Allelic difference in Mhc2ta confers altered microglial activation and susceptibility to α-synuclein-induced dopaminergic neurodegeneration.
Parkinson's Disease (PD) is a complex and heterogeneous neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta and pathological intracellular accumulation of alpha-synuclein (α-syn). In the vast majority of PD patients, the disease has a complex etiology, defined by multiple genetic and environmental risk factors. Common genetic variants in the human leukocyte-antigen (HLA) region have been associated to PD risk and the carriage of these can double the risk to develop PD. Among these common genetic variants are the ones that modulate the expression of MHCII genes. MHCII molecules encoded in the HLA-region are responsible for antigen presentation to the adaptive immune system and have a key role in inflammatory processes. In addition to cis‑variants affecting MHCII expression, a transactivator encoded by the Mhc2ta gene is the major regulator of MHCII expression. We have previously identified variations in the promoter region of Mhc2ta, encoded in the VRA4 region, to regulate MHCII expression in rats. The expression of MHCII is known to be required in the response to α-syn. However, how the expression of MHCII affects the activation of microglial or the impact of physiological, differential Mhc2ta expression on degeneration of dopaminergic neurons has not previously been addressed. Here we addressed the implications of common genetic allelic variants of the major regulator of MHCII expression on α-syn-induced microglia activation and the severity of the dopaminergic neurodegeneration. We used a viral vector technology to overexpress α-syn in two rat strains; Dark agouti (DA) wild type and DA.VRA4-congenic rats. The congenic strain carries PVG alleles in the VRA4 locus and therefore displays lower Mhc2ta expression levels compared to DA rats. We analyzed the impact of this physiological differential Mhc2ta expression on gliosis, inflammation, degeneration of the nigro-striatal dopamine system and behavioral deficits after α-syn overexpression. We report that allelic variants of Mhc2ta differently modified the microglial activation in response to overexpression of human α-syn in rats. Overexpression of α-syn led to a larger denervation of the nigro-striatal system and significant behavioral deficits in DA.VRA4 congenic rats with lower Mhc2ta expression compared to DA rats. These results indicate that Mhc2ta is a key upstream regulator of the inflammatory response in PD pathology.


A seven-year survey of susceptibility to marbofloxacin of pathogenic strains isolated from pets.
This study, Vetoquinol S.A. epidemiosurveillance, was conducted from 1994 to 2001 in order to determine the susceptibility (by MIC determination) to marbofloxacin (a third generation fluoroquinolone used only in individual administration for animals). Strains from infected pets originated from six European countries. Isolates were collected from urinary infections (Escherichia coli), respiratory infections (Pasteurella multocida), dermatological infections (Staphylococcus intermedius, Pseudomonas aeruginosa) and otitis (S. intermedius, P. aeruginosa). The MIC distribution for each species was the same both before and after the launch of marbofloxacin in 1995. In E. coli, a resistant population was present before the use of marbofloxacin; this resistance was induced by co- or cross-resistance to other antibiotics used previously. Over this period, there was no significant evolution of MIC(90) for any bacterial species studied and no development of resistance was observed. Marbofloxacin was the most active antibiotic against P. multocida isolates and had the lowest MIC. No difference in MIC distribution was seen between the S. intermedius (unimodal distribution) isolated from dermatological infections and those from otitis. This was also true for P. aeruginosa. The use of marbofloxacin was not found to have induced a significant increase or spread of resistant bacteria.


Electron-transfer oxidation properties of DNA bases and DNA oligomers.
Kinetics for the thermal and photoinduced electron-transfer oxidation of a series of DNA bases with various oxidants having the known one-electron reduction potentials (E(red)) in an aqueous solution at 298 K were examined, and the resulting electron-transfer rate constants (k(et)) were evaluated in light of the free energy relationship of electron transfer to determine the one-electron oxidation potentials (E(ox)) of DNA bases and the intrinsic barrier of the electron transfer. Although the E(ox) value of GMP at pH 7 is the lowest (1.07 V vs SCE) among the four DNA bases, the highest E(ox) value (CMP) is only 0.19 V higher than that of GMP. The selective oxidation of GMP in the thermal electron-transfer oxidation of GMP results from a significant decrease in the pH dependent oxidation potential due to the deprotonation of GMP*+. The one-electron reduced species of the photosensitizer produced by photoinduced electron transfer are observed as the transient absorption spectra when the free energy change of electron transfer is negative. The rate constants of electron-transfer oxidation of the guanine moieties in DNA oligomers with Fe(bpy)3(3+) and Ru(bpy)3(3+) were also determined using DNA oligomers containing different guanine (G) sequences from 1 to 10 G. The rate constants of electron-transfer oxidation of the guanine moieties in single- and double-stranded DNA oligomers with Fe(bpy)3(2+) and Ru(bpy)3(3+) are dependent on the number of sequential guanine molecules as well as on pH.


Genetics of congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV. Clinical, biological and molecular aspects of mutations in TRKA(NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor.
Congenital insensitivity to pain with anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV (HSAN-IV) is an autosomal recessive disorder characterized by recurrent episodic fevers, anhidrosis (inability to sweat), absence of reaction to noxious (or painful) stimuli, self-mutilating behavior and mental retardation. The anomalous pain and temperature sensation and anhidrosis in CIPA are due to the absence of afferent neurons activated by tissue-damaging stimuli and a loss of innervation of eccrine sweat glands, respectively. Nerve growth factor (NGF) supports the survival of nociceptive sensory and autonomic sympathetic neurons as well as cholinergic neurons of the basal forebrain. The human TRKA (NTRKI) gene located on chromosome 1 (1q21-q22) encodes a receptor tyrosine kinase (RTK) which is autophosphorylated in response to NGF, thus, activating various pathways of intracellular signal transduction. We earlier identified the genetic basis of CIPA by detecting mutations in TRKA gene of patients. Defects in NGF signal transduction at its receptor lead to failure to survive as various NGF dependent neurons are not maintained, most probably due to apoptosis during development. TRKA mutations are distributed in an extracellular domain involved in NGF binding, as well as in the intracellular signal-transduction domain. Missense mutations with loss of function provide considerable insight into the structure-function relationship in the RTK family. In view of the fact that defects in TRKA cause CIPA, the molecular pathology of CIPA provides unique opportunities to explore critical roles of the NGF-TRKA receptor system. Thus, CIPA can serve as a useful model to determine mechanisms of development and maintenance of NGF-dependent neurons in autonomic, sensory and central nervous systems, as well as the physiology of these neurons in humans.


Abnormal site occupancy and high performance in warm WLEDs of a novel red phosphor, NaHF2:Mn4+, synthesized at room temperature.
A novel red phosphor, NaHF2:Mn4+ (NHF:Mn), was obtained via substituting Na+ located at the center of the octahedron coordinated with six F- ions with Mn4+ in the host lattice of NHF. The phase purity and the exact composition of the obtained NHF:Mn were confirmed by X-ray powder diffraction (XRD), Rietveld refinement, energy dispersive spectroscopy (EDS), transmission electron microscopy (TEM), and infrared (IR) spectroscopy, respectively. The luminescence intensity of NHF:Mn was enhanced by optimizing the synthetic conditions. A series of warm white light-emitting diodes (WLEDs) with a color rendering index (CRI) higher than 88.0 and correlated color temperatures (CCT) between 3146 and 5172 K were obtained by encapsulating the as-prepared red phosphor NHF:Mn with the yellow one Y3Al5O12:Ce3+ (YAG:Ce) on blue chips. The advantage of the synthetic strategy to obtain NHF:Mn can be extended to develop novel Mn4+ doped red phosphors via substituting for central ions with unequal electric charge in the centers of octahedra.


Paraneoplastic anti-neuronal nuclear IgG autoantibodies (type I) localize antigen in small cell lung carcinoma.
Type I anti-neuronal nuclear autoantibodies (ANNA-I, also known as "Hu") are a distinctive serologic marker of small cell lung carcinoma (SCLC) in patients who have peripheral neuropathies or encephalomyeloradiculopathies. A tumor antigen reactive with these antibodies has been identified by other investigators by Western blot analyses, but an antigen has not been localized in SCLC immunohistochemically. We therefore tested, by indirect immunofluorescence, the sera of 49 sequential ANNA-I-positive patients and 30 control subjects for IgG reactive with SCLC. Two tumor cell lines were tested, one established from the primary tumor of a patient with Lambert-Eaton syndrome and the second from the metastatic lesion of a patient without neurologic disease. IgG in all ANNA-I-positive sera bound to both tumors. In most instances, the pattern resembled that seen in neurons, with strong homogeneous nuclear staining, sparing of nucleoli, and faint cytoplasmic staining. A highly significant correlation was noted between endpoint dilutions obtained on SCLC substrates and on central and peripheral neurons (r = 0.863; P less than 0.001). IgG in 3 of 30 control sera bound in low titer to SCLC cells but not to neurons, and 9 control sera contained non-organ-specific anti-nuclear antibodies (ANA). The ANA IgG was absorbed equivalently by homogenates of SCLC or colonic adenocarcinoma cells. In contrast, the reactivity of ANNA-I IgG with cerebellar and myenteric plexus neurons was absorbed only by homogenized SCLC cells. These findings suggest that SCLC antigens account for all neuronal reactivity of ANNA-I. IgG of this specificity may serve as a useful reagent for identifying SCLC cells in surgical pathologic and cytologic specimens.


Operative outcomes of hallux valgus with painful osteoarthritis of the lesser tarsometatarsal joints.
Hallux valgus is sometimes accompanied by osteoarthritis of the lesser tarsometatarsal joint. However, information on the operative procedures and outcomes for the treatment of hallux valgus with osteoarthritis of the lesser tarsometatarsal joint simultaneously is limited. We aimed to describe this operative procedure and evaluate the outcomes of the treatment of hallux valgus with osteoarthritis of the lesser tarsometatarsal joint. Fifteen patients (17 feet; average age, 66.9 years; average follow-up, 59.4 months; and minimum follow-up, 24 months) with symptomatic hallux valgus accompanied by painful osteoarthritis of the lesser tarsometatarsal joint were enrolled. All feet showed osteoarthritis of the second and/or third tarsometatarsal joint on dorsoplantar weight-bearing radiograph. The operative procedure included a proximal osteotomy of the first metatarsal and arthrodesis of the lesser tarsometatarsal joint with an autologous bone graft. The mean Japanese Society for Surgery of the Foot hallux metatarsophalangeal-interphalangeal score significantly improved from 54.8 points preoperatively to 91.7 points postoperatively (P <0.001). The mean postoperative visual analog score (15 feet) was 1.0 (0-3.9). Preoperative midtarsal pain disappeared in 14 feet and decreased in one foot postoperatively. Preoperative metatarsalgia was found in five feet, of which, it disappeared in two feet, decreased in two feet, and transferred to another region in one foot at the latest follow-up. The mean hallux valgus and intermetatarsal angles were 42.4° and 18.4° preoperatively, which decreased significantly to 12.5° and 6.9° postoperatively, respectively (P <0.001, all). Recurrence of hallux valgus (hallux valgus angle ≥20°) was observed in two feet (11.8%). Nonunion of the third tarsometatarsal joint was observed in one foot (3.1% among 32 joints). The clinical and radiographic results indicated that operative treatment for hallux valgus with painful osteoarthritis of the lesser tarsometatarsal joint significantly improves forefoot and midfoot pain and function and has low complication rates. Level IV, retrospective case series.


