[Mumps virus and orchitis: towards a physiopathologic approach].
Mumps orchitis is a dreaded complication of mumps is pubescent men. The literature on this subject includes epidemiological, clinical, histological and endocrine findings, indicating a marked variability of the clinical features from one patient to another, an alteration of endocrine function that can persist in the long term and finally post-mumps infertility, which is exceptional. On the other hand, relatively few studies have investigated the pathophysiological mechanisms, and suggest replication of the mumps virus in the testis. Based on these data from the literature, this article reviews or proposes various hypotheses concerning the various pathophysiological aspects of this disease and discusses the lines of research that could advance the current knowledge in order to improve the therapeutic management of patients, while also providing a better knowledge of the mumps virus and basic testicular physiology.


Depression and anxiety in patients undergoing elective and emergency surgery: Cross-sectional study from Allama Iqbal Memorial Teaching Hospital, Sialkot.
To determine the frequency of depression and anxiety in post-operative patients undergoing elective and emergency surgery. The cross-sectional analytical study was conducted at the Department of Surgery and Department of Psychiatry of the Allama Iqbal Memorial Teaching Hospital, Sialkot, Pakistan, from September 2013 to April 2016, and comprised patients due for elective or emergency surgery. Patients admitted to the surgical wards, including general surgical, neurosurgical, urological and orthopaedic wards, undergoing major surgical procedures were enrolled. The patients were divided into elective surgery group 1 and emergency surgery group 2. The hospital anxiety and depression scale was used to screen for symptoms of anxiety and depression. SPSS 22 was used for data analysis. Of the 6,624 patients, 4,635(69.97%) were in group 1 and 1,989(30.03%) in group 2.The mean age of patients was 36.75±10.3years in group 1 and 39.11±11.4 years in group 2. There were 1,715(37%) males and 2,920(63%) females in group 1, while 518(26%) males and 1,471(74%) females were in group 2. Anxiety was present in 914(45.95%) and 656(32%) patients at 0 and 3 weeks in patients undergoing emergency surgery, while in elective surgery patients it was noted in 509(10.93%) and 1,390(29.87%) subjects, respectively. Depression was present in 218(10.96%) and 616(30.97%) patients at 0 and 3 weeks in patients undergoing emergency surgery, while in elective surgery it was noted in 463(9.98%) and 1,488(32.1%) respectively. Depression and anxiety were quite frequent in patients undergoing major surgeries. Anxiety was more common in patients who underwent emergency surgeries.


Effects of Systemic Magnesium on Post-operative Analgesia: Is the Current Evidence Strong Enough?
Clinical studies have been previously carried out on the efficacy of systemic magnesium to minimize postoperative pain, however, with controversial results. A quantitative meta-analysis was performed to evaluate the analgesic efficacy and safety of systemic magnesium on post-operative pain. Comprehensive systematic review of all relevant, publsished randomized controlled trials. A search was conducted of published literature in MEDLINE, PsycINFO, Scopus, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to Sep-Oct 2014. Randomized controlled trials (RCTs) that compared magnesium with placebo were identified. Effects were summarized using standardized mean differences (SMDs), weighed mean differences (WMD), or odds ratio (OR) with suitable effect model. Twenty-seven RCTs involving 1,504 patients were included. In total, peri-operative magnesium significantly reduced the pain score at rest (SMD, -1.43, 95% CI, -2.74 to -0.12, < 0.01). Magnesium significantly reduced analgesic consumption (SMD, -1.72, 95% CI, -3.21 to -0.23) in patients undergoing urogenital, orthopaedic, and cardiovascular surgeries, but was inconclusive for patients receiving gastrointestinal surgeries. The obvious analgesia of systemic magnesium was observed on reducing the pain score during movement at 24 hours after operation (SMD, -0.05, 95% CI, -0.43 to 0.32). Moreover, magnesium administration showed a beneficial effect with regard to intra-operative hemodynamics and reduced extubation time in the cardiovascular surgery patients (WMD, -29.34 min, 95% CI, -35.74 to -22.94, P < 0.01). Focused only on the quality of analgesia on postoperative pain with regards to surgery type. Our study suggests that systemic magnesium during general anesthesia significantly decreases post-operative pain scores without increasing adverse events. It should be noted that since there are 18 ongoing RCTs without published data, it is still premature to draw conclusions on the long-term analgesic effects of magnesium as well as potential gender or age difference.


Comparison of hypertension and its risk factors between the Guangxi Bai Ku Yao and Han populations.
Little is known about the prevalence of hypertension in Bai Ku Yao, an isolated subgroup of the Yao minority in China. The aim of this study was to compare the difference in the prevalence of hypertension and its risk factors between the Guangxi Bai Ku Yao and Han populations. A cross-sectional study of hypertension in 1170 subjects of Bai Ku Yao and 1173 participants of Han Chinese aged 15-89 was conducted by a stratified randomized cluster sampling. Information on diet and lifestyle was collected with standardized questionnaires. Blood pressure, serum lipids and several anthropometric parameters were obtained in all subjects. Systolic, diastolic and pulse pressure levels and hypertension prevalence (10.85% vs 16.45%, p<0.001) were lower in Bai Ku Yao than in Han. Hypertension was positively correlated with male, age, physical activity, body mass index, waist circumference, total energy, total fat and sodium intakes, and negatively associated with education level and total dietary fibre intake in both ethnic groups (p<0.05-0.001). Hypertension was also positively associated with alcohol consumption in Han. The rates of awareness, treatment and control were lower in Bai Ku Yao than in Han (p<0.05 for all). The difference in the hypertension prevalence between the two ethnic groups might result from different diet, lifestyle, physical activity level, sodium intake and genetic factors.


Crystal plane dependent growth of aligned single-walled carbon nanotubes on sapphire.
On single-crystal substrates, such as sapphire (alpha-Al 2O 3) and quartz (SiO 2), single-walled carbon nanotubes (SWNTs) align along specific crystallographic axes of the crystal, indicating that the SWNT growth is influenced by the crystal surface. Here, we show that not only the orientation, but also the diameter and chirality of SWNTs are affected by the crystal plane of the sapphire substrate. The aligned SWNTs grown on the A- and R-planes of sapphire have narrower diameter distributions than randomly oriented tubes produced on the C-plane sapphire and amorphous SiO 2. Photoluminescence measurements reveal a striking difference between the aligned SWNTs: near-zigzag tubes are observed on the A-plane and near-armchair tubes on the R-plane. This study shows the route for the diameter and chirality control of SWNTs by surface atomic arrangements of a single-crystal substrate.


Two-dimensional echocardiographic assessment of right cardiac pressure overload in patients with chronic obstructive airway disease.
Two-dimensional echocardiography was used to estimate right cardiac pressure overload in patients with chronic obstructive airway disease. Area measurements of the four heart chambers were carried out from the apical four-chamber view. Additionally, the respiratory behaviour of the inferior vena cava was examined from the subcostal view. A good apical imaging of the four-chamber view for area measurement was obtained in 44 out of 48 patients with chronic obstructive airway disease. The respiratory behaviour of the inferior vena cava was investigated from the subcostal view in 38 patients. Within 8 days after echocardiography, right cardiac catheterization was carried out in order to measure pulmonary artery and right atrial mean pressures and to determine pulmonary vascular resistance. A good correlation was found between pulmonary artery mean pressure and the following echocardiographic parameters: area index (area/body surface) of the two right heart cavities (r = 0.83), right-to-left ventricular area ratio (r = 0.82) and right-to-left cardiac area ratio (ratio between the added areas of both right heart cavities on the one side and the added areas of both left heart cavities on the other; r = 0.82). Correlation between these parameters and pulmonary vascular resistance (r = 0.71, 0.66 and 0.71, respectively) and between the right atrial mean pressure and the right atrial area index was less close (r = 0.64). On the other hand, the respiratory behaviour of the inferior vena cava proved to be highly specific but not very sensitive in predicting a pathological right atrial pressure.(ABSTRACT TRUNCATED AT 250 WORDS)


Genetic and physical map of a P1 miniplasmid.
The prophage form of bacteriophage P1 is a unit-copy plasmid which is maintained with great fidelity in its Escherichia coli host. The plasmid maintenance functions of P1 are clustered in one region of the genome. An 11.5-kilobase fragment from this region has been cloned into a lambda delta att vector and promotes stable unit-copy plasmid maintenance. The properties of the lambda vector facilitated the isolation of deletion mutants affecting the P1 DNA. Twenty-eight deletion mutants were isolated, and their lesions were mapped by physical techniques. The genetic properties of the mutants with respect to plasmid replication, stability of plasmid maintenance, and ability to exert incompatibility effects against P1 and P7 plasmids were determined. These properties, along with those of several subfragments of the P1 insert cloned into high-copy-number plasmid vectors, allow the construction of an unambiguous genetic and physical map of the maintenance functions. A region of less than 3 kilobases, the rep region, is essential for plasmid replication and contains the incA incompatibility determinant within an 800-base-pair segment. Immediately adjacent to rep is a second region of approximately 3 kilobases which is required for stable plasmid maintenance, but not replication. This region, par, contains a second incompatibility element incB which is approximately 1 kilobase in size. The par region appears to specify equipartition of plasmid copies to daughter cells during cell division.


Mild intraoperative hypothermia increases duration of action and spontaneous recovery of vecuronium blockade during nitrous oxide-isoflurane anesthesia in humans.
We compared the duration of action and recovery times for vecuronium in normothermic and mildly hypothermic patients. Ten patients were actively cooled to a central body temperature near 34.5 degrees C, and ten were maintained at a normothermic central temperature (greater than 36.5 degrees C); temperature was measured in the distal esophagus. Vecuronium 0.1 mg/kg was administered as an intravenous (iv) bolus to all patients, and the evoked mechanical response to train-of-four stimulation was recorded. Five hypothermic and five normothermic patients were allowed to recover spontaneously. In the remaining five in each group, neostigmine (40 micrograms/kg) and atropine (20 micrograms/kg) was administered when the first twitch (T1) height spontaneously recovered to 10% of control (T1 = 10% of the pre-vecuronium twitch tension). Vecuronium's duration of action (from injection of drug until T1 = 10%) was 28 +/- 4 and 62 +/- 8 min during normothermia and hypothermia, respectively (P less than 0.05). The corresponding values for spontaneous recovery from T1 = 10% to TOF ratio greater than 75% were 37 +/- 15 and 80 +/- 24 min (P less than 0.05), and for neostigmine-induced recovery were 10 +/- 3 and 16 +/- 11 min (difference not significant). We conclude that mild hypothermia increases the duration of action of and time for spontaneous recovery from vecuronium-induced neuromuscular blockade.


