing capability, in addition to ventricular sensing capability, an alternative strategy that potentially could enhance diagnostic accuracy, is discussed. The incorporation of time and frequency analysis, arterial pressure, and stroke volume are also examined.


The melanocortin circuit in obese and lean strains of chicks.
Agonists of membranal melanocortin 3 and 4 receptors (MC3/4Rs) are known to take part in the complex control mechanism of energy balance. In this study, we compared the physiological response to an exogenous MC3/4R agonist and the hypothalamic expression of proopic melanocortin (POMC) gene, encoding few MC3/4R ligands, between broiler and layer chicken strains. These strains, representing the two most prominent commercial strains of chickens grown for meat (broilers) and egg production (layers), differ in their food intake, fat accumulation, and reproductive performance and, therefore, form a good model of obese and lean phenotypes, respectively. A single i.v. injection of the synthetic peptide melanotan-II (MT-II; 1 mg/kg body weight) into the wing vein of feed-restricted birds led to attenuation of food intake upon exposure to feeding ad libitum in both broiler and layer chickens. A study of the POMC mRNA encoding the two prominent natural MC3/4R agonists, alpha-MSH and ACTH, also revealed a general similarity between the strains. Under feeding conditions ad libitum, POMC mRNA levels were highly similar in chicks of both strains and this level was significantly reduced upon feed restriction. However, POMC mRNA down-regulation upon feed restriction was more pronounced in layers than in broilers. These results suggest: (i) a role for MC3/4R agonists in the control of appetite; (ii) that the physiological differences between broilers and layers are not related to unresponsiveness of broiler chickens to the satiety signal of MC3/4R ligands. Therefore, these findings suggest that artificial activation of this circuit in broiler chicks could help to accommodate with their agricultural shortcomings of overeating, fattening, and impaired reproduction.


Influence of cellulose nanocrystal surface functionalization on the bending response of cellulose nanocrystal/ionic liquid soft actuators.
This work reports the development of renewable cellulose nanocrystal (CNC) and ionic liquid (IL) hybrid materials for bending actuator applications. For this purpose, cellulose nanocrystals with different surface charges (neutral, positive and negative) were prepared and increasing amounts of the IL 2-hydroxy-ethyl-trimethylammonium dihydrogen phosphate ([Ch][DHP]) (10 and 25 wt%) were incorporated into the CNC hosting matrix. The morphology of the samples was evaluated, proving that both surface charge and IL incorporation do not affect the characteristic layered structure of the CNC. Atomic force microscopy results reveal a sea-island morphology in the hybrid films, where CNC bundles are surrounded by [Ch][DHP]-rich regions. An increase in the electrical conductivity is observed upon IL incorporation into the CNC matrix, regardless of the CNC surface charge. The highest electrical conductivity values are observed for IL/CNC (+) 25 wt% with an electrical conductivity of 3.18 × 10-5± 2.75 × 10-7 S cm-1 and IL/CNC (-) 10 wt% (1.26 × 10-5± 5.92 × 10-6 S cm-1). The highest bending displacement of 2.1 mm for an applied voltage of 4.0 Vpp at a frequency of 100 mHz was obtained for the IL/CNC (+) 25 wt% composite, demonstrating the suitability of cellulose to develop soft actuators.


How much remnant is enough in liver resection?
Liver resection represents the first choice of treatment for primary and secondary liver malignancies, offering the patient the best chance of long-term survival. The extensive use of major hepatectomy increases the risk of post-hepatectomy liver failure (PHLF), which is associated with a high frequency of postoperative complications, mortality and increased length of hospital stay. The aim of this review is to investigate the different risk factors related to the occurrence of PHLF and to identify the limits for a safe liver resection in patients with normal liver and injured liver (cirrhosis, cholestasis, steatosis and post-chemotherapy liver injury). A literature search was undertaken in PubMed and related search engines, looking for articles relating to hepatic failure following hepatectomy in normal liver or injured liver. In spite of improvements in surgical and postoperative management, the parameters determining how much liver can be resected are still largely undefined. A number of preoperative, intraoperative and postoperative factors all contribute to the likelihood of liver failure after surgery. The safe limits for liver resection can be estimated from the data of the literature for patients with normal liver and for those with different types of liver injury. Preoperative assessment that includes evaluation of liver volume and function of the remnant liver is a mandatory prerequisite before major hepatectomy. The critical residual liver volume for patients able to predict PHLF is mainly related to the presence of pre-existing liver disease and liver function. Among patients with normal liver, the limit for safe resection ranges from 20 to 30% future remnant liver of total liver volume. In patients with injured liver (cirrhosis, cholestasis or steatosis), preoperative assessment of the risk of PHLF should include future remnant liver volumetry and accurate liver function evaluation, including different dynamic liver function tests.


The latency of the light response is modulated by the phosphorylation state of Drosophila TRP at a specific site.
Drosophila photoreceptors respond to oscillating light of high frequency (∼100 Hz), while increasing the oscillating light intensity raises the maximally detected frequency. Recently, we reported that dephosphorylation of the light-activated TRP ion channel at S936 is a fast, graded, light-, and Ca2+-dependent process. We further found that this process affects the detection limit of high frequency oscillating light. Accordingly, transgenic Drosophila, which do not undergo phosphorylation at the S936-TRP site (trpS936A), revealed a short time-interval before following the high stimulus frequency (oscillation-lock response) in both dark- and light-adapted flies. In contrast, the trpS936D transgenic flies, which mimic constant phosphorylation, showed a long-time interval to oscillation-lock response in both dark- and light-adapted flies. Here we extend these findings by showing that dark-adapted trpS936A flies reveal light-induced current (LIC) with short latency relative to trpWT or trpS936D flies, indicating that the channels are a limiting factor of response kinetics. The results indicate that properties of the light-activated channels together with the dynamic light-dependent process of TRP phosphorylation at the S936 site determine response kinetics.


2,3,5-triphenyl tetrazolium chloride as colorimetric indicator for drug susceptibility testing against nontuberculous mycobacteria.
This study aimed to propose and evaluate a drug susceptibility testing (DST) using the 2,3,5-triphenyl tetrazolium chloride (TTC) as a colorimetric indicator against Mycobacterium abscessus complex (MABC), M. avium complex (MAC), and M. kansasii strains, main nontuberculous mycobacteria (NTM) of clinical relevance. Our results demonstrated that the assay using TTC and the broth microdilution method recommended by the Clinical and Laboratory Standards Institute had essential agreement above 91%, 92%, and 100%, for drugs tested against MABC, MAC, and M. kansasii strains, respectively. Categorical agreement above 91% was obtained for most drugs tested against MABC, except to cefoxitin (76.5%). For drugs tested against MAC and M. kansasii, categorical agreement above 92% and 100% was observed, respectively. TTC showed to be a promising colorimetric indicator of growth to be used in DST for NTM, allowing an easier reading of results.