[Long-Term Survival after Locally Advanced Pancreatic Ductal Adenocarcinoma Treated with Multidisciplinary Therapy - A Case Report].
A 60-year-old man visited a hospital with concerns about his physical health, including weight loss, thirst, and polyuria. He was diagnosed with acute onset of diabetes, and a pancreatic head tumor was observed on imaging studies. Computed tomography(CT)indicated that the tumor infiltrated the surrounding major vessels, portal vein(PV, 360 degrees), and superior mesenteric artery(SMA, <180 degrees). Endoscopic ultrasound-guided fine needle aspiration(EUS-FNA)was performed, and he was diagnosed with a borderline resectable(BR)clinical Stage IV a pancreatic ductal adenocarcinoma (PDAC). Chemoradiation therapy(CRT, S-1 plus gemcitabine [GEM] concurrent with 50.4 Gy radiation)followed by chemotherapy( GEM)was performed until a tumor response indicating sufficient reduction of SMA infiltration was observed on imaging studies. Twelve months after initiation of treatment, a pancreaticoduodenectomy and PV resection/reconstruction were performed. The pathological stage was ypT3N0M0(ypStage III ), and SMA infiltration was not detected in the resected specimen. He was discharged after an uneventful course following surgery, and adjuvant S-1 chemotherapy was continued from post-operative day 67 for 4 months. Now at post-operative 57 month, he has survived without recurrence. There have been some reports detailing long-term survival of patients with BR tumors who underwent multidisciplinary therapy as curative resection following preoperative CRT and postoperative adjuvant chemotherapy. During preoperative treatment, it is important to monitor the effects and determine the suitable timing to perform surgery to achieve long-term survival.


Determining the coronavirus awareness of the Turkish society and the anxiety stress levels.
The aim of the study is to determine the awareness of the Turkish society in COVID-19, and determine the anxiety stress levels. Research two months after the start of the outbreak in Turkey has reached 2163 individuals completed the online platform. The Integrated Anxiety Stress Scale significantly changed according to age, gender, marital status and working status after the pandemic. According to the results of multiple binary logistic regression analysis, individuals aged 50 and over, female gender, being single and not working after the pandemic for anxiety; female gender, being married, and post-pandemic study were found to be risk factors for Covid awareness. It is recommended that epidemic awareness studies and information sharing on controlled healing measures are planned considering the anxiety levels.


Physical activity phenotyping with activity bigrams, and their association with BMI.
Analysis of physical activity usually focuses on a small number of summary statistics derived from accelerometer recordings: average counts per minute and the proportion of time spent in moderate-vigorous physical activity or in sedentary behaviour. We show how bigrams, a concept from the field of text mining, can be used to describe how a person's activity levels change across (brief) time points. These variables can, for instance, differentiate between two people spending the same time in moderate activity, where one person often stays in moderate activity from one moment to the next and the other does not. We use data on 4810 participants of the Avon Longitudinal Study of Parents and Children (ALSPAC). We generate a profile of bigram frequencies for each participant and test the association of each frequency with body mass index (BMI), as an exemplar. We found several associations between changes in bigram frequencies and BMI. For instance, a one standard deviation decrease in the number of adjacent minutes in sedentary then moderate activity (or vice versa), with a corresponding increase in the number of adjacent minutes in moderate then vigorous activity (or vice versa), was associated with a 2.36 kg/m2 lower BMI [95% confidence interval (CI): -3.47, -1.26], after accounting for the time spent in sedentary, low, moderate and vigorous activity. Activity bigrams are novel variables that capture how a person's activity changes from one moment to the next. These variables can be used to investigate how sequential activity patterns associate with other traits.


Comparing the results of Pap smear and Direct Visual Inspection (DVI) with 5% acetic acid in cervical cancer screening.
Cervical cancer is the most second common cancer among Iranian women. This study was carried out to compare the results of Pap smear method and Direct Visual Inspection (DVI) with 5% acetic acid in cervical cancer screening in Tabriz, Iran. This cross-sectional study was carried out in Alzahra Therapeutic-Educational Centre, Tabriz, Iran in 2013 on 1000 women. First, Pap smear was done for all women, and then the cervix exposed with 5% acetic acid by cotton swab for 30 seconds and observed under adequate light. At the end, women with abnormal results in Pap smear or DVI method were referred to colposcopy and biopsy. Test's sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), LR+, LR- and confidence interval (CI) were determined (P < 0.05). Nine-hundred and seventy-four (94.7%) cases were normal and had no abnormal findings and 26 (2.6%) participants had positive results in Pap smear or DVI test. Twelve women had abnormal Pap smear (nine women with atypical squamous cells of undetermined significance, ASCUS, three women with dysplasia, atypical endocervical, and low-grade squamous intraepithelial lesion, LSIL results) and 14 women had positive DVI (four women with human papillomavirus, HPV or koilocyte,) and one women with abnormality in both method had carcinoma in biopsy that referred to oncologist. In this study the sensitivity, specificity, PPV and NPV for DVI were 71.4%, 50%, 35.7%, and 81.8% respectively in comparison with 14.3%, 50%, 10%, and 60% for Pap smear. As the DVI method has higher sensitivity and positive predictive value than Pap smear, it could be used as a useful method beside the Pap smear.


Identifying Candidate Biomarkers of Ionizing Radiation in Human Pulmonary Microvascular Lumens Using Microfluidics-A Pilot Study.
The microvasculature system is critical for the delivery and removal of key nutrients and waste products and is significantly damaged by ionizing radiation. Single-cell capillaries and microvasculature structures are the primary cause of circulatory dysfunction, one that results in morbidities leading to progressive tissue and organ failure and premature death. Identifying tissue-specific biomarkers that are predictive of the extent of tissue and organ damage will aid in developing medical countermeasures for treating individuals exposed to ionizing radiation. In this pilot study, we developed and tested a 17 µL human-derived microvascular microfluidic lumen for identifying candidate biomarkers of ionizing radiation exposure. Through mass-spectrometry-based proteomics, we detected 35 proteins that may be candidate early biomarkers of ionizing radiation exposure. This pilot study demonstrates the feasibility of using humanized microfluidic and organ-on-a-chip systems for biomarker discovery studies. A more elaborate study of sufficient statistical power is needed to identify candidate biomarkers and test medical countermeasures of ionizing radiation.


Phase II Trial Evaluating Esophageal Anastomotic Reinforcement with a Biologic, Degradable, Extracellular Matrix after Total Gastrectomy and Esophagectomy.
A biologic, degradable extracellular matrix (ECM) has been shown to support esophageal tissue remodeling, which could reduce the risk of anastomotic leak following total gastrectomy and esophagectomy. We evaluated the safety and efficacy of reinforcing the anastomosis with ECM in reducing anastomotic leak as compared to a matched cohort. In this single-center, nonrandomized phase II trial, gastric or esophageal adenocarcinoma patients undergoing total gastrectomy or esophagectomy were recruited from November 2013 through December 2018. ECM was surgically wrapped circumferentially around the anastomosis. Anastomotic leak was assessed clinically and by contrast study and defined as clinically significant if requiring invasive treatment (grade 3 or higher). Anastomotic stenosis, other adverse events, symptoms, and dysphagia score were collected by standardized forms at regular follow-up visits at approximately postoperative days (POD) 21 and 90. Patients receiving ECM were compared to a cohort matched for surgery type and age. ECM placement was not feasible in 9 of 75 patients (12%), resulting in 66 patients receiving ECM. Total gastrectomy was performed in 50 patients (76%) and esophagectomy in 16 (24%). Clinically significant anastomotic leak was diagnosed in 6 of 66 patients (9.1%) (3/50 [6.0%] after gastrectomy, 3/16 [18.8%] after esophagectomy); this rate did not differ from that in the matched cohort (p = 0.57). Stenosis requiring invasive treatment occurred in 8 patients (12.5%), and 10 patients (15.6%) reported not being able to eat a normal diet at POD 90. No adverse events related to ECM were reported. Esophageal anastomotic reinforcement after total gastrectomy or esophagectomy with a biologic, degradable ECM was mostly feasible and safe, but was not associated with a statistically significant decrease in anastomotic leak.


The association between nursing factors and patient mortality in the Veterans Health Administration: the view from the nursing unit level.
Nurse staffing is not the same across an entire hospital. Nursing care is delivered in geographically-based units, with wide variation in staffing levels. In particular, staffing in intensive care is much richer than in nonintensive care acute units. To evaluate the association of in-hospital patient mortality with registered nurse staffing and skill mix comparing hospital and unit level analysis using data from the Veterans Health Administration (VHA). A retrospective observational study using administrative data from 129,579 patients from 453 nursing units (171 ICU and 282 non-ICU) in 123 VHA hospitals. We used hierarchical multilevel regression models to adjust for patient, unit, and hospital characteristics, stratifying by whether or not patients had an ICU stay during admission. In-hospital mortality. : Of the 129,579 patients, mortality was 2.9% overall: 6.7% for patients with an ICU stay compared with 1.6% for those without. Whether the analysis was done at the hospital or unit level affected findings. RN staffing was not significantly associated with in-hospital mortality for patients with an ICU stay (OR, 1.02; 95% CI, 0.99-1.03). For non-ICU patients, increased RN staffing was significantly associated with decreased mortality risk (OR, 0.91; 95% CI, 0.86-0.96). RN education was not significantly associated with mortality. Our findings suggest that the association between RN staffing and skill mix and in-hospital patient mortality depends on whether the analysis is conducted at the hospital or unit level. Variable staffing on non-ICU units may significantly contribute to in-hospital mortality risk.