Child sex differences in primary care clinicians' mental health care of children and adolescents.
Sex differences in the medical and mental health care of adults are well established. To study the effect of child patient's sex on whether primary care clinicians (PCCs), including pediatricians, family physicians, and nurse practitioners, found or treated mental health problems in primary care settings. The data were collected by clinicians and parents from 21 065 individual child visits (50.3% girls) in 204 primary care practices. Each PCC enrolled a consecutive sample of approximately 55 children and adolescents aged 4 to 15 years. Parents filled out questionnaires, including the Pediatric Symptom Checklist, before seeing the clinician. Clinicians completed a survey after the visit about the psychosocial problems and recommended treatments, but they did not see the results of the Pediatric Symptom Checklist or any other data collected from the parents. Boys were more likely to be seen for a mental health-related visit and by a clinician who identified them as "my patient." Boys with parent-reported symptom profiles that were similar to those of girls were more likely to be identified as having attention-deficit/hyperactivity problems or behavior or conduct problems and less likely to be identified as having internalizing problems. Adjusting for parent-reported symptoms, PCCs were more likely to prescribe medications for boys. Child sex differences in referrals to mental health specialists and the provision of counseling to families were not statistically significant. There are substantial sex differences in the mental health care of children in the primary care system.


Solid-State Electron Transport Through Carbon Dots Junctions: The Role of Boron and Phosphorus Doping.
Carbon dots (CDs) are a new class of nanoparticles that gained widespread attention recently because of their easy preparation, water solubility, biocompatibility, and bright luminescence, leading to their integration in various applications. Despite their nm-scale and proven electron transfer capabilities, the solid-state electron transport (ETp) across single CDs was never explored. Here, a molecular junction configuration is used to explore the ETp across CDs as a function of their chemical structure using both DC-bias current-voltage and AC-bias impedance measurements. CDs are used with Nitrogen and Sulfur as exogenous atoms and doped with small amounts of Boron and Phosphorous. It is shown that the presence of P and B highly improves the ETp efficiency across the CDs, yet without an indication of a change in the dominant charge carrier. Instead, structural characterizations reveal significant changes in the chemical species across the CDs: the formation of sulfonates and graphitic Nitrogen. Temperature-dependent measurements and normalized differential conductance analysis reveal that the ETp mechanism across the CDs behaves as tunneling, which is common to all CDs used here. The study shows that the conductivity of CDs is on par with that of sophisticated molecular wires, suggesting CDs as new 'green' candidates for molecular electronics applications.


Formation of carbonyls during attack on insulin by submolar amounts of hypochlorite.
Bovine insulin was reacted at pH 4.0 with submolar amounts of hypochlorite. At least one molecule of insulin was modified per two molecules of hypochlorite added, as estimated by HPLC of native and modified insulin. About 5% of the hypochlorite-modified insulin reacted with dinitrophenylhydrazine (DNPH), a reagent which specifically labels carbonyl groups. The major DNPH-labeled product was isolated from the native insulin on reverse-phase HPLC, using trifluoroacetic acid/water/acetonitrile gradients. The UV spectrum of the major peak on the HPLC diode-array detector was representative of DNPH adducts, with lambda max = 365 nm. Several methods, including total amino acid analysis, tryptic digestion, and collision-induced dissociation-electrospray MS, indicate that the major carbonyl in the DNPH-labeled product was on the amino-terminal phenylalanine of the insulin B-chain. Amino acid analysis indicated that tyrosine was also degraded by hypochlorite, but we could not detect a carbonyl group formed at tyrosine. These findings suggest that the terminal amino groups of proteins are highly vulnerable to carbonyl formation during hypochlorite attack. The use of relatively low amounts of active oxygen species (such as hypochlorite), followed by chromatographic isolation of the protein labeled with a carbonyl-specific reagent, can be a useful approach to the study of reactive sites on proteins.


Xpert HIV-1 point-of-care test for neonatal diagnosis of HIV in the birth testing programme of a maternity hospital: a field evaluation study.
Point-of-care testing (POCT) among HIV-exposed infants might improve linkage to care relative to laboratory-based testing (LABT). We evaluated HIV-1 POCT at birth in the context of universal LABT in a maternity hospital and describe our implementation experience. We did a field evaluation study between Oct 1, 2014, and April 30, 2016, at the urban Rahima Moosa Mother and Child Hospital (RMMCH), Johannesburg, South Africa. We aimed to sample consecutive neonates at birth with POCT (Cepheid Xpert HIV-1 Qualitative test) and compared results with those of LABT (Roche COBAS TaqMan HIV-1 Qualitative test) with respect to performance in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Cohen's κ coefficient, result return, antiretroviral treatment (ART) initiation, and coverage. 18 268 women delivered livebirths at RMMCH and 4267 (23%) were HIV-positive with 4336 HIV-exposed neonates delivered. Mothers of 4141 (96%) HIV-exposed neonates were offered infant birth testing. Mothers of 4112 (99%) neonates consented. In 78 neonates with consent (2%), a test was not done due to early neonatal death (n=13), mother departing before venesection, or staff unavailability. Among 3970 infants who had LABT, 57 (1%) tested positive, 3906 (99%) tested negative, two (<1%) were indeterminate, and five (<1%) had an error result. 2238 (56%) of these infants had concurrent POCT. POCT detected all 30 HIV-infected neonates (sensitivity 100%; 95% CI 88·4-100) with two additional false-positive results (specificity 99·9%; 99·7-100). All positive and 96·2% of negative POCT results were returned compared with 88·9% of positive and 52·8% of negative LABT results. Although every POCT required 90 min of instrument time, 2·6 h (IQR 2·3-3·1) elapsed between phlebotomy and result return. In days, median time of result return for POCT was 1 day, significantly earlier than 10 days for LABT (p<0·0001). ART was initiated in 30 neonates (100%) with positive POCT compared with 24 (88·9%, p=0·10) of 27 infants who had LABT only, with initiation occurring a median of 5 days earlier in the POCT group (p<0·0001). POCT implementation required additional staff and weekend cover. Compared with LABT, POCT was associated with good performance, improved rates of result return, and reduced time to ART initiation. Resources needed to integrate POCT into a routine birth testing programme require further evaluation. National Institutes of Health.


A comparison of the incidence of undiagnosed congenital heart disease in hospital born and home born children.
To evaluate the incidence of otherwise undiagnosed congenital heart disease (CHD) in a population of children born in a hospital with routine pulse oximetry (RPO) screening compared to children born at home. We reviewed 15 years of births at 2 hospitals for incidence of undiagnosed CHD with RPO. The Health Department reviewed the same data for out of hospital births. A total of 50,545 hospital births were screened and 1,274 children were born outside the hospital. There were 28 hospital-born babies diagnosed with cyanotic CHD prior to nursery discharge. Only one of these babies would not have been diagnosed without RPO. Three children were missed and there were 3 false positives. Sensitivity and positive predictive value of RPO was 25%, specificity and negative predictive value of RPO exceed 99%. The incidence of CHD requiring RPO diagnosis was roughly one birth per 50,000. Two children born at home with undiagnosed CHD were missed. One of these children presented with neonatal demise. RPO screening is still valuable in diagnosing CHD only diagnosable with RPO. However, the incidence of CHD requiring RPO to diagnose is similar to other congenital diseases which are not mandated national screening tests. In our limited experience a patient is roughly 25 times more likely to have undiagnosed CHD if they are born outside of a hospital.


An in situ hybridization histochemistry method for the use of alkaline phosphatase-labeled oligonucleotide probes in small intestine.
We have developed a method of non-radioactive in situ hybridization histochemistry using alkaline phosphatase-labeled oligonucleotide probes to detect gene expression in the intestine. Because the intestine contains a large amount of endogenous alkaline phosphatase activity, mild acid pretreatment of the tissue sections was required to inactivate the alkaline phosphatase. Acid pre-treatment dramatically reduced the endogenous activity without affecting the efficiency of hybridization or the probe's ability to reveal a positive mRNA signal. Furthermore, the addition of polyvinyl alcohol to the substrate solution helped to keep the background staining low without adversely affecting the intensity of the signal. The current protocol allows rapid and sensitive detection of sites of gene expression in intestinal tissue.


Transcriptional co-activator PGC-1 alpha drives the formation of slow-twitch muscle fibres.
The biochemical basis for the regulation of fibre-type determination in skeletal muscle is not well understood. In addition to the expression of particular myofibrillar proteins, type I (slow-twitch) fibres are much higher in mitochondrial content and are more dependent on oxidative metabolism than type II (fast-twitch) fibres. We have previously identified a transcriptional co-activator, peroxisome-proliferator-activated receptor-gamma co-activator-1 (PGC-1 alpha), which is expressed in several tissues including brown fat and skeletal muscle, and that activates mitochondrial biogenesis and oxidative metabolism. We show here that PGC-1 alpha is expressed preferentially in muscle enriched in type I fibres. When PGC-1 alpha is expressed at physiological levels in transgenic mice driven by a muscle creatine kinase (MCK) promoter, a fibre type conversion is observed: muscles normally rich in type II fibres are redder and activate genes of mitochondrial oxidative metabolism. Notably, putative type II muscles from PGC-1 alpha transgenic mice also express proteins characteristic of type I fibres, such as troponin I (slow) and myoglobin, and show a much greater resistance to electrically stimulated fatigue. Using fibre-type-specific promoters, we show in cultured muscle cells that PGC-1 alpha activates transcription in cooperation with Mef2 proteins and serves as a target for calcineurin signalling, which has been implicated in slow fibre gene expression. These data indicate that PGC-1 alpha is a principal factor regulating muscle fibre type determination.


EPR studies of the photodynamic properties of a novel potential photodynamic therapeutic agent: photogeneration of semiquinone radical anion and active oxygen species (O2*-, OH*, H2O2 and 1O2).
Cyclohexylamino-substituted hypocrellin B (CHAHB) has been synthesized with the aim of improving the red absorption and specific affinity for malignant tumors over those of the parent compound. Irradiation of a deoxygenated DMSO solution of CHAHB generates a strong electron paramagnetic resonance (EPR) signal, which is assigned to the semiquinone radical anion of CHAHB with the aid of a series of experimental results. In the presence of oxygen, superoxide radical anions (O2*-) are generated via electron transfer from CHAHB*-, the precursor, to ground-state molecular oxygen. Hydroxyl radicals were detected by spin-trapping EPR when an oxygen-saturated aqueous solution containing CHAHB and DMPO was irradiated. Singlet oxygen (1O2) is produced via energy transfer from triplet CHAHB to ground-state oxygen molecules, with a sharply decreased quantum yield, i.e. 0.11. Furthermore, cell survival studies reveal CHAHB exhibits much higher photodynamic activities than its parent hypocrellins. The strongly enhanced photodynamic activities and sharply decreased quantum yield of 1O2 generation suggest that the type I (free radical) mechanism may play a significant role in CHAHB-PDT, rather than the type II (singlet oxygen) mechanism found in photofrin-PDT.


