The epidemiology and prognosis of glomerulonephritis in Denmark 1985-1997.
The existence of a national renal biopsy register and a national terminal uraemia status register in Denmark provides an opportunity to study the prognosis of glomerulonephritis (GN), and factors influencing prognosis. Multivariate analysis of 2380 renal biopsies with GN performed between 1985 and 1997 was done to determine the influence of clinical and histological factors on prognosis. The incidence of GN (39/mo/year) and individual diagnoses did not change during the period. After 10 years, 32%, were dead, 13% terminally uraemic, 5%, uraemic and 50% well. Older age increased mortality, but not the incidence of renal failure after the first year. Male sex increased both mortality and incidence of renal failure (34 vs 24% at 10 years, P < 0.001). The diagnoses could be divided into three prognostic groups compared with the general population: a good prognostic group (minimal change GN and membranous GN ), with a relative mortality of three and a combined renal and patient mortality of four; a poor prognostic group [crescentic GN, HUS/TTP, chronic GN] with relative mortalities of 8-19 and 13-33, respectively; and the remainder with mortalities of 4-7 and 6-12. The presence of multiple glomerular pathology, chronic GN, nephrosclerosis and chronic interstitial nephropathy worsened the prognosis, while the presence of immune deposits only worsened the prognosis of focal segmental glomerulopathy. Mortality was related to uraemia and co-morbidity at biopsy, and to the incidence of renal failure. Renal failure was correlated to uraemia and hypertension at biopsy but not to nephrotic syndrome or atherosclerosis. All vascular complications were increased and were positively related to hypertension and negatively correlated to the incidence of uraemia. Crescentric glomerulonephritis combined with anti-GBM disease had a worse prognosis than Wegener's granulomatosis, with microscopic polyangiitis and pauci-immune disease occupying an intermediate position. The prognosis of mesangioproliferative GN was unaffected by the presence of IgA nephropathy and systemic lupus erythematosus.


Involvement of hippocampal neuropeptide Y in mediating the chronic actions of lithium, electroconvulsive stimulation and citalopram.
Neuropeptide Y (NPY) has been considered to be involved in the pathogenesis of affective disorders, and chronic treatment with lithium or electroconvulsive stimuli (ECS) has been shown to increase mRNA and peptide levels of NPY in rat brain tissue. Consequently, parameters reflective of NPYergic neurotransmission were studied in the hippocampus of rats following chronic treatment with lithium, ECS or the selective serotonin re-uptake inhibitor (SSRI), citalopram. Lithium (28 days, diet) and ECS (10 days, once daily) treatments caused a marked increase in levels of preproNPY mRNA in the CA1 area and dentate gyrus (DG). This increase was accompanied by an increase in extracellular levels of NPY in the dorsal hippocampus of freely moving rats as determined by microdialysis, suggesting that lithium and ECS treatments lead to an increased biosynthesis and release of NPY in this area. (125)I-peptide YY (PYY) binding was reduced by 40 and 60% respectively in the DG following the same treatments, showing that the increased release is accompanied by a down-regulation of corresponding binding sites. In contrast, citalopram (10 mg/kg i.p., twice daily for 28 days) caused a 100% increase in (125)I-PYY binding in CA, CA3 and DG while levels of preproNPY mRNA and extracellular NPY in the hippocampus were unaffected. The results indicate that various agents and stimuli exerting antidepressant effects in humans, such as chronic lithium, ECS and citalopram all increase NPYergic neurotransmission in the hippocampus by distinct modes of action. Moreover, NPY (6 microg) given intracerebroventricularly (i.c.v.) induced an antidepressant-like effect in the forced swim test. It is hypothesised that the increase in NPYergic neurotransmission may be associated with the mechanism of action of various antidepressant treatments in the alleviation of depression.


