Identifying Significantly Perturbed Subnetworks in Cancer Using Multiple Protein-Protein Interaction Networks.
The identification of cancer driver genes and key molecular pathways has been the focus of large-scale cancer genome studies. Network-based methods detect significantly perturbed subnetworks as putative cancer pathways by incorporating genomics data with the topological information of PPI networks. However, commonly used PPI networks have distinct topological structures, making the results of the same method vary widely when applied to different networks. Furthermore, emerging context-specific PPI networks often have incomplete topological structures, which pose serious challenges for existing subnetwork detection algorithms. In this paper, we propose a novel method, referred to as MultiFDRnet, to address the above issues. The basic idea is to model a set of PPI networks as a multiplex network to preserve the topological structure of individual networks, while introducing dependencies among them, and, then, to detect significantly perturbed subnetworks on the modeled multiplex network using all the structural information simultaneously. To illustrate the effectiveness of the proposed approach, an extensive benchmark analysis was conducted on both simulated and real cancer data. The experimental results showed that the proposed method is able to detect significantly perturbed subnetworks jointly supported by multiple PPI networks and to identify novel modular structures in context-specific PPI networks.


A balanced translocation t(11;16)(q13;p11), a cytogenetic study and an attempt at gene localization.
Members of three generations of a single family were examined and found to have a balanced translocation t(11;16)(q13;p11). Cytogenetic investigation and investigation of a number of gene markers is consistent with the current view that the Hp-alpha locus is situated in the proximity of band 16q22.


The anemia of vitamin E deficiency in swine: an experimental model of the human congenital dyserythropoietic anemias.
The ultrastructural and erythrokinetic characteristics of vitamin E deficiency in swine were investigated in an effort to evaluate the suitability of the swine disorder as a model of the human congenital dyserythropoietic anemias. The dominant erythrokinetic abnormality in vitamin E deficient pigs, as in the CDAs, is ineffective erythropoiesis. As in some patients with CDA, the activity of a number of erythrocyte enzymes was increased. Distinctive ultrastructual changes previously described in patients with CDA were found in normoblasts from vitamin E deficient pigs. The morphologic, erythrokinetic, biochemical and ultrastructural similarities between vitamin E deficiency in swine and the CDAs in man appear to justify the study of the animal disorder as a model of the human disease. A complete hematologic response was elicited by the administration not only of vitamin E, but also, as in the previous studies of vitamin E deficiency in monkeys, by hexahydrocoenzyme Q4. The partial hematologic response occurring after deletion of tocopherol stripped corn oil from the diet indicates that factors other than the dietary lack of vitamin E are important in the pathogenesis of this disorder.


Microvascular dysfunction and skeletal muscle oxygenation assessed by phase-modulation near-infrared spectroscopy in patients with septic shock.
Sepsis is now considered a disease of the microcirculation. Little is known about the various sepsis-induced changes responsible for microvascular dysfunction. We investigated human microvascular function, regulation, oxygenation, and cellular metabolism during subacute septic shock. Prospective case-control study in a nine-bed polyvalent surgical ICU of a university hospital. A prospectively enrolled group of 26 patients (13 with septic shock, 13 nonseptic postsurgical patients) and 15 healthy volunteer controls. The absolute tissue hemoglobin concentrations (oxygenated hemoglobin and deoxyhemoglobin) were measured noninvasively in arterioles, capillaries, and venules by phase-modulation near-infrared spectroscopy in the human brachioradial muscle during a series of venous occlusions and an arterial occlusion (ischemia) induced by applying a pneumatic cuff. These measurements were used to calculate tissue blood volume, postischemic hemoglobin resaturation time, microvascular compliance, and O2 consumption. Patients with sepsis had significantly higher tissue blood volume values and lower compliance than healthy controls. They also had longer postischemic hemoglobin resaturation times than the other two groups and blunted resaturation curves. O2 consumption was lower in patients with sepsis than in healthy controls. In patients with septic shock cuff-induced ischemia left O2 consumption unchanged, whereas in healthy volunteers it reduced O2 consumption to values almost matching those of patients with septic shock. These findings show that septic shock alters microvascular muscle function and regulation. Diminished local VO2 presumably reflects maldistribution and faulty autoregulation of local blood flow.


Gads is a novel SH2 and SH3 domain-containing adaptor protein that binds to tyrosine-phosphorylated Shc.
Shc proteins are important substrates of receptor and cytoplasmic tyrosine kinases that couple activated receptors to downstream signaling enzymes. Phosphorylation of Shc tyrosine residues 239 and 317 leads to recruitment of the Grb2-Sos complex, thus linking Shc phosphorylation to Ras activation. We have used phosphorylated peptides corresponding to the regions spanning tyrosine 239/240 and 317 of Shc in an expression library screen to identify additional downstream targets of Shc. Here we report the identification of Gads, a novel adaptor protein most similar to Grb2 and Grap that contains amino and carboxy terminal SH3 domains flanking a central SH2 domain and a 120 amino acid unique region. Gads is most highly expressed in the thymus and spleen of adult animals and in human leukemic cell lines. The binding specificity of the Gads SH2 domain is similar to Grb2 and mediates the interaction of Gads with Shc, Bcr-Abl and c-kit. Gads does not interact with Sos, Cbl or Sam68, although the isolated carboxy terminal Gads SH3 domain is able to bind these molecules in vitro. Our results suggest that the unique structure of Gads regulates its interaction with downstream SH3 domain-binding proteins and that Gads may function to couple tyrosine-phosphorylated proteins such as Shc, Bcr-Abl and activated receptor tyrosine kinases to downstream effectors distinct from Sos and Ras.


To what extent is mean EMG frequency during gait a reflection of functional muscle strength in children with cerebral palsy?
The aim of the current paper was to analyze the potential of the mean EMG frequency, recorded during 3D gait analysis (3DGA), for the evaluation of functional muscle strength in children with cerebral palsy (CP). As walking velocity is known to also influence EMG frequency, it was investigated to which extent the mean EMG frequency is a reflection of underlying muscle strength and/or the applied walking velocity. Surface EMG data of the lateral gastrocnemius (LGAS) and medial hamstrings (MEH) were collected during 3DGA. For each muscle, 20 CP children characterized by a weak and 20 characterized by a strong muscle (LGAS or MEH) were selected. A weak muscle was defined as a manual muscle testing score <3; a strong muscle was defined as a manual muscle testing score ≥4. Patient selection was based on the following inclusion criteria: (a) predominantly spastic type of CP (3-15 years old), (b) either (near) normal muscle strength or muscle weakness in at least one of the studied lower limb muscles, (c) no lower limb Botulinum Toxin-A treatment within 6 months prior to the 3DGA, (d) no history of lower limb surgery, and (e) high-quality noise-free EMG-data. For each muscle, twenty age-related typically developing (TD) children were included as controls. In both muscles a consistent pattern of increasing mean EMG frequency with decreasing muscle strength was observed. This was significant in the LGAS (TD versus weak CP). Walking velocity also had a significant effect on mean EMG frequency in the LGAS. Furthermore, based on R(2) and partial correlations, it could be concluded that both walking velocity and muscle strength have an impact on EMG, but the contribution of muscle strength was always higher. These findings underscore the potential of the mean EMG frequency recorded during 3DGA, for the evaluation of functional muscle strength in children with CP.


Synthesis and pharmacokinetic profile of 3-methoxymethyl cephalosporin prodrugs.
Preparation and biological activity of prodrug-type 3-methoxymethyl cephalosporins were described. From the mixtures, R- and S-prodrugs were separated and their absolute configurations were determined, and also their bioavailability was investigated.


Video-assisted thoracic surgery is minimally invasive, but is it less traumatic?
Video-assisted thoracic surgery (VATS) is a minimally invasive procedure. This study aimed to evaluate whether the procedure is less traumatic to the ipsilateral non-diseased lobe(s) than open thoracotomy (OT) during pulmonary resection by a comparison of alveolar-capillary membrane (A/C) permeability. Wedge resections were performed in twenty-seven patients with various types of primary and secondary malignant, solitary, pulmonary nodules. Fifteen patients had OT, while 12 patients had VATS. (99 m)Tc-DTPA radioaerosol studies were performed on the day before surgery and on the third or fourth day postoperatively. The images of the ipsilateral non-diseased lobe(s) were compared. Postoperatively, all patients had significantly increased A/C permeability at the ipsilateral non-diseased lobe(s). However, the degree of increase in the VATS group was the same as that of the OT group. Postoperative A/C permeability of the contralateral lung was not significantly different. Both procedures caused injury to the ipsilateral non-diseased lobe(s) in terms of A/C permeability at the same degree. Although VATS has been considered as a minimally invasive procedure, the trauma caused by VATS to the "disease-free lung" is the same as that caused by open thoracotomy.


A couple returning from Peru with persistent fever: think of histoplasmosis.
A couple presented with fever and strikingly similar symptoms starting exactly on the same day after returning from an adventurous journey in Peru. Symptom onset was 12 days after exposure to bats from a hollow tree. The further evolution underscores the disparate disease course of Histoplasmosis in different individuals, despite similar radiological findings. Our case highlights the importance of careful history taking in returning travelers since exposure to bat (or fowl) excrement can be easily overlooked.


The beneficial effects of tomatoes.
Dietary intake of tomatoes and tomato products containing lycopene has been shown to be associated with a decreased risk of chronic diseases such as cancer and cardiovascular disease in several recent studies. Serum and tissue lycopene levels have also been inversely related to the risk of chronic disease. While the antioxidant properties of lycopene are thought to be primarily responsible for its beneficial effects, evidence is accumulating to suggest that other mechanisms, such as modulation of intercellular gap junction communication, hormonal and immune systems, and metabolic pathways, may also be involved. Lycopene inhibited the activity of an essential enzyme involved in cholesterol synthesis in an in vitro study and a small clinical study, suggesting a hypocholesterolemic effect.