Microsurgical anatomy of the inferior limiting insular sulcus and the temporal stem.
The purpose of this study was to describe the location of each white matter pathway in the area between the inferior limiting insular sulcus (ILS) and temporal horn that may be crossed in approaches through the temporal stem to the medial temporal lobe. The fiber tracts in 14 adult cadaveric cerebral hemispheres were examined using the Klingler technique. The fiber dissections were completed in a stepwise manner, identifying each white matter pathway in different planes and describing its position in relation to the anterior end of the ILS. The short-association fibers from the extreme capsule, which continue toward the operculae, are the most superficial subcortical layer deep to the ILS. The external capsule fibers are found deeper at an intermediate layer and are formed by the uncinate fasciculus, inferior frontooccipital fasciculus, and claustrocortical fibers in a sequential anteroposterior disposition. The anterior commissure forms the next deeper layer, and the optic radiations in the sublenticular part of the internal capsule represent the deepest layer. The uncinate fasciculus is found deep to the anterior third of the ILS, whereas the inferior frontooccipital fasciculus and optic radiations are found superficial and deep, respectively, at the posterior two-thirds of this length. The authors' findings suggest that in the transsylvian approach, a 6-mm incision beginning just posterior to the limen insula through the ILS will cross the uncinate fasciculus but not the inferior frontooccipital fasciculus or optic radiations, but that longer incisions carry a risk to language and visual functions.


Functions of pregnane X receptor in self-detoxification.
Pregnane X receptor (PXR, NR1I2), a member of the nuclear receptor superfamily, is a crucial regulator of nutrient metabolism and metabolic detoxification such as metabolic syndrome, xenobiotic metabolism, inflammatory responses, glucose, cholesterol and lipid metabolism, and endocrine homeostasis. Notably, much experimental and clinical evidence show that PXR senses xenobiotics and triggers the detoxification response to prevent diseases such as diabetes, obesity, intestinal inflammatory diseases and liver fibrosis. In this review we summarize recent advances on remarkable metabolic and regulatory versatility of PXR, and we emphasizes its role and potential implication as an effective modulator of self-detoxification in animals and humans.


Postmatch recovery of physical performance and biochemical markers in team ball sports: a systematic review.
Insufficient postmatch recovery in elite players may cause an increased risk of injuries, illnesses and non-functional over-reaching. To evaluate postmatch recovery time courses of physical performance and biochemical markers in team ball sport players. Systematic review. PubMed and Web of Science. This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Critical Review Form for Quantitative Studies was used to evaluate quality. Studies were included if they met the following criteria: (1) original research evaluated players' physical recovery postmatch; (2) team/intermittent sports; and (3) at least two postmeasurements were compared with baseline values. Twenty-eight studies were eligible. Mean methodological quality was 11.2±1.11. Most used performance tests and biochemical markers were the countermovement jump test, sprint tests and creatine kinase (CK), cortisol (C) and testosterone (T), respectively. The current evidence demonstrates that underlying mechanisms of muscle recovery are still in progress while performance recovery is already reached. CK recovery time courses are up to ≥72 hours. Soccer and rugby players need more time to recover for sprint performance, CK and C in comparison to other team ball sports. There are more high-quality studies needed regarding recovery in various team sports and recovery strategies on an individual level should be evaluated. Ongoing insufficient recovery can be prevented by the use of the presented recovery time courses as specific practical recovery guidelines.


Studies on the electron transfer pathway, topography of iron-sulfur centers, and site of coupling in NADH-Q oxidoreductase.
Electron transfer activities and steady state reduction levels of Fe-S centers of NADH-Q oxidoreductase were measured in mitochondria, submitochondrial particles (ETPH), and complex I after treatment with various reagents. p-Chloromercuribenzenesulfonate destroyed the signal from center N-4 (gx = 1.88) in ETPH but not in mitochondria, showing that N-4 is accessible only from the matrix side of the inner membrane. N-Bromosuccinimide also destroyed the signal from N-4 but without inhibiting rotenone-sensitive electron transfer to quinone, suggesting a branched pathway for electron transfer. Diethylpyrocarbonate caused oxidation of N-3 and N-4 in the steady state without changing N-1, suggesting N-1 is before N-3 and N-4. Difluorodinitrobenzene and dicyclohexylcarbodiimide inhibited oxidation of all Fe-S centers and tetranitromethane inhibited reduction of all Fe-S centers. Titrations of the rate of superoxide (O2-) generation in rotenone-treated submitochondrial particles were similar with the ratio [NADH]/[NAD] and that of 3-acetyl pyridine adenine nucleotide in spite of different midpoint potentials of the two couples. On reaction with inhibitors the inhibition of O2- formation was similar to that of ferricyanide reductase rather than quinone reductase. The rate of O2- formation during ATP-driven reverse electron transfer was 16% of the rate observed with NADH. The presence of NAD increased the rate to 83%. The results suggest that bound, reduced nucleotide, probably E-NAD., is the main source of O2- in NADH dehydrogenase. The effect of ATP on the reduction levels of Fe-S centers in well-coupled ETPH was measured by equilibrating with either NADH/NAD or succinate/fumarate redox couples. With NADH/NAD none of the Fe-S centers showed ATP induced changes, but with succinate/fumarate all centers showed ATP-driven reduction with or without NAD present. The effect on N-2 was smaller than that on N-1, N-3, and N-4. These observations indicate that the major coupling interaction is between N-2 and the low potential centers, N-1, N-3, and N-4. Possible schemes of coupling in this segment are discussed.


Prevalence and molecular characterization of Listeria monocytogenes isolated from wastewater of cattle slaughterhouses in Turkey.
The study aimed to investigate the role of cattle slaughterhouse wastewater as a possible source for the environmental distribution of Listeria monocytogenes. Listeria spp. isolation was performed by collecting 117 wastewater samples from four different cattle slaughterhouses in Turkey. Species-specific identification was performed biochemically, and L. monocytogenes isolates were confirmed with polymerase chain reaction (PCR). In all, 71 (62.2%) of the wastewater samples were found to be positive for Listeria spp., and 17 (14.9%) of these samples were contaminated with L. monocytogenes. Pulsed field gel electrophoresis (PFGE) analysis revealed that all L. monocytogenes isolates were of different pulsotypes and isolates belonged to seven different phylogenetic clusters. Multiplex PCR analysis for genoserotypes and lineage determination showed that the isolates were divided into genoserotypes IVb and IIc in Lineages I and II. Also, it has been investigated with SYBR-Green Real-time PCR whether the L. monocytogenes isolates harboured virulence genes (hly, sigB, plcA, plcB, inlA, inlB, inlC and inlJ), and it was found that all isolates were substantially positive. Antibiotic resistance profiles and MIC values of the isolates were determined, and all L. monocytogenes isolates were found susceptible to ampicillin. In contrast, two isolates were resistant to meropenem and erythromycin, and three isolates were resistant to trimethoprim/sulfamethoxazole. L. monocytogenes, which pose a threat to public health and resists to antibiotics effectively used in treatments, can environmentally spread via wastewater of cattle slaughterhouses. The wastewater of the food industry, which has rich microbiota, should be treated carefully, and possible environmental contamination should be prevented. This is the first study that investigates the molecular characterization of L. monocytogenes isolated from cattle slaughterhouse wastewater and the findings represent the importance of cattle wastewater in the epidemiology of L. monocytogenes in Turkey.


Tennis elbow in aviators.
Tennis elbow, or lateral epicondylitis, is described in three aviators. In two of the three aviators, the tennis elbow was felt to be caused by duties involving flight operations and resulted in temporary suspension from flight operations. Relief of the symptoms was obtained with conservative therapy. The symptomatology, predisposing factors, physical findings, treatment, and prevention of tennis elbow are discussed.


The TRIM-NHL protein LIN-41 and the OMA RNA-binding proteins antagonistically control the prophase-to-metaphase transition and growth of Caenorhabditis elegans oocytes.
In many animals, oocytes enter meiosis early in their development but arrest in meiotic prophase I. Oocyte growth, which occurs during this arrest period, enables the acquisition of meiotic competence and the capacity to produce healthy progeny. Meiotic resumption, or meiotic maturation, involves the transition to metaphase I (M phase) and is regulated by intercellular signaling and cyclin-dependent kinase activation. Premature meiotic maturation would be predicted to diminish fertility as the timing of this event, which normally occurs after oocyte growth is complete, is crucial. In the accompanying article in this issue, we identify the highly conserved TRIM-NHL protein LIN-41 as a translational repressor that copurifies with OMA-1 and OMA-2, RNA-binding proteins redundantly required for normal oocyte growth and meiotic maturation. In this article, we show that LIN-41 enables the production of high-quality oocytes and plays an essential role in controlling and coordinating oocyte growth and meiotic maturation. lin-41 null mutants display a striking defect that is specific to oogenesis: pachytene-stage cells cellularize prematurely and fail to progress to diplotene. Instead, these cells activate CDK-1, enter M phase, assemble spindles, and attempt to segregate chromosomes. Translational derepression of the CDK-1 activator CDC-25.3 appears to contribute to premature M-phase entry in lin-41 mutant oocytes. Genetic and phenotypic analyses indicate that LIN-41 and OMA-1/2 exhibit an antagonistic relationship, and we suggest that translational regulation by these proteins could be important for controlling and coordinating oocyte growth and meiotic maturation.


AENET-LAMMPS and AENET-TINKER: Interfaces for accurate and efficient molecular dynamics simulations with machine learning potentials.
Machine-learning potentials (MLPs) trained on data from quantum-mechanics based first-principles methods can approach the accuracy of the reference method at a fraction of the computational cost. To facilitate efficient MLP-based molecular dynamics and Monte Carlo simulations, an integration of the MLPs with sampling software is needed. Here, we develop two interfaces that link the atomic energy network (ænet) MLP package with the popular sampling packages TINKER and LAMMPS. The three packages, ænet, TINKER, and LAMMPS, are free and open-source software that enable, in combination, accurate simulations of large and complex systems with low computational cost that scales linearly with the number of atoms. Scaling tests show that the parallel efficiency of the ænet-TINKER interface is nearly optimal but is limited to shared-memory systems. The ænet-LAMMPS interface achieves excellent parallel efficiency on highly parallel distributed-memory systems and benefits from the highly optimized neighbor list implemented in LAMMPS. We demonstrate the utility of the two MLP interfaces for two relevant example applications: the investigation of diffusion phenomena in liquid water and the equilibration of nanostructured amorphous battery materials.