Vaccinia virus E2L null mutants exhibit a major reduction in extracellular virion formation and virus spread.
The vaccinia virus E2L (VACWR058) gene is conserved in all sequenced chordopoxviruses and is predicted to encode an 86-kDa protein with no recognizable functional motifs or nonpoxvirus homologs. Although the region immediately upstream of the open reading frame lacked optimal consensus promoter motifs, expression of the E2 protein occurred after viral DNA replication. Transfection studies, however, indicated that the promoter was weak compared to well-characterized intermediate and late promoters. The E2 protein was present in mature virions purified from infected cells but was more abundant in extracellular enveloped forms. Despite the conservation of the E2L gene in chordopoxviruses, deletion mutants could be isolated from both the WR and IHD-J strains of vaccinia virus. These null mutants produced very small plaques in all cell lines tested, reduced amounts of mature infectious virions, and very low numbers of extracellular virions. Nevertheless, viral protein synthesis appeared qualitatively and quantitatively normal. The defect in extracellular virus formation was corroborated by electron microscopy, which also showed some aberration in the wrapping of virions by cisternal membranes. Extracellular virions that did form, however, were able to induce actin tail formation.


Demonstration of a frequency spectral compression effect through an up-conversion interferometer.
This paper reports on the experimental implementation of an interferometer featuring sum frequency generation (SFG) processes powered by a pump spectral doublet. The aim of this configuration is to allow the use of the SFG process over an enlarged spectral domain. By analyzing the converted signal, we experimentally demonstrate a frequency spectral compression effect from the infrared input signal to the visible one converted through the SFG process. Recently, such a compression effect has been numerically demonstrated by Wabnitz et al. We also verify experimentally that we fully retrieve the temporal coherence properties of the infrared input signal in the visible field. The experimental setup permits to demonstrate an experimental frequency spectral compression factor greater than 4. This study takes place in the general field of coherence analysis through second order non-linear processes.


The role of serotonin and p53 status in the radiation-induced bystander effect.
The aim of this study was to investigate the role of serotonin and protein 53 (p53) status of the cells in the radiation-induced bystander effects (RIBE). The radiation-induced bystander response was investigated in human MCF-7 breast cancer cells and human HCT116 colorectal cancer cells employing medium-transfer experiments and micronuclei (MN) induction as an end-point. Irradiated cell conditioned medium (ICCM) from cells exposed to α-particle or γ-radiation was filtered and transferred to unirradiated cells 2 h following irradiation. MCF-7 cells were irradiated with 0.5 Gy α-particles, while HCT116 p53(+/+) and HCT116 p53(-/-) cells were irradiated with 0.5 Gy γ-radiation. Bystander MCF-7 cells, recipient of ICCM from 0.5 Gy α-particle irradiated MCF-7 cells grown in high serotonin conditions showed a modest but significant increase in MN, while MCF-7 cells receiving ICCM with low serotonin levels did not show any bystander effect. Added serotonin (100 ng/ml) led to a bystander effectin HCT116 p53(-/-) cells recipient of ICCM from 0.5 Gy γ-irradiated HCT116 p53(+/+) cells, but had no effect when the ICCM was from γ-irradiated HCT116 P53(-/-) cells. The results indicate that serotonin levels in the medium play a role in the RIBE and that there may be an interaction between the role of serotonin and the p53 status of the irradiated cells.


Teachers' work and health in Brazil: thoughts on the history of research, strides, and challenges.
This Essay discusses the theme of teachers' work and health in Brazil. The objectives are to describe the initial history of research on teachers' health, discuss elements leading to a consensus on the characterization of the group's work and principal health problems, and systematize the main strides and challenges. The Essay draws on more than two decades of research and practice in this field. Based on this experience, the authors identify the movements, the accumulated evidence, and prospects for future development. The elements brought to the discussion point to substantial growth in the field: the number of studies, the diversity and scope of topics, the groups of men and women teachers studied, and the experiences with application of the knowledge (programs and interventions). Despite these strides, the studies and practices still emphasize the individual and the disease, with little or no attention to work factors (work process and management) in the health/disease process. Issues pertaining to gender differences (in work and in health status) also remain invisible. There is little linkage between researchers and teachers' movements (a relevant characteristic of the first initiatives in the field). There are no public policies to regulate the workplace and work management. The contributions to the discussion provide insight for thought to assist the identification of critical nodes and analytical scenarios with the potential for progress in this field of research and intervention.