Hyponatraemia in adults with community-acquired bacterial meningitis.
Hyponatraemia in adults with bacterial meningitis has been described as a common complication, but its true prevalence and clinical importance are unknown. To investigate the prevalence, clinical characteristics and consequences of hyponatraemia in bacterial meningitis in adults. Nationwide observational cohort study. We prospectively assessed the prevalence and clinical characteristics of hyponatraemia among 696 adults with community-acquired bacterial meningitis. Symptoms and signs on admission, blood and CSF test results, radiological examinations and complications during admission were recorded. Sodium levels were determined at admission in 685/696 episodes of bacterial meningitis (98%). Hyponatraemia (<135 mmol/l) was seen in 208/685 (30%) and was classified as severe (<130 mmol/l) in 38 (6%). Hyponatraemia developed during admission in an additional 53 episodes. Hyponatraemia was not associated with an increase in symptoms, with complications or with unfavourable outcome. Treatment for hyponatraemia was initiated in 16% of episodes, but did not influence its duration. Hyponatraemia appears both common and benign in adults with bacterial meningitis. In cases of severe hyponatraemia, we suggest the use of fluid maintenance therapy.


Efficacy and tolerability of 0.2% brimonidine tartrate for the treatment of acute non-arteritic anterior ischemic optic neuropathy (NAION): a 3-month, double-masked, randomised, placebo-controlled trial.
Neuroprotection may be an option in ischemic optic nerve disease. There have been promising reports about the neuroprotective ability of topical brimonidine in animal studies. Therefore, we tested whether 0.2% brimonidine tartrate could improve the outcome of patients with non-arteritic anterior ischemic optic neuropathy (NAION). The study was stopped after an interim analysis, having not proven its feasibility within practicable time frame. A 3-month, double-masked, placebo-controlled, randomised European multicenter trial conducted according to good clinical practice rules. Thirty-six patients (22 m, 14 f), older than 40 years with first eye involvement and typical signs of NAION were included in the study within the 1st week after visual loss (VA 0.05-1.0) and were randomized to treatment with either brimonidine 0.2% (Alphagan) or placebo. Visual acuity (VA, primary endpoint), visual field (VF, Humphrey 30-2 and Goldmann, quantified by a modified Esterman grid) and automated swinging flashlight test (SWIFT) were performed at baseline, 2 weeks, 4 weeks and 12 weeks after first visit. Primary analysis aimed at intention-to-treat group (ITT, n=29), secondary analysis to the per protocol population (PP, n=25). Tolerability and safety were tested in the safety group (n=36). A two-sample two-sided t-test was used for statistical analysis (alpha level at 0.05). VA did not show statistically significant difference by treatment. There were non-significant trends for better visual field results in the brimonidine group. Adverse events consisting of local irritation were observed six times in the verum and three times in the placebo group. No serious adverse events occurred. In contradiction to an open-labeled, retrospective study published by Fazzone et al., the results of this trial did not indicate any harmful effect of brimonidine in patients suffering from NAION. However, a statistically significant advantage for the patients receiving brimonidine tartrate could not be shown.


Chromogranin A and biochemical progression-free survival in prostate adenocarcinomas submitted to radical prostatectomy.
The primary aim of the present study was to determine the prognostic role of elevated levels of chromogranin A (CgA) in terms of biochemical prostate-specific antigen (PSA) progression after radical prostatectomy (RRP) for prostate adenocarcinoma. Two hundred and sixty-four consecutive men with non-metastatic prostate adenocarcinoma submitted to RRP represented our population. In all cases, a blood sample for the determination of serum total PSA and CgA levels was obtained (RIA). Two different upper reference values for serum CgA levels were used: > 60 and > 90 ng/ml. The main end point of this study was biochemical (PSA) progression-free survival. In our population, 35.0% (91/264 cases) of cases presented a serum CgA level > 60 ng/ml and only 6.4% (17/264) presented CgA > 90 ng/ml. After RRP, during a mean follow-up of 64.59 +/- 26.34 months (median 60 months; range 12-120 months), 59 patients (22.3%) showed a biochemical (PSA) progression. Using 60 ng/ml as upper reference value for CgA, 10.4 and 45.0% of cases showed PSA progression after RRP in the group with preoperative CgA levels < or = 60 and > 60 ng/ml respectively. The proportion of PSA progression-free survival was significantly lower in cases with preoperative CgA > 60 ng/ml than in cases with CgA < or = 60 ng/ml (P < 0.0001). In addition, at the multivariate analysis, preoperative serum CgA levels were confirmed as an independent prognostic factor for PSA progression after RRP. In non-metastatic prostate carcinomas, we described a significant prognostic role of CgA in terms of biochemical progression-free survival.


Repeated exacerbations of ocular inflammation with vitreous hemorrhage in a patient with HLA-B27 associated uveitis.
HLA-B27 associated uveitis is characterized by recurrent alternating acute unilateral attacks of intraocular inflammation in the anterior chamber. The aim of this study was to report an unusual case of repeated exacerbations with vitreous hemorrhage in HLA-B27 associated uveitis. Thirty four-year-old man was diagnosed as HLA-B27 associated uveitis in his right eye. He showed repeated exacerbation of ocular inflammation with retinal vein dilation and small retinal hemorrhage following vitreous hemorrhage. Fluorescein fundus angiography a week before the appearance of vitreous hemorrhage showed no neovascularization. Oral prednisolone administration was started from 40mg/day with gradual tapering. About 3 weeks after the onset, most of the vitreous hemorrhage disappeared and visual acuity was improved to 20/20. Through the decreased vitreous hemorrhage, Weiss ring was detected later. The vitreous hemorrhage found in this patient is a severe exacerbation, and might be a consequence of the vitritis that leads to posterior vitreous detachment.


[Effect of picrotoxin on the Cl-activated ATPase microsomal fraction of bream brain (Abramis brama L.)].
It is found that picrotoxine in range concentrations 0.1-10 microM stimulates the basal Mg(2+)-ATPase from microsomal fraction of fish bream (Abramis brama L.), however decreases activating effect of 10(-5) M GABA on the enzyme. The stimulative effect of picrotoxine dependants on duration of preincubation with microsomes. It was established that basal Mg(2+)-ATP-ase activity was activated by anions (Cl- > Br- > I-). The activated effect of anions on the Mg(2+)-ATP-ase is decreased in the presence 1 microM picrotoxine. It was shown that in the dependence on concentration of the Mg(2+)-ATP (0.2 or 1 mM) in the incubation medium the picrotoxine serves as on activator or inhibitor of the enzyme activity. It is supposed that picrotoxine allosterially influences on the enzyme by the receptor-dependent way.


Changes in the Phosphoproteome and Metabolome Link Early Signaling Events to Rearrangement of Photosynthesis and Central Metabolism in Salinity and Oxidative Stress Response in Arabidopsis.
Salinity and oxidative stress are major factors affecting and limiting the productivity of agricultural crops. The molecular and biochemical processes governing the plant response to abiotic stress have often been researched in a reductionist manner. Here, we report a systemic approach combining metabolic labeling and phosphoproteomics to capture early signaling events with quantitative metabolome analysis and enzyme activity assays to determine the effects of salt and oxidative stress on plant physiology. K(+) and Na(+) transporters showed coordinated changes in their phosphorylation pattern, indicating the importance of dynamic ion homeostasis for adaptation to salt stress. Unique phosphorylation sites were found for Arabidopsis (Arabidopsis thaliana) SNF1 kinase homolog10 and 11, indicating their central roles in the stress-regulated responses. Seven Sucrose Non-fermenting1-Related Protein Kinase2 kinases showed varying levels of phosphorylation at multiple serine/threonine residues in their kinase domain upon stress, showing temporally distinct modulation of the various isoforms. Salinity and oxidative stress also lead to changes in protein phosphorylation of proteins central to photosynthesis, in particular the kinase State Transition Protein7 required for state transition and light-harvesting II complex proteins. Furthermore, stress-induced changes of the phosphorylation of enzymes of central metabolism were observed. The phosphorylation patterns of these proteins were concurrent with changes in enzyme activity. This was reflected by altered levels of metabolites, such as the sugars sucrose and fructose, glycolysis intermediates, and amino acids. Together, our study provides evidence for a link between early signaling in the salt and oxidative stress response that regulates the state transition of photosynthesis and the rearrangement of primary metabolism.


Breaking self-tolerance to tumor-associated antigens by in vivo manipulation of dendritic cells.
Dendritic cells (DC) are extremely potent antigen-presenting cells, which can prime both naive CD4+ and CD8+ T lymphocytes. In their immature state, DC continuously sample and process antigens from the surrounding environment, but only mature DC express sufficient levels of costimulatory molecules to activate naive T cells. DC present in tumors are functionally immature owing to the immunosuppressive actions of tumor-derived factors and regulatory T cells, and such immature DC promote immune tolerance to the tumor. Recent studies from animal models suggest that Toll-like receptor (TLR) agonists such as CpG can reverse the tolerogenic state of tumoral DC. Strategies that allow DC to gain access to both tumor antigens and TLR agonists, in situ, can overcome tumor tolerance leading to the induction of potent systemic antitumor immunity.


Aftereffects of 2 noninvasive brain stimulation techniques on corticospinal excitability in persons with chronic stroke: a pilot study.
Noninvasive brain stimulation, including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), have gained popularity in the stroke rehabilitation literature. Little is known about the time course and duration of effects of noninvasive brain stimulation on corticospinal excitability in individuals with stroke. We examined the aftereffects of a single session of high-frequency rTMS (5 Hz) and anodal tDCS on corticospinal excitability in the same sample of participants with chronic stroke. Ten individuals with chronic stroke participated in this randomized cross-over study. Participants received 1 session of rTMS and 1 session of tDCS, with 1 week between sessions. During the rTMS session, 5-Hz rTMS (total of 1200 stimuli) was administered to the ipsilesional primary motor cortex (M1). For anodal tDCS, 1 mA of direct current was delivered to the ipsilesional M1 for 20 minutes. Motor evoked potentials were measured before and after (immediately, 15 minutes, 30 minutes, and 60 minutes) each stimulation session. Both 5-Hz rTMS and anodal tDCS significantly increased corticospinal excitability for 30 to 60 minutes after stimulation. There was no statistically significant difference between the 2 stimulation techniques in their effects on motor evoked potentials. No changes in measures of motor or cognitive performance were observed. Both 5-Hz rTMS and anodal tDCS induced effects on corticospinal excitability in persons with chronic stroke lasting at least 1 hour after stimulation. In the absence of concurrent motor practice, neither form of stimulation applied in a single session was associated the changes in motor performance. These approaches to increased cortical excitability may be of value as adjuncts to training. See Video (Supplemental Digital Content 1, http://links.lww.com/JNPT/A83) for more insights from the authors.