Longitudinal change in basal ganglia volume in patients with Huntington's disease.
Cross-sectional MRI studies demonstrating an association between caudate atrophy and symptom severity and duration of symptoms in patients with Huntington's disease (HD) have been assumed to reflect longitudinal changes in basal ganglia, but such neuropathologic progression has never been directly demonstrated. Subjects in the current study were 23 HD patients at various stages of the disorder who had two MRI images at least 10 months apart (mean interimage interval = 20.8 months). We measured volumes of caudate, putamen, and globus pallidus blind to the order of the images. For each structure, we calculated a change score by subtracting the volume obtained on the follow-up imaging from that obtained on the initial imaging. Results indicated significant decreases over time in caudate, putamen, and total basal ganglia volume. Age at onset and length of trinucleotide repeat correlated significantly with amount of volume change in caudate and total basal ganglia, even after controlling for length of interimage interval, duration of disease, and measures of symptom severity. Amount of change in basal ganglia structures was not significantly correlated with neurologic symptom severity at the time of the initial imaging or duration of symptoms. This is the first longitudinal MRI study to document progressive basal ganglia atrophy in HD, and suggests that quantitative neuroimaging with serial MRI may be useful in monitoring effectiveness of potential treatments. In addition, demonstration of greater rate of basal ganglia atrophy in patients with earlier symptom onset suggests that treatment effects may be more quickly observed in this subgroup of patients than in the general HD population.


MNS1 variant associated with situs inversus and male infertility.
Ciliopathy disorders due to abnormalities of motile cilia encompass a range of autosomal recessive conditions typified by chronic otosinopulmonary disease, infertility, situs abnormalities and hydrocephalus. Using a combination of genome-wide SNP mapping and whole exome sequencing (WES), we investigated the genetic cause of a form of situs inversus (SI) and male infertility present in multiple individuals in an extended Amish family, assuming that an autosomal recessive founder variant was responsible. This identified a single shared (2.34 Mb) region of autozygosity on chromosome 15q21.3 as the likely disease locus, in which we identified a single candidate biallelic frameshift variant in MNS1 [NM_018365.2: c.407_410del; p.(Glu136Glyfs*16)]. Genotyping of multiple family members identified randomisation of the laterality defects in other homozygous individuals, with all wild type or MNS1 c.407_410del heterozygous carriers being unaffected, consistent with an autosomal recessive mode of inheritance. This study identifies an MNS1 variant as a cause of laterality defects and male infertility in humans, mirroring findings in Mns1-deficient mice which also display male infertility and randomisation of left-right asymmetry of internal organs, confirming a crucial role for MNS1 in nodal cilia and sperm flagella formation and function.


Full-range, high-speed, high-resolution 1 microm spectral-domain optical coherence tomography using BM-scan for volumetric imaging of the human posterior eye.
An alternative optical coherence tomography (OCT) to clinical ophthalmic 830 nm spectral-domain OCTs (SD-OCT) is demonstrated. An axial resolution of 7.4 microm, ranging depth of 4.2 mm in tissue, sensitivity of 98.5 dB, and detection speed of 38,300 axial scans/s have been achieved. These are comparable or superior to those of recently commercially available ophthalmic 830 nm SD-OCTs in clinics. In addition, fast volumetric imaging for the in vivo human posterior eye with high-contrast of the choroid is achieved. A broadband 1.04 microm light source enables the high-contrast and high resolution imaging of the retina and choroid. The ranging depth is extended by applying a full-range imaging method with an electro-optic modulator (BM-scan method). A prototype high-speed InGaAs line scan camera with 1024 pixels is used. A newly reported sensitivity improvement property of the BM-scan method demonstrates a sensitivity enhancement of 5.1 dB. We also introduce a newly developed resampling calibration method of spectrum that is independent of the intrinsic dispersion mismatch of the interferometer. The three-dimensional structure of the in vivo human optic nerve head with a very deep cupping is successfully visualized.


Endoplasmic reticulum stress causes autophagy and apoptosis leading to cellular redistribution of the autoantigens Ro/Sjögren's syndrome-related antigen A (SSA) and La/SSB in salivary gland epithelial cells.
The aim of this study was to examine the levels of endoplasmic reticulum (ER) stress in minor salivary glands, to investigate the interplay between ER stress-induced autophagy and apoptosis in human salivary gland (HSG) cells and to test the effect of ER stress-induced apoptosis on the cellular redistribution of the two major Sjögren's syndrome (SS) autoantigens Ro/Sjögren's syndrome-related antigen A (SSA) and La/Sjögren's syndrome-related antigen B (SSB). Minor salivary gland biopsies from SS patients and sicca controls were examined by immunohistochemistry for the expression of 78 kDa glucose-regulated protein/binding immunoglobulin protein (GRP78/BiP) as an indicator of unfolded protein response (UPR). HSG cells were treated with thapsigargin (TG) and cell viability, autophagy and apoptosis were assessed. Immunoblot was applied to detect the conversion of LC3I to LC3II and the protein levels of GRP78/BiP and X-box binding protein-1 (XBP-1). Apoptosis was evaluated by a single-stranded DNA enzyme-linked immunosorbent assay (ELISA). Ro/SSA and La/SSB localization was visualized using immunofluorescence. GRP78/BiP was expressed by acinar and ductal epithelial cells in salivary glands of patients and sicca controls. TG treatment induced autophagy, as indicated by enhanced protein expression of LC3II. The protein levels of UPR marker XBP-1 were increased after TG treatment, while GRP78/BiP levels were decreased. TG treatment resulted in induction of HSG apoptosis. Ro/SSA and La/SSB autoantigens were localized predominantly to the cytoplasm in resting cells, while they were redistributed to cell membrane and blebs in the apoptotic cells. In conclusion, ER stress is activated in minor salivary gland epithelial cells from SS patients and controls. ER stress-induced apoptosis in HSG cells leads to cell surface and apoptotic blebs relocalization of Ro/SSA and La/SSB autoantigens.


Biology of the Precambrian Genus Kakabekia: New Observations on Living Kakabekia barghoorniana.
Kakabekia barghoorniana Siegel, living species of a fossil genus Kakabekia, has now been cultured from Alaskan soil samples obtained from the Mendenhall Glacier near Juneau and from the Point Barrow region above the Arctic Circle. Morphological comparisons, especially of mantle variations, show that fossil and living populations overlap in many details. Cytochemical tests demonstrate that living Kakabekia has no storage forms of lipid or polysaccharide and no phenoloxidase. Some individuals (19-33%) contain heme enzymes but most do not; hence they cannot utilize O(2) even in air.


Rapid voltage-dependent dissociation of scorpion alpha-toxins coupled to Na channel inactivation in amphibian myelinated nerves.
The voltage-dependent action of several scorpion alpha-toxins on Na channels was studied in toad myelinated nerve under voltage clamp. These toxins slow the declining phase of macroscopic Na current, apparently by inhibiting an irreversible channel inactivation step and thus permitting channels to reopen from a closed state in depolarized membranes. In this article, we describe the rapid reversal of alpha-toxin action by membrane depolarizations more positive than +20 mV, an effect not achieved by extensive washing. Depolarizations that were increasingly positive and of longer duration caused the toxin to dissociate faster and more completely, but only up to a limiting extent. Repetitive pulses had a cumulative effect equal to that of a single pulse lasting as long as their combined duration. When the membrane of a nonperfused fiber was repolarized, the effects of the toxin returned completely, but if the fiber was perfused during the conditioning procedure, recovery was incomplete and occurred more slowly, as it did at lower applied toxin concentrations. Other alpha-type toxins, from the scorpion Centruroides sculpturatus (IVa) and the sea anemone Anemonia sulcata (ATXII), exhibited similar voltage-dependent binding, though each had its own voltage range and dissociation rate. We suggest that the dissociation of the toxin molecule from the Na channel is coupled to the inactivation process. An equivalent valence for inactivation gating, of less than 1 e per channel, is calculated from the voltage-dependent change in toxin affinity.