Choice of cooking oils--myths and realities.
In contrast to earlier epidemiologic studies showing a low prevalence of atherosclerotic heart disease (AHD) and type-2 dependent diabetes mellitus (Type-2 DM) in the Indian subcontinent, over the recent years, there has been an alarming increase in the prevalence of these diseases in Indians--both abroad and at home, attributable to increased dietary fat intake. Replacing the traditional cooking fats condemned to be atherogenic, with refined vegetable oils promoted as "heart-friendly" because of their polyunsaturated fatty acid (PUFA) content, unfortunately, has not been able to curtail this trend. Current data on dietary fats indicate that it is not just the presence of PUFA but the type of PUFA that is important--a high PUFA n-6 content and high n-6/n-3 ratio in dietary fats being atherogenic and diabetogenic. The newer "heart-friendly" oils like sunflower or safflower oils possess this undesirable PUFA content and there are numerous research data now available to indicate that the sole use or excess intake of these newer vegetable oils are actually detrimental to health and switching to a combination of different types of fats including the traditional cooking fats like ghee, coconut oil and mustard oil would actually reduce the risk of dyslipidaemias, AHD and Type-2 DM.


A set of genes associated with the interferon-γ response of lung cancer patients undergoing α-galactosylceramide-pulsed dendritic cell therapy.
Invariant natural killer T (iNKT) cells possess potent antitumor effects after activation with a specific glycolipid antigen, α-galactosylceramide (αGalCer). A phase I-II clinical study of αGalCer-pulsed dendritic cells (DC) to activate endogenous iNKT cells was previously performed in patients with non-small-cell lung cancer (NSCLC). In this clinical trial, the patients with increased interferon-γ (IFN-γ) production (>two-fold) in PBMC after the DC treatment (good responder group) experienced a prolonged overall survival time in comparison with the poor responder group. We extended the previous study and performed a microarray-based gene expression analysis using peripheral blood CD56(+) cells and CD56(-) CD3(+) T cells from patients enrolled in the above-mentioned clinical study. We sought to identify any biomarkers associated with the immune responses in this immunotherapy trial. Six patient samples corresponding to three subjects in the good responder group and three subjects in the poor responder group were included in the microarray analysis. Genes differentially expressed between pre-treatment and post-treatment samples were selected for analysis. Subsequently, genes that were only expressed in the good responder group or poor responder group were chosen. After these procedures, four selected genes were quantified by reverse transcriptase-polymerase chain reaction in another eight patient samples, and two genes, LTB4DH and DPYSL3, were confirmed to be candidate genes for the predictor of a good immune response. The expression profile of these two genes may be associated with the responsiveness of IFN-γ production after αGalCer-pulsed DC treatment.


Thermal gradient driven domain wall dynamics.
The issue of whether a thermal gradient acts like a magnetic field or an electric current in the domain wall (DW) dynamics is investigated. Broadly speaking, magnetization control knobs can be classified as energy-driving or angular-momentum driving forces. DW propagation driven by a static magnetic field is the best known example of the former in which the DW speed is proportional to the energy dissipation rate, and the current-driven DW motion is an example of the latter. Here we show that DW propagation speed driven by a thermal gradient can be fully explained as the angular momentum transfer between thermally generated spin current and DW. We found DW-plane rotation speed increases as DW width decreases. Both DW propagation speed along the wire and DW-plane rotation speed around the wire decrease with the Gilbert damping. These facts are consistent with the angular momentum transfer mechanism, but are distinct from the energy dissipation mechanism. We further show that magnonic spin-transfer torque (STT) generated by a thermal gradient has both damping-like and field-like components. By analyzing DW propagation speed and DW-plane rotational speed, the coefficient ([Formula: see text]) of the field-like STT arising from the non-adiabatic process, is obtained. It is found that [Formula: see text] does not depend on the thermal gradient; increases with uniaxial anisotropy [Formula: see text] (thinner DW); and decreases with the damping, in agreement with the physical picture that a larger damping or a thicker DW leads to a better alignment between the spin-current polarization and the local magnetization, or a better adiabaticity.


[Toxicogenetic effects of azo- and arylmethane dyes].
The haploid strain 15B-II4 of Saccharomyces cerevisiae was used to study in an acute experiment the toxic and mutagenic effects of arylmethane dyes Victory Blue (C.I. 44040), Methyl Violet (C.I. 42535), Brilliant Green (C.I. 42040) and cancerogenic aminoazo dye Chrysoidine (C.I. 11270). High biological activity of all the dyes tested was found, based on such toxic effects as cell killing and growth inhibition. Also, it was shown that the dyes could increase the frequency of appearance of nuclear point mutations and cytoplasmic mutations of respiratory deficiency.


Phosphodiesterases in endocrine physiology and disease.
The cAMP-protein kinase A pathway plays a central role in the development and physiology of endocrine tissues. cAMP mediates the intracellular effects of numerous peptide hormones. Various cellular and molecular alterations of the cAMP-signaling pathway have been observed in endocrine diseases. Phosphodiesterases (PDEs) are key regulatory enzymes of intracellular cAMP levels. Indeed, PDEs are the only known mechanism for inactivation of cAMP by catalysis to 5'-AMP. It has been suggested that disruption of PDEs could also have a role in the pathogenesis of many endocrine diseases. This review summarizes the most recent advances concerning the role of the PDEs in the physiopathology of endocrine diseases. The potential significance of this knowledge can be easily envisaged by the development of drugs targeting specific PDEs.


Physician agreement with evidence-based recommendations for the treatment of severe traumatic brain injury in children.
The aim of this study was to evaluate physician agreement with published recommendations and guidelines for the management of severe traumatic brain injury (TBI) in children and to identify markers associated with physician responses matching published guidelines. An Internet survey was created based on recommendations and guidelines published in 2003 and was sent to US physicians and neurosurgeons caring for pediatric patients with severe TBI. Agreement with each recommendation was tabulated. Characteristics of the surveyed physicians and their institutions were compared to identify markers of conformity with first-tier recommendations (intracranial pressure [ICP] treatment threshold, monitoring cerebral perfusion pressure, use of sedation/neuromuscular blockade, and use of hyperosmolar therapy). One hundred ninety-four US physicians responded: 36 neurosurgeons and 158 nonsurgeons. Overall, physician responses matched most recommendations more than 60% of the time. The serum osmolality threshold of hypertonic saline, use of prophylactic hyperventilation, and differences in ICP thresholds based on a child's age comprised the recommendations with the least agreement. No physician variable was linked to increased agreement with first-tier recommendations. Overall, physician responses coincided with the published guidelines and recommendations. Examples of variable conformance most likely reflect the paucity of available data and lack of randomized controlled trials in the field of severe TBI.


Pharmacokinetics of tulathromycin in plasma and milk samples after a single subcutaneous injection in lactating goats (Capra hircus).
Eight adult female dairy goats received one subcutaneous administration of tulathromycin at a dosage of 2.5 mg/kg body weight. Blood and milk samples were assayed for tulathromycin and the common fragment of tulathromycin, respectively, using liquid chromatography/mass spectrometry. Pharmacokinetic disposition of tulathromycin was analyzed by a noncompartmental approach. Mean plasma pharmacokinetic parameters (±SD) following single-dose administration of tulathromycin were as follows: C(max) (121.54 ± 19.01 ng/mL); T(max) (12 ± 12-24 h); area under the curve AUC(0→∞) (8324.54 ± 1706.56 ng·h/mL); terminal-phase rate constant λz (0.01 ± 0.002 h⁻¹); and terminal-phase rate constant half-life t1/2λz (67.20 h; harmonic). Mean milk pharmacokinetic parameters (±SD) following 45 days of sampling were as follows: Cmax (1594 ± 379.23 ng/mL); Tmax (12 ± 12-36 h); AUC(0→∞) (72,250.51 ± 18,909.57 ng·h/mL); λz (0.005 ± 0.001 h⁻¹); and t(1/2λz) (155.28 h; harmonic). All goats had injection-site reactions that diminished in size over time. The conclusions from this study were that tulathromycin residues are detectable in milk samples from adult goats for at least 45 days following subcutaneous administration, this therapeutic option should be reserved for cases where other treatment options have failed, and goat milk should be withheld from the human food chain for at least 45 days following tulathromycin administration.


Differences in base of articulation for consonants among Catalan dialects.
Electropalatographic data for several front lingual consonants, i.e., the dental /t/, the alveolars /n, l, s, r/ and the alveolopalatals /t∫, ∫, ʎ, ɲ/, show differences in constriction anteriority among Catalan dialects varying in the progression Valencian > Eastern, with the Majorcan dialect occupying an intermediate position. These differences do not conform to speaker- dependent differences in palate morphology and, to the extent that they operate on a varied range of consonants, may be attributed to base of articulation. Deviations from this pattern are associated with manner of articulation and symmetry demands. A specific dialect- dependent relationship between tongue dorsum contact and constriction fronting is interpreted assuming the existence of less laminal, more apical dental and alveolar stops, and less dorsal, more laminal alveolopalatals, in Valencian than in the other two dialects. These data are interpreted in terms of the articulatory characteristics for different tongue front settings which have been proposed in the literature.


Effects of carbonylcyanide-m-chlorophenylhydrazone (CCCP) and acetate on Escherichia coli O157:H7 and K-12: uncoupling versus anion accumulation.
Non-growing cells of Escherichia coli O157:H7 and K-12 that were incubated anaerobically in sodium phosphate buffer at pH 6.5 consumed glucose at a rate of approximately 8 mumol.(mg protein)-1.h-1 and had intracellular pH values of 7.3 and 7.5, respectively. The uncoupler, carbonylcyanide-m-chlorophenylhydrazone (CCCP), caused a marked decrease in intracellular pH, ATP and potassium of both strains. Low concentrations of CCCP stimulated glucose consumption rate, but higher concentrations were inhibitory. Acetate also caused a decrease in intracellular pH, but it never caused a large decrease in glucose consumption rate. Acetate decreased the intracellular ATP of E. coli K-12, but it had no effect on the ATP of O157:H7. Acetate had no effect on the intracellular potassium of E. coli O157:H7, and acetate-treated K-12 cells had even more potassium than untreated controls. Based on these results, acetate and CCCP appear to have different effects on E. coli. The comparison of E. coli O157:H7 and K-12 indicated that intracellular pH, acetate accumulation and intracellular potassium were related. E. coli K-12 maintained a higher intracellular pH than O157:H7, accumulated more acetate and had a greater intracellular potassium.