A Multicenter Phase 1 Trial Evaluating Nanoliposomal Irinotecan for Heated Intraperitoneal Chemotherapy Combined with Cytoreductive Surgery for Patients with Peritoneal Surface Disease.
Nanoliposomal irinotecan (nal-IRI) is a promising novel hyperthermic intraperitoneal chemotherapy (HIPEC) agent given its enhanced efficacy against gastrointestinal tumors, safety profile, thermo-synergy, and heat stability. This report describes the first in-human phase 1 clinical trial of nal-IRI during cytoreductive surgery (CRS) and HIPEC. Patients with peritoneal surface disease (PSD) from appendiceal and colorectal neoplasms were enrolled in a 3 + 3 dose-escalation trial using nal-IRI (70-280 mg/m2) during HIPEC for 30 min at 41 ± 1 °C. The primary outcome was safety. The secondary outcomes were pharmacokinetics (PK) and disease-free survival. Adverse events (AEs) categorized as grade 2 or higher were recorded. The serious AEs (SAEs) were mortality, grade ≥ 3 AEs, and dose-limiting toxicity (DLT). Irinotecan and active metabolite SN38 were measured in plasma and peritoneal washings. The study enrolled 18 patients, who received nal-IRI during HIPEC at 70 mg/m2 (n = 3), 140 mg/m2 (n = 6), 210 mg/m2 (n = 3), and 280 mg/m2 (n = 6). No DLT or mortality occurred. The overall morbidity for CRS/HIPEC was 39% (n = 7). Although one patient experienced neutropenia, no AE (n = 131) or SAE (n = 3) was definitively attributable to nal-IRI. At 280 mg/m2, plasma irinotecan and SN38 measurements showed maximum concentrations of 0.4 ± 0.6 µg/mL and 3.0 ± 2.4 ng/mL, a median time to maximum concentration of 24.5 and 26 h, and areas under the curve of 22.6 h*µg/mL and 168 h*ng/mL, respectively. At the 6-month follow-up visit, 83% (n = 15) of the patients remained disease-free. In this phase 1 HIPEC trial (NCT04088786), nal-IRI was observed to be safe, and PK profiling showed low systemic absorption overall. These data support future studies testing the efficacy of nal-IRI in CRS/HIPEC.


Do neighborhoods affect individual mortality? A systematic review and meta-analysis of multilevel studies.
There has been increasing interest in investigating whether inhabitants in socially or physically deprived neighborhoods have higher mortality when individual socioeconomic status is adjusted for. Results so far appear ambiguous and the objective of this study was to conduct a systematic literature review of previous studies and to quantify the association between area-level socioeconomic status (ALSES) and all-cause mortality in a meta-analysis. Current guidelines for systematic reviews and meta-analyses were followed. Articles were retrieved from Medline, Embase, Social Sciences Citation Index and PsycInfo and individually evaluated by two researchers. Only peer-reviewed multilevel studies from high-income countries, which analyzed the influence of at least one area-level indicator and which controlled for individual SES, were included. The ALSES estimates in each study were first combined into a single estimate using weighted linear regression. In the meta-analysis we calculated combined estimates with random effects to account for heterogeneity between studies. Out of the 40 studies found eligible for the systematic review 18 studies were included in the meta-analysis. The systematic review suggests that there is an association between social cohesion and mortality but found no evidence for a clear association for area-level income inequality or for social capital. Studies including more than one area level suggest that characteristics on different area levels contribute to individual mortality. In the meta-analysis we found significantly higher mortality among inhabitants living in areas with low ALSES. Associations were stronger for men and younger age groups and in studies analyzing geographical units with fewer inhabitants.


Correction: Whole exome sequencing reveals HSPA1L as a genetic risk factor for spontaneous preterm birth.
[This corrects the article DOI: 10.1371/journal.pgen.1007394.].


Isolated congenital agenesis of the gallbladder and cystic duct: report of a case.
Congenital agenesis of the gallbladder and cystic duct represents a rare anomaly of the biliary system. It likely results from an embryologic mishap in the development of the hepatobiliary bud and can occur with other associated malformations. We report the case of congenital absence of the gallbladder and cystic duct incidentally found during laparoscopy in a 44-year-old Caucasian female. Based on the clinical presentation and ultrasonography findings, the patient was presumed to have symptomatic cholelithiasis and chronic cholecystitis. A laparoscopic cholecystectomy was planned. After introducing the laparoscope, the gallbladder and cystic duct were absent and the procedure aborted. Gallbladder and cystic duct agenesis was confirmed by magnetic resonance cholangiopancreatography. We describe here the difficulties with diagnosis and pain management, and review the literature of this rare pathology.


Preparation of ultrathin grafts for Descemet-stripping endothelial keratoplasty with a single microkeratome pass.
We present a technique to achieve ultrathin Descemet-stripping automated endothelial keratoplasty (DSAEK). Using a simple method of controlling artificial anterior chamber pressure and drying the corneal surface, it was possible to thin the donor cornea at a rate of 11 μm a minute. When the donor cornea was between 500 μm and 510 μm, a single pass was made using a 350 μm microkeratome head followed by a peripheral dissection. The resulting mean graft thickness was 83.2 μm ± 14.9 (SD) (range 50 to 98 μm) with a mean peripheral graft edge thickness of 106.8 ± 10.9 μm (range 90 to 120 μm). There were no surgical complications, and all grafts remained attached. This is a reliable method for preparing ultrathin donor corneal lenticules for DSAEK in the operating room or eye bank without using multiple microkeratome heads or risking double passes.


Identification of ETFB as a candidate protein that participates in the mechanoregulation of fibroblast cell number in collagen gel culture.
Fibroblast activation is strongly influenced by mechanical environment in the wound-healing process, especially in fibrosis. Mechanically stressed three-dimensional collagen embedded culture is a useful model representing fibroblasts in morphological as well as biochemical situations encountered during fibrosis. To find key proteins involved in reducing the number of fibroblasts during mechanical stress, we performed two-dimensional gel electrophoresis (2DE)-based differential display and siRNA-based functional screening with collagen gel culture focusing on the differences between attached and detached culture environments. Membrane extracts of fibroblasts from 1 day of attached or detached cultures were subjected to 2DE. We compared protein expression levels and identified the attached-culture-dominant proteins by MALDI-TOF-MS. Next, fibroblasts were transfected with siRNA and embedded in collagen gel. Cell number was counted after 3 days in culture. Eight attached culture dominant proteins were identified with MALDI-TOF-MS. Transfection of siRNA against these proteins demonstrated that electron transfer flavoprotein β subunit (ETFB)-specific siRNA reduced the cell number in the attached culture without a decrease in the detached culture. ETFB participates in the mechanoregulation of fibroblast cell number in collagen gel culture.


Qualities of Children's Fear in Therapeutic Action Groups Addressing Post-separation Parental Stalking.
This paper examines the way in which parental stalking - as a form of domestic abuse - raises fear in children and affects their sense of safety. The study draws on three therapeutic action groups involving 13 children who have experienced stalking by their fathers/stepfathers after the parents' separation. The research question is as follows: How does children's sense of fear manifest in therapeutic action groups? The qualitative analysis revealed three qualities of fear among the children: (1) internalised, (2) constant and (3) episodic. Internalised fear appeared as a child's mental state that materialised as an overwhelming sentiment in the group sessions and elsewhere. Constant fear activated at times, and the senses of fear and security alternated both in the sessions and elsewhere. Episodic fear related to the children's memories of violent events and father's stalking behaviour. The children were able to sense security in the group and in daily life owing to a temporal distance to their father's stalking. Our findings underscore the importance of professionals' awareness of the qualities of children's fear and the significance of assessing their fear and sense of safety in a child-centered manner in therapeutic practices.


Traumatic Brain Injury Model Systems of Care 2002-2007.
During the years 2002 to 2007, 16 Traumatic Brain Injury Model Systems of Care (TBIMS) were funded by the National Institute on Disability and Rehabilitation Research to conduct site-specific and collaborative research projects, including contribution to a longitudinal database, within comprehensive systems of care specialized for people with traumatic brain injury. The TBIMS program has been in existence since 1987 and has undergone significant modifications over these years. Herein I provide an overview of the changes that occurred in the 2002-2007 funding cycle, the research initiatives that were carried out during that time, and brief descriptions of the 13 original TBIMS research articles included in this issue of Archives.


A bisphosphonite calix[5]arene ligand that stabilizes η6 arene coordination to palladium.
Treatment of a bis(phenylphosphonite)calix[5]arene ligand with either palladium(II) chloride or 1,5-cyclooctadieneplatinum(II) chloride yields square planar metal complexes in which the two phosphorus atoms bind cis to the MCl(2) moiety (M = Pd, Pt). Chloride was removed from the palladium complex to open a coordination site at the metal for catalysis. The chloride removal resulted in a rare and unexpected η(6) coordination of an arene to the metal. The reaction is reversible upon addition of tetra-n-butyl ammonium chloride.


Reagent elution combined with positive pressure filtration: A zero-discharge method for cyanide tailings remediation.
At present, the cyanide gold extraction process is still the main technology for gold production. Generated cyanide tailings containing highly toxic substances exhibit potential environmental risks. These tailings are in urgent need of purification treatment, especially after being classified as hazardous waste. In this study, the impacts of elution methods, operating time, tailings/water ratios, reagent types on the elution rates of cyanide were investigated. Furthermore, the composite elution method developed in this research was extended for engineering. Results showed that the optimum elution conditions were determined to be: stirring elution, tailings/water ratio (M/V; 1:1) and operating time (10-20 min). Besides, 4 reagents (sodium dodecyl benzene sulfonate, cyclodextrin, sodium silicate and calcium hydroxide) were selected from four categories of 21 reagents for further composite elution. The cyanide elution rate was the highest (90.7%±0.1%) while the molar ratio of these 4 reagents was 5:2:2:1. Moreover, the combination of reagent elution and positive pressure filtration improved the elution efficiency of cyanide (92.6%±0.8%). And the cyanide content in the toxic leaching solution was lower than the standard value (5.0 mg/L). Furthermore, the composite elution method developed in this study was also extended for engineering. The concentration of cyanide in the leachate was < 5.0 mg/L, and was stable during 189 days of detection. Notably, the effluent can be reused directly, or reused after further treatment. The zero discharge of effluents and solid wastes was realized in the processes. The above results provided supports for the engineering treatment of cyanide tailings.


Simultaneous RT/PCR detection and differentiation of arabis mosaic and grapevine fanleaf nepoviruses in grapevines with a single pair of primers.
The movement protein genes from several isolates of ArMV and GFLV of different geographical origins were amplified by RT/PCR using degenerate primers, cloned and sequenced. A single pair of degenerate primers was designed from these sequences to allow the simultaneous amplification of parts of the movement protein genes of ArMV and GFLV. Their use in an immunocapture-RT/PCR for the detection of ArMV or GFLV in infected grapevines proved to be ten times more sensitive than the corresponding ArMV or GFLV ELISA tests. A Sph1 restriction site found in the sequences corresponding to the amplified products from the GFLV isolates, but not in the amplified products from the ArMV isolates, allowed the differentiation between ArMV and GFLV in the infected grapevines by a Sph1 restriction digestion of the amplified products.