Effect of pulse temporal shape on optical trapping and impulse transfer using ultrashort pulsed lasers.
We investigate the effects of pulse duration on optical trapping with high repetition rate ultrashort pulsed lasers, through Lorentz-Mie theory, numerical simulation, and experiment. Optical trapping experiments use a 12 femtosecond duration infrared pulsed laser, with the trapping microscope's temporal dispersive effects measured and corrected using the Multiphoton Intrapulse Interference Phase Scan method. We apply pulse shaping to reproducibly stretch pulse duration by 1.5 orders of magnitude and find no material-independent effects of pulse temporal profile on optical trapping of 780nm silica particles, in agreement with our theory and simulation. Using pulse shaping, we control two-photon fluorescence in trapped fluorescent particles, opening the door to other coherent control applications with trapped particles.


Polypyrimidine tract binding protein functions as a repressor to regulate alternative splicing of alpha-actinin mutally exclusive exons.
The smooth muscle (SM) and nonmuscle (NM) isoforms of alpha-actinin are produced by mutually exclusive splicing of an upstream NM exon and a downstream SM-specific exon. A rat alpha-actinin genomic clone encompassing the mutually exclusive exons was isolated and sequenced. The SM exon was found to utilize two branch points located 382 and 386 nucleotides (nt) upstream of the 3' splice site, while the NM exon used a single branch point 191 nt upstream. Mutually exclusive splicing arises from the proximity of the SM branch points to the NM 5' splice site, and this steric repression could be relieved in part by the insertion of spacer elements. In addition, the SM exon is repressed in non-SM cells and extracts. In vitro splicing of spacer-containing transcripts could be activated by (i) truncation of the transcript between the SM polypyrimidine tract and exon, (ii) addition of competitor RNAs containing the 3' end of the actinin intron or regulatory sequences from alpha-tropomyosin (TM), and (iii) depletion of the splicing extract by using biotinylated alpha-TM RNAs. A number of lines of evidence point to polypyrimidine tract binding protein (PTB) as the trans-acting factor responsible for repression. PTB was the only nuclear protein observed to cross-link to the actinin RNA, and the ability of various competitor RNAs to activate splicing correlated with their ability to bind PTB. Furthermore, repression of alpha-actinin splicing in the nuclear extracts depleted of PTB by using biotinylated RNA could be specifically restored by the addition of recombinant PTB. Thus, alpha-actinin mutually exclusive splicing is enforced by the unusual location of the SM branch point, while constitutive repression of the SM exon is conferred by regulatory elements between the branch point and 3' splice site and by PTB.


Canavan's spongiform leukodystrophy: a clinical anatomy of a genetic metabolic CNS disease.
Canavan disease (CD) is a globally distributed early-onset leukodystrophy. It is genetic in nature, and results from an autosomally inherited recessive trait that is characterized by loss of the axon's myelin sheath while leaving the axons intact, and spongiform degeneration especially in white matter. There is also a buildup of N-acetyl-L-aspartate (NAA) in brain, as well as NAA acidemia and NAA aciduria. The cause of the altered NAA metabolism has been traced to several mutations in the gene for the production of aspartoacylase, located on chromosome 17, which is the primary enzyme involved in the catabolic metabolism of NAA. In this review, an attempt is made to correlate the change in NAA metabolism that results from the genetic defects in CD with the processes involved in the development of the CD syndrome. In addition, present efforts to counter the results of the genetic defects in this disease are also considered.


Conservation of the prion properties of Ure2p through evolution.
The yeast inheritable [URE3] element corresponds to a prion form of the nitrogen catabolism regulator Ure2p. We have isolated several orthologous URE2 genes in different yeast species: Saccharomyces paradoxus, S. uvarum, Kluyveromyces lactis, Candida albicans, and Schizosaccharomyces pombe. We show here by in silico analysis that the GST-like functional domain and the prion domain of the Ure2 proteins have diverged separately, the functional domain being more conserved through the evolution. The more extreme situation is found in the two S. pombe genes, in which the prion domain is absent. The functional analysis demonstrates that all the homologous genes except for the two S. pombe genes are able to complement the URE2 gene deletion in a S. cerevisiae strain. We show that in the two most closely related yeast species to S. cerevisiae, i.e., S. paradoxus and S. uvarum, the prion domains of the proteins have retained the capability to induce [URE3] in a S. cerevisiae strain. However, only the S. uvarum full-length Ure2p is able to behave as a prion. We also show that the prion inactivation mechanisms can be cross-transmitted between the S. cerevisiae and S. uvarum prions.


Experimental implication of celiac ganglionotropic invasion of pancreatic-cancer cells bearing c-ret proto-oncogene with reference to glial-cell-line-derived neurotrophic factor (GDNF).
Perineural invasion is a prominent clinical feature of pancreatic cancer which causes difficulty in curative resection. In the present study, the human pancreatic cancer cell lines, PaCa-2, AsPC-1, SW1990 and Capan-2, were all found to express abundant c-ret proto-oncogene mRNA and RET protein, a member of the receptor-tyrosine-kinase superfamily, identified as being a receptor for glial-cell-line-derived neurotrophic factor (GDNF). In an invasion assay, the migration of pancreatic cancer cells was markedly induced by co-cultivation with human glioma cells, T98G or A172, capable of producing and secreting GDNF. Anti-GDNF antibody in conditioned media of glioma cells suppressed much of the migratory activity. Checkerboard analysis of the migration showed both chemotactic and chemokinetic activity of GDNF. There was no detectable expression of another GDNF receptor component, a glycosyl-phosphatidylinositol-linked receptor (GFR alpha-1), in pancreatic-cancer cell lines, suggesting that the neural invasion of pancreatic-cancer cells spreads along a concentration gradient of GDNF produced from peripheral ganglions through direct interaction of GDNF with its receptor, the c-ret proto-oncogene product. Immunochemical localization of GDNF in human celiac ganglionic tissue supported this contention.


Consumption of pornographic materials among Hong Kong early adolescents: a replication.
Consumption of pornographic materials was examined in 3,638 secondary 2 students in Hong Kong. Results showed that over 80% of the respondents had never consumed pornographic materials in the past year. Internet pornography was the most common medium that adolescents used when viewing pornographic materials. Males reported a higher level of pornography consumption than did females. Participants who were born in mainland China were more likely to consume pornographic materials than their Hong Kong counterparts. Regardless of the types of pornographic materials, the levels of pornography consumption significantly increased over time. Results also showed that higher levels of positive youth development and better family functioning were concurrently related to a lower level of pornography consumption at secondary 2. The relative contribution of positive youth development and family factors to pornographic material consumption was also explored.


Temperament and Social Problem Solving Competence in Preschool: Influences on Academic Skills in Early Elementary School.
The goals of the current study were to examine whether children's social problem solving (SPS) skills are a mechanism through which temperament influences later academic achievement and whether sex moderates these associations. Participants included 1,117 children enrolled in the NICHD Early Child Care Study. During preschool, mothers and childcare providers rated children's temperamental shyness and inhibitory control, and SPS was assessed using a hypothetical-reflective measure during a laboratory visit. During kindergarten and first grade, teacher-report of math and language skills was collected. Results indicated that high ratings of inhibitory control in preschool, but not shyness, predicted better kindergarten and first grade academic skills. Furthermore, children's SPS competence mediated the relations between both shyness and inhibitory control on later academic skills. The child's sex did not moderate these associations. Results suggest that preventative efforts targeting early SPS skills may buffer against later academic adjustment problems among temperamentally extreme children.