[Possibilities and limitations of the direct radioimmunological method with double guinea-pig antibody in the detection of serum Australia antigen].
The results obtained with the direct radioimmunological method and electrosyneresis in the search for Australia antigen were compared in 3100 donor sera. In a limited number of sera, the positivity of radioimmunological examination was tested by neutralization tests with human antibody and with the serum of normal guinea-pigs. Electrosyneresis proved positive in 4% of cases, while radioimmunological examination produced a clearly positive result in 6.7% of cases and a faintly positive or doubtful result in 1.8%. The presence of doubtful results is due to the fact that the distribution of values obtained shows some overlapping between normal population and population of subjects carrying the antigen. The neutralization tests have shown a high incidence (45%) of aspecific positivity between the sera proving positive at radioimmunological examination and negative at electrosyneresis. This inconvenience should be resolved by the recent introduction of a radioimmunological method which provides for use of labelled antibody of human origin.


Cocrystallization with syringic acid presents a new opportunity for effectively reducing the hepatotoxicity of isoniazid.
Objective: With the aim of surmounting the severe hepatotoxicity induced by antituberculosis drug isoniazid (INH), a novel cocrystal of INH with hepatoprotective nutraceutical syringic acid (SYA), namely INH-SYA, was designed and prepared through cocrystallization strategy, which is an intriguing attempt to reduce the toxic side effects of INH.Significance: The study not only provides new thinking for inhibiting toxic side effects of drugs through cocrystallization strategy, but also opens a new pathway for the application of nutraceuticals in the pharmacy.Methods: INH and SYA were successfully crystallized into the same crystal lattice through combining volatilization with solvent assisted methods. The resulting cocrystal was structurally characterized by single crystal X-ray diffraction (SCXRD), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC).Results: The SCXRD analysis for the present cocrystal revealed that it has a 1:1 ratio of INH to SYA with two molecules INH homodimers and two SYA molecules, in which they are arranged alternately linked by hydrogen bonds to form a six molecules ring structure (R66(40)) in crystal. The systematic evaluation of the in vitro/in vivo suggested that, owing to the formation of cocrystal, the dissolution efficiency of SYA was increased 5.85-fold compared with that of coarse SYA, and the oral bioavailability of the cocrystal in rats was enhanced by 3.66 times. As a result, the present INH-SYA cocrystal almost removed INH induced serious hepatotoxicity, which was further demonstrated by the hepatotoxicity studies in rats.Conclusion: INH-SYA cocrystal could effectively reduce the hepatotoxicity of INH.


Clustering of meiotic double-strand breaks on yeast chromosome III.
In the yeast Saccharomyces cerevisiae, meiotic recombination is initiated by transient DNA double-strand breaks (DSBs) that are repaired by interaction of the broken chromosome with its homologue. To identify a large number of DSB sites and gain insight into the control of DSB formation at both the local and the whole chromosomal levels, we have determined at high resolution the distribution of meiotic DSBs along the 340 kb of chromosome III. We have found 76 DSB regions, mostly located in intergenic promoter-containing intervals. The frequency of DSBs varies at least 50-fold from one region to another. The global distribution of DSB regions along chromosome III is nonrandom, defining large (39-105 kb) chromosomal domains, both hot and cold. The distribution of these localized DSBs indicates that they are likely to initiate most crossovers along chromosome III, but some discrepancies remain to be explained.


Chemoattractant activity of tris-(hydroxymethyl)aminomethane for Brugia pahangi infective third-stage larvae.
Urocanic acid (UCA) is known as a major chemoattractant for Strongyloides stercoralis infective third-stage larvae (L3). Since Brugia pahangi is a skin-penetrating parasitic nematode similar to S. stercoralis, UCA was expected to be a chemoattractant for B. pahangi L3. Thus, the chemoattractant activity of UCA for B. pahangi L3 was assessed. The chemotactic responses of B. pahangi L3 to UCA or acetic acid (CH3COOH) dissolved in amine solutions were assessed using an agar-plate assay. A test solution of 200 mm UCA dissolved in aqueous 270 mm tris(hydroxymethyl)aminomethane (Tris) significantly attracted B. pahangi L3 compared with deionized water (DW), while neither a solution of 200 mm UCA dissolved in aqueous 230 mm ammonia (NH3) nor 290 mm triethylamine (TEA) significantly attracted L3. Similarly, a test solution of 200 mm CH3COOH dissolved with 200 mm Tris significantly attracted L3, but neither a test solution of 200 mm CH3COOH plus 200 mm NH3 nor 200 mm TEA attracted L3. Furthermore, L3 were significantly attracted to 200 mm Tris alone, compared with DW, but avoided 200 mm NH3 and 200 mm TEA. Moreover, the chemoattractant activity of Tris for L3 was observed even at a low concentration of 25 mm, and it was observed in a mild alkaline condition but not in an acidic condition. The present study reveals that Tris is a potential chemoattractant for B. pahangi L3 while UCA is not. This finding will contribute to an understanding of the mechanisms of skin-penetrating infection of filarial L3.


Oxygen free radical-induced histamine release during intestinal ischemia and reperfusion.
Acute mesenteric ischemia is highly lethal and therefore a serious problem for surgery and intensive care medicine; accordingly its pathophysiology warrants further study. Oxygen free radicals (OFR) play a role in the intestinal mucosal damage that develops during reperfusion after ischemia. Histamine (H) is generally released in various types of tissue ischemia. The link between H release and OFR has only been studied in in vitro systems. We tested the hypothesis that OFR may be involved in H release following reperfusion of the ischemic gut. The artery supplying a segment of the ileum was occluded for 1 or 2 h in anesthetized dogs. On reperfusion, a release of H into the venous effluent of the segment was demonstrated. Pretreatment of the animals with allopurinol (an inhibitor of xanthine oxidase), or with MTDQ-DA [6,6'-methylene-bis(2,2-dimethyl-4-methanesulfonic acid sodium-1,2-dihydroquinoline)], a superoxide anion scavenger, or with a combination of allopurinol and MTDQ-DA resulted in an inhibition of H release. We conclude that OFR may play a role in the local H release following intestinal ischemia.


Relationship between angiotensin-converting enzyme gene insertion/deletion polymorphism, angiographically defined coronary artery disease and myocardial infarction in patients with type 2 diabetes mellitus.
The insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been implicated in the pathogenesis of cardiovascular diseases. The objective of the present study was to investigate the influence of ACE gene I/D polymorphism on the development and progression of coronary artery disease (CAD) and myocardial infarction (MI) in type 2 diabetic (T2DM) patients. We screened 283 T2DM patients, inclusive of 160 patients with angiographically defined CAD, 73 patients with MI, 89 patients without MI and 121 T2DM individuals with no evidence of CAD for ACE gene I /D polymorphism. There was no significant difference in the distribution of genotypes and alleles of ACE gene I/D polymorphism between T2DM+CAD and T2DM (non-CAD) groups. However, a significant association of this polymorphism with MI in T2DM+CAD patients (p=0.024) was observed. Further analysis revealed that the frequencies of the DD and ID genotypes increased with the number of stenosed coronary vessels (p=0.026). The DD genotype and the D allele were more frequent in the subgroup of T2DM patients with multivessel CAD (p=0.01) than in individuals with single vessel stenosis. These findings reveal a significant relationship between ACE gene I/D polymorphism, multivessel CAD and also the occurrence of MI in T2DM individuals with significant coronary stenoses in our population.


Aging alters the details recollected from emotional narratives.
Although it is known that aging impairs episodic memory, the precise effect of aging on emotional memory is not fully understood. In this study, younger and older adults listened to narratives that contained general and emotional (positive, negative, or neutral) details as they viewed related images. When participants later recalled the narratives, both age groups remembered more emotional details from the negative than the positive or neutral narratives. Interestingly, the enhanced recall for the negative narratives came with a reduced ability to remember the associated images for both younger and older adults. For all narrative types, older adults recalled a similar number of general but fewer emotional details than younger adults. Although there were no age-specific emotional effects, memory functioning of the older adults related to better recall of the positive narratives and associated images. These results provide insight into the similarities and differences in how younger and older adults encode and retrieve complex emotional memories.


Magnetic nanoparticle-mediated hyperthermia therapy induces tumour growth inhibition by apoptosis and Hsp90/AKT modulation.
We have evaluated the hyperthermia efficacy of oleic acid-functionalised Fe(3)O(4) magnetic nanoparticles (MN-OA) under in vivo conditions and elucidated the underlying mechanism of tumour growth inhibition. The efficacy and mechanism of tumour growth inhibition by MN-OA-mediated magnetic hyperthermia therapy (MHT) was evaluated in a murine fibrosarcoma tumour model (WEHI-164) using techniques such as TUNEL assay, Western blotting (WB), immunofluorescence (IF) staining and histopathological examination. In addition, bio-distribution of MN-OA in tumour/other target organs and its effect on normal organ function were studied by Prussian blue staining and serum biochemical analysis, respectively. MN-OA-induced MHT resulted in significant inhibition of tumour growth as determined by measurement of tumour volume, as well as by in vivo imaging of tumour derived from luciferase-transfected WEHI-164 cells. Histopathology analysis showed presence of severe apoptosis and reduced tumour cells proliferation, which was further confirmed by TUNEL assay, reduced expression of Ki-67 and enhanced level of cleaved caspase-3, in tumours treated with MHT. Moreover, expression of heat stress marker, Hsp90 and its client protein, AKT/PKB was reduced by ∼50 and 80%, respectively, in tumours treated with MHT as studied by WB and IF staining. Serum analysis suggested insignificant toxicity of MN-OA (in terms of liver and kidney function), which was further correlated with minimal accumulation of MN-OA in target organs. These results suggest the involvement of apoptosis and Hsp90/AKT modulation in MN-OA-mediated MHT-induced tumour growth inhibition.