New alternatives in the management of gastroesophageal reflux disease.
To date the mainstay of surgical treatment for gastroesophageal reflux disease (GERD) has been achieved with either open or laparoscopic fundoplication. Several new treatment modalities are attempting to augment the gastroesophageal (GE) junction function by various endoscopic means. The Medline database from 1980 to 2002 was searched for studies on endoscopic techniques for antireflux procedures. Product investigators were contacted for data presented in abstract form only. Recent improvements in equipment and technique with excellent long-term follow-up have made laparoscopic Nissen fundoplication the gold standard in antireflux surgery. New techniques include using radiofrequency energy, injection of silicon type polymer and using endoluminal sutures to narrow the gastroesophageal junction. Early results have encouraging aspects, but should be evaluated thoroughly and with caution before widespread use. Endoscopic treatment of gastroesophageal reflux has future promise. However, more experience and perhaps further improvement in techniques and technology must occur before wide application can be encouraged.


Relative Risk Ratios of Foodborne Illness in Foodservice Establishments: An Aid in Deployment of Environmental Health Manpower.
By using "relative risk ratios", various types of foodservice establishments were shown to pose significantly different risks of food poisoning. This implies that there is no solid basis for the traditional belief that all foodservice establishments must be inspected a given number of times.


Caenorhabditis elegans SORB-1 localizes to integrin adhesion sites and is required for organization of sarcomeres and mitochondria in myocytes.
We have identified and characterized sorb-1, the only sorbin and SH3 domain-containing protein family member in Caenorhabditis elegans SORB-1 is strongly localized to integrin adhesion complexes in larvae and adults, including adhesion plaques and dense bodies (Z-disks) of striated muscles and attachment plaques of smooth muscles. SORB-1 is recruited to the actin-binding, membrane-distal regions of dense bodies via its C-terminal SH3 domains in an ATN-1(α-actinin)- and ALP-1(ALP/Enigma)-dependent manner, where it contributes to the organization of sarcomeres. SORB-1 is also found in other tissues known to be under mechanical stress, including stress fibers in migratory distal tip cells and the proximal gonad sheath, where it becomes enriched in response to tissue distention. We provide evidence for a novel role for sorbin family proteins: SORB-1 is required for normal positioning of the mitochondrial network in muscle cells. Finally, we demonstrate that SORB-1 interacts directly with two other dense body components, DEB-1(vinculin) and ZYX-1(zyxin). This work establishes SORB-1 as a bona fide sorbin family protein-one of the late additions to the dense body complex and a conserved regulator of body wall muscle sarcomere organization and organelle positioning.


ddRAD sequencing-based genotyping for population structure analysis in cultivated tomato provides new insights into the genomic diversity of Mediterranean 'da serbo' type long shelf-life germplasm.
Double digest restriction-site associated sequencing (ddRAD-seq) is a flexible and cost-effective strategy for providing in-depth insights into the genetic architecture of germplasm collections. Using this methodology, we investigated the genomic diversity of a panel of 288 diverse tomato (Solanum lycopersicum L.) accessions enriched in 'da serbo' (called 'de penjar' in Spain) long shelf life (LSL) materials (152 accessions) mostly originating from Italy and Spain. The rest of the materials originate from different countries and include landraces for fresh consumption, elite cultivars, heirlooms, and breeding lines. Apart from their LSL trait, 'da serbo' landraces are of remarkable interest for their resilience. We identified 32,799 high-quality SNPs, which were used for model ancestry population structure and non-parametric hierarchical clustering. Six genetic subgroups were revealed, clearly separating most 'da serbo' landraces, but also the Spanish germplasm, suggesting a subdivision of the population based on type and geographical provenance. Linkage disequilibrium (LD) in the collection decayed very rapidly within <5 kb. We then investigated SNPs showing contrasted minor frequency allele (MAF) in 'da serbo' materials, resulting in the identification of high frequencies in this germplasm of several mutations in genes related to stress tolerance and fruit maturation such as CTR1 and JAR1. Finally, a mini-core collection of 58 accessions encompassing most of the diversity was selected for further exploitation of key traits. Our findings suggest the presence of a genetic footprint of the 'da serbo' germplasm selected in the Mediterranean basin. Moreover, we provide novel insights on LSL 'da serbo' germplasm as a promising source of alleles for tolerance to stresses.


Immunocytologic localization of herpes simplex type 1 viral antigens in herpetic retinitis and encephalitis in an adult.
An immunoperoxidase technique was utilized to identify herpes simplex type I viral antigens in the retina, optic nerve and brain of an adult with herpetic retinitis and encephalitis. Viral antigens were demonstrated in all layers of retina, retinal pigment epithelium and to a lesser extent, in choroid. Oligodendroglia in the right optic nerve and neuronal and glial cells in the grey and white matter of the left frontal, inferior parietal and temporal lobes of the brain also expressed herpes simplex antigens. The sensitive immunoperoxidase method allowed detection of viral antigens in many cells without intranuclear inclusions or surrounding inflammation, and thereby added valuable information regarding the anatomic and cellular localization of herpetic infection. The clinicopathologic features that characterize herpes simplex retinitis in the adult are compared to cytomegalovirus retinopathy.


Increased extracellular vesicles (EVs) related to T cell-mediated inflammation and vascular function in familial hypercholesterolemia.
OxLDL modulates innate and adaptive immunity, and extracellular vesicles (EVs) released from both non-immune and immune cells are proposed key players in atherosclerosis development. In the present study, we aimed to investigate EVs expressing markers related to adaptive immunity-driven inflammation and endothelial activation/dysfunction in hypercholesterolemic patients. EVs were phenotyped in thirty patients with familial hypercholesterolemia (FH) and twenty-three healthy controls using the Extracellular Vesicle (EV) Array with antibodies targeting proteins expressed on B and T cells, and endothelial cells. FH patients had a higher atherosclerotic burden, as determined by the mean carotid intima-media thickness (IMT) (0.64 ± 0.12 mm vs. 0.58 ± 0.07 mm; p = 0.033), higher oxLDL levels (p < 0.0001), and showed increased levels of EV-specific markers: CD9 (p = 0.017), CD63 (p = 0.045), CD81 (p = 0.003), Annexin V (p = 0.018), and EV markers related to adaptive/lymphocyte immunity: CD28 (p = 0.034), CD4 (p = 0.049), CD152 (p = 0.029), LFA-1 (p = 0.024), and endothelial function: CD62E (p = 0.032), CD144 (p = 0.018), tPA (p = 0.017), CD31 (p = 0.024). Linear regression revealed a positive relationship between carotid IMT and several of the increased markers observed within the FH group, including CD9 (β = 0.33; p = 0.022), CD63 (β = 0.35; p 225 = 0.026), CD28 (β = 0.37; p = 0.026), CD4 (β = 0.40; p = 0.025), CD152 (β = 0.41; p = 0.017), LFA-1 (β = 0.42; p = 0.014) and CD62E (β = 0.38; p = 0.024). EVs associated with adaptive immunity and endothelial dysfunction are elevated in FH patients, and several markers related to a higher atherosclerotic burden.


Pain and its treatment in hospitalized patients with metastatic cancer.
The aim of this prospective study was to assess the quality of pain management hospitalized cancer patients. In a quantitative and qualitative evaluation from six oncology centers in Italy, all consecutive cancer patients complaining of pain and hospitalized during the same 2 weeks were requested to fill in a McGill pain questionnaire (MPQ), a present pain intensity scale (PPI), and a hospital anxiety and depression acale (HADS), and to answer a questionnaire focused (QF) on the quality of medical and nursing care. The healthcare provider's antalgic prescriptions were assessed by an index of pain management (IPM). Of 120 patients with pain admitted to oncology divisions (65 men and 52 women; mean age 57 years, range 21-79 years), 117 completed the questionnaires. The quantitative evaluation (PPI) showed a significant pain reduction between admission and discharge pain levels-from 2.65 to 1.50 ( p<0.001). While a significant reduction of anxiety (HADS) was also found-from 10.24 to 9.11 ( p<0.001)-depression did not improve (9.83 and 9.72). The most relevant information from qualitative evaluation (QF) was: in 37.6% of patients, pain level was higher overnight; 47% waited for spontaneous decrease of pain intensity before asking for nurse or physician intervention; 69% asked for nurse help when pain level was really high. The health care response to patients' pain was not completely satisfactory, since analgesic prescription was adequate in 56.52% but inadequate in 43.47%. Pain control in hospitalized cancer patients is not completely satisfactory. The physician's attitude is to underestimate and undertreat pain, while nurses are not adequately trained for timely intervention despite published guidelines for pain management. The findings of this study support the concern of inadequate knowledge and inappropriate attitudes regarding pain management, even in cancer patients hospitalized in medical oncology divisions.


Short and long term determinants of incident multimorbidity in a cohort of 1988 earthquake survivors in Armenia.
Multimorbidity, presence of two or more health conditions, is a widespread phenomenon affecting populations' health all over the world. It becomes a serious public health concern due to its negative consequences on quality of life, mortality, and cost of healthcare services utilization. Studies exploring determinants of multimorbidity are limited, particularly those looking at vulnerable populations prospectively over time. This study aimed at identifying short and long term socioeconomic, psychosocial, and health behavioral determinants of incident multimorbidity among a cohort of the 1988 Armenian earthquake survivors. The study included a representative subsample of 725 from a larger initial cohort of the earthquake survivors. Data on this subsample were collected via four phases of this cohort study during the period 1990-2012. The final logistic regression analysis eliminated all those cases with baseline multimorbidity to investigate short and long term determinants of incident multimorbidity; this subsample included 600 participants. More than 75% of the studied sample had multimorbidity. Perceived low affordability of healthcare services, poor living standards during the post-earthquake decade, and lower education were independent predictors of incident multimorbidity developed during the period 1990-2012. Stressful life events and poor social support were among psychosocial determinants of incident multimorbidity. Participants' baseline BMI reported in 1990 was independently associated with incident multimorbidity. Most of the identified determinants of incident multimorbidity in our study population were markers of social inequities, indicating that inequities pose a serious threat to both individual and public health-related outcomes. Strategies targeting to decrease such inequities along with promotion of healthy lifestyle and strengthening of social networks may considerably reduce multimorbidity among population groups with similar socioeconomic and cultural profiles.