Evaluating self-directed learning abilities as a prerequisite of health literacy among older people: Findings from a validation and a cross-sectional study.
To validate a tool measuring self-directed learning (SDL) abilities and to determine these abilities among older individuals attending the University of the Third Age. Health literacy (HL) and SDL abilities have been documented as being closely linked to each other and as prerequisites in enhancing self-management competences required by older people to protect their health and to manage health issues. Furthermore, individuals with SDL abilities have been documented to have a full understanding of their health treatment prescriptions, to be able to demonstrate increased compliance and to further develop self-care competences. A validation and a cross-sectional study design. A consecutive sample of 313 older people (68.7% female) who attended lessons in two Italian Universities of the Third Age and who were willing to participate in the study were enrolled. The Self-Rating Scale of Self-Directed Learning (SRSSDL) validated previously in the healthcare context, was used. At the exploratory and confirmatory factor analysis, the SRSSDL in Older people (SRSSDLO) has demonstrated good psychometric properties: the tool is composed by four factors ("Awareness," "Attitudes," "Availability" and "Motivation") and 13 items. According to the findings, the average SDL score was 54.27 ± 6.69 out of 65, and women achieved significantly higher scores compared with men (54.81 ± 6.69 vs. 53.08 ± 6.54, p = .033), while participants with a university degree (55.95 ± 6.56) or secondary education (54.75 ± 6.13) had higher scores than those with lower secondary education (50.37 ± 7.34, p = .002). Participants were responsible for their learning processes and were capable of identifying learning needs and goals. They were also internally motivated to develop learning methods and to organise learning activities. However, they were less able to keep up to date with the learning resources available. The SRSSDLO can help nurses identify healthy older people that lack SDL abilities and design tailored educational interventions to prevent health conditions and/or promote self-care management in chronic conditions.


Cell lineage tracing reveals the plasticity of the hemocyte lineages and of the hematopoietic compartments in Drosophila melanogaster.
Much of our knowledge on hematopoiesis, hematopoietic compartments, hematopoietic cell lineages and immunity has been derived from studies on the vertebrate immune system. The sophisticated innate immunity of insects, the phylogenetic conservation and the power of Drosophila genetics allowed the investigation of immune cell (hemocyte) lineage relationships in Drosophila melanogaster. The development of the hemocyte lineages in Drosophila is a result of a precisely regulated succession of intracellular and intercellular events, though the nature and extent of these interactions are not known. We describe here a cell lineage tracing system set up to analyze the development of hemocyte lineages and functionally distinct hemocyte subsets. This system allowed us to distinguish two major embryonic hemocyte lineages, the crq and Dot lineages, in two, physically separated compartments, the embryonic macrophages and the embryonic lymph gland. We followed the fate and development of these lineages in the construction of the larval hematopoietic compartments and during the cell-mediated immune response, the encapsulation reaction. Our results revealed the considerable plasticity and concerted action of the hematopoietic compartments and the hemocyte lineages in the development of the innate immune system and in the course of the cell-mediated immune response in Drosophila.


Membrane properties of excitatory and inhibitory neurons in the rat prepositus hypoglossi nucleus.
The prepositus hypoglossi nucleus (PHN) is thought to be a neural structure involved in transforming eye or head velocity signals into eye position signals for horizontal eye movements. In this study, we investigated the relationship between electrophysiological membrane properties and expression patterns of cellular markers for excitatory and inhibitory neurons by whole-cell patch clamp recordings followed by reverse transcription polymerase chain reaction (RT-PCR) analysis in rat brainstem slices. Three types of voltage response properties, namely afterhyperpolarization (AHP), firing pattern, and response to hyperpolarizing current pulses, were characterized in each neuron. Following RT-PCR analysis, we identified PHN neurons as either glutamatergic (n = 22) or GABAergic (n = 43), although a small number of cholinergic (n = 2) and glycinergic neurons (n = 1) were also identified. Both glutamatergic and GABAergic neurons showed a wide variety of membrane properties; however, we found several characteristic relationships between neuronal type and membrane properties. Most neurons exhibiting (i) AHP without a slow component, (ii) a firing pattern with a delay in the generation of the first spike, (iii) a firing pattern with a transient burst and (iv) a firing pattern with a prolonged initial interspike interval were GABAergic. On the other hand, glutamatergic neurons were primarily characterized by a low firing rate. These results indicate that there is a close relationship between specific electrophysiological membrane properties and expression of chemical markers in some types of glutamatergic and GABAergic PHN neurons.


Confounding factors in diagnostics of MGMT promoter methylation status in glioblastomas in stereotactic biopsies.
In nonresectable glioblastoma (GBM), stereotactic biopsies are performed to retrieve tissue for diagnostic purposes. The analysis of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation adds prognostic and predictive information. The aim of the study was to detect confounding factors that limit the number of conclusive MGMT promoter methylation results. We analyzed 71 consecutive GBM patients undergoing stereotactic biopsy on whom MGMT analysis was performed by methylation-specific polymerase chain reaction. Specimens were correlated to imaging by coregistration and prospective documentation of biopsy localization. Our findings were validated in an additional 62 GBM stereotactic biopsies. Our results demonstrate that the best MGMT promoter methylation results were obtained from samples (n = 71) taken in a tangential manner from tumor areas showing contrast enhancement in magnetic resonance imaging. In the additional validation series of 62 stereotactically biopsied GBM, we were able to increase the rate of conclusive MGMT promoter methylation results from 76.1 to 85.48% by strictly planning the route of biopsy in a tangential manner if possible. These results underline that within the contrast-enhanced tumor part, choosing the trajectory in a tangential manner increases the diagnostic yield for conclusive MGMT promoter methylation analyses in stereotactic biopsies as a basis for patient stratification and individualized therapy.


Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function.
The formation of G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor (GPCR) heteromers enables signaling diversification and holds great promise for improved drug selectivity. Most studies of these oligomerization events have been conducted in heterologous expression systems, and in vivo validation is lacking in most cases, thus questioning the physiological significance of GPCR heteromerization. The melatonin receptors MT1 and MT2 exist as homomers and heteromers when expressed in cultured cells. We showed that melatonin MT1/MT2 heteromers mediated the effect of melatonin on the light sensitivity of rod photoreceptors in mice. This effect of melatonin involved activation of the heteromer-specific phospholipase C and protein kinase C (PLC/PKC) pathway and was abolished in MT1(-/-) or MT2(-/-) mice, as well as in mice overexpressing a nonfunctional MT2 mutant that interfered with the formation of functional MT1/MT2 heteromers in photoreceptor cells. Not only does this study establish an essential role of melatonin receptor heteromers in retinal function, it also provides in vivo support for the physiological importance of GPCR heteromerization. Thus, the MT1/MT2 heteromer complex may provide a specific pharmacological target to improve photoreceptor function.