Distance and location cues in retention of movements by a congenitally blind subject.
Retention of linear arm-positioning movements in a congenitally blind university student was tested with either distance or location cues and under retention conditions of rest, location, and distance interpolated tasks. Results revealed a consistent superiority for retention with location cues. The conclusion is drawn that these data would support a dual proprioceptive storage mode hypothesis.


Interface-confined oxide nanostructures for catalytic oxidation reactions.
Heterogeneous catalysts, often consisting of metal nanoparticles supported on high-surface-area oxide solids, are common in industrial chemical reactions. Researchers have increasingly recognized the importance of oxides in heterogeneous catalysts: that they are not just a support to help the dispersion of supported metal nanoparticles, but rather interact with supported metal nanoparticles and affect the catalysis. The critical role of oxides in catalytic reactions can become very prominent when oxides cover metal surfaces forming the inverse catalysts. The source of the catalytic activity in homogeneous catalysts and metalloenzymes is often coordinatively unsaturated (CUS) transition metal (TM) cations, which can undergo facile electron transfer and promote catalytic reactions. Organic ligands and proteins confine these CUS cations, making them highly active and stable. In heterogeneous catalysis, however, confining these highly active CUS centers on an inorganic solid so that they are robust enough to endure the reaction environment while staying flexible enough to perform their catalysis remains a challenge. In this Account, we describe a strategy to confine the active CUS centers on the solid surface at the interface between a TM oxide (TMO) and a noble metal (NM). Among metals, NMs have high electron negativity and low oxygen affinity. This means that TM cations of the oxide bind strongly to NM atoms at the interface, forming oxygen-terminated-bilayer TMO nanostructures. The resulting CUS sites at the edges of the TMO nanostructure are highly active for catalytic oxidation reactions. Meanwhile, the strong interactions between TMOs and NMs prevent further oxidation of the bilayer TMO phases, which would otherwise result in the saturation of oxygen coordination and the deactivation of the CUS cations. We report that we can also tune the oxide-metal interactions to modulate the bonding of reactants with CUS centers, optimizing their catalytic performance. We review our recent progress on oxide-on-metal inverse catalysts, mainly the TMO-on-Pt (TM = Fe, Co, and Ni) systems and discuss the interface-confinement effect, an important factor in the behavior of these catalytic systems. We have studied both model catalyst systems and real supported nanocatalysts. Surface science studies and density functional theory calculations in model systems illustrate the importance of the oxide-metal interfaces in the creation and stabilization of surface active centers, and reveal the reaction mechanism at these active sites. In real catalysts, we describe facile preparation processes for fabricating the oxide-on-metal nanostructures. We have demonstrated excellent performance of the inverse catalysts in oxidation reactions such as CO oxidation. We believe that the interface confinement effect can be employed to design highly efficient novel catalysts and that the inverse oxide-on-metal catalysts may find wide applications in heterogeneous catalysis.


Rare etiology of mechanical intestinal obstruction: Abdominal cocoon syndrome.
Abdominal cocoon syndrome is a rare cause of intestinal obstruction with unknown etiology. Diagnosis of this syndrome, which can be summarized as the small intestine being surrounded by a fibrous capsule not containing the mesothelium, is difficult in the preoperative period. A 47-year-old male patient was referred to the emergency department with complaints of abdominal pain, nausea, and vomiting for two days. The abdominal computed tomography examination detected dilated small intestinal loops containing air-fluid levels clustered in the left upper quadrant of the abdomen and surrounded by a thick, saclike, contrast-enhanced membrane. During exploratory surgery, a capsular structure was identified in the upper left quadrant with a regular surface that was solid-fibrous in nature. Abdominal cocoon syndrome is a rarely seen condition, for which the preoperative diagnosis is difficult. The combination of physical examination and radiological signs, and the knowledge of "recurrent characteristics of the complaints" that can be learned by a careful history, may be helpful in diagnosis.


In vivo recruitment by painful stimuli of AMPA receptor subunits to the plasma membrane of spinal cord neurons.
The persistent increase in pain sensitivity observed after injury, known as hyperalgesia, depends on synaptic plasticity in the pain pathway, particularly in the spinal cord. Several potential mechanisms have been proposed, including post-synaptic exocytosis of the AMPA subclass of glutamate receptors (AMPA-R), which is known to play a critical role in synaptic plasticity in the hippocampus. AMPA-R trafficking has been described in spinal neurons in culture but it is unknown if it can also occur in spinal neurons in vivo, or if it can be induced by natural painful stimulation. Here we have induced referred mechanical hyperalgesia in vivo by intracolonic instillation of capsaicin in mice and have observed a recruitment of GluR1 AMPA-R subunits to neuronal plasma membranes in the lumbar spinal cord. Intracolonic capsaicin induced a rapid (10 min) increase in GluR1, but not GluR2/3 in the synaptosomal membrane fraction which lasted at least 3 h and a decrease in GluR1 subunit in the cytosolic fraction. Capsaicin treatment also provoked CaMKII activation and pre-treatment with a specific CaMKII inhibitor prevented the GluR1 trafficking. Brefeldin-A, an antibiotic that inhibits exocytosis of proteins, not only prevented GluR1 trafficking to the membrane but also inhibited referred hyperalgesia in capsaicin-treated mice. Our results show that delivery of GluR1 AMPA receptor subunits to the cell membrane through a CaMKII activity-dependent exocytotic regulated pathway contributes to the development of hyperalgesia after a painful stimulus. We conclude that AMPA-R trafficking contributes to the synaptic strengthening induced in the pain pathway by natural stimulation.


Nutritional factors and hypospadias risks.
We examined whether hypospadias was associated with several aspects of the diet, including intake of animal products, intake of several nutrients and food groups related to a vegetarian diet and oestrogen metabolism, and diet quality. The study included deliveries from 1997 to 2005 that were part of the National Birth Defects Prevention Study. Diet was assessed by food frequency questionnaire during maternal telephone interviews, and two diet quality indices were developed based on existing indices. Analyses included 1250 cases with second- or third-degree hypospadias (urethra opened at the penile shaft, scrotum or perineum) and 3118 male, liveborn, non-malformed controls. All odds ratios (OR) and 95% confidence intervals [CI] were estimated from logistic regression models that included several potential confounders, including energy intake. Intake of animal products was not associated with hypospadias; for example, the adjusted OR for any vs. no intake of meat was 1.0 [95% CI 0.6, 1.6]. Frequency of intake of meat or other animal products was also not associated with hypospadias, nor was intake of iron or several nutrients that are potentially related to oestrogen metabolism. Diet quality was also not associated with hypospadias; the OR for diet quality in the highest vs. lowest quartile for the two diet quality indices were 1.0 [95% CI 0.6, 1.6] and 0.9 [95% CI 0.7, 1.1]. This large study does not support an association of a vegetarian diet or worse diet quality with hypospadias.


Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine when administered to healthy Japanese adults aged ≥50 years. An open-label trial.
This open-label study was designed to assess immunogenicity and safety of 13-valent pneumococcal conjugate vaccine (PCV13) when administered to Japanese adults aged ≥50 years not previously vaccinated with 23-valent pneumococcal polysaccharide vaccine and to compare this Japanese study population with similar study populations in the United States (US; 50-64 years age group) and European Union (EU; ≥65 years age group). Functional antibody immune responses were measured by opsonophagocytic activity assays. Immune responses in both Japanese age groups showed significant pre/postvaccination fold rises for each serotype. In the Japanese 50-64 years age group, immune responses for the majority of serotypes were significantly lower than in the ≥65 years Japanese age group and generally lower than in the 50-64 years age group in the US study. Immune responses in the Japanese ≥65 years age group were significantly higher for the majority of serotypes compared with the ≥65 years age group in the EU study. The safety profiles across age groups and studies were generally similar. In conclusion, PCV13 elicited robust immune responses in the Japanese study population. The unanticipated higher immune responses observed in the older age group in the Japanese study are of interest and of potential benefit given the higher incidence of pneumococcal disease in older adults. PCV13 was well tolerated and safe.


In vitro effects of radiation on human retinoblastoma cells.
Retinoblastoma (Rb) is the most common intraocular tumor of childhood and has been demonstrated clinically to be very sensitive to external beam radiation (EBR). The purpose of this study was to determine the survival of Rb cell lines at different endpoints following irradiation. We also studied Rb-reconstituted cell lines postirradiation to gain insight into the role of Rb following DNA damage. Suspension cultures were exposed to single doses of 1, 2, 5, and 10 Gy. Following irradiation, cell viability and cell death was assessed for up to 72 hr using Trypan blue exclusion and acridine orange/ethidium bromide (AO/EB) staining, respectively. Morphological features were examined with light and electron microscopy (LM and EM). Clonogenic survival was assessed 2 weeks postirradiation. Cell cycle distribution was analyzed by flow cytometry. A time- and dose-dependent decrease in cell viability was induced in Y79 and WERI-Rb1 cells following irradiation, although not below approximately 45% for the times and doses used. A similar but much-reduced effect on viability was observed in Rb-reconstituted cells. AO/EB staining, LM, and EM revealed features characteristic of apoptosis following irradiation and a time- and dose-dependent increase in apoptosis was observed. For Y79 and WERI-Rb1 cells, 30-40% apoptosis was observed 72 hr after 10 Gy irradiation; however, apoptosis was much reduced in Rb-reconstituted cells (approximately 8% Y79LxRb28; approximately 18% WERILxRb8). Rb cell lines were extremely sensitive to radiation, although less so in Rb-reconstituted lines, with clonogenic survivals after 2 Gy (SF2) of 0.14 for Y79, 0.06 for WERI-Rb1, 0.36 for Y79LxRb28, and 0.19 for WERILxRb8. Postirradiation, a sub-G1 population was observed, consistent with radiation-induced apoptosis, and Rb-reconstituted cells displayed a prolonged G2 phase. The clonogenic survival parameters of Rb cell lines are consistent with clinical observations, where extreme sensitivity to irradiation has been reported. Additionally, Rb protein protected cells from DNA damage and may also play a role in radiation-induced G2 delay. This in vitro approach provides a useful model for further radiobiological studies of Rb.