Carbon dioxide milliwatt laser in the vasovasostomy of vas deferens in dogs: Part I.
This is the first arm of a two prong study conducted to learn two different aspects of vasovasostomy in dog vas deferens using the milliwatt carbon dioxide laser. The first study involved the evaluation of patency without collection of sperm. Six dogs were evaluated and all underwent vasectomy and subsequently had vasovasostomies performed between 4 and 12 weeks utilizing two approximating sutures and welding with the milliwatt carbon dioxide laser. Metal clips were used for both X-ray analysis and localization of the vasovasostomy site. In this investigation a vasogram was performed. Dogs were sacrificed at 4, 6, and 8 weeks postvasovasostomy. The vasovasostomy specimens were studied with electron microscopy and histological evaluation. The vasovasostomy was completed in under 120 minutes using this laser-assisted technique and was found to be a viable and promising technique for vasovasostomy.


Incidence and type of cervical spine injuries associated with mandibular fractures.
The incidence of facial fractures accompanied by spinal injuries, while low, is of significant concern to the craniomaxillofacial surgeon. There are conflicting reports on the association between facial fractures and concomitant spinal damage. This retrospective study of 424 patients with mandibular fractures examines the relationship of mandibular fractures and concomitant spinal injuries. The incidence of concurrent mandibular and cervical fractures was 2.6%, predominantly associated with motor vehicle accidents. The purpose of this study is to examine the incidence of cervical spine injury associated with mandibular fractures, in order to improve the diagnosis and treatment of spinal injury associated with mandibular fractures.


Ontogeny and dopaminergic regulation in brain of Ras homolog enriched in striatum (Rhes).
Rhes is one of several signaling molecules preferentially expressed in the striatum. This GTP-binding protein affects dopamine-mediated signaling and behavior. Denervating the striatum of its dopaminergic inputs in adulthood reduces rhes mRNA expression. Here we show that dopamine depletion in adult rats by 6-hydroxydopamine caused a significant decrease in striatal Rhes protein levels as measured by Western blotting. The role of dopamine input on rhes mRNA induction during ontogeny was also examined. Rhes mRNA was measured on postnatal days 4, 6, 8, 10, 15, and 24 with in situ hybridization to determine its normal ontogeny. Signal in striatum was detectable, but very low, on postnatal day 4 and increased gradually to peak levels at days 15 and 24. Outside of the striatum, rhes mRNA was expressed at high levels in hippocampus and cerebellum during the postnatal period. Hippocampal signal was initially highest in CA3 and dentate gyrus, but shifted to higher expression in CA1 by the late postnatal period. Several other nuclei showed low levels of rhes mRNA during ontogeny. Depletion of dopamine by 6-hydroxydopamine injection on postnatal day 4 did not affect the ontogenetic development of rhes mRNA, such that expression did not differ statistically in lesioned versus vehicle-treated animals tested in adulthood. These findings suggest that although dopamine input is not necessary for the ontogenetic development of rhes mRNA expression, changes in both rhes mRNA and Rhes protein are integral components of the response of the adult striatum to dopamine depletion.


Unexpected synergy between N-phosphonacetyl-L-aspartate and cytidine against human tumor cells.
Cytidine, a non-toxic endogenous nucleoside, was found unexpectedly to augment the cytotoxicity of a pyrimidine antimetabolite N-phosphonacetyl-L-aspartate (PALA) in human ovarian carcinoma cells. The PALA/cytidine synergy is confirmed here in other human tumor cells (T242 melanoma, HL60 promyelocytic leukemia and SKOV3 ovarian carcinoma) in the cytidine concentration range of 1-10 micromolar. The synergy was not observed in Chinese hamster ovary (CHO) cells. Exogenous uridine (5-50 microM) completely reversed the PALA/cytidine cytotoxicity in a concentration-dependent manner. Measurements of cellular ribonucleotide levels revealed that the PALA treated cells had reduced UTP and CTP pools (10% and 40% of control respectively); and the PALA/cytidine treated cells had elevated CTP and GTP levels while their UTP levels remained at 10% of control. Deoxyribonucleotide levels were unremarkable except for a slight elevation of dCTP in the PALA/cytidine treated cells. Uridine competitively inhibited radioactive cytidine transport into 2008 cells, which may explain its ability to antagonize the PALA/cytidine synergy. These results suggest that the ribonucleotide biosynthetic mechanism is the primary cellular target for PALA/cytidine activity, and that the ratio of ribonucleotides to each other is an important determinant of tumor cell viability. The use of non-cytotoxic nucleosides to augment the activity of antimetabolites may have clinical relevance in cancer therapy.


The influence of life on the evolution of the atmosphere.
The early history of life on earth may have been characterized by coevolution of microbial metabolism and atmospheric composition. Metabolic developments affected the composition of the atmosphere, and the resulting changes in the atmosphere stimulated the evolution of new metabolic capabilities. The first organisms eked out an existence by deriving energy from the fermentation of organic compounds abiotically synthesized. The abiotic source was meager, however, and when autotrophy arose, life was freed from its dependence on abiotic synthesis. The expanded level of biological activity made possible by autotrophy resulted in an increased rate of burial of reduced organic matter in sea floor sediments. The resultant drain on the concentration of electron donors in the biosphere caused a decline in the hydrogen content of the atmosphere. Biological productivity was limited by the supply of reduced compounds. This paper explores the biogeochemical circulation of electron donors in the primitive anaerobic ocean, concluding that their shortage was so critical as to provide strong selective pressure for the evolution of algal photosynthesis.


Haemoglobin and vascular function in the human retinal vascular bed.
Haemoglobin is a potential nitric oxide (NO) scavenger. Haemoglobin is associated with blood viscosity and the red blood cell free layer width of microvessels that impact on shear stress in the microcirculation. We hypothesized that haemoglobin modulates retinal vascular function. In 139 nondiabetic male patients with haemoglobin levels within the normal range, the vasodilatatory response of retinal capillary blood flow (RCF) to flicker light exposure and the vasoconstrictor response of RCF to infusion of NO synthase inhibitor N-monomethyl-L-arginine (L-NMMA) were assessed. The latter, because of the selective nature of L-NMMA, reflects a parameter of basal NO activity of retinal vasculature. Examinations of retinal parameters were performed noninvasively and in vivo using scanning laser Doppler flowmetry. Patients with haemoglobin greater or equal the median revealed reduced increase of RCF to flicker light exposure (2.83 ± 12 vs. 9.52 ± 14 (%), P adjusted = 0.002), and greater decrease of RCF to L-NMMA infusion (-7.35 ± 13 vs. -0.92 ± 14 (%), P adjusted = 0.008), compared with patients with haemoglobin below the median. Haemoglobin was negatively related to the percentage change of RCF to flicker light exposure (r = -0.249, P = 0.004) and to L-NMMA infusion (r = -0.201, P = 0.018). In multiple linear regression analysis haemoglobin was an independent determinant of the percentage change of RCF to flicker light exposure (model 1: ß = -0.278, P = 0.003 and model 2: ß = -0.283, P = 0.002) and to L-NMMA infusion (model 1: ß = -0.256, P = 0.005 and model 2: ß = -0.269, P = 0.004). Haemoglobin emerged as an independent determinant of vascular function in the human retinal vascular bed.


Identification of human immunodeficiency virus type 1 non-B subtypes and antiretroviral drug-resistant strains in United States blood donors.
In this study, human immunodeficiency virus type 1 (HIV-1)-infected blood donors were evaluated for genetic subtype and drug resistance to determine the prevalence of divergent HIV strains in the US donor population. Subtype was determined by phylogenetic analysis of viral sequences amplified by reverse transcription-polymerase chain reaction. The drug resistance profile of the protease and reverse transcriptase (RT) genes was determined using an HIV-1 genotyping system (ViroSeq). From 1999 through 2005, 26 recently infected donors, defined as HIV-1 RNA-positive, antibody-negative (RNA+/Ab-), were identified (yield, 1:1.61 million). Over the same period, the frequency of anti-HIV-positive donors was 1:34,700. Twenty RNA+/Ab- specimens were evaluated; all were infected with HIV-1 subtype B. Drug resistance profiles obtained for 18 donors identified one strain with protease mutation L90M that confers resistance to nelfinavir and one with RT mutation Y188H that confers resistance to nevirapine. Genetic subtype was determined for 44 of 46 HIV antibody-reactive and confirmed-positive (Ab+) specimens. Three infections (6.8%) were due to circulating recombinant forms: 2 CRF01_AE and 1 CRF02_AG. In the Ab+ group, one strain was resistant to all nucleoside RT inhibitors and one had mutations that confer resistance to protease inhibitors. The data show that antiretroviral drug-resistant HIV strains are being transmitted in the United States. Overall 6.5 percent (4 of 62) of HIV-1-infected donors harbored drug-resistant strains. HIV-1 non-B strains accounted for 4.7 percent (3 of 64) of the infections in donors. HIV-1 subtype B is still the predominant strain in the United States; however, non-B strains are increasing.


Peripheral neuropathic symptoms in celiac disease and inflammatory bowel disease.
An association between celiac disease (CD) and peripheral neuropathy (PN) has been reported. Patients with CD and/or inflammatory bowel disease (IBD) were recruited from the gastroenterology clinics at a medical center and local support groups. Control subjects without CD or IBD were recruited from the staff of the medical center as well as relatives and attendees at support groups. Each participant completed a survey that used two validated PN instruments to define and characterize PN. In the CD group, 38.9% met criteria for PN compared with 38.7% in the IBD group (P = 0.97) and 20.5% in the control group (P < 0.001). On multiple logistic regression, the odds of PN after adjusting for age, gender, diabetes, vitamin B12 deficiency, and cancer history were increased for CD (odds ratio, 2.51; 95% confidence interval, 1.82-3.47) and IBD (odds ratio, 2.78; 95% confidence interval, 1.85-4.18). PN is more often found in patients with CD and/or IBD than in the general population.


Personal relative deprivation impairs the ability to inhibit impulsive responses: an exploratory ERP study.
Evidence indicates that personal relative deprivation (PRD) can lead to various impulsive behaviors. Given that impulsive behaviors are usually caused by a failure to exert cognitive control, the purpose of this study was to explore whether PRD affects the ability to exert cognitive control on behavior. Forty-six healthy participants were randomly assigned to PRD or non-PRD group. Participants of the PRD group were told their income would lie below the Chinese average. While their electrophysiological responses were recorded, they underwent a Go/No-Go task simultaneously assessing the ability to detect response conflict and inhibit the predominant response. We found that the individuals with induced PRD show diminished ability to inhibit predominant response. We suggest this is because PRD-related concerns consume cognitive resources, leaving less for other tasks. However, we also found that individuals with induced PRD show enhanced ability to detect conflict. This might be because that individuals with induced PRD were sensitive to potentially threatening information (high-conflict No-Go trials) and they can detect conflict with less cognitive resources. These findings may facilitate future attempts to design interventions for relatively deprived individuals to manage their impulsive behavior.