Time-Transgressive Nature of the Magnetic Susceptibility Record across the Chinese Loess Plateau at the Pleistocene/Holocene Transition.
The loess stratigraphic boundary at the Pleistocene/Holocene transition defined by the magnetic susceptibility (MS) has previously been assumed to be synchronous with the Marine Isotope Stage (MIS) 2/1 boundary, and approximately time-synchronous at different sections across the Chinese Loess Plateau (CLP). However, although this assumption has been used as a basis for proxy-age model of Chinese loess deposits, it has rarely been tested by using absolute dating methods. In this study, we applied a single-aliquot regenerative-dose (SAR) protocol to the 45-63 μm quartz grain-size fraction to derive luminescence ages for the last glacial and Holocene sections of three loess sections on a transect from southeast to northwest across the CLP. Based on the 33 closely spaced optically stimulated luminescence (OSL) samples from the three sections, OSL chronologies were established using a polynomial curve fit at each section. Based on the OSL chronology, the timing of the Pleistocene/Holocene boundary, as defined by rapid changes in MS values, is dated at ~10.5 ka, 8.5 ka and 7.5 ka in the Yaoxian section, Jingchuan and Huanxian sections respectively. These results are clearly inconsistent with the MIS 2/1 boundary age of 12.05 ka, and therefore we conclude that the automatic correlation of the Pleistocene/Holocene transition, as inferred from the MS record, with the MIS 2/1 boundary is incorrect. The results clearly demonstrate that the marked changes in MS along the southeast to northwest transect are time-transgressive among the different sites, with the timing of significant paleosol development as indicated by the MS record being delayed by 3-4 ka in the northwest compared to the southeast. Our results suggest that this asynchronous paleosol development during the last deglacial was caused by the delayed arrival of the summer monsoon in the northwest CLP compared to the southeast.


Seek and destroy process: Listeria monocytogenes process controls in the ready-to-eat meat and poultry industry.
The majority of human listeriosis cases appear to be caused by consumption of ready-to-eat (RTE) foods contaminated at the time of consumption with high levels of Listeria monocytogenes. Although strategies to prevent growth of L. monocytogenes in RTE products are critical for reducing the incidence of human listeriosis, control of postprocessing environmental contamination of RTE meat and poultry products is an essential component of a comprehensive L. monocytogenes intervention and control program. Complete elimination of postprocessing L. monocytogenes contamination is challenging because this pathogen is common in various environments outside processing plants and can persist in food processing environments for years. Persistent L. monocytogenes strains in processing plants have been identified as the most common postprocessing contaminants of RTE foods and the cause of multiple listeriosis outbreaks. Identification and elimination of L. monocytogenes strains persisting in processing plants is thus critical for (i) compliance with zero-tolerance regulations for L. monocytogenes in U.S. RTE meat and poultry products and (ii) reduction of the incidence of human listeriosis. The seek-and-destroy process is a systematic approach to finding sites of persistent strains (niches) in food processing plants, with the goal of either eradicating or mitigating effects of these strains. This process has been used effectively to address persistent L. monocytogenes contamination in food processing plants, as supported by peer-reviewed evidence detailed here. Thus, a regulatory environment that encourages aggressive environmental Listeria testing is required to facilitate continued use of this science-based strategy for controlling L. monocytogenes in RTE foods.


Chronic pelvic pain and gynecological symptoms in women with irritable bowel syndrome.
Chronic pelvic pain and irritable bowel syndrome are common disorders, yet very little is known about their comorbidity. As part of an epidemiological study of patients with irritable bowel syndrome or irritable bowel disease we inquired about a history of chronic pelvic pain and related gynecological problems, and hypothesized that distress associated with either of these conditions was additive in women with both syndromes. A medically trained interviewer evaluated a sequential sample of 60 women with irritable bowel syndrome and 26 women with inflammatory bowel disease in an urban gastroenterology clinic using the National Institute of Mental Health Diagnostic Interview Schedule, the Briere Child Maltreatment Interview (emotional, physical and sexual abuse), and a structured interview to elicit a lifetime history of chronic pelvic pain that was distinct from the history of bowel distress. Chronic pelvic pain was reported in 21 (35.0%) of the irritable bowel syndrome patients vs. 4 (13.8%) of the inflammatory bowel disease group (p < 0.05). Compared to women with irritable bowel syndrome alone, those with both irritable bowel syndrome and chronic pelvic pain were significantly more likely to have a lifetime history of dysthymic disorder, current and lifetime panic disorder, somatization disorder, childhood sexual abuse and hysterectomy. Logistic regression showed that mean number of somatization symptoms was the best predictor of a history of both irritable bowel syndrome and chronic pelvic pain compared either to inflammatory bowel disease or irritable bowel syndrome alone. Many women with irritable bowel syndrome may have a history of chronic pelvic pain as well. The high rates of psychopathology associated with irritable bowel syndrome and chronic pelvic pain independently are even higher in women with both syndromes, and women who present with either irritable bowel syndrome or chronic pelvic pain should probably be evaluated for both disorders.


IFN-γ alters the expression of diverse immunity related genes in a cell culture model designed to represent maturing neutrophils.
The cytokine interferon-γ (IFN-γ) is approved as a drug to treat chronic granulomatous disease (CGD) and osteopetrosis and is also used in hyperimmunoglobulin E syndromes. Patients with CGD have defects in proteins of the NOX2 NADPH oxidase system. This leads to reduced production of microbicidal ROS by PMNs and recurrent life threatening infections. The goal of this study was to better understand how IFN-γ might support phagocyte function in these diseases, and to obtain information that might expand potential uses for IFN-γ. Neutrophils mature in the bone marrow and then enter the blood where they quickly undergo apoptotic cell death with a half-life of only 5-10 hours. Therefore we reasoned that IFN-γ might exert its effects on neutrophils via prolonged exposure to cells undergoing maturation in the marrow rather than by its brief exposure to short-lived circulating cells. To explore this possibility we made use of PLB-985 cells, a myeloblast-like myeloid cell line that can be differentiated into a mature, neutrophil-like state by treatment with various agents including DMSO. In initial studies we investigated transcription and protein expression in PLB-985 cells undergoing maturation in the presence or absence of IFN-γ. We observed IFN-γ induced differences in expression of genes known to be involved in classical aspects of neutrophil function (transmigration, chemotaxis, phagocytosis, killing and pattern recognition) as well as genes involved in apoptosis and other mechanisms that regulating neutrophil number. We also observed differences for genes involved in the major histocompatibility complex I (MHCI) and MHCII systems whose involvement in neutrophil function is controversial and not well defined. Finally, we observed significant changes in expression of genes encoding guanylate binding proteins (Gbps) that are known to have roles in immunity but which have not as yet been linked to neutrophil function. We propose that changes in the expression within these classes of genes could help explain the immune supportive effects of IFN-γ. Next we explored if the effect of IFN-γ on expression of these genes is dependent on whether the cells are undergoing maturation; to do this we compared the effects of IFN-γ on cells cultured with and without DMSO. For a subset of genes the expression level changes caused by IFN-γ were much greater in maturing cells than non-maturing cells. These findings indicate that developmental changes associated with cell maturation can modulate the effects of IFN-γ but that this is gene specific. Since the effects of IFN-γ depend on whether cells are maturing, the gene expression changes observed in this study must be due to more than just prolonged application of IFN-γ and are instead the result of interplay between cell maturation and changes caused by the chemokine. This supports our hypothesis that the effects of IFN-γ on developing neutrophils in the bone marrow may be very different from its effects on mature cells in the blood. Collectively the findings in this study enhance our understanding of the effects of IFN-γ on maturing myeloid cells and indicate possible mechanisms by which this cytokine could support immune function.