Gcn5 and PCAF regulate PPARγ and Prdm16 expression to facilitate brown adipogenesis.
The acetyltransferase Gcn5 is critical for embryogenesis and shows partial functional redundancy with its homolog PCAF. However, the tissue- and cell lineage-specific functions of Gcn5 and PCAF are still not well defined. Here we probe the functions of Gcn5 and PCAF in adipogenesis. We found that the double knockout (DKO) of Gcn5/PCAF inhibits expression of the master adipogenic transcription factor gene PPARγ, thereby preventing adipocyte differentiation. The adipogenesis defects in Gcn5/PCAF DKO cells are rescued by ectopic expression of peroxisome proliferator-activated receptor γ (PPARγ), suggesting Gcn5/PCAF act upstream of PPARγ to facilitate adipogenesis. The requirement of Gcn5/PCAF for PPARγ expression was unexpectedly bypassed by prolonged treatment with an adipogenic inducer, 3-isobutyl-1-methylxanthine (IBMX). However, neither PPARγ ectopic expression nor prolonged IBMX treatment rescued defects in Prdm16 expression in DKO cells, indicating that Gcn5/PCAF are essential for normal Prdm16 expression. Gcn5/PCAF regulate PPARγ and Prdm16 expression at different steps in the transcription process, facilitating RNA polymerase II recruitment to Prdm16 and elongation of PPARγ transcripts. Overall, our study reveals that Gcn5/PCAF facilitate adipogenesis through regulation of PPARγ expression and regulate brown adipogenesis by influencing Prdm16 expression.


Discordance across Phenotypic and Molecular Methods for Drug Susceptibility Testing of Drug-Resistant Mycobacterium tuberculosis Isolates in a Low TB Incidence Country.
With increasing incidence of multidrug-resistant tuberculosis (MDR-TB), accurate drug susceptibility testing (DST) of Mycobacterium tuberculosis to first-line drugs has become crucial for proper patient management. We evaluated concordance of DST results for 70 M. tuberculosis isolates across two phenotypic and two molecular methods: BACTEC 460TB, MGIT 960 system, GenoType MTBDRplus and DNA sequencing of gene segments most commonly implicated in conferring resistance to anti-TB drugs. Most (84%) M. tuberculosis isolates were multidrug-resistant. Twenty-four isolates yielded discrepant DST results. For rifampicin, isoniazid and streptomycin, 96%, 97% and 93% of isolates, respectively, were susceptible or resistant by all four methods, whereas for ethambutol, this agreement was observed for only 76% of isolates (P<0.05 for rifampicin or isoniazid or streptomycin versus ethambutol). Occurrence of rare mutations in three isolates that confer low-level resistance caused lower agreement for rifampicin among the four methods (kappa coefficient (κ) range, 0.84 to 0.95). For isoniazid, there was perfect agreement among phenotypic methods and molecular methods (κ, 1.00) but lower agreement between phenotypic and molecular methods. Three isolates were detected as polydrug-resistant by MGIT 960 system but as multidrug-resistant by DNA sequence-based method. The agreement was higher for streptomycin among the two phenotypic methods (κ, 0.97) while targeted sequencing yielded lower agreement (κ range, 0.86 to 0.89). The discrepancy for ethambutol resulted largely due to lower concordance of MGIT 960 results (κ range, 0.53 to 0.64). The MGIT 960 system is an accurate method for DST of M. tuberculosis against isoniazid and streptomycin while the results of rifampicin susceptibility should be complemented with DNA sequencing-based method when the suspicion for resistance is high. The possibility of false susceptibility to ethambutol with MGIT 960 system suggests that molecular or other phenotypic methods may be more useful when accurate ethambutol susceptibility results are warranted.


Effect of in vitro DNA rearrangement in the NH2-terminal region of the penicillinase gene from Bacillus licheniformis on the mode of expression in Bacillus subtilis.
We have constructed secretion vector plasmids that have unique BglII sites within or near the signal sequence of Bacillus licheniformis penicillinase, and have also constructed penicillinase cartridges that lack either one, two or three of the processing sites for the membrane-bound, exo-large and exo-small enzymes. Each of these penicillinase cartridges was cloned on secretion vectors in Bacillus subtilis, and enzyme production was examined. The presence of both the signal sequence and the three host-specific processing sites on the secretion vector was required for an effective expression of the enzyme in B. subtilis. The presence of any of the processing sites on the cartridge reduced the accumulation of penicillinase in the culture medium. When a vector plasmid lacking part of the hydrophobic region of the signal sequence and lacking the three processing sites was used, total penicillinase production decreased and enzyme accumulation in the medium was extremely low, despite the complete or incomplete presence of the processing sites on the cartridge. Molecular mass determination of these extracellular penicillinases suggested the existence of a new cleavage site for the enzyme.


The A3 adenosine receptor mediates cell spreading, reorganization of actin cytoskeleton, and distribution of Bcl-XL: studies in human astroglioma cells.
The pathophysiological role of the adenosine A3 receptor in the central nervous system is largely unknown. We have investigated the effects of the selective A3 receptor agonist 2-chloro-N6-(3-iodobenzyl)-adenosine, Cl-IB-MECA, in cells of the astroglial lineage (human astrocytoma ADF cells). A marked reorganization of the cytoskeleton, with appearance of stress fibers and numerous cell protrusions, was found following exposure of cells to low (nM) concentrations of Cl-IB-MECA. These "trophic" effects were accompanied by induction of the expression of Rho, a small GTP-binding protein, which was virtually absent in control cells, and by changes of the intracellular distribution of the antiapoptotic protein Bcl-XL, that, in agonist-exposed cells, became specifically associated to cell protrusions. This is the first demonstration that the intracellular organization of Bcl-XL can be modulated by the activation of a G-protein-coupled membrane receptor, such as the A3 adenosine receptor. Moreover, modulation of the astrocytic cytoskeleton by adenosine may have intriguing implications in both nervous system development and in the response of the brain to trauma and ischemia.


Gradual molding of the hand to object contours.
Subjects were asked to reach to and to grasp 15 similarly sized objects with the four fingers opposed to the thumb. The objects' contours differed: some presented a concave surface to the fingers, others a flat one, and yet others a convex surface. Flexion/extension at the metacarpal-phalangeal and proximal interphalangeal joints of the fingers was recorded during the reaching movement. We used discriminant analysis, cluster analysis, and information theory to determine the extent to which the shape of the hand was affected by the objects' shapes along a convexity/concavity gradient. Maximum aperture of the hand was reached about midway in the reaching movement. At that time, the hand's posture was influenced by the shape of the object to be grasped but imperfectly. The information transmitted by hand posture about object shape increased gradually and monotonically as the hand approached the object, reaching a maximum at the time the object was in the grasp of the hand. We also asked subjects to shape the hand so as to grasp the object without moving the arm. Their performance was poorer on this task in the sense that hand shape discriminated among fewer objects and that trial-to-trial variability was greater than when the distal and proximal components of the motion were linked. The results indicate that the hand is molded only gradually to the contours of an object to be grasped. Because other parameters of the motion, such as movement direction, for example, already are specified fully early on in a movement, the results also suggest that the specification of diverse aspects of a movement does not evolve at a uniform rate.


[Effect of serotonin on thermoregulation in normothermic hibernators and during arousal from deep hypothermia].
Serotonin, intraperitoneally injected (10 mg/kg) to arousing from hibernation ground squirrels, blocked the increase of body temperature and shivering thermogenesis and decreased O2 consumption. Serotonin administered to normothermic active animals also decreased body temperature and O2 consumption. However, compensative increase of muscle electrical activity in response to considerable decrease of the body temperature was not observed. Serotonin is suggested to take part in the control of body temperature set-point.


Circular RNA circ_0006282 Contributes to the Progression of Gastric Cancer by Sponging miR-155 to Upregulate the Expression of FBXO22.
There is increasing evidence that circular RNAs (circRNAs) play an important role in human cancers. As a newly identified human circular RNA, circ_0006282 is abnormally expressed in several types of cancers and promotes the development of cancers. However, the expression and function of circ_0006282 in gastric cancer (GC) remain unclear. The expression of circ_0006282 in cancer tissues and adjacent non-cancer tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR) method, and the relationship between circ_0006282 expression and clinicopathological parameters was analyzed. After knockdown of circ_0006282 by RNA interference in GC cells, CCK-8 assay, colony formation and transwell assays were conducted to examine the effects of circ_0006282 on GC cells. The influence of circ_0006282 on tumor growth in vivo was assessed in a xenograft model. Furthermore, regulatory relationship between circ_0006282, miR-155 and FBXO22 was detected by luciferase assay, qRT-PCR and Western blot. The expression of circ_0006282 in GC tissues was significantly higher than its adjacent non-cancer tissues and over-expression of circ_0006282 was associated with tumor size, lymph nodes metastasis and TNM stage, but no obvious links with other pathological parameters. Knockdown of circ_0006282 inhibited the proliferation and metastasis ability of GC cells in vitro and suppressed the tumor growth in vivo. Furthermore, mechanistic investigations suggested that circ_0006282 served as a competing endogenous RNA (ceRNA) of miR-155. Moreover, FBXO22 was identified as the functional target of miR-155 and down-expression of circ_0006282 inhibited FBXO22 expression. Rescue assays also demonstrated that the oncogenic function of circ_0006282 is partly attributed to its regulation on miR-155/FBXO22 axis. Our findings indicated that over-expression of circ_0006282 down‑regulated miR-155 to activate the expression of FBXO22, thus promoting proliferation and metastasis of GC cells, which provides a promising therapeutic target for GC treatment.


Psychosocial adjustment and quality of life of adolescents and adults with congenital heart disease.
The incidence of people living with congenital heart disease (CHD) has been increasing every year owing to remarkable advances in surgical and catheter intervention techniques and devices, and improved knowledge of critical care for patients with CHD. However, these patients continue to face physical, psychosocial, and environmental challenges, and a number of studies have shown higher rates of depression and anxiety disorders than the general population. To improve psychosocial functioning and quality of life for adults with CHD, health care providers are recommended to inform CHD patients of an accurate diagnosis, and overall treatment process, beginning in adolescence to facilitate a smooth transition from adolescence to adulthood. Active cooperation with psychiatrists, psychologists, social workers, chaplains, and family members is highly recommended to help CHD patients feel normal and optimistic and to promote good social interactions, close family relationships, and a strong sense of coherence.


New transgenic NIS reporter rats for longitudinal tracking of fibrogenesis by high-resolution imaging.
Fibrogenesis is the underlying mechanism of wound healing and repair. Animal models that enable longitudinal monitoring of fibrogenesis are needed to improve traditional tissue analysis post-mortem. Here, we generated transgenic reporter rats expressing the sodium iodide symporter (NIS) driven by the rat collagen type-1 alpha-1 (Col1α1) promoter and demonstrated that fibrogenesis can be visualized over time using SPECT or PET imaging following activation of NIS expression by rotator cuff (RC) injury. Radiotracer uptake was first detected in and around the injury site day 3 following surgery, increasing through day 7-14, and declining by day 21, revealing for the first time, the kinetics of Col1α1 promoter activity in situ. Differences in the intensity and duration of NIS expression/collagen promoter activation between individual RC injured Col1α1-hNIS rats were evident. Dexamethasone treatment delayed time to peak NIS signals, showing that modulation of fibrogenesis by a steroid can be imaged with exquisite sensitivity and resolution in living animals. NIS reporter rats would facilitate studies in physiological wound repair and pathological processes such as fibrosis and the development of anti-fibrotic drugs.