[Development of an immunoenzyme test system for detecting antibodies to commercial strains of feed yeasts].
ELISA as a specific and highly sensitive test system was used for the examination of large groups of workers employed in the production of fodder protein to detect antibodies to the production strains of fodder yeast. The results yielded by ELISA correlated well with those obtained by the serological luminescent techniques, but antibody titers determined by means of ELISA are 10-20 times higher.


Seroepidemiology of bovine brucellosis in Colombia's preeminent dairy region, and its potential public health impact.
A cross-sectional study was conducted to determine the associated factors of brucellosis in Colombia's preeminent dairy region declared in quarantine. A total of 656 samples were collected from cows ≥ 2-year-old from 40 herds. Samples were screened by the Rose Bengal Plate Test, and the Fluorescence Polarized Assay test and Competitive ELISA were used as confirmatory tests. A cow was classified as positive if the screening and both confirmatory tests were positive. A herd was classified as positive if at least one cow was seropositive. The factors associated to seropositivity were tested using a logistic regression model with explanatory variables regarding cattle management, zootechnical parameters, and sanitary practices. The seroprevalence at the animal level was 6.6% (43/656) and at herd level 27.5% (11/40). In the model, five variables explained the animal cases: purchase or animal transfer between owner's farms (OR = 2.79, 95% CI 1.42, 5.49), history of abortion (OR = 4.22, 95% CI 1.91, 9.33), birth of weak calves (OR = 13.77, 95% CI 2.75, 68.91), use of a bull for mating (OR = 9.69, 95% CI 2.23, 42.18), and the vaccination in adulthood (OR = 3.03, 95% CI 1.04.8.78). In the model at the herd level, two variables explained the cases: birth of weak calves (OR = 9.60, 95% CI 1.54, 59.76) and purchase or animal transfer between owner's farms (OR = 7.22, 95% CI 1.03, 50.62). These results justify the need for a quarantine declaration in the region and the implementation of epidemiological studies as a public health measures used to combat outbreak.


[Methods of evidence mapping. A systematic review].
Evidence mapping is an increasingly popular approach to systematically evaluate published research. While there are methodological standards for systematic reviews, discrepancies exist between the terminology and methods used within evidence mapping. The aim of this systematic review is to describe the methodology and terminology used in evidence mapping and to demonstrate the continuum between evidence mapping and traditional systematic reviews. A systematic literature search was conducted in 10 databases in order to obtain a comprehensive picture of the state of the research standards for evidence mapping. In addition, websites of institutions which are already conducting evidence mapping were searched. The included study pool (n = 12) shows that the terms 'evidence map' and 'scoping review' are widely used within evidence mapping. Evidence maps are an approach to depict both the number and characteristics of studies in tabular form that exist as well as evidence gaps based on primary studies and systematic reviews of broad clinical questions. Scoping reviews also summarize the literature in a tabular form but also give a descriptive narrative summary of the results. A quality assessment of the studies is generally not included. Evidence mapping allows the identification of research gaps. This aspect is particularly important for interventions which are used without sufficient evidence. In contrast, systematic reviews are mainly used to estimate effects for interventions and evaluate whether the included studies are reliable.


Mediating process between fine motor skills, finger gnosis, and calculation abilities in preschool children.
Previous studies have found a relationship between fine motor skills, finger gnosis, and calculation skill. However, what mediates this association remains unclear. Therefore, this study investigated whether fine motor skills and finger gnosis are selectively associated with counting and symbolic comparison, and whether fine motor skills and finger gnosis are associated with calculation skills through numerical concepts to which they are selectively associated. We measured the counting, symbolic comparison, fine motor skills, finger gnosis, and working memory in preschool children (N = 48). The hierarchical multiple regression analysis results demonstrated that fine motor skills were selectively associated with counting, and finger gnosis with symbolic comparison. Moreover, based on the results of the mediation analysis, counting mediated the relationship between fine motor and calculation skills. However, the direct effects of fine motor skills and finger gnosis on calculation skills were also maintained. The findings were that fine motor skills and finger gnosis were related to numerical abilities, including counting, symbolic comparison, and calculations. Therefore, the findings were discussed in terms of the functional view and redeployment views, suggesting that the two views were complementary rather than exclusive.


Current concepts in plate and screw fixation of osteoporotic proximal humerus fractures.
Most surgeons feel that angular stable implants have improve the ability to obtain reliable fixation of an osteoporotic fracture of the proximal humerus fracture, but complications such as varus fracture collapse and screw penetration of the articular surface remain problematic. The use of limited drilling, blunt tipped locking bolts and routine incorporation of the rotator cuff into the internal fixation construct may help limit these complications. It may be of benefit to replace the concept of standard screw fixation of the osteoporotic proximal humerus with a concept of an angular stable scaffold support of the subchondral bone combined with fixation that does not rely on bone quality and utilizes the more predictable fixation of sutures through the rotator cuff attachments.


Human natural killer cell line modified with a chimeric immunoglobulin T-cell receptor gene leads to tumor growth inhibition in vivo.
The gene transfer of tumor-specific chimeric immunoglobulin T-cell receptors (cIgTCRs) combining antibody-like specificity with the effector cell function could be an attractive tool in immunotherapy. In this study, we directed the human natural killer (NK) cell line YT to tumor cells by gene transfer of a cIgTCR with specificity against the human carcinoembryonic antigen (CEA). The cIgTCR was constructed of a CEA-specific humanized single-chain Fv antibody fragment fused to the IgG1 Fc domain and the CD3 zeta chain. YT cells were transfected with the cIgTCR gene by electroporation and cIgTCR-expressing cells were enriched by immunoaffinity purification. cIgTCR-expressing YT cells specifically lysed CEA(+) colon carcinoma cell lines, which were resistant to the parental YT cell line. The lysis was not inhibited in the presence of soluble CEA. Receptor gene-modified YT cells retained their CEA-specific cytolytic activity after gamma-irradiation in vitro and inhibited the tumor growth in vivo after adoptive transfer into NOD/SCID mice. This gene-modified NK cell line available in unlimited source might be useful in clinical immunotherapy of CEA(+) cancer.


Complete remission of brain metastases in renal cell carcinoma treated with axitinib after failure with nivolumab and ipilimumab treatment.
Complete remission of cerebral metastasis is a rare consequence of tyrosine kinase inhibitor monotherapy in patients with metastatic renal cell carcinoma. A 68-year-old woman, who presented with dyspnea, was diagnosed with left renal cell carcinoma with multiple brain and pleural metastases. Although nivolumab and ipilimumab combination treatment was initiated, it was discontinued because of an immune-related adverse event. Two months after treatment cessation, brain metastases progressed regardless of shrinkage of primary renal tumor and pleural metastases. Therefore, axitinib was started as a second-line treatment, which resulted in the complete disappearance of the brain metastases along with the stable disease of the other tumor lesions. This is the first report of complete remission of brain metastases in renal cell carcinoma treated by axitinib.


Association of Helicobacter pylori-dependent gastritis with gastric carcinomas in young Japanese patients: histopathological comparison of diffuse and intestinal type cancer cases.
The causal relationship of H. pylori gastric colonization with gastric cancer development has not as yet been fully elucidated. The prevalence of H. pylori infection increases with age in the asymptomatic population in Japan, and reaches a high plateau in those older than 40 years. The objective of this study was to assess the link between H. pylori and gastric carcinomas in patients younger than 40 years. Detection of H. pylori and assessment of background mucosa based on the Sydney system was performed histopathologically for 40 Japanese gastric cancer cases younger than 40 years and compared with 40 age- and sex-matched controls. H. pylori infection in gastric mucosa was detected significantly more frequently (P < 0.001) in patients with cancer (29/40; 72.5%) than in controls (11/40; 27.5%). Additionally, by histopathological comparison between intestinal (18 cases) and diffuse (70 cases) types of young gastric cancer patients, mucosal atrophy and intestinal metaplasia were found to coexist with acute and chronic inflammation in the background mucosa of both intestinal and diffuse types, being significantly more prevalent than in young controls. As well as the high prevalence of H. pylori in young subjects with gastric cancer, it is clear that persistent infection induces mucosal damage, resulting in atrophy and intestinal metaplasia. Thus, acute/chronic gastritis could play an essential role in the early development of neoplasia in the stomach.


Functional roles of microbial cell-to-cell heterogeneity and emerging technologies for analysis and control.
Clonal cell populations often display significant cell-to-cell phenotypic heterogeneity, even when maintained under constant external conditions. This variability can result from the inherently stochastic nature of transcription and translation processes, which leads to varying numbers of transcripts and proteins per cell. Here, we showcase studies that reveal links between stochastic cellular events and biological functions in isogenic microbial populations. Then, we highlight emerging tools from engineering, computation, and synthetic and molecular biology that enable precise measurement, control, and analysis of gene expression noise in microorganisms. The capabilities offered by this sophisticated toolbox will shape future directions in the field and generate insight into the behavior of living systems at the single-cell level.


Tydeus shabestariensis sp. nov. and description of the male of Neopronematus sepasgosariani (Acari: Tydeoidea), with a key to the Iranian species of Tydeus.
A new species of the family Tydeidae from Iran, Tydeus shabestariensis sp. nov., is described from adult males and females collected from soil in apple orchards. A key to species of Tydeus of Iran, based on females, is provided. The male of Neopronematus sepasgosariani (Tydeoidea: Iolinidae) is also described and illustrated for the first time.


Web resources for drug toxicity.
Information on drug toxicity is used primarily by three segments of the health care industry: the consumer or patient, healthcare practitioners, and research and development (R&D) scientists in the pharmaceutical industry. The major focus of both consumers and health care practitioners is the provision of suitable information for the safe use of drugs for both individuals and specific patient populations. Therefore, accurate information on potential side effects and drug-drug and food-drug interactions is critical. For pharmaceutical scientists, the use of toxicity information is more complex and has become an essential part of the R&D process. The high rate of failures in drug development has precipitated the utilization of all available resources to gather relevant information that may improve the process of drug development. The web is a growing source of information and services for the pharmaceutical industry. Web-based resources for non-clinical drug development include tools for virtual discovery such as silico ADME/Toxicity programs, access to information regarding in vitro and in vivo testing, new data management options, and the latest regulatory guidelines and industry news. These resources are reviewed from the perspective of a toxicologist.