[Ways of thinking: personality affects reasoning].
Ways of thinking: Personality affects reasoning. This paper presents an investigation testing the idea that personality affects the way people reason in a predictable way. That is to say, traits may affect the particular possibilities that individuals envisage and so, in turn, how they reason. Different traits can elicit different ways of thinking and as a result, individuals would reason better in the fields that are pertinent to their personality. We tested 94 participants with the NEO-PI-R and with a conditional inference task that was tailored based on the items in the NEO-PI-R personality test. We found, in general, that our participants reasoned better (higher rate of Modus Tollens) with the materials that were related to the personality trait in which they scored highest. Also, the participants who scored high in Extraversion or Neuroticism produced more valid inferences for the items related to their personality than those who scored low in the same trait. These results are in accordance with the principle of inferential consequences and the Mental Models Theory of Reasoning.


Licensing of primordial germ cells for gametogenesis depends on genital ridge signaling.
In mouse embryos at mid-gestation, primordial germ cells (PGCs) undergo licensing to become gametogenesis-competent cells (GCCs), gaining the capacity for meiotic initiation and sexual differentiation. GCCs then initiate either oogenesis or spermatogenesis in response to gonadal cues. Germ cell licensing has been considered to be a cell-autonomous and gonad-independent event, based on observations that some PGCs, having migrated not to the gonad but to the adrenal gland, nonetheless enter meiosis in a time frame parallel to ovarian germ cells -- and do so regardless of the sex of the embryo. Here we test the hypothesis that germ cell licensing is cell-autonomous by examining the fate of PGCs in Gata4 conditional mutant (Gata4 cKO) mouse embryos. Gata4, which is expressed only in somatic cells, is known to be required for genital ridge initiation. PGCs in Gata4 cKO mutants migrated to the area where the genital ridge, the precursor of the gonad, would ordinarily be formed. However, these germ cells did not undergo licensing and instead retained characteristics of PGCs. Our results indicate that licensing is not purely cell-autonomous but is induced by the somatic genital ridge.


Human V4 Activity Patterns Predict Behavioral Performance in Imagery of Object Color.
Color is special among basic visual features in that it can form a defining part of objects that are engrained in our memory. Whereas most neuroimaging research on human color vision has focused on responses related to external stimulation, the present study investigated how sensory-driven color vision is linked to subjective color perception induced by object imagery. We recorded fMRI activity in male and female volunteers during viewing of abstract color stimuli that were red, green, or yellow in half of the runs. In the other half we asked them to produce mental images of colored, meaningful objects (such as tomato, grapes, banana) corresponding to the same three color categories. Although physically presented color could be decoded from all retinotopically mapped visual areas, only hV4 allowed predicting colors of imagined objects when classifiers were trained on responses to physical colors. Importantly, only neural signal in hV4 was predictive of behavioral performance in the color judgment task on a trial-by-trial basis. The commonality between neural representations of sensory-driven and imagined object color and the behavioral link to neural representations in hV4 identifies area hV4 as a perceptual hub linking externally triggered color vision with color in self-generated object imagery.SIGNIFICANCE STATEMENT Humans experience color not only when visually exploring the outside world, but also in the absence of visual input, for example when remembering, dreaming, and during imagery. It is not known where neural codes for sensory-driven and internally generated hue converge. In the current study we evoked matching subjective color percepts, one driven by physically presented color stimuli, the other by internally generated color imagery. This allowed us to identify area hV4 as the only site where neural codes of corresponding subjective color perception converged regardless of its origin. Color codes in hV4 also predicted behavioral performance in an imagery task, suggesting it forms a perceptual hub for color perception.


Dynamics and Energetics of the Explosive Vaporization of Fog Droplets by a 10.6-microm Laser Pulse.
The explosive vaporization of individual water droplets (5 microm to 25 microm radius) by a 10.6-microm laser pulse has been observed with a high speed schlieren photography system. The hot vapor and the shock wave produced by the explosive vaporization can be clearly seen in the schlieren photographs. The expansion rate of the heated air mass has been measured. Factors affecting the shape of the volume of heated air are discussed, and the energy balance of the process is considered.


Five top stories in cytopathology.
Cytology relies heavily on morphology to make diagnoses, and morphologic criteria have not changed much in recent years. The field is being shaped predominantly by new techniques for imaging and for acquiring and processing samples, advances in molecular diagnosis and therapeutics, and regulatory issues. To review the importance of classical morphology in the future of cytopathology, to identify areas in which cytology is expanding or contracting in its scope, and to identify factors that are shaping the field. Literature review. Five stories paint a picture in which classical cytomorphology will continue to have essential importance, both for diagnosis and for improving our understanding of cancer biology. New endoscopy and imaging techniques are replacing surgical biopsies with cytology samples. New molecularly targeted therapies offer a chance for cytology to play a major role, but they pose new challenges. New molecular tests have the potential to synergize with, but not replace, morphologic interpretation of thyroid fine-needle aspirations. Ultrasound-guided fine-needle aspiration performed by cytopathologists is opening a new field of "interventional cytopathology" with unique value. For the productive evolution of the field, it will be important for cytopathologists to play an active role in clinical trials that document the ability of cytology to achieve cost-effective health care outcomes.


Accuracy of patient-reported spell duration: A comparative study.
Clinicians rely heavily on patient histories to make medical diagnoses, most of which are inherently subjective and prone to inaccuracies. The aim of this study is to compare the subjective versus objective duration of spells through a retrospective chart review of patients admitted to the epilepsy monitoring unit at our tertiary care medical center. One hundred patients were analyzed. Differences in the accuracy of subjective estimations versus objective duration were compared by age, sex, focal versus generalized, location (frontal versus non-frontal), and spell type (focal aware versus impaired awareness and epileptic versus non-epileptic). Our data show that patients are poor subjective estimators, with 73% of patients overestimating the duration of their spells. We did not find differences in estimated duration by age, sex, seizure location or spell type. A notable exception was patients with generalized convulsive seizures, who accurately reported spell duration to within 17 s. This is likely because these seizures are stereotypical, and patients/family time them. Moreover, patients with non-epileptic spells were worse estimators of their spell duration than those with epileptic spells. In addition, although the prefrontal lobe plays a role in time estimation, we did not find that patients with frontal lobe seizures were worse estimators than those with non-frontal seizures, but invasive monitoring can more precisely localize seizures within areas of the frontal lobe responsible for time estimation. Our data emphasize the importance of not relying solely on patient-reported time estimation in diagnosing and developing treatment plans and instead instructing patients to time their spells.


The all2 gene is required for the induction of the purine deamination pathway in Schizosaccharomyces pombe.
Five mutants were isolated at the all2 gene on the basis of their inability to utilize hypoxanthine as a sole source of nitrogen. These mutants failed to utilize the purines adenine, hypoxanthine, xanthine, uric acid, allantoin and allantoic acid, although they could utilize urea and ammonium. The all2 mutants appeared to be defective in purine induction of uricase, allantoinase, allantoicase and ureidoglycollase activities but retained wild-type activity of the constitutively synthesized urease. The all2 mutations were recessive.