Metabolite profiles of flutamide in serum from patients with flutamide-induced hepatic dysfunction.
Hepatic dysfunction due to flutamide administration has been reported and this side effect often limits the use of the agent. The prediction of flutamide-induced hepatotoxicity is attributed to the proper use of the antiandrogen. In this study, we investigated whether hepatic dysfunction could be assessed by the metabolite profile in serum from patients receiving this drug. Serum samples were obtained from 15 patients with prostate cancer, 12 patients with no sign of hepatotoxicity and 3 patients with slight hepatic dysfunction during long-term flutamide treatment. We analyzed the metabolite profiles by LC/MS in selected ion monitoring mode and detected a new metabolite (M3) that was an oxidation product of flutamide. However, there were no consistent differences in the serum flutamide metabolites between patients with normal function and those suffering hepatic dysfunction. The metabolite profiles in the beta-glucuronidase-treated serum showed a similar pattern between normal functioning and dysfunctional groups. Thus, the profile of flutamide metabolites determined in serum may not contribute to the risk prediction of flutamide-related hepatotoxicity.


Modification in activity of medullary respiratory-related neurons for vocalization and swallowing.
1. The medullary ventral respiratory group (VRG) in and near the nucleus ambiguus contains neurons related to respiration. Also found here are neurons related to vocalization and swallowing as well as motoneurons of laryngeal, pharyngeal, palatal, and esophageal muscles. Previous reports in anesthetized animals have characterized discharge properties of neurons as they relate to a single behavior, e.g., respiration. Relatively few studies have documented discharge properties during more than one behavior, e.g., respiration and swallowing. Neurons were recorded extracellularly from awake Macaca nemestrina monkeys engaged in a vocalization task. The present paper describes how respiratory-related neurons (RRNs) modify their discharge during vocalization and swallowing. 2. The temporal relation between vocalization, subglottal pressure (SP), and diaphragm electromyogram (EMG) was established from recordings in anesthetized monkeys. Vocalization was elicited by electrical stimulation of the midbrain periaqueductal gray (PAG). Vocalization is preceded by deep inspiration and a brief pause in diaphragm EMG and begins with a rapid increase in positive SP. 3. Extracellularly recorded neural potential from the VRG in three awake monkeys were related to respiration by correlating their discharge with EMGs from the posterior cricoarytenoid or intercostal muscles during quiet respiration. Neurons were classified as inspiratory (INSP; N = 27), phase spanning (PS; N = 20), or expiratory (N = 6) on this basis. 4. A fourth category of cells was defined as a subgroup of INSP cells on the basis of their discharge during vocalization. This group, inspiratory-pause (INSP-PS; N = 10), paused for approximately 100 ms just before vocalization and resumed their activity during vocalization. 5. Of 63 fully analyzed RRNs, 40 (63%) also modulated their activity with vocalization and 3 (5%) with swallowing. Thirteen (21%) RRNs modulated with vocalization, respiration, and swallowing. Seven (11%) cells were modulated only with respiration. 6. Most cells demonstrated a shorter period of activity and a higher discharge rate associated with vocalization in comparison with quiet respiration. Six (30%) of the PS cells demonstrated an augmenting discharge pattern before vocalization, which was different from the other PS cells and different from their pattern during quiet respiration. Thirteen RRNs showed a pause in activity during vocal fold closure associated with swallowing, whereas three cells gave a burst at this time. 7. The higher discharge rate and shorter burst duration preceding vocalization, compared with quiet respiration, may be related to the greater positive SP necessary to support vocalization.(ABSTRACT TRUNCATED AT 400 WORDS)


The Influence of Arbuscular Mycorrhizal Fungi on Plant Reproduction.
Arbuscular mycorrhizal (AM) fungi can influence all components of plant reproduction including pollen delivery, pollen germination, pollen tube growth, fertilization, and seed germination. AM fungi associate with plant roots, uptake nutrients, and prime plants for faster defense responses. Our literature review first identified four testable hypotheses describing how AM fungi could alter pollen delivery: (1) We hypothesize AM fungi promote floral display size. The influence of AM fungi on flower size and number is supported by literature, however there are no studies on floral color. (2) We hypothesize AM fungi promote pollen and nectar quality and quantity, and, as reported before, AM fungi promote male fitness over female fitness. (3) We hypothesize AM fungi promote both earlier and longer flowering times, but we found no consistent trend in the data for earlier or later or longer flowering times. (4) We hypothesize AM fungi alter floral secondary chemistry and VOCs, and find there is clear evidence for the alteration of floral chemistry but little data on VOCs. Second, we focus on how AM fungi could alter pollen germination, pollen tube growth, and fertilization, and present three testable hypotheses. We found evidence that AM fungi influence pollen germination and pollen tube growth, production of seeds, and seed germination. However, while most of these influences are positive they are not conclusive, because studies have been conducted in small numbers of systems and groups. Therefore, we conclude that the majority of research to date may not be measuring the influence of AM fungi on the most important components of plant reproduction: pollen germination, pollen tube growth, fertilization, and seed germination.


Damage integral and other predictive formulas for nonisothermal heating during laser exposure.
Physics-based models supply simulated temperature rises to photothermal damage rate models and provide comprehensive risk assessments for laser-induced damage. As the physics-based models continue to be refined, the damage rate models have not advanced. This peculiar lack of improvement is counterintuitive considering the damage integral (Ω), originally derived for isothermal heating events, and fails to accurately represent the nonisothermal heating from short laser exposures. Derive a nonisothermal form of the damage integral and predict more accurately the damage induced by short laser exposures, as well as identify the role of heating rate in laser damage. From first principles, we derived a version of the damage integral specific to the shape of thermal profiles rather than the square function provided by Arrhenius plots. We used previously published threshold thermal profiles, where all nonisothermal frequency factors (Anon) solved all Ωnon values to unity. Nonisothermal correction factors correct isothermal Aiso values. The Ea values were identical for both the isothermal and nonisothermal conventions. Correction factor values for Ωiso ranged from 0.0 (20-s exposures at thermal steady state) to -0.93 (0.05-s exposures). Based on empirical results, we have derived a two-dimensional empirical formula that predicts the heating rate as a function of exposure duration and ambient temperature. Threshold peak temperatures (Tpthr) and threshold critical temperatures are mathematically determined without thermal profiles when appropriate Ea and Anon values are established. We have identified a modified damage integral that does not rely on the Arrhenius plot and provides a value for the frequency factor (A) that accounts for the nonisothermal nature of short laser exposures. The method, validated in our in vitro retinal model, requires thermal profiles recorded under threshold conditions, such as at minimum visible lesions or the boundary of cell death. The method is a new option for laser damage modelers.


[Frequency of TS1494del6 polymorphism in colorectal patients from west of Mexico].
Thymidylate synthase (TYMS) converts dUMP to dTMP, the rate-limiting nucleotide in DNA synthesis. It is also the target for 5-flurouracil, the most common chemotherapy agent for treatment of colorectal cancer (CRC). We designed a case-control study to investigate the frequency of TS 1494del6 polymorphism in patients with CRC and controls from Mexican population. The study consists of 253 patients with CRC and 200 control subjects. Risk of CRC was estimated by use of Odds ratio (95% CI) analysis. The genotype 6bp-/6bp- in CRC patients was 18% (45/253) and in controls was 11% (22/200) with Odds ratio of 1.8 (1 - 4) with P = 0.059. When stratifying the training groups by age (< 50 years), male gender, stage III-IV and presence of metastasis, the genotype 6bp-/6bp- was as risk (p < 0.05). The genotype 6bp-/6bp- in the region untranslated 3' of TS gene, in the analyzed sample participates in important way in the development of CRC of the Mexican population.


The inositol-1,2-cyclic phosphate moiety of the cross-reacting determinant, carbohydrate chains, and proteinaceous components are all responsible for the cross-reactivity of trypanosome variant surface glycoproteins.
Salivarian trypanosomes evade the host immune system by continually swapping their protective variant surface glycoprotein (VSG) coat. Given that VSGs from various trypanosome stocks exhibited cross-reactivity (Camargo et al., Vet. Parasitol. 207, 17-33, 2015), we analyzed here which components are the antigenic determinants for this cross-reaction. Soluble forms of VSGs were purified from four Venezuelan animal trypanosome isolates: TeAp-N/D1, TeAp-ElFrio01, TeAp-Mantecal01, and TeGu-Terecay323. By using the VSG soluble form from TeAp-N/D1, we found that neither the inositol-1,2-cyclic phosphate moiety of the cross-reacting determinant nor the carbohydrate chains were exclusively responsible for its cross-reactivity. Then, all four purified glycoproteins were digested with papain and the resulting peptides were separated by high-performance liquid chromatography. Dot blot evaluation of the fractions using sera from trypanosome-infected animals yielded peptides that possessed cross-reaction activity, demonstrating for the first time that proteinaceous epitopes are also responsible for the cross-reactivity of trypanosome VSGs.


Noninvasive nocturnal ventilatory support in advanced lung disease from cystic fibrosis.
Respiratory failure is the most common cause of death among people with cystic fibrosis (CF). The role of noninvasive positive-pressure ventilation (NPPV) in severe but stable lung disease from CF has not been adequately determined. We therefore sought to determine the tolerability and efficacy of NPPV in people with advanced lung disease from CF. We studied 13 patients with CF, severe air flow limitation (mean +/- SD forced expiratory volume in the first second 0.8 +/- 0.3 L), and chronic respiratory failure (mean +/- SD P(aO2) 67 +/- 19 mm Hg and P(aCO2) 51 +/- 8 mm Hg). All patients were awaiting lung transplantation. NPPV was prescribed for 2 months. Overnight polysomnography, arterial blood gas values, pulmonary function, exercise capacity, and health-related quality of life were evaluated at baseline, after 2 months of NPPV, and again after a 1-month wash-out period off NPPV. Eight patients completed the study and tolerated NPPV extremely well. These patients subjectively noted improvement in their symptoms and requested that they restart NPPV after completing the protocol. Nevertheless, NPPV did not improve objective measures of sleep quality, daytime blood gas values, pulmonary function, respiratory muscle strength, or exercise tolerance. All 8 patients were continued on NPPV and underwent successful lung transplantation. NPPV is well tolerated by most patients with CF and severe lung disease and may be a useful bridge to support CF patients awaiting lung transplantation. However, despite subjective improvement, standard objective measures did not improve and cannot explain the reduced symptoms reported by these patients.


Serological relationship between rat and human carcinoembryonic antigen.
Enzyme immunoassays showed that a rabbit antiserum to rat carcinoembryonic antigen (CEA) had high activity with extracts containing human CEA, which was almost completely inhibited by extracts containing human or rat CEA. Little or no inhibition was obtained with extracts of normal human or rat tissues or by human blood group A or B substances. A monkey antiserum to human CEA had strong activity against extracts containing rat CEA, and little or no activity against extracts of normal rat liver or kidney or a CEA-negative rat colon tumor. Activity of the monkey antiserum against rat CEA was almost completely inhibited by extracts containing rat or human CEA. Little or no inhibition was obtained with extracts of normal rat or human tissues. These results suggest that human and rat CEA share antigenic determinants and that they may be analogous moieties.