Boric acid improves the behavioral, electrophysiological and histological parameters of cisplatin-induced peripheral neuropathy in rats.
Boric acid (BA) has been used in many diseases because it increases the amount of reduced glutathione in the body and reduces oxidative damage. This study aims to investigate the effects of boric acid in cisplatin-induced neuropathy, in which oxidative stress is also effective in its pathophysiology. In this study, 8-10 weeks old, 170-190 g Wistar Albino rats were used. Each group contained seven rats (n = 35). Experimental groups consist of control, sham, neuropathy, treatment, and boric acid groups. For the neuropathy model, a single dose of cisplatin (3 mg/kg, i.p) was administered once a week for five weeks, and for the treatment group, boric acid was administered daily (100 mg/kg, intragastric) for five weeks. After drug administration, the rotarod test to evaluate motor performance, the tail-flick and hot/cold plate tests to evaluate sensory conduction states, the von Frey filament test to evaluate the mechanical allodynia, and the adhesive removal test to assess sensorimotor function were performed. The sciatic nerve's motoric conduction velocity was also assessed electrophysiologically. Oxidative stress parameters were also assessed biochemically in sciatic nerve tissue and serum. Hematoxylin and eosin staining was used to evaluate the sciatic nerve tissue histopathologically. The motor conduction velocity of the sciatic nerve, impaired by cisplatin, was increased considerably by boric acid (p < 0.05). It also reduced the latency time of the compound muscle action potential (CMAP), which was increased by cisplatin. (p < 0.05). The von Frey filament test results demonstrated increased pain sensitivity of the cisplatin group increased, and mechanical allodynia was observed. Boric acid significantly alleviated this condition (p < 0.05). In the cold plate, adhesive removal, and rotarod tests, boric acid attenuated the adverse effects of cisplatin (p < 0.05). Biochemically, BA reduced the level of MDA, which was raised by cisplatin, and significantly increased the level of SOD, which was lowered by cisplatin (p < 0.05). Histopathologically; BA reduced neuronal degeneration and vacuolization caused by cisplatin. As a consequence, it has been determined that boric acid alleviates the adverse effects of cisplatin. BA reduced the destructive effect of cisplatin by reducing oxidative stress, and this effect was verified electrophysiologically, behaviorally, and histopathologically.


The Influence of C(sp3 )H-Selenium Interactions on the 77 Se NMR Quantification of the π-Accepting Properties of Carbenes.
Selenium NMR has become a standard tool for scaling the π-accepting character of carbenes. Herein, we highlight that non-classical hydrogen bonding (NCHB), likely resulting from hyperconjugation, can play a significant role in the carbene-selenium 77 Se NMR chemical shift, thus triggering a non-linear behavior of the Se-Scale.


Clinical features and prognosis of heart failure in women. A 5-year prospective study.
Although heart failure (HF) is frequent and causes significant morbidity and mortality in women, data on the prognosis of women hospitalized for a first episode of HF are scarce. This study was designed to describe the clinical characteristics and treatment of HF in women and to assess the effect of gender on long-term survival. We prospectively included consecutive patients admitted for a first episode of HF in all healthcare establishments of the Somme department (France) during the year 2000. Baseline characteristics and long-term prognosis were evaluated and compared according to gender. 799 patients were included (389 women and 410 men). Women were older, had a higher prevalence of hypertension and renal insufficiency, and a lower prevalence of coronary artery disease. Prescription of HF medication at discharge was not significantly different between women and men. The prevalence of HF with preserved ejection fraction was higher in women. Five-year overall survival rates were not significantly different between women and men (39% vs. 41%, p=0.58). Cardiovascular mortality in women with HF was comparable with that observed in men. The 5-year survival in women was dramatically lower than the expected 5-year survival of the age-matched general population of women. On multivariable analysis, older age, cancer, stroke, diabetes, renal insufficiency, and lower natraemia were independent predictors of 5-year mortality in women. The prognosis after a first episode of HF in women is severe, comparable to that observed in men, with a 5-year survival rate of 39% and a dramatic excess mortality compared to the general population of women.


Risk indicators for dental caries, and gingivitis among 6-11-year-old children in Nigeria: a household-based survey.
There is little is known about the factors associated with caries experience and gingivitis among 6-11-year-old children in Nigeria. The aim of the study was to determine the prevalence and preventive oral health behaviors associated with caries and gingivitis among 6-11-year-old children in Nigeria. A cross-sectional questionnaire-based survey was conducted in Ile-Ife, Nigeria. The dependent variables were caries and gingivitis. The dmft/DMFT index was used to assess dental caries experience (present or absent) and caries severity. The gingival index was used to assess the prevalence (present or absent) and severity of gingivitis (healthy gingiva/mild gingivitis versus moderate/severe gingivitis). The independent variables were preventive oral health behaviors (frequency of daily tooth brushing, frequency of consumption of refined carbohydrates in-between-meals, use of fluoridated toothpaste, and use of dental floss, history of dental service utilization). A series of logistic regression analysis models were constructed to determine the associations between the dependent and independent variables after adjusting for confounders (age, sex, and socioeconomic status). There were 69 (5.2%) children with caries. The mean (standard deviation) dmft was 0.08 (0.457) and the mean DMFT was 0.02 (0.159). There were 839 (63.3%) children with gingivitis with a mean (SD) gingival index score of 0.503 (0.453). Children who seldom or never used fluoride toothpaste had significantly higher odds of developing moderate to severe gingivitis (AOR; 1.671; 95% CI: 1.003-2.786; p = 0.049). Children with middle socio-economic status had significantly lower odds of developing moderate to severe gingivitis (AOR: 0.573; 95%CI: 0.330-0.994; p = 0.048). There were no risk indicators identified for caries. The prevalence of dental caries was low while the prevalence of gingivitis was high in the study population. The daily used of fluoridated toothpaste seem to reduce the risk for moderate/severe gingivitis. Further studies are needed to understand these findings.


Screening participation predictors for people at familial risk of colorectal cancer: a systematic review.
People with a family history of colorectal cancer (CRC) are at increased risk of developing the disease. Information on the screening practices of this segment of the population is scarce. A systematic review was conducted of observational studies to identify factors associated with CRC screening participation for people at increased risk due to family history of the disease.MEDLINE, Cinahl Information Sevices, Embase, and PsycINFO databases were searched comprehensively between January 1995 and May 2012 to identify relevant articles. To be included, studies had to report on screening for people who had at least one first-degree relative with CRC, have described the study design, and reported on at least two predictors of adherence to CRC screening using a multivariate analysis. The search identified a total of 4986 articles, of which ten met the review's inclusion criteria. There were important inconsistencies among studies in the factors that were associated with screening. Receiving recommendations from clinicians was the most consistent predictor identified across studies. The review also revealed a consistent pattern of association with predictors related to familial aspects of CRC, such as strength of family history, and relationship to the affected relative. Among the psychological constructs, "social influence" emerged as the most consistent predictor of screening participation. This review provides evidence that clinicians, as well as use of family history and social networks, offer the most promising avenues to promoting and improving screening participation by individuals at increased risk of colorectal cancer.


The role of nutrients in the biodegradation of 2,4,6-trinitrotoluene in liquid and soil.
The widely used explosive 2,4,6-trinitrotoluene (TNT) has residues that are potentially explosive, toxic, and mutagenic. TNT and other explosives can be degraded by microorganisms; however, biostimulation is needed for process efficiency. To investigate the effectiveness of using biostimulation to degrade TNT, we added varying concentrations of a nutrient amendment consisting of inorganic salts, plant extracts, and molasses to soil and liquid media. For the inoculum we used a consortium of bacteria AM 06 that had exhibited the ability to degrade TNT and which had been previously isolated from explosives-contaminated soils. Phylogenetically, the clones clustered into seven different genera: Klebsiella, Raoultella, Serratia, Stenotrophomonas, Pseudoxanthomonas, Achromobacter and Pseudomonas. The addition of AM 06 consortium to a liquid environment along with 100% nutrient amendment decreased the amount of TNT (and its degradation products) by up to 90% after 14 days incubation. At the total amount of TNT was less than 100 mg/l, the concentration of TNT did not influence the amount of sugar consumed by the bacteria consortium. In soil media, the TNT degradation process was dependent on the concentration of nutrient amendment added. At higher initial concentrations of TNT (500 mg/kg), bioaugmentation (i.e., addition of bacteria inoculum) had a demonstrated effect, especially when nutrient concentrations of 50% and 100% were added to the soil. Findings of this study could further the understanding of the TNT biodegradation processes in water and soil and provide for optimization of the technological conditions for bioremediation.


Influence of the wastewater composition on denitrification and biological p-removal in the S-DN-P-process (b) Effect of acetate.
The effect of acetate was examined during the p-removal and denitrification of wastewater. The plant was operated based on the sequencing-batch-biofilm-reactor (SBBR) process. As microbial media, ca. 9 mm Bio-Flow granules made from polyethylene and polypropylene were used. Three preparations were made to compare the level of biological p-removal and denitrification. In comparison to the batch test, 42 mg/L (AC 30) and 84 mg/L (AC 60) of NaCH(3)COO were mixed with the 500 mL of raw wastewater and the effect of the acetate concentration on the level of p-removal was monitored. All samples were immediately filtered with 0.45 microm membrane filter, and PO(4)-P, NO(3)-N, NO(2)-N and acetate were analyzed using Ion Chromatography, whereas P(total) and chemical oxygen demand (COD) were measured by a spectrophotometer. The p-removals for the WW, WW+AC 30 and WW+AC 60 preparations were found to be 9.4, 9.1 and 13.1mg/L, respectively. The WW+AC 30 preparation did not show any significant effect on the p-removal, while p-removal in WW+AC 60 preparation was higher than that in the other two preparations. A comparison of the data revealed the COD: NO(3)-N:AC:P ratio of the WW, WW+AC 30 and WW+AC 60 preparations to be 18.07:2.90:6.87:1, 21.28:2.45:5.98:1 and 15.95:2.75:6.18:1, respectively. The experimental results showed that approximately 7 mg/L of acetate was consumed per 1mg/L of p-removal.