Use of Colorectal Cancer Screening Among People With Mobility Disability.
We aimed to assess use of colorectal cancer screening (CRCS) as per United States Preventive Task Force guidelines among people with mobility disability using a nationally representative data set. Individuals with mobility disability have decreased access to health care services, but the impact of mobility disability on CRCS has not been investigated. Data from the 2013 National Health Interview Survey were used to estimate sociodemographic characteristics of adults with mobility disability, prevalence of CRCS, and odds of CRCS given mobility disability among Americans aged 50 to 75. In total, 56.8% of the entire sample (n=81,953,585) were up-to-date with CRCS. Mobility disability was not associated with CRCS status on univariable analysis but was significantly associated after adjustment for covariates including age and comorbidities, with an inverse relationship between the degree of mobility disability and odds of CRCS. Odds ratio for CRCS given progressively severe disability were 0.78 (0.66 to 0.93), 0.71 (0.53 to 0.94), 0.65 (0.31 to 1.19). The present study indicates reduced CRCS among people with mobility disability and highlights the need for CRCS to be especially targeted toward this group. Future research should identify the specific systemic, social, and/or physical barriers to CRCS for this subgroup so that they can be addressed.


The effects of slow- and fast-rhythm classical music on progressive cycling to voluntary physical exhaustion.
To investigate, based on the parallel information processing model and arousal hypothesis, whether musical tempo and its manipulation during exercise affect the maximal workload (watts) achieved during progressive cycling. repeated measures experiment that involved one control and four treatment conditions. the experiment was performed in a controlled laboratory environment. twenty-four male and female volunteers, recruited from among a University population, were tested. the data collection proceeded in five counterbalanced test-sessions that included control (C), slow music (SM), fast music (FM) slow to fast music (SFM) and fast to slow music (FSM) interventions. In the last two conditions, musical tempo was changed when the participant's maximal HR reserve has reached 70%. In all test-sessions, participants started to cycle at 50 watts and then the workload was increased in increments of 25 watts every minute until self-declared exhaustion. Maximal ergometer cycling was defined as the workload at the last completed minute of exercise. workload, HR, and postexperimental ratings of test-session preferences were the dependent measures. Significantly higher workload was accomplished in the SFM condition. No between-session differences were seen in HR. The results also yielded significantly better "efficiency", in terms of workload/HR reserve ratio, in the SFM session. PARTICIPANTS preferred the FM and SFM sessions more than the other sessions. Switching to FM during progressive exercise results in the accomplishment of more work without proportional changes in HR. These effects may be due to distraction from fatigue and are, apparently, dependent on the attention capturing strength of the distracting stimulus.


Differences in notifiable infectious disease morbidity among adult women--United States, 1992-1994.
By 1990, all 50 states were using the Centers for Disease Control and Prevention (CDC) National Electronic Telecommunications System for Surveillance to report individual case data that included demographic information (without personal identifiers) about most notifiable diseases. This analysis of National Notifiable Diseases Surveillance System (NNDSS) data is useful for evaluating the distribution of reported notifiable infectious diseases among adult women by age and race. The number of cases of the 48 nationally notifiable infectious diseases reported among adult women (i.e., women > or = 15 years of age) were compiled for 1992-1994. These data were then analyzed by age and race, and rates per 100,000 adult women were calculated. During 1992-1994, the 10 most commonly reported nationally notifiable diseases among adult women in the United States were, in descending order of frequency, gonorrhea, primary/secondary syphilis, acquired immunodeficiency syndrome (AIDS), salmonellosis, tuberculosis, hepatitis A, hepatitis B, shigellosis, Lyme disease, and hepatitis C/non-A non-B. Gonorrhea was the most commonly reported notifiable infectious disease for women of all ages, except those ages > or = 55 years, and for women of all races, except Asian/Pacific Islanders. Tuberculosis was the most commonly reported infectious disease among women of Asian/Pacific Island descent. Analysis of NNDSS data provides information about the relative reported burden of diseases among women of all ages and different races. This information may be used for targeting research, prevention, and control efforts.


Large Block Copolymer Self-Assembly for Fabrication of Subwavelength Nanostructures for Applications in Optics.
Nanostructured surfaces are common in nature and exhibit properties such as antireflectivity (moth eyes), self-cleaning (lotus leaf), iridescent colors (butterfly wings), and water harvesting (desert beetles). We now understand such properties and can mimic some of these natural structures in the laboratory. However, these synthetic structures are limited since they are not easily mass produced over large areas due to the limited scalability of current technologies such as UV-lithography, the high cost of infrastructure, and the difficulty in nonplanar surfaces. Here, we report a solution process based on block copolymer (BCP) self-assembly to fabricate subwavelength structures on large areas of optical and curved surfaces with feature sizes and spacings designed to efficiently scatter visible light. Si nanopillars (SiNPs) with diameters of ∼115 ± 19 nm, periodicity of 180 ± 18 nm, and aspect ratio of 2-15 show a reduction in reflectivity by a factor of 100, <0.16% between 400 and 900 nm at an angle of incidence of 30°. Significantly, the reflectivity remains below 1.75% up to incident angles of 75°. Modeling the efficiency of a SiNP PV suggests a 24.6% increase in efficiency, representing a 3.52% (absolute) or 16.7% (relative) increase in electrical energy output from the PV system compared to AR-coated device.


Receptors for E and F prostaglandins in airways.
Determination of dose/response relationships for E and F PGs in guinea pig trachea and human bronchial muscle in vitro indicates that mixed contractant and relaxant activities are present in different proportions in each PG. Further analysis of these effects, using (a) tachyphylaxis to individual PGs and (b) indomethacin as a PG antagonist, argues that two PG receptors exist on tracheobronchial muscle. Activation of one of these (chi receptor) leads to contraction, and of the other (psi receptor) to relaxation. Individual E and F PGs interact with these two receptors in different proportions. A third potent effect of PGs on airways is to elicit cough. That PGF2 alpha elicits cough but has very little relaxant activity, whereas certain PG analogs and PGE1 elicit cough but possess either no bronchomotor or almost entirely relaxant activity, argues that a third receptor (omega) exists, the activation of which elicits cough.


Confirmatory data from EU study supports Apligraf for the treatment of neuropathic diabetic foot ulcers.
A study of 72 subjects conducted in the European Union and Australia assessed the safety and efficacy of Apligraf (Organogenesis, Inc, Canton, Massachusetts), a bilayered cell therapy composed of living keratinocytes and living fibroblasts in the treatment of non-infected, diabetic foot ulcers (DFU). The design and patient population of this study were similar to a 208-subject United States study (Veves et al., 2001), which led to FDA approval of Apligraf for the treatment of DFU. EU patient outcomes were compared and contrasted to established US-based patient outcome parameters. Subjects with a non-infected neuropathic diabetic foot ulcer present for at least two weeks were enrolled in these prospective, multicenter, randomized, controlled, open-label studies that compared Apligraf used in conjunction with standard therapy (sharp debridement, standard wound care, and off-loading) against standard therapy alone. The design, conduct, and patient populations of the EU and US studies were comparable. Pooling of data was able to be performed because of the similarity and consistency of the two studies. Efficacy and safety results remained consistent across studies independent of mean ulcer duration that was significantly longer in the EU study (21 months, compared to 10 months in the US). Reported adverse events through 12 weeks were comparable across treatment groups in the two studies. Multiple efficacy measures consistently demonstrated superiority of Apligraf treatment over control treated groups in both studies. Combining the data from both studies, 55.2% (80/145) of Apligraf subjects had complete would closure by 12 weeks, compared to 34.3% (46/134) of Control subjects (P = 0.0005; Fisher's exact test), and Apligraf subjects had a significantly shorter time to complete wound closure (P = 0.0004; log-rank test). Both the EU and US studies exhibited superior efficacy and comparable safety for subjects treated with Apligraf compared to control treated subjects. The similar outcomes of the two studies provide robust, consistent evidence of the benefit of Apligraf in treating geographically disparate DFU patient populations.