Could a nonfunctional adrenal incidentaloma be a risk factor for increased carotid intima-media thickness and 10-year cardiovascular mortality based on the SCORE algorithm? A study from a single centre in Poland.
Adrenal incidentaloma (AI) secreting small amounts of glucocorticoids may cause morphological and functional changes in the blood vessels. Early stages of cardiovascular remodeling may be observed among asymptomatic patients with AI. But it is unclear whether the nonfunctional adrenal incidentalomas (NFAI) may also be a risk factor for cardiovascular diseases. The aim of this study was to determine the relationship between NFAI, carotid intima-media thickness (CIMT), and cardiovascular risk (CVR) based on Systematic Coronary Risk Evaluation (SCORE) prediction models for Europe. This study from a single centre in Poland included 48 NFAI patients and 44 individuals in the control group matched for age, sex, and body mass index (BMI). All participants underwent adrenal imaging, biochemical evaluation, measurement of CIMT, and assessment of the 10-year risk of cardiovascular mortality based on the SCORE algorithm. Hormonal evaluation was conducted in AI patients. The NFAI group showed significantly higher sodium (p = 0.02) and glucose levels in the 2-h oral glucose tolerance test (OGTT) (p = 0.04), a higher CIMT (p < 0.01), and a higher CVR calculated according to the SCORE algorithm (p = 0.03). The estimated glomerular filtration rate (eGFR) was higher in the NFAI group (p = 0.015). Hypertension (p < 0.01) and IGT (p = 0.026) were more common in the NFAI group. Statistically significant positive correlations were found between CIMT and age (r = 0.373, p = 0.003), waist circumference (r = 0.316, p = 0.029), diastolic blood pressure (r = 0.338, p = 0.019), and CVR based on the SCORE algorithm (r = 0.43, p = 0.004). There was a statistically significant positive correlation between CIMT and serum cortisol levels after 1 mg dexamethasone suppression test (r = 0.33, p = 0.02). Non-functional adrenal adenomas are associated with increased CIMT and CVR. Early stages of cardiovascular remodelling can be observed in asymptomatic NFAI patients.


Primary malignant fibrous histiocytoma of the lung. A clinicopathologic and ultrastructural study of five cases.
Primary sarcomas of the lung are rare malignant neoplasms which have usually been classified as fibrosarcomas or as leiomyosarcomas. Only five cases of primary malignant fibrous histiocytoma (MFH) of the lung have previously been reported in the literature. The authors reviewed 10 cases of primary pulmonary sarcoma of the lung seen at their institution during the last 12 years, and five of these cases met the morphologic criteria for the diagnosis of MFH. The morphology in these cases is identical to MFH of other body locations, and shows a combination of fibroblast-like and histiocyte-like cells at both the light and electron microscopic level. By electron microscopic examination there was no evidence for anaplastic carcinoma, rhabdomyosarcoma, or leiomyosarcoma. Of the three patients with adequate follow-up, one patient is alive without evidence of disease at 10 years, one died at 5 years without evidence of recurrent sarcoma, and one died at 7 months with liver metastasis. Two other patients are alive without recurrence at 8 months and 1 year, respectively, following surgery. Because MFH is primarily a tumor of the soft tissues of the extremities, patients with MFH of the lung must be carefully evaluated to rule out a metastatic origin. The reported prognosis in patients with primary MFH of the lung is poor, but early surgical resection does offer the possibility of a cure.


Alcohol and basal ganglia circuitry: Animal models.
Brain circuits that include the cortex and basal ganglia make up the bulk of the forebrain, and influence behaviors related to almost all aspects of affective, cognitive and sensorimotor functions. The learning of new actions as well as association of existing action repertoires with environmental events are key functions of this circuitry. Unfortunately, the cortico-basal ganglia circuitry is also the target for all drugs of abuse, including alcohol. This makes the circuitry susceptible to the actions of chronic alcohol exposure that impairs circuit function in ways that contribute to cognitive dysfunction and drug use disorders. In the present review, we describe the connectivity and functions of the associative, limbic and sensorimotor cortico-basal ganglia circuits. We then review the effects of acute and chronic alcohol exposure on circuit function. Finally, we review studies examining the roles of the different circuits and circuit elements in alcohol use and abuse. We attempt to synthesize information from a variety of studies in laboratory animals and humans to generate hypotheses about how the three circuits interact with each other and with the other brain circuits during exposure to alcohol and during the development of alcohol use disorders. This article is part of the Special Issue entitled "Alcoholism".


Diagnostic Accuracy of Nasopharyngeal Swab Cultures in Children Less Than Five Years with Chronic Wet Cough.
It is necessary to find a non-invasive and accurate procedure to predict persistent bacterial bronchitis (PBB) causative organisms and guide antibiotic therapy. The study objective was to compare the diagnostic accuracy of nasopharyngeal swab cultures with bronchoalveolar lavage (BAL) cultures in children with PBB. Nasopharyngeal swab and BAL fluid specimens were collected and cultured for bacterial pathogens prospectively from less than five-year-old children undergoing flexible bronchoscopy for chronic wet cough. Of the 59 children included in the study, 26 (44.1%) patients had a positive BAL bacterial culture with neutrophilic inflammation. Prevalence of positive cultures for any of the four common respiratory pathogens implicated in PBB (Moraxella catarrhalis, Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae) was significantly higher (p = 0.001) in NP swabs compared to BAL fluids (86.4% and 44.1% of PBB cases, respectively). NP swab cultures for any of the four main bacterial pathogens had 85% (95% CI: 65-96%) and 48% (95% CI: 31-66%) sensitivity and specificity of detecting PBB, respectively. Positive and negative predictive values were 56% (95% CI: 47-65%) and 80% (95% CI: 60-91%), respectively. In conclusion, in children less than 5 years of age with chronic wet cough (PBB-clinical), a negative NP swab result reduces the likelihood of lower airway infection; however, a positive NP swab does not accurately predict the presence of lower airway pathogens. Flexible bronchoscopy should be considered in those with recurrent PBB-clinical or with clinical pointers of central airway anomalies.


Identification of multiple independent horizontal gene transfers into poxviruses using a comparative genomics approach.
Poxviruses are important pathogens of humans, livestock and wild animals. These large dsDNA viruses have a set of core orthologs whose gene order is extremely well conserved throughout poxvirus genera. They also contain many genes with sequence and functional similarity to host genes which were probably acquired by horizontal gene transfer.Although phylogenetic trees can indicate the occurrence of horizontal gene transfer and even uncover multiple events, their use may be hampered by uncertainties in both the topology and the rooting of the tree. We propose to use synteny conservation around the horizontally transferred gene (HTgene) to distinguish between single and multiple events. Here we devise a method that incorporates comparative genomic information into the investigation of horizontal gene transfer, and we apply this method to poxvirus genomes. We examined the synteny conservation around twenty four pox genes that we identified, or which were reported in the literature, as candidate HTgenes. We found support for multiple independent transfers into poxviruses for five HTgenes. Three of these genes are known to be important for the survival of the virus in or out of the host cell and one of them increases susceptibility to some antiviral drugs. In related genomes conserved synteny information can provide convincing evidence for multiple independent horizontal gene transfer events even in the absence of a robust phylogenetic tree for the HTgene.


[Evaluation of extensive visual field defects with computer-assisted kinetic perimetry].
Conventional kinetic perimetry is of especial use in case of advanced scotoma. However, examiner dependency is a major drawback. Purpose of this study was to evaluate the clinical feasibility and intraindividual scatter of computer-assisted kinetic perimetry in monitoring advanced visual field defects of various origins. Examinations were carried out with the Tuebingen Computer Campimeter (background lumincance 10 cd/m2). In an initial session, the localization of the scotoma border is estimated with conventional manual kinetic perimetry. In the subsequent computer assisted kinetic mode, an individually adjusted set of vectors is designed. Each vector crosses the manually assessed visual field defect border almost perpendicularly, starting approximately 3 degrees within the scotoma. Each individual set of vectors can be stored and recalled for follow-up. Stimuli move along these vectors with identical characteristics as in manual kinetic perimetry. Stimulus presentations are repeated six times in a randomized order. Patients' responses are recorded and additionally corrected for mean individual reaction time. A "local kinetic threshold" (mean) and a related parameter for dispersion (standard deviation) are assessed. Four subjects with advanced visual field loss of various origin (retinitis pigmentosa, vigabatrin-associated visual field defect, glaucomatous nerve fibre layer defect, and postgeniculate visual pathway defect) participated in this study. Maximal difference between manual-kinetic and automated kinetic thresholds reaches from 1.7 degrees to 5 degrees. Local scatter (standard deviation) of kinetic threshold, assessed by computer-assisted perimetry, varies between 0.1 degree and 3.0 degrees. Computer assisted kinetic perimetry is a new, useful, examiner-independent, reliable method for effective evaluation and monitoring of advanced visual field loss.


Consensus-based care recommendations for adults with myotonic dystrophy type 2.
Myotonic dystrophy type 2 (DM2) is a rare, progressive multisystem disease particularly affecting the skeletal muscle. A causal therapy is not yet available; however, prompt, appropriate symptomatic treatments are essential to limit disease-related complications. Evidence-based guidelines to assist medical practitioners in the care of DM2 patients do not exist. The Myotonic Dystrophy Foundation (MDF) previously worked with an international group of 66 clinicians to develop consensus-based care recommendations for myotonic dystrophy type 1. Following a similar approach, the MDF recruited 15 international clinicians with long-standing experience in the care of DM2 patients to develop consensus-based care recommendations. The single text procedure was adopted. This process generated a 4-page Quick Reference Guide and a comprehensive 55-page document that provides care recommendations for DM2 patients. The resulting recommendations will help standardize and improve care for DM2 patients and facilitate appropriate management in centers without neuromuscular specialists.