The antigenic structure of the acetylcholine receptor from Torpedo californica.
The immunological structure of the acetylcholine receptor (AChR) from the electric organ of Torpedo californica was studied using a large number of monoclonal antibodies which were initially selected for their abilities to bind to intact AChRs. The monoclonal antibodies were tested for their ability to bind to denatured AChR subunits labeled with 125I. Antibodies derived from rats immunized with individual denatured subunits or a mixture of subunits of Torpedo AChR reacted well in the assay. A much smaller proportion of antibodies derived from rats immunized with native Torpedo AChR or native AChR from Electrophorus electricus electric organ, bovine muscle, or human muscle reacted with denatured subunits of Torpedo AChR. Many monoclonal antibodies reacted with more than one subunit, but they always reacted best with the subunit used for immunization. Those monoclonal antibodies that bound to intact subunits were mapped more precisely by their ability to bind characteristic fragments of each subunit generated by proteolysis with Staphylococcal V8 protease. These fragments were analyzed by SDS polyacrylamide gel electrophoresis, and monoclonal antibodies that precipitated the same fragment pattern were placed in groups. By this method, we define a minimum of 28 determinants on Torpedo AChR.


Bioimaging: An Useful Tool to Monitor Differentiation of Human Embryonic Stem Cells into Chondrocytes.
To improve the recovery of damaged cartilage tissue, pluripotent stem cell-based therapies are being intensively explored. A number of techniques exist that enable monitoring of stem cell differentiation, including immunofluorescence staining. This simple and fast method enables changes to be observed during the differentiation process. Here, two protocols for the differentiation of human embryonic stem cells into chondrocytes were used (monolayer cell culture and embryoid body formation). Cells were labeled for markers expressed during the differentiation process at different time points (pluripotent: NANOG, SOX2, OCT3/4, E-cadherin; prochondrogenic: SOX6, SOX9, Collagen type II; extracellular matrix components: chondroitin sulfate, heparan sulfate; beta-catenin, CXCR4, and Brachyury). Comparison of the signal intensity of differentiated cells to control cell populations (articular cartilage chondrocytes and human embryonic stem cells) showed decreased signal intensities of pluripotent markers, E-cadherin and beta-catenin. Increased signal intensities of prochondrogenic markers and extracellular matrix components were observed. The changes during chondrogenic differentiation monitored by evaluation of pluripotent and chondrogenic markers signal intensity were described. The changes were similar to several studies over chondrogenesis. These results were confirmed by semi-quantitative analysis of IF signals. In this research we indicate a bioimaging as a useful tool to monitor and semi-quantify the IF pictures during the differentiation of hES into chondrocyte-like.


The influence of watering practices on the transmission of Fasciola among sheep in the Ethiopian highlands.
As many ewes and lambs watered at concrete ponds in well-drained sites acquired fluke infection as those watered at natural ponds in areas suitable for the snail intermediate hosts of Fasciola hepatica. Fasciola transmission, as evidenced by the increasing number of seropositive hosts in an enzyme-linked immunosorbent assay (ELISA), occurred during the heavy rainy period of July-September and declined with the onset of the dry season, being succeeded by the emergence of faecal positive hosts. This indicates the superiority of ELISA over coprological techniques in the early diagnosis and seroepidemiology of this parasitic infection. Host productivity, as reflected in weight gains and haematological parameters, was not significantly affected by the fluke infections.


Effects of suboccipital release with craniocervical flexion exercise on craniocervical alignment and extrinsic cervical muscle activity in subjects with forward head posture.
Forward head posture is a head-on-trunk malalignment, which results in musculoskeletal dysfunction and neck pain. To improve forward head posture, both the craniocervical flexion exercise and the suboccipital release technique have been used. The purpose of this study was to compare the immediate effects of craniocervical flexion exercise and suboccipital release combined with craniocervical flexion exercise on craniovertebral angle, cervical flexion and extension range of motion, and the muscle activities of the sternocleidomastoid, anterior scalene, and splenius capitis during craniocervical flexion exercise in subjects with forward head posture. In total, 19 subjects (7 males, 12 females) with forward head posture were recruited using G-power software. Each subject performed craniocervical flexion exercise and suboccipital release combined with craniocervical flexion exercise in random order. After one intervention was performed, the subject took a 20min wash out period to minimize any carry-over effect between interventions. Craniovertebral angle, cervical flexion and extension range of motion, and the muscle activities of the sternocleidomastoid, anterior scalene, and splenius capitis were measured. A one-way, repeated-measures ANOVA was used to assess differences between the effects of the craniocervical flexion exercise and suboccipital release combined with craniocervical flexion exercise interventions in the same group. Craniovertebral angle (p<0.05), cervical flexion range of motion (p<0.05), and cervical extension range of motion (p<0.001) were significantly greater after suboccipital release combined with craniocervical flexion exercise compared to craniocervical flexion exercise alone. The muscle activities of the sternocleidomastoid, anterior scalene, and splenius capitis were significantly lower during suboccipital release combined with craniocervical flexion exercise than during craniocervical flexion exercise alone across all craniocervical flexion exercise phases except the first (all p<0.05). The addition of suboccipital release to craniocervical flexion exercise provided superior benefits relative to craniocervical flexion exercise alone as an intervention for subjects with forward head posture.


Purification and characterization of a nitric oxide inhibitory peptide from Ruditapes philippinarum.
Ruditapes philippinarum (R. philippinarum) were hydrolyzed using 8 proteases to produce an anti-inflammatory peptide of the various hydrolysates produced, the Alcalase hydrolysate exhibited the highest nitric oxide (NO) inhibitory activity. The derived peptide was purified using high performance liquid chromatography (HPLC) and NO-inhibitory activity of the purified compound was evaluated. The sequence of the NO-inhibitory peptide obtained was composed of 10 amino acid residues, Gln-Cys-Gln-Gln-Ala-Val-Gln-Ser-Ala-Val at N-terminal position. In addition, we investigated the inhibitory effect of the purified peptide from R. philippinarum on NO production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. In this analysis the purified peptide from R. philippinarum was shown to inhibit LPS-induced NO production in RAW264.7 cells. The present results indicate that the purified peptide displayed potent anti-inflammation activity in RAW264.7 cells.


Characterization and management of cardiac involvement of thymic epithelial tumors.
Although thymic epithelial tumors (TETs) commonly infiltrate mediastinal structures, cardiac involvement is uncommon and has not been systematically studied. The purpose of this study was to describe our single-institution experience of the clinical presentation, treatment, and follow-up of cardiac involvement in patients with TETs. A single-institution retrospective review of cardiac involvement among patients with TETs from 2008 to 2012. The frequency of cardiac involvement was 4%. All five patients with confirmed cardiac disease had left heart involvement. Only one patient was symptomatic. Myocardial invasion was the most common mode of involvement followed by transvenous spread. Surgical resection of the involved area was attempted in three patients: in one, surgery was aborted because of extensive myocardial involvement; in the other two patients, resection was incomplete. Surgery averted a potentially catastrophic hemodynamic complication in one patient. However, cardiac tumor recurred in both patients who underwent incomplete resection. One patient underwent radiation therapy resulting in complete regression of an aortic root mass. This study represents the most comprehensive review of cardiac involvement in patients with TETs. In contrast to previous single-case reports, we found a preponderance of asymptomatic presentation, left heart involvement, and myocardial invasion. Dynamic cardiovascular magnetic resonance imaging should be considered in cases when cardiac involvement is suspected. Although immediate surgical resection is indicated for impending hemodynamic compromise, long-term palliation with surgery for myocardial involvement seems poor, especially when complete resection cannot be performed. Radiation therapy should be considered in selected patients.


Benzodiazepines and postoperative delirium: should we be as cautious as we are?
A recent systematic review and meta-analysis by Wang and colleagues in the British Journal of Anaesthesia calls into question the concept that perioperative benzodiazepine administration is associated with development of postoperative delirium in older individuals after anaesthesia and surgery. This editorial focuses on potential bias within the systematic review and addresses major concerns surrounding benzodiazepine use in the older perioperative population.


A radioimmunoassay for 11-oxotestosterone: its application in the measurement of levels in blood serum of rainbow trout (S. Gairdneri).
17beta-Hydroxyandrost-4-ene-3,11-dione was linked via its 3-(O-carboxymethyl) oxime to bovine serum albumin to give a conjugate which was used to generate antiserum in rabbits. The antiserum, at an overall dilution of 1 in 16,000, together with [1,2-3H] 17beta-hydroxyandrost-4-ene-3,11-dione synthesized from [1,2-3H] cortisone have been used to develop a radioimmunoassay for the parent steroid. The assay incorporates a purification step in which serum or plasma extracts are chromatographed on silica gel layers bound to plastic or aluminum sheets and the steroid containing zones cut out and eluted directly with assay buffer. The cross-reactivities of several steroids with the antiserum and the specificity, sensitivity, accuracy and precision of the assay are described. Blood sera from immature male rainbow trout contain ca 0.2-0.4 mature, serum levels rise sharply to reach values of 2 to greater than 9 microng/100 ml of 17beta-hydroxyandrost-4-ene-3,11 dione. As male fish mature, serum levels rise sharply to reach values of 2 to greater than 9 microng/100 ml. Levels in immature females rarely exceeded the assay sensitivity but serum from three ripe females showed low but detectable levels (ca 0.2 microng/100 ml) of steroid. The assay has found application in sexing live fish for experimental purposes.


Design and Rationale for a Cognitive Outcome Substudy in Ischemic Stroke Patients with High Risk of Cerebral Hemorrhage.
Cognitive impairment and dementia are common disabilities after stroke and are associated with increased risks of mortality and recurrent stroke. The prevention of dementia and preserving cognitive function are also important in stroke patients, but its strategy is not established yet. This PICASSO-COG (PreventIon of CArdiovascular events in iSchemic Stroke patients with high risk of cerebral hemOrrhage for reducing COGnitive decline) substudy aims to assess the effects of cilostazol and/or probucol on cognitive function. The substudy aims to assess the reduction in cognitive decline of patients treated with cilostazol and/or probucol in the PICASSO trial. Patients will be assessed using the Korean version of mini-mental state examination and Montreal Cognitive Assessment at 4, 7, 10, 13, 25, 37, and 49 months after randomization. The primary outcome is the change in mini-mental status examination score, compared between treatment groups, with a modified intention-to-treat population using a restricted maximum likelihood-based mixed effects model repeat measurement. This will allow a within-subject correlation due to repeated cognitive tests as well as a different number of measurements among subjects at baseline and each follow-up period. PICASSO-COG is a novel study for assessing the effect on cognitive function of different antiplatelet regimens and the addition of a nonstatin lipid-lowering agent to the current standard statin therapy in patients who have a recent ischemic lesion and prior intracerebral macro- or microbleeds.