Development of a Novel Endoscopic Scoring System to Predict Relapse after Surgery in Intestinal Behçet's Disease.
The cumulative surgery rate and postoperative relapse of intestinal Behçet's disease (BD) have been reported to be high. This study aimed to establish a scoring system based on follow-up endoscopic findings that can predict intestinal BD recurrence after surgery. Fifty-four patients with intestinal BD who underwent surgery due to bowel complications and underwent follow-up colonoscopy were retrospectively investigated. Their clinical data, including colonoscopic findings, were retrieved. Classification and regression tree analysis was used to develop an appropriate endoscopic classification model that can explain the postsurgical recurrence of intestinal BD most accurately based on the following classification: e0, no lesions; e1, solitary ulcer <20 mm in size; e2, solitary ulcer ≥20 mm in size; and e3, multiple ulcers regardless of size. Clinical relapse occurred in 37 patients (68.5%). Among 38 patients with colonoscopic recurrence, only 29 patients had clinically relapsed. Multivariate analysis identified higher disease activity index for intestinal BD at colonoscopy (hazard ratio [HR], 1.013; 95% confidence interval [CI], 1.005 to 1.021; p=0.002) and colonoscopic recurrence (HR, 2.829; 95% CI, 1.223 to 6.545; p=0.015) as independent risk factors for clinical relapse of intestinal BD. Endoscopic findings were classified into four groups, and multivariate analysis showed that the endoscopic score was an independent risk factor of clinical relapse (p=0.012). The risk of clinical relapse was higher in the e3 group compared to the e0 group (HR, 6.284; 95% CI, 2.036 to 19.391; p=0.001). This new endoscopic scoring system could predict clinical relapse in patients after surgical resection of intestinal BD.


Google Trends Analysis of Peripheral Nerve Disease and Surgery.
Despite advances in the surgical management of peripheral nerve pathologies over the past several decades, it is unknown how public awareness of these procedures has changed. We hypothesize that Google searches for peripheral nerve surgery have increased over time. Google Trends was queried for search volumes of a list of 40 keywords related to the following topics in peripheral nerve surgery: spasticity, nerve injury, prosthetics, and nerve pain. Monthly relative search volume over the first 5 years of the study period (2010-2014) was compared with that of the last 5 years (2018-2022) of the study period. Search volumes for keywords "nerve injury," "nerve laceration," "peripheral nerve injury," "nerve repair," "nerve transfer", "neuroma," "neuroma pain," "nerve pain," "nerve pain surgery," and "neuroma pain surgery" all increased more than 10% points in relative search volume over the study period (P < 0.0001 for each keyword). In contrast, searches for "rhizotomy," "spasticity surgery," "targeted muscle reinnervation," "bionic arm," and "myoelectric prosthesis" either decreased or remained stable. Technical terms such as "selective neurectomy," "hyperselective neurectomy," "regenerative peripheral nerve interface," and "regenerative peripheral nerve interface surgery" did not have adequate search volume to be reported by Google Trends. The increase in Google searches related to nerve injury and pain between 2010 and 2022 may reflect increasing public recognition of these clinical entities and surgical techniques addressing them. Technical terms relating to nerve pain are infrequently searched, surgeons should use plain English terms for online discovery. Interest in spasticity and myoelectric prosthetics remains stable, indicating an opportunity for better public outreach.


Failure of functional imaging with gallium-68-DOTA-D-Phe1-Tyr3-octreotide positron emission tomography to localize the site of ectopic adrenocorticotropic hormone secretion: a case report.
The diagnostic efficacy of biochemical and imaging modalities for investigating the causes of Cushing's syndrome are limited. We report a case demonstrating the limitations of these modalities, especially the inability of functional imaging to help localize the site of ectopic adrenocorticotropic hormone secretion. A 37-year-old Arabian woman presented with 12 months of progressive Cushing's syndrome-like symptoms. Biochemical evaluation confirmed adrenocorticotropic hormone -dependent Cushing's syndrome. However, the anatomical site of her excess adrenocorticotropic hormone secretion was not clearly delineated by further investigations. Magnetic resonance imaging of our patient's pituitary gland failed to demonstrate the presence of an adenoma. Spiral computed tomography of her chest only revealed the presence of a non-specific 7 mm lesion in her left inferobasal lung segment. Functional imaging, including a positron emission tomography scan using 18-fluorodeoxyglucose and gallium-68-DOTA-D-Phe1-Tyr3-octreotide, also failed to show increased metabolic activity in the lung lesion or in her pituitary gland. Our patient was commenced on medical treatment with ketoconazole and metyrapone to control the clinical features associated with her excess cortisol secretion. Despite initial normalization of her urinary free cortisol excretion rate, levels began to rise eight months after commencement of medical treatment. Repeated imaging of her pituitary gland, chest and pelvis again failed to clearly localize a source of her excess adrenocorticotropic hormone secretion. The bronchial nodule was stable in size on serial imaging and repeatedly reported as having a nonspecific appearance of a small granuloma or lymph node. We re-explored the treatment options and endorsed our patient's favored choice of resection of the bronchial nodule, especially given that her symptoms of cortisol excess were difficult to control and refractory. Subsequently, our patient had the bronchial nodule resected. The histological appearance of the lesion was consistent with that of a carcinoid tumor and immunohistochemical analysis revealed that the tumor stained strongly positive for adrenocorticotropic hormone. Furthermore, removal of the lung lesion resulted in a normalization of our patient's 24-hour urinary free cortisol excretion rate and resolution of her symptoms and signs of hypercortisolemia. This case report demonstrates the complexities and challenges in diagnosing the causes of adrenocorticotropic hormone -dependent Cushing's syndrome. Functional imaging may not always localize the site of ectopic adrenocorticotropic hormone secretion.


[Immunotherapy of cancer].
Significant advances in the understanding of the cells and molecules involved in tumour/host interactions in humans have been made over the last decades. Thus, through studies of the interactions between cells of the immune system and cancer cells, several tumour antigens and their epitopes recognised by human leucocyte antigen class I-restricted cytotoxic T lymphocytes have been identified. Likewise, specialised antigen presenting cells have been characterised and methods developed that allow the use of such cells in clinical immunology. In the clinic, systemic administration of immune stimulatory cytokines, in particular IL-2, has strengthened the notion that the immune system is capable of mediating rejection of cancer. More recently, more sophisticated methods of inducing anti-cancer immune responses have been pursued, for instance the use of antigen presenting cells in combination with various sources of antigen and cytokines for therapeutic vaccinations against cancer. The present paper summarizes current knowledge in the field of tumour immunology, and reviews various approaches undertaken with the aim of inducing strong anti-tumour responses. To this end, we review data from clinical trials, and discuss the potential of these treatment modalities as an adjunct to conventional modes of cancer treatment. Further, novel methodologies for monitoring and analysing cancer patients over the course of immunotherapeutic treatments are described, and future directions put forward.