Tubulolobular carcinoma of the breast: an analysis of 27 cases of a tumor with a hybrid morphology and immunoprofile.
Tubulolobular carcinoma (TLC) is a rare subtype of mammary carcinoma that has eluded precise classification, exhibiting features of both ductal and lobular differentiation. The clinicopathologic features of 27 cases of TLC were analyzed by both hematoxylin and eosin and immunohistochemical stains for E-cadherin and 34betaE12 (high molecular weight cytokeratin). Five cases of both pure tubular and classic lobular carcinoma were included as controls. Patients with TLC ranged in age from 43 to 79 years (median, 60 years). Tumor characteristics were as follows: size, 0.5 cm to 2.5 cm (median, 1.4 cm); bilaterality, 1 of 27 (4%); and multifocality, 5 of 27 (19%). Twenty-two of the 27 cases (81%) contained an in situ component: 8 (36%) lobular (LIN); 4 (18%) ductal (DIN); and 10 (46%) mixed. All 27 cases were intensely positive (3+) for E-cadherin, a feature of ductal differentiation, while 25 of 27 (93%) cases showed variable positivity for 34betaE12 (1 to 3+), a feature far more common in tumors with lobular differentiation. Clinical follow-up was available on 25 of 27 (93%) patients. Three of 24 (13%) patients developed axillary lymph node metastases and 1 of 25 (4%) patients developed a local recurrence over a follow-up period of 2 to 91 months (median, 39 months). In conclusion, TLCs are a distinct subtype of mammary carcinoma with overlapping morphologic features that are mirrored by a hybrid immunohistochemical profile. The uniform 3+ expression of E-cadherin in TLC supports the ductal differentiation of these tumors, despite a dominant lobular growth pattern. The prognosis of these tumors appears to be excellent, especially in those cases that are unilateral and less than 2 cm in size.


Adherence in paediatric renal failure and dialysis: an ethical analysis of nurses' attitudes and reported practice.
Minors have difficulty adhering to the strict management regimen required whilst on renal dialysis for chronic renal failure. This leads to ethical tensions as healthcare professionals (HCPs) and parents try, in the minor's best interests, to ensure s/he adheres. All 11 dialysis nurses working in a large, regional paediatric dialysis unit were interviewed about their perceptions and management of non-adherence and the ethical issues this raised for them. Participants reported negative attitudes to non-adherence alongside sympathy and feelings of frustration. They discussed the competing responsibilities between nurses, parents and minors, and how responsibility ought to be transferred to the minor as s/he matures; the need for minors to take responsibility ahead of transferring to adult services; and, the process of transferring this responsibility. Our discussion concentrates on the ethical issues raised by the participants' reports of how they respond to non-adherence using persuasion and coercion. We consider how understandings of capacity, traditional individual autonomy, and willpower can be used to comprehend the issue of non-adherence. We consider the relational context in which the minor receives, and participates in, healthcare. This exposes the interdependent triad of relationships between HCP, parent and minor and aids understanding of how to provide care in an ethical way. Relational ethics is a useful alternative understanding for professionals reflecting upon how they define their obligations in this context.


Variables Associated With Perceived Work Role Performance Among Professionals in Multidisciplinary Mental Health Teams Overall and in Primary Care and Specialized Service Teams, Respectively.
This study had a dual purpose (1) to identify variables associated with perceived work role performance (WRP) among 315 mental health professionals (MHPs) in Quebec and (2) to compare variables related to WRP in MH primary care teams (PCTs) and specialized service teams (SSTs), respectively. WRP was measured using an adapted version of the work role questionnaire. Variables were organized within five areas: individual characteristics, perceived team attributes, perceived team processes, perceived team emergent states, and geographical and organizational context. Half of the WRP variables were linked to team processes. Knowledge sharing correlated with WRP in both MH PCTs and SSTs. Team attributes had more impact on MH PCTs, while team processes and team emergent states played a larger role among SSTs. The association between WRP and knowledge sharing confirms the need for a systematic training program to promote interdisciplinary collaboration. Integration strategies (e.g., service agreements) could improve collaboration between MH PCTs and SSTs and help MHPs perform more effectively within PCTs.


Ionizing radiation and teniposide increase p21(waf1/cip1) and promote Rb dephosphorylation but fail to suppress E2F activity in MCF-7 breast tumor cells.
Ionizing radiation and the topoisomerase II inhibitor, teniposide (VM-26) both increase levels of the cyclin dependent kinase inhibitor, p21(waf1/cip1) and promote dephosphorylation of the retinoblastoma tumor suppressor protein, Rb, in MCF-7 breast tumor cells, perturbations associated with suppression of the activity of the transcription factor, E2F. However, studies using an E2F binding site-luciferase reporter plasmid transfected into MCF-7 cells failed to demonstrate a reduction in E2F activity in response to VM-26 or to ionizing radiation. In contrast, E2F activity (both basal and E1A stimulated) could be suppressed by transfection with a plasmid expressing Rb, indicating that the capacity of E2F to bind to Rb and to be inactivated by Rb is functionally intact in MCF-7 cells. These findings in MCF-7 breast tumor cells suggest that E2F activity may not be directly susceptible to modulation by endogenous p21(waf1/cip1) and Rb.


Effect of Low-Intensity Physical Activity and Moderate- to High-Intensity Physical Exercise During Adjuvant Chemotherapy on Physical Fitness, Fatigue, and Chemotherapy Completion Rates: Results of the PACES Randomized Clinical Trial.
We evaluated the effectiveness of a low-intensity, home-based physical activity program (Onco-Move) and a moderate- to high-intensity, combined supervised resistance and aerobic exercise program (OnTrack) versus usual care (UC) in maintaining or enhancing physical fitness, minimizing fatigue, enhancing health-related quality of life, and optimizing chemotherapy completion rates in patients undergoing adjuvant chemotherapy for breast cancer. We randomly assigned patients who were scheduled to undergo adjuvant chemotherapy (N = 230) to Onco-Move, OnTrack, or UC. Performance-based and self-reported outcomes were assessed before random assignment, at the end of chemotherapy, and at the 6-month follow-up. We used generalized estimating equations to compare the groups over time. Onco-Move and OnTrack resulted in less decline in cardiorespiratory fitness (P < .001), better physical functioning (P ≤ .001), less nausea and vomiting (P = .029 and .031, respectively) and less pain (P = .003 and .011, respectively) compared with UC. OnTrack also resulted in better outcomes for muscle strength (P = .002) and physical fatigue (P < .001). At the 6-month follow-up, most outcomes returned to baseline levels for all three groups. A smaller percentage of participants in OnTrack required chemotherapy dose adjustments than those in the UC or Onco-Move groups (P = .002). Both intervention groups returned earlier (P = .012), as well as for more hours per week (P = .014), to work than the control group. A supervised, moderate- to high-intensity, combined resistance and aerobic exercise program is most effective for patients with breast cancer undergoing adjuvant chemotherapy. A home-based, low-intensity physical activity program represents a viable alternative for women who are unable or unwilling to follow the higher intensity program.


Hyperspectral microscopy can detect metabolic heterogeneity within bovine post-compaction embryos incubated under two oxygen concentrations (7% versus 20%).
Can we separate embryos cultured under either 7% or 20% oxygen atmospheres by measuring their metabolic heterogeneity? Metabolic heterogeneity and changes in metabolic profiles in morula exposed to two different oxygen concentrations were not detectable using traditional fluorophore and two-channel autofluorescence but were detectable using hyperspectral microscopy. Increased genetic and morphological blastomere heterogeneity is associated with compromised developmental competence of embryos and currently forms the basis for embryo scoring within the clinic. However, there remains uncertainty over the accuracy of current techniques, such as PGS and time-lapse microscopy, to predict subsequent pregnancy establishment. The impact of two oxygen concentrations (7% = optimal and 20% = stressed) during post-fertilisation embryo culture was assessed. Cattle embryos were exposed to the different oxygen concentrations for 8 days (D8; embryo developmental competence) or 5 days (D5; metabolism measurements). Between 3 and 4 experimental replicates were performed, with 40-50 embryos per replicate used for the developmental competency experiment, 10-20 embryos per replicate for the fluorophore and two-channel autofluorescence experiments and a total of 21-22 embryos used for the hyperspectral microscopy study. In-vitro produced (IVP) cattle embryos were utilised for this study. Post-fertilisation, embryos were exposed to 7% or 20% oxygen. To determine impact of oxygen concentrations on embryo viability, blastocyst development was assessed on D8. On D5, metabolic heterogeneity was assessed in morula (on-time) embryos using fluorophores probes (active mitochondria, hydrogen peroxide and reduced glutathione), two-channel autofluorescence (FAD and NAD(P)H) and 18-channel hyperspectral microscopy. Exposure to 20% oxygen following fertilisation significantly reduced total blastocyst, expanded and hatched blastocyst rates by 1.4-, 1.9- and 2.8-fold, respectively, compared to 7% oxygen (P < 0.05), demonstrating that atmospheric oxygen was a viable model for studying mild metabolic stress. The metabolic profiles of D5 embryos was determined and although metabolic heterogeneity was evident within the cleavage stage (i.e. arrested) embryos exposed to fluorophores, there were no detectable difference in fluorescence intensity and pattern localisation in morula exposed to the two different oxygen concentrations (P > 0.05). While there were no significant differences in two-channel autofluorescent profiles of morula exposed to 7% and 20% oxygen (main effect, P > 0.05), morula that subsequently progressed to the blastocyst stage had significantly higher levels of FAD and NAD(P)H fluorescence compared to arrested morula (P < 0.05), with no change in the redox ratio. Hyperspectral autofluorescence imaging (in 18-spectral channels) of the D5 morula revealed highly significant differences in four features of the metabolic profiles of morula exposed to the two different oxygen concentrations (P < 0.001). These four features were weighted and their linear combination revealed clear discrimination between the two treatment groups. Metabolic profiles were assessed at a single time point (morula), and as such further investigation is required to determine if differences in hyperspectral signatures can be detected in pre-compaction embryos and oocytes, using both cattle and subsequently human models. Furthermore, embryo transfers should be performed to determine the relationship between metabolic profiles and pregnancy success. Advanced autofluorescence imaging techniques, such as hyperspectral microscopy, may provide clinics with additional tools to improve the assessment of embryos prior to transfer. This study was funded by the Australian Research Council Centre of Excellence for Nanoscale BioPhotonics (CE140100003). The Fluoview FV10i confocal microscope was purchased as part of the Sensing Technologies for Advanced Reproductive Research (STARR) facility, funded by the South Australian Premier's Science and Research Fund. The authors declare there are no conflict of interest.