Comparing the cost of spinal MR with conventional myelography and radiculography.
All spinal magnetic resonance imaging examinations carried out during a three month period were analysed retrospectively in order to determine the clinical reasons for the scan requests. Technical details of the examinations they received and the clinical profiles formed a data set which revealed 10 separate "Clinical groups" for management purposes. Hardware, salary and expendables were costed as though the imaging unit had been sited within a National Health Service radiology department. A spread sheet was designed capable of calculating costs per patient for a variety of types of working week and of different staffing structures, sensitive to the mixture of clinical groups referred for examination. The spreadsheet also accomodated straight line depreciation for hardware value and interest rates for borrowed capital. A second, prospectively observed, sample of spinal MR examinations was used to improve the accuracy of the timing of the length of patient examinations. Costs were compared with those for patients submitted for myelography and radiculography at the adjacent hospital during the same period. The comparison indicated that spinal MR was less costly than myelography and radiculography. The most important element of the extra cost of myelography related to the need to admit patients to hospital for at least one night for this examination because of the likelihood of headache and other common (though usually minor) complications following lumbar puncture and/or the injection of contrast medium. From the limited information that it was possible to obtain in the period of follow up, it appeared that MR had either been superior or equivalent to myelography or radiculography in all the clinical groups of patients where both could be tested. There were a number of groups in which no myelograms had been requested, presumably because clinical suspicions had pointed toward conditions like tumours, developmental abnormalities and demyelinating diseases in which neurologists and neurosurgeons have already made up their minds about the superiority of MR.


Steroid Hormone Ecdysone Signaling Specifies Mushroom Body Neuron Sequential Fate via Chinmo.
The functional variety in neuronal composition of an adult brain is established during development. Recent studies proposed that interactions between genetic intrinsic programs and external cues are necessary to generate proper neural diversity [1]. However, the molecular mechanisms underlying this developmental process are still poorly understood. Three main subtypes of Drosophila mushroom body (MB) neurons are sequentially generated during development and provide a good example of developmental neural plasticity [2]. Our present data propose that the environmentally controlled steroid hormone ecdysone functions as a regulator of early-born MB neuron fate during larval-pupal transition. We found that the BTB-zinc finger factor Chinmo acts upstream of ecdysone signaling to promote a neuronal fate switch. Indeed, Chinmo regulates the expression of the ecdysone receptor B1 isoform to mediate the production of γ and α'β' MB neurons. In addition, we provide genetic evidence for a regulatory negative feedback loop driving the α'β' to αβ MB neuron transition in which ecdysone signaling in turn controls microRNA let-7 depression of Chinmo expression. Thus, our results uncover a novel interaction in the MB neural specification pathway for temporal control of neuronal identity by interplay between an extrinsic hormonal signal and an intrinsic transcription factor cascade.


Hasty sensorimotor decisions rely on an overlap of broad and selective changes in motor activity.
Humans and other animals are able to adjust their speed-accuracy trade-off (SAT) at will depending on the urge to act, favoring either cautious or hasty decision policies in different contexts. An emerging view is that SAT regulation relies on influences exerting broad changes on the motor system, tuning its activity up globally when hastiness is at premium. The present study aimed to test this hypothesis. A total of 50 participants performed a task involving choices between left and right index fingers, in which incorrect choices led either to a high or to a low penalty in 2 contexts, inciting them to emphasize either cautious or hasty policies. We applied transcranial magnetic stimulation (TMS) on multiple motor representations, eliciting motor-evoked potentials (MEPs) in 9 finger and leg muscles. MEP amplitudes allowed us to probe activity changes in the corresponding finger and leg representations, while participants were deliberating about which index to choose. Our data indicate that hastiness entails a broad amplification of motor activity, although this amplification was limited to the chosen side. On top of this effect, we identified a local suppression of motor activity, surrounding the chosen index representation. Hence, a decision policy favoring speed over accuracy appears to rely on overlapping processes producing a broad (but not global) amplification and a surround suppression of motor activity. The latter effect may help to increase the signal-to-noise ratio of the chosen representation, as supported by single-trial correlation analyses indicating a stronger differentiation of activity changes in finger representations in the hasty context.


Meta-analysis: diagnostic medical radiation exposure in inflammatory bowel disease.
Diagnostic imaging plays a pivotal role in the diagnosis and management of inflammatory bowel disease (IBD); however, increasing use has led to concerns about the malignant potential of ionising radiation. Several studies have demonstrated that diagnostic imaging can result in exposure to potentially harmful levels of ionising radiation in IBD patients. To determine the pooled prevalence of increased exposure and pooled odds ratio of risk factors associated with exposure to potentially harmful levels of diagnostic medical radiation. We searched Medline, EMBASE, CINHAL and reference lists of identified articles, without language restrictions in October 2011. Six studies with 1704 participants provided data on the proportion of patients receiving potentially harmful levels of radiation defined as ≥50 milli-sieverts (mSv)-equivalent to 5 CT abdomen scans. The pooled prevalence was 8.8% (95% CI 4.4-16.8) for IBD patients and 11.1% (95% CI 5.7-20.5%) and 2% (95% CI 0.8-4.9%) for Crohn's disease and ulcerative colitis patients respectively. Five studies involving 2627 participants provided data for risk factors. IBD-related surgery and corticosteroid use were significant with pooled adjusted odds ratio of 5.4 (95% CI 2.6-11.2) and 2.4 (95% CI 1.7-3.4) respectively. About 1 in 10 patients may be exposed to potentially harmful levels of diagnostic medical radiation. Corticosteroid use and IBD related surgery increased this risk. Strategies to reduce radiation exposure while assessing disease activity need to be considered.


Towards adult vaccination in India: a narrative literature review.
Despite vast improvements in childhood vaccination coverage in India, adult vaccination coverage is negligible. Our aim was, therefore, to create awareness about the importance of adult immunization. Although the true burden of vaccine-preventable diseases (VPDs) among Indian adults is unknown, adults are particularly vulnerable during outbreaks, due to a lack of immunization, waning immunity, age-related factors (e.g. chronic conditions and immunosenescence), and epidemiological shift. There are no national adult immunization guidelines in India, and although several medical societies have published adult immunization guidelines, these vary, making it unclear who should receive which vaccines (based on age, underlying conditions, etc.). Other barriers to adult immunization include vaccine hesitancy, missed opportunities, and cost. Steps to improve adult vaccination could include: adoption of national guidelines, education of healthcare providers and the public, and promotion of life-course immunization. Improving adult vaccine coverage could help reduce the burden of VPDs, particularly among older adults.


Hypofractionated, 3-week, preoperative radiotherapy for patients with soft tissue sarcomas (HYPORT-STS): a single-centre, open-label, single-arm, phase 2 trial.
The standard preoperative radiotherapy regimen of 50 Gy delivered in 25 fractions for 5 weeks for soft tissue sarcomas results in excellent local control, with major wound complications occurring in approximately 35% of patients. We aimed to investigate the safety of a moderately hypofractionated, shorter regimen of radiotherapy, which could be more convenient for patients. This single-centre, open-label, single-arm, phase 2 trial (HYPORT-STS) was done at a single tertiary cancer care centre (MD Anderson Cancer Center, Houston, TX, USA). We administered preoperative radiotherapy to a dose of 42·75 Gy in 15 fractions of 2·85 Gy/day for 3 weeks (five fractions per week) to adults (aged ≥18 years) with non-metastatic soft tissue sarcomas of the extremities or superficial trunk and an Eastern Cooperative Oncology Group performance status of 0-3. The primary endpoint was a major wound complication occurring within 120 days of surgery. Major wound complications were defined as those requiring a secondary operation, or operations, under general or regional anaesthesia for wound treatment; readmission to the hospital for wound care; invasive procedures for wound care; deep wound packing to an area of wound measuring at least 2 cm in length; prolonged dressing changes; repeat surgery for revision of a split thickness skin graft; or wet dressings for longer than 4 weeks. We analysed our primary outcome and safety in all patients who enrolled. We monitored safety using a Bayesian, one-arm, time-to-event stopping rule simulator comparing the rate of major wound complications at 120 days post-surgery among study participants with the historical rate of 35%. This trial is registered with ClinicalTrials.gov, NCT03819985, recruitment is complete, and follow-up continues. Between Dec 18, 2018, and Jan 6, 2021, we assessed 157 patients for eligibility, of whom 120 were enrolled and received hypofractionated preoperative radiotherapy. At no time did the stopping rule computation indicate that the trial should be stopped early for lack of safety. Median postoperative follow-up was 24 months (IQR 17-30). Of 120 patients, 37 (31%, 95% CI 24-40) developed a major wound complication at a median time of 37 days (IQR 25-59) after surgery. No patient had acute radiation toxicity (during radiotherapy or within 4 weeks of the radiotherapy end date) of grade 3 or worse (Common Terminology Criteria for Adverse Events [CTCAE] version 4.0) or an on-treatment serious adverse event. Four (3%) of 115 patients had late radiation toxicity (≥6 months post-surgery) of at least grade 3 (CTCAE or Radiation Therapy Oncology Group/European Organisation for Research and Treatment of Cancer Late Radiation Morbidity Scoring Scheme): femur fractures (n=2), lymphoedema (n=1), and skin ulceration (n=1). There were no treatment-related deaths. Moderately hypofractionated preoperative radiotherapy delivered to patients with soft tissue sarcomas was safe and could therefore be a more convenient alternative to conventionally fractionated radiotherapy. Patients can be counselled about these results and potentially offered this regimen, particularly if it facilitates care at a sarcoma specialty centre. Results on long-term oncological, late toxicity, and functional outcomes are awaited. The National Cancer Institute.


Components of verbal learning and hippocampal damage assessed by T2 relaxometry.
We studied a group of 31 temporal lobe epilepsy patients (25 left, 6 right) with unilateral hippocampal sclerosis evident on magnetic resonance imaging. Single slice T2 relaxation times were acquired for the left and right hippocampi. Principal components analysis of preoperative memory data resulted in two factors that reflect a distinction between arbitrary and semantic forms of verbal recall. The former component correlated with left hippocampal T2 relaxation time, while the latter component did not. This study suggests that variation in left hippocampal integrity is more related to the acquisition of arbitrary associates than semantically structured material, and reinforces the possibility that the left temporal lobe is functionally heterogeneous with respect to memory.