Investigation into the suitability and accessibility of catering practices to inpatients from minority ethnic groups in Brent.
The Borough of Brent has one of the largest ethnic minority populations in England, with a growing number of refugee communities from Africa and Europe. Two important issues to be considered when developing culturally sensitive services in the hospital (including food provision) are that practices meet the religious and cultural requirements of the population that the hospital serves and that staff are equipped with the skills to understand cultural differences in illness and treatment. To review accessibility and suitability of multicultural meals to minority ethnic communities across five hospital sites in Brent and determine the level of nursing staff knowledge of multicultural dietary competencies. One survey was completed in each of the five hospital sites to gather information about current catering practices. Two separate questionnaires obtained information of the level of inpatient satisfaction with multicultural meals amongst Hindu, Muslim, Caribbean and Jewish patient groups and knowledge of nursing staff about multicultural competencies. Community groups representing minority ethnic populations participated in focus groups to establish feedback about dietary requirements in hospitals. Access to multicultural meals varied across hospital sites. Of 98 patients in the inpatient satisfaction survey, 74% were aware of the availability of multicultural meals with 51% of these patients not ordering any of the Asian vegetarian, Asian halal, Caribbean or kosher meals, citing satisfaction with European food as the main reason. Those ordering multicultural meals reported satisfaction most of the time (42%), satisfied most of the time (38%) and never satisfied (19%). The African Muslim group was the least satisfied with current halal meal provision. Forty-seven per cent of nurses questioned could accurately answer questions about multicultural dietary competencies. Improvements could be made to improve accessibility and improve suitability of meal choices to inpatients from minority ethnic groups.


Adenine Nucleotides Attenuate Murine T Cell Activation Induced by Concanavalin A or T Cell Receptor Stimulation.
Extracellular ATP and its metabolites affect various cellular immune responses, including T cell function, but there are apparently conflicting reports concerning the effects of adenine nucleotides on T cells. For example, it has been reported that ATP-mediated activation of P2 receptor is involved in T cell activation; activation of adenosine receptors suppresses T cell function; and 1 mM ATP induces T cell death via activation of P2X7 receptor. Therefore, in this work we investigated in detail the effects of 100-250 μM ATP, ADP, or AMP on murine T cell activation. First, an in vitro study showed that pretreatment of murine splenic T cells with 100-250 μM ATP, ADP, or AMP significantly suppressed the concanavalin A (ConA)-induced release of cytokines, including IL-2. This suppression was not due to induction of cell death via the P2X7 receptor or to an immunosuppressive effect of adenosine. ATP attenuated the expression of CD25, and decreased the cell proliferation ability of activated T cells. The release of IL-2 by ConA-stimulated lymphocytes was suppressed by post-treatment with ATP, as well as by pretreatment. These results suggest that exogenous ATP suppresses the activation of T cells. Secondly, we evaluated the effect of ATP in a ConA-treated mice. Treatment with ATP attenuated the increase of IL-2 concentration in the blood. Overall, these results suggest that adenine nucleotides might have potential as supplemental therapeutic agents for T cell-mediated immune diseases, by suppressing T cell activation.


Directed evolution of a bacterial WS/DGAT acyltransferase: improving tDGAT from Thermomonospora curvata.
Some bacteria belonging to the actinobacteria and proteobacteria groups can accumulate neutral lipids expressing enzymes of the wax ester synthase/acyl coenzyme A: diacylglycerol acyltransferase (WS/DGAT) family. tDGAT is a WS/DGAT-like enzyme from Thermomonospora curvata able to produce TAGs and WEs when heterologously expressed in Escherichia coli. In this study, a protocol for the directed evolution of bacterial lipid-producing enzymes based on fluorimetry is developed and tested. tDGAT has been successfully evolved towards the improvement of TAG production with an up to 2.5 times increase in TAG accumulation. Mutants with no ability to produce TAGs but able to accumulate waxes were also selected during the screening. The localization of the mutations that enhance TAG production in the outer surface of tDGAT points out possible new mechanisms that contribute to the activity of this family of enzymes. This Nile red-based high throughput screening provides an evolution platform for other WS/DGAT-like enzymes.


Safety Analysis of Apatinib Combined with Chemotherapy in the Treatment of Advanced Gastric Carcinoma: A Randomised Controlled Trial.
To study the safety of apatinib combined with chemotherapy in the treatment of advanced gastric carcinoma (GCA). 74 patients with advanced GCA treated in the oncology department of Weifang People's Hospital (January 2019-January 2020) were enrolled in this study and equally split into study group (SG) and reference group (RG) according to the odd and even admission numbers. RG underwent chemotherapy alone, while SG received apatinib combined with chemotherapy. The clinical indicators of serum matrix metalloproteinase 9 (MMP-9), serum interleukin-2 receptor (SIL-2R), and immune cell level were detected in the two groups before and after treatment to analyze the therapeutic effect of different treatment methods on patients with advanced gastric carcinoma. No obvious differences in gender ratio, average age, average BMI, pathological staging, pathological types, organ metastasis types, and residence were observed between the two groups (P > 0.05). The short-term follow-up results showed that the disease control rate (DCR) in SG was markedly higher compared with RG (P < 0.05). The MMP-9 and SIL-2R levels in both groups after treatment decreased (P < 0.05), and the levels in SG after treatment were notably lower compared with RG (P < 0.001). Compared with RG, CD3+, CD4+, and CD4+/CD8+ levels in SG after treatment were notably higher (P < 0.001), while the CD8+ level was notably lower (P < 0.001). The median progression-free survival (MPFS) and overall survival (OS) in SG were markedly higher compared with RG (P < 0.001). The GQOLI-74 scores in both groups after treatment increased (P < 0.001), and the GQOLI-74 score in SG after treatment was markedly higher compared with RG (P < 0.001). The total incidence of adverse reactions was lower in SG than in RG (P < 0.05). Apatinib combined with chemotherapy is superior to chemotherapy alone in effectively improving treatment outcomes in patients with advanced GCA.


Small airways dysfunction: The importance of utilising Z-scores to define MMEF abnormalities in clinical practice.
The small airways comprise the largest cross-sectional area of the lungs, however, assessing and reporting abnormalities for this region of the bronchial tree has been practically and scientifically uncertain. Using routinely collected spirometry data for patients with either asthma or COPD, the accuracy of % predicted values for defining small airways dysfunction was assessed. A z-score of ≤ -1.645 of the maximal-mid expiratory flow (MMEF) was used as the gold standard for defining abnormality in the small airways. Records of 3396 patients were included in the analysis. The false positive (FP) rates were 24.6 %, 16.1 %, 11.5 %, or 7.9 % when the % predicted value of 80 %, 70 %, 65 %, or 60 % were used, respectively. Sex, age, and BMI were associated with FP rates. Males were more likely to be categorised as FP with odds ratio (OR) between 1.10 and 1.49 across % predicted groups. Age was associated with FP rates with an OR between 1.01 and 1.08. The BMI was also associated with FP rates with an OR of 1.03 across all % predicted groups. Assessing the association of age groups with FP rate showed that those above 60 years old were more likely to be categorised as FP with an OR between 1.23 and 73.2 compared to those less than 30 years old. When assessing the small airways in clinical practice or for scientific purposes, the % predicted values overestimate the actual impairment leading to FP interpretation. Utilising z-score values are recommended to assess the small airways using the spirometric index, MMEF.


Assessing lung function using contrast-enhanced dual-energy computed tomography for potential applications in radiation therapy.
There is an increasing interest in the evaluation of lung function from physiological images in radiation therapy treatment planning to reduce the extent of postradiation toxicities. The purpose of this work was to retrieve reliable functional information from contrast-enhanced dual-energy computed tomography (DECT) for new applications in radiation therapy. The functional information obtained by DECT is also compared with other methods using single-energy CT (SECT) and single-photon emission computed tomography (SPECT) with CT. The differential function between left and right lung, as well as between lobes is computed for all methods. Five lung cancer patients were retrospectively selected for this study; each underwent a SPECT/CT scan and a contrast-injected DECT scan, using 100 and 140 Sn kVp. The DECT images are postprocessed into iodine concentration maps, which are further used to determine the perfused blood volume. These maps are calculated in two steps: (a) a DECT stoichiometric calibration adapted to the presence of iodine and followed by (b) a two-material decomposition technique. The functional information from SECT is assumed proportional to the HU numbers from a mixed CT image. The functional data from SPECT/CT are considered proportional to the number of counts. A radiation oncologist segmented the entire lung volume into five lobes on both mixed CT images and low-dose CT images from SPECT/CT to allow a regional comparison. The differential function for each subvolume is computed relative to the entire lung volume. The differential function per lobe derived from SPECT/CT correlates strongly with DECT (Pearson's coefficient r = 0.91) and moderately with SECT (r = 0.46). The differential function for the left lung shows a mean difference of 7% between SPECT/CT and DECT; and 17% between SPECT/CT and SECT. The presence of nonfunctional areas, such as localized emphysema or a lung tumor, is reflected by an intensity drop in the iodine concentration maps. Functional dose volume histograms (fDVH) are also generated for two patients as a proof of concept. The extraction of iodine concentration maps from a contrast-enhanced DECT scan is achieved to compute the differential function for each lung subvolume and good agreement is found in respect to SPECT/CT. One promising avenue in radiation therapy is to include such functional information during treatment planning dose optimization to spare functional lung tissues.


Haematologic disorders and cerebral venous thrombosis.
This review focuses on the several coagulation disorders (the so called hypercoagulable states) that are associated with cerebral venous thrombosis. Hypercoagulable states likely explain the high percentage of cases of cryptogenic cerebral infarction in young people. The most common of the hereditary defects appear to be deficiency of antithrombin III, protein C or protein S, activated protein C resistance and prothrombin 20211A mutation. In a large majority of cases activated protein C resistance is due to the presence of factor V Leiden. Antiphospholipid antibodies (lupus anticoagulant and anticardiolipin antibodies) represent an acquired disorder of coagulation. Rare defects include heparin cofactor II (HC II), plasminogen or tissue plasminogen activator deficiency (TPA), elevated plasminogen activator inhibitor-1 (PAI-1) and dysfibrinogenemia. Hyperhomocystinemia is responsible for both arterial and venous thrombosis. A work-up to identify one of the recognizable hypercoagulable states is indicated, especially in younger patients with stroke. Laboratory evaluation for hypercoagulable states may also often be indicated in those patients who do not have other obvious risk factors for their stroke. If from clinical history, family history and/or laboratory studies, a patient is felt to have a hypercoagulable state, the decision for long term chronic anticoagulation needs to be individualized. If a hereditary hypercoagulable state is found, it also may be appropriate to recommend screening of other family members.