Amphipathic helical peptides hamper protein-protein interactions of the intrinsically disordered chromatin nuclear protein 1 (NUPR1).
NUPR1 is a multifunctional intrinsically disordered protein (IDP) involved, among other functions, in chromatin remodelling, and development of pancreatic ductal adenocarcinoma (PDAC). It interacts with several biomolecules through hydrophobic patches around residues Ala33 and Thr68. The drug trifluoperazine (TFP), which hampers PDAC development in xenografted mice, also binds to those regions. Because of the large size of the hot-spot interface of NUPR1, small molecules could not be adequate to modulate its functions. We explored how amphipathic helical-designed peptides were capable of interacting with wild-type NUPR1 and the Thr68Gln mutant, inhibiting the interaction with NUPR1 protein partners. We used in vitro biophysical techniques (fluorescence, circular dichroism (CD), nuclear magnetic resonance (NMR) and isothermal titration calorimetry (ITC)), in silico studies (docking and molecular dynamics (MD)), and in cellulo protein ligation assays (PLAs) to study the interaction. Peptide dissociation constants towards wild-type NUPR1 were ~ 3 μM, whereas no interaction was observed with the Thr68Gln mutant. Peptides interacted with wild-type NUPR1 residues around Ala33 and residues at the C terminus, as shown by NMR. The computational results clarified the main determinants of the interactions, providing a mechanism for the ligand-capture that explains why peptide binding was not observed for Thr68Gln mutant. Finally, the in cellulo assays indicated that two out of four peptides inhibited the interaction of NUPR1 with the C-terminal region of the Polycomb RING protein 1 (C-RING1B). Designed peptides can be used as lead compounds to inhibit NUPR1 interactions. Peptides may be exploited as drugs to target IDPs.


A novel platform for detection of CK+ and CK- CTCs.
Metastasis is a complex, multistep process that begins with the epithelial-mesenchymal transition (EMT). Circulating tumor cells (CTC) are believed to have undergone EMT and thus lack or express low levels of epithelial markers commonly used for enrichment and/or detection of such cells. However, most current CTC detection methods target only EpCAM and/or cytokeratin (CK) to enrich epithelial CTCs, resulting in failure to recognize other, perhaps more important, CTC phenotypes that lack expression of these markers. Here, we describe a population of complex aneuploid CTCs that do not express CK or CD45 antigen in patients with breast, ovarian, or colorectal cancer. These cells were not observed in healthy subjects. We show that the primary epithelial tumors were characterized by similar complex aneuploidy, indicating conversion to an EMT phenotype in the captured cells. Collectively, our study provides a new method for highly efficient capture of previously unrecognized populations of CTCs. Current assays for CTC capture likely miss populations of cells that have undergone EMT. Capture and study of CTCs that have undergone EMT would allow a better understanding of the mechanisms driving metastasis.


A new automated chilled adult release system for the aerial distribution of sterile male tsetse flies.
Tsetse eradication continues to be a top priority for African governments including that of Senegal, which embarked on a project to eliminate Glossina palpalis gambiensis from the Niayes area, following an area-wide integrated pest management approach with an SIT component. A successful SIT programme requires competitive sterile males of high biological quality. This may be hampered by handling processes including irradiation and the release mechanisms, necessitating continued improvement of these processes, to maintain the quality of flies. A new prototype of an automated chilled adult release system (Bruno Spreader Innovation, (BSI™)) for tsetse flies was tested for its accuracy (in counting) and release rate consistency. Also, its impact on the quality of the released sterile males was evaluated on performance indicators, including flight propensity, mating competitiveness, premating and mating duration, insemination rate of mated females and survival of male flies. The BSITM release system accurately counted and homogenously released flies at the lowest motor speed set (0.6 rpm), at a consistent rate of 60±9.58 males/min. Also, the release process, chilling (6 ± 1°C) and passing of flies through the machine) had no significant negative impact on the male flight propensity, mating competitiveness, premating and mating durations and the insemination rates. Only the survival of flies was negatively affected whether under feeding or starvation. The positive results of this study show that the BSI™ release system is promising for use in future tsetse SIT programmes. However, the negative impact of the release process on survival of flies needs to be addressed in future studies and results of this study confirmed under operational field conditions in West Africa.


Implication of inhibin and related proteins in fetal development.
Initial studies on inhibin, activin and follistatin focussed on their role as regulators of adult gonadal function via feedback regulation of anterior pituitary hormones and via intragonadal control of steroid hormones. The discovery of isoforms of follistatin which are either secreted or retained on the cell surface and which bind activin and, to a lesser extent, inhibin adds a further dimension to the regulation of these peptides. More recently, the cloning of inhibin and activin, and the observation of their close homology to the transforming growth factor-beta family of peptides, has led to an interest in their possible role as growth and differentiation factors. Activin, inhibin and follistatin are expressed in embryonic and fetal tissues, as well as in the placenta. However, although activin is a potent regulator of growth and differentiation in a number of cell types, their role in embryonic and fetal development has yet to be established. High concentrations of inhibin have been observed in the fetal gonads, particularly the testes, and in the fetal adrenals of a number of species and a sex difference in fetal plasma concentrations has also been observed. Although the stimulus for high concentrations of inhibin in the fetus is not know, they are associated with decreased testicular testosterone and a decrease in the concentration of circulating follicle-stimulating hormone (FSH); this suggests that, as in the adult, inhibin may be involved in the regulation of fetal testicular androgen and pituitary FSH secretion during late gestation. The recent reports of elevated concentrations of inhibin and, particularly, activin in amniotic fluid during late gestation and its ability to stimulate the production of prostaglandin E2 by fetal membranes provides yet another potential role for this hormone in the regulation of events leading to parturition.


Waste plastics recycling for producing high-value carbon nanotubes: Investigation of the influence of Manganese content in Fe-based catalysts.
Thermo-chemical conversion is a promising technology for the recycle of waste plastics, as it can produce high-value products such as carbon nanotubes (CNTs) and hydrogen. However, the low yield of CNTs is one of the challenges. In this work, the addition of Mn (0 wt.%, 1 wt.%, 5 wt.%, and 10 wt.%) to Fe-based catalyst to improve the production of CNTs has been investigated. Results show that the increase of Mn content from 0 wt.% to 10 wt.% significantly promotes CNTs yield formed on the catalyst from 23.4 wt.% to 32.9 wt.%. The results show that Fe-particles in the fresh catalysts are between 10-25 nm. And the addition of Mn in the Fe-based catalyst enhanced the metal-support interactions and the dispersion of metal particles, thus leading to the improved catalytic performance in relation to filamentous carbon growth. In addition, the graphitization of CNTs is promoted with the increase of Mn content. Overall, in terms of the quantity and quality of the produced CNTs, 5 wt.% of Mn in Fe-based catalyst shows the best catalytic performance, due to the further increase of Mn content from 5 wt.% to 10 wt.% led to a dramatic decrease of purity by 10 wt.%.


Thrombotic thrombocytopenic purpura: 2008 update.
Thrombotic thrombocytopenic purpura (TTP) is a spectrum of syndromes characterized by thrombocytopenia and microangiopathic hemolytic anemia, manifested by an elevated blood lactate dehydrogenase (LDH) concentration and red blood cell fragments. It classically occurs in patients with a hereditary or acquired lack of ADAMTS13, a metalloproteinase that cleaves large multimers of von Willebrand factor. Other TTP-like syndromes, including TTP associated with pregnancy, organ transplantation, and certain medications, likely have different underlying causes and may require different treatment. Unless TTP is recognized promptly and treated aggressively, most patients die of it.


Transient adaptation and sensitization in the retina of Necturus.
Responses to repetitive stimulation were monitored at several retinal levels in the eyecup of the mudpuppy Necturus maculosus. When alternating sequences of low-intensity small and large spots were presented, two effects were found, which could be localized to the proximal retina: (a) response decrement (RD), in which, after the first small spot response, subsequent small spot responses are decreased in amplitude and (b) transient response enhancement (TRE), in which the first small spot response after a large spot sequence is larger than preceding or subsequent small spot responses. RD and TRE are absent or weak in sustained on or off responses (horizontal and bipolar cells, and ON and OFF ganglion cell post-stimulus time histograms (PSTH) but are particularly well developed in the on/off responses of the proximal retina (proximal negative response, M-wave, PSTHs of ON/OFF ganglion cells, and intracellular responses from on/off neurons and Müller cells). RD and TRE appear to arise from a stimulus-evoked slow depolarization in on/off neurons that interacts with the amplitude of succeeding responses. We conclude that RD and TRE are a form of neural adaptation that is largely specific to the on/off channels of the proximal retina.


Vascular access in children.
Establishment of stable vascular access is one of the essential and most challenging procedures in a pediatric hospital. Many clinical specialties provide vascular service in a pediatric hospital. At the top of the "expert procedural pyramid" is the pediatric interventional radiologist, who is best suited and trained to deliver this service. Growing awareness regarding the safety and high success rate of vascular access using image guidance has led to increased demand from clinicians to provide around-the-clock vascular access service by pediatric interventional radiologists. Hence, the success of a vascular access program, with the pediatric interventional radiologist as the key provider, is challenging, and a coordinated multidisciplinary team effort is essential for success. However, there are few dedicated pediatric interventional radiologists across the globe, and also only a couple of training programs exist for pediatric interventions. This article gives an overview of the technical aspects of pediatric vascular access and provides useful tips for obtaining vascular access in children safely and successfully using image guidance.


[Calcaneus fractures. Open reduction and internal fixation].
Critical analysis of the medium-term results of open reduction and internal fixation (ORIF) of displaced intra-articular calcaneus fractures with a standardized protocol in a greater patient cohort. From October 1993 to December 1999 314 patients (mean age 42.3 years) with 348 calcaneus fractures were seen at the Dresden University Hospital. 41 fractures were open, 4 with 1st degree, 28 with 2nd and 9 with 3rd degree soft tissue damage. 275 displaced intra-articular fractures were treated with ORIF, 262 (95.3 %) with plate osteosynthesis via an extended lateral approach. 169 patients could be evaluated at a mean of 18 months (range 10-47 months) postoperatively with an extended protocol of questionnaire, physical and radiographic examination. The Maryland Foot Score after 18 months follow-up averaged 80.8/100, the mean Zwipp score averaged 146.4/200. The functional result with the Merle d'Aubigné score was judged good to excellent in 86% of cases. Rates of deep infection and superficial wound edge necrosis increased significantly with open fractures and delay in surgery of more than 2 weeks after injury in closed fractures. Clinical results were adversely affected by even minor residual steps in the posterior facet (1-2 mm) as judged by CT or Brodén views (p < 0.001). Böhler's tuberosity-joint-angle had an impact on the final result when falling short compared to the unaffected contralateral side by more than 30% (p < 0.001). Management of intra-articular calcaneus fractures with a standardized protocol of ORIF and early mobilization leads to reproducible good or excellent clinical results in a majority of patients. New approaches like an interlocking calcaneus plate, the use of subtalar arthroscopy, early soft tissue coverage for complex open injuries and percutaneous screw fixation for selected fractures should further improve prognosis.