Prevalence of anxiety and depression symptoms in adolescents with Type 1 diabetes (T1D) and their parents.
Chronic somatic diseases are significant risk factors for the development of depression. Fourteen studies identified symptoms of depression and anxiety in children and adolescents with type 1 diabetes mellitus. The overall prevalence of the symptoms of depression in the study population was 30.04%. The study population has been divided into two sub-groups: the target group consisting of adolescents with T1D aged 12-18 and their parents (N = 64), and the control group consisting of somatic healthy adolescents and their parents (N = 36). Anxiety symptoms have been evaluated applying the Generalized Anxiety Disorder 7-item (GAD-7) scale. Depression symptoms have been evaluated using the Patient Health Questionnaire 9 (PHQ-9) scale. 100 respondents were eligible for screening. Severe, generalised anxiety was detected in 13% adolescents suffering from T1D and 47% of their parents. In contrast, no severe anxiety was detected in the control group by any of the respondents. In adolescents with T1D, 9% of cases experienced symptoms of severe depression, 16% experiencing symptoms of moderate depression. Moderate and severe anxiety and depression symptoms were seen significantly more frequently in the study group than in the control group, both in the child and in the parent subgroups. (1) Adolescents with Type 1 diabetes and their parents are more predisposed to anxiety and depression symptoms than somatic healthy children and their parents. (2) Further multiprofessional research is necessary for children with T1D and their families, in order to avoid the development of stress-related mental health disorders.


Glycoside hydrolase family 32 is present in Bacillus subtilis phages.
Glycoside hydrolase family 32 (GH32) enzymes cleave the glycosidic bond between two monosaccharides or between a carbohydrate and an aglycone moiety. GH32 enzymes have been studied in prokaryotes and in eukaryotes but not in viruses. This is the first analysis of GH32 enzymes in Bacillus subtilis phage SP10, ϕNIT1 and SPG24. Phylogenetic analysis, molecular docking and secretability predictions suggest that phage GH32 enzymes function as levan (fructose homopolysaccharide) fructotransferase. We showed that viruses also contain GH32 enzymes and that our analyses in silico strongly suggest that these enzymes function as levan fructotransferase.


Comparison of different models of rat liver carcinogenesis: conclusions from a systemic analysis.
Different protocols of chemically induced hepatocarcinogenesis were applied to Wistar rats under identical experimental conditions. The following conclusions may be drawn after an analytic comparison of these results. Various chemical carcinogens show different carcinogenic capacities. Diethylnitrosamine is more potent than N-nitrosomorpholine which is more active than 2-acetylaminofluorene. A short-term exposure to such carcinogens is sufficient to initiate but not necessarily to complete the carcinogenic process. It can be promoted to completion by either a noncarcinogenic promoter or a carcinogen. From a systemic point of view, it appears that, as in the skin models, two-step protocols are not always equivalent to protocols using the same agent during the whole treatment. Moreover, the results observed with a multistep protocol indicate that during the initiating phase the carcinogen plays a selective role distinct both from a pure initiating role and from the promoting effect. The results obtained lead to the conclusion that the distinction between initiation and promotion remains purely operational as it still does not correspond to the nature of well-established biologic processes.


Functional analyses of phosphorylation events in human Argonaute 2.
Argonaute 2 (Ago2) protein is a central effector of RNA interference (RNAi) pathways and regulates mammalian genes on a global level. The mechanisms of Ago2-mediated silencing are well understood, but less is known about its regulation. Recent reports indicate that phosphorylation significantly affects Ago2 activity. Here, we investigated the effect of mutating all known phospho-residues within Ago2 on its localization and activity. Ago2 associates with two different cytoplasmic RNA granules known as processing bodies (P-bodies) and stress granules, but the nature of this phenomenon is controversial. We report that replacing serine with a phospho-mimetic aspartic acid at position 798 completely abrogates association of Ago2 with P-bodies and stress granules. The effect of this mutation on its activity in gene silencing was modest, which was surprising because association of Ago2 with cytoplasmic RNA granules is thought to be a consequence of its role in RNAi. As such, our data indicate that targeting of Ago2 to P-bodies and stress granules is separable from its role in RNAi and likely requires dynamic phosphorylation of serine 798.


Detection of anti-lipoarabinomannan antibodies for the diagnosis of active tuberculosis.
A serological test that contributes in diagnosing tuberculosis would aid patient management. To evaluate MycoDot, a new commercially available serological test, for the detection of immunoglobulin G antibodies to lipoarabinomannan (LAM), a glycolipid common to mycobacteria. Serum samples from 102 non-human immunodeficiency virus (HIV)-infected patients with no previous history of tuberculosis and with suspected active pulmonary (66) and/or extra-pulmonary (36) tuberculosis were investigated; 50 HIV-negative healthy subjects, sputum culture-negative, tuberculin skin test negative and with no history of tuberculosis, were used as controls. In 28 patients with microbiologically ascertained tuberculosis 25/28 serum samples were positive, whereas the test was negative in two patients with renal tuberculosis and in one with pulmonary tuberculosis. The remaining 74 serum samples were negative. The follow-up of these patients excluded a mycobacterial infection. Control subjects were negative. On the basis of our design, the MycoDot test, with its rapidity and degree of sensitivity, is suitable for routine use in laboratory diagnosis of both pulmonary and extrapulmonary tuberculosis.


Degradation of cells dying by apoptosis leads to accumulation of epsilon(gamma-glutamyl)lysine isodipeptide in culture fluid and blood.
epsilon(gamma-Glutamyl)lysine isodipeptide, the end-product of proteolytic digestion of proteins cross-linked by transglutaminase, was detected in culture fluid of neonatal rat hepatocytes and plasma of adult rats. The concentration of the isodipeptide was significantly increased in both when high rate of apoptosis with phagocytosis of dying hepatocytes was produced either by epidermal growth factor in the culture or by lead nitrate-induced hyperplasia with subsequent involution in rats. Specific induction of tissue transglutaminase and the consequent formation of highly cross-linked protein envelopes in apoptotic cells have been previously demonstrated by us in both systems.


What goes down must come up: role of the posteromedial cortices in encoding and retrieval.
The hypothesis that the neural network supporting successful episodic memory retrieval overlaps with the regions involved in episodic encoding has garnered much interest; however, the role of the posteromedial regions remains to be fully elucidated. Functional magnetic resonance imaging (fMRI) studies during successful encoding typically demonstrate deactivation of posteromedial cortices, whereas successful retrieval of previously encoded information has been associated with activation of these regions. Here, we performed an event-related fMRI experiment during an associative face-name encoding and retrieval task to investigate the topography and functional relationship of the brain regions involved in successful memory processes. A conjunction analysis of novel encoding and subsequent successful retrieval of names revealed an anatomical overlap in bilateral posteromedial cortices. In this region, a significant negative correlation was found: Greater deactivation during encoding was related to greater activation during successful retrieval. In contrast, the hippocampus and prefrontal cortex demonstrated positive activation during both encoding and retrieval. Our results provide further evidence that posteromedial regions constitute critical nodes in the large-scale cortical network subserving episodic memory. These results are discussed in relation to the default mode hypothesis, the involvement of posteromedial cortices in successful memory formation and retention, as well as potential implications for aging and neurodegenerative disease.


Reasons for tobacco use and symptoms of nicotine withdrawal among adolescent and young adult tobacco users--United States, 1993.
Cigarettes and other forms of tobacco are addictive because of the presence of nicotine(1). Among adults in the United States who have ever smoked daily, 91.3% tried their first cigarette and 77.0% became daily smokers before age 20 years (2). Among high school seniors who had ever tried smokeless tobacco (SLT), 73% did so by the ninth grade (2). To further characterize the development of nicotine addiction among persons aged 10-22 years, CDC analyzed data from the 1993 Teenage Attitudes and Practices Survey (TAPS-II). This report summarizes the results of that analysis and focuses on assessments of reasons for using tobacco and symptoms of nicotine withdrawal.


Continuous Cuffless Blood Pressure Estimation Using Pulse Transit Time and Photoplethysmogram Intensity Ratio.
Pulse transit time (PTT) has attracted much interest for cuffless blood pressure (BP) measurement. However, its limited accuracy is one of the main problems preventing its widespread acceptance. Arterial BP oscillates mainly at high frequency (HF) because of respiratory activity, and at low frequency (LF) because of vasomotor tone. Prior studies suggested that PTT can track BP variation in HF range, but was inadequate to follow the LF variation, which is probably the main reason for its unsatisfactory accuracy. This paper presents a new indicator, the photoplethysmogram intensity ratio (PIR), which can be affected by changes in the arterial diameter, and, thus, trace the LF variation of BP. Spectral analysis of BP, PTT, PIR, and respiratory signal confirmed that PTT was related to BP in HF at the respiratory frequency, while PIR was associated with BP in LF range. We, therefore, develop a novel BP estimation algorithm by using both PTT and PIR. The proposed algorithm was validated on 27 healthy subjects with continuous Finapres BP as reference. The results showed that the mean ± standard deviation (SD) for the estimated systolic, diastolic, and mean BP with the proposed method against reference were -0.37 ±5.21, -0.08 ±4.06, -0.18 ±4.13 mmHg, and mean absolute difference (MAD) were 4.09, 3.18, 3.18 mmHg, respectively. Furthermore, the proposed method outperformed the two most cited PTT algorithms for about 2 mmHg in SD and MAD. These results demonstrated that the proposed BP model using PIR and PTT can estimate continuous BP with improved accuracy.


Inferring local structure from pairwise correlations.
To construct models of large, multivariate complex systems, such as those in biology, one needs to constrain which variables are allowed to interact. This can be viewed as detecting "local" structures among the variables. In the context of a simple toy model of two-dimensional natural and synthetic images, we show that pairwise correlations between the variables-even when severely undersampled-provide enough information to recover local relations, including the dimensionality of the data, and to reconstruct arrangement of pixels in fully scrambled images. This proves to be successful even though higher order interaction structures are present in our data. We build intuition behind the success, which we hope might contribute to modeling complex, multivariate systems and to explaining the success of modern attention-based machine learning approaches.