The Frog Motor Nerve Terminal Has Very Brief Action Potentials and Three Electrical Regions Predicted to Differentially Control Transmitter Release.
The action potential (AP) waveform controls the opening of voltage-gated calcium channels and contributes to the driving force for calcium ion flux that triggers neurotransmission at presynaptic nerve terminals. Although the frog neuromuscular junction (NMJ) has long been a model synapse for the study of neurotransmission, its presynaptic AP waveform has never been directly studied, and thus the AP waveform shape and propagation through this long presynaptic nerve terminal are unknown. Using a fast voltage-sensitive dye, we have imaged the AP waveform from the presynaptic terminal of male and female frog NMJs and shown that the AP is very brief in duration and actively propagated along the entire length of the terminal. Furthermore, based on measured AP waveforms at different regions along the length of the nerve terminal, we show that the terminal is divided into three distinct electrical regions: A beginning region immediately after the last node of Ranvier where the AP is broadest, a middle region with a relatively consistent AP duration, and an end region near the tip of nerve terminal branches where the AP is briefer. We hypothesize that these measured changes in the AP waveform along the length of the motor nerve terminal may explain the proximal-distal gradient in transmitter release previously reported at the frog NMJ.SIGNIFICANCE STATEMENT The AP waveform plays an essential role in determining the behavior of neurotransmission at the presynaptic terminal. Although the frog NMJ is a model synapse for the study of synaptic transmission, there are many unknowns centered around the shape and propagation of its presynaptic AP waveform. Here, we demonstrate that the presynaptic terminal of the frog NMJ has a very brief AP waveform and that the motor nerve terminal contains three distinct electrical regions. We propose that the changes in the AP waveform as it propagates along the terminal can explain the proximal-distal gradient in transmitter release seen in electrophysiological studies.


[Genetic analysis of predisposition to cancer of the stomach].
The results of a complex family and population epidemiologic study of gastric cancer pointed to inheritance as an important factor of the incidence of this disease. However, there may be different combinations of genetic factors, on the one hand, and genetic and environmental ones, on the other, versus age and sex. This should be considered in conducting screening for families at genetic risk for stomach cancer and taking measures aimed at eliminating carcinogenic factors which increase the likelihood of familial cancer incidence. Such considerations should contribute to a certain degree to early diagnosis and prevention of the disease.


Thermally stable single atom Pt/m-Al2O3 for selective hydrogenation and CO oxidation.
Single-atom metal catalysts offer a promising way to utilize precious noble metal elements more effectively, provided that they are catalytically active and sufficiently stable. Herein, we report a synthetic strategy for Pt single-atom catalysts with outstanding stability in several reactions under demanding conditions. The Pt atoms are firmly anchored in the internal surface of mesoporous Al2O3, likely stabilized by coordinatively unsaturated pentahedral Al3+ centres. The catalyst keeps its structural integrity and excellent performance for the selective hydrogenation of 1,3-butadiene after exposure to a reductive atmosphere at 200 °C for 24 h. Compared to commercial Pt nanoparticle catalyst on Al2O3 and control samples, this system exhibits significantly enhanced stability and performance for n-hexane hydro-reforming at 550 °C for 48 h, although agglomeration of Pt single-atoms into clusters is observed after reaction. In CO oxidation, the Pt single-atom identity was fully maintained after 60 cycles between 100 and 400 °C over a one-month period.


Development of multiplex polymerase chain reaction assays for detecting enterotoxigenic Escherichia coli and their application to field isolates from piglets with diarrhea.
Fimbriae and enterotoxins are major virulence factors associated with enterotoxigenic Escherichia coli (ETEC). In this study, 3 sets of multiplex polymerase chain reaction (mPCR) assays targeting fimbriae, enterotoxins, and other adherence factors were developed for detecting ETEC. A total number of 188 E. coli field isolates were examined, and percentages of E. coli strains carrying each virulence factors were as follows: F4 (7.45%), F5 (29.79%), F6 (6.38%), F18 (15.43%), F41 (3.72%), STa (10.11%), STb (20.74%), LT (9.57%), Stx2e (2.13%), EAST1 (42.02%), F1 (67.55%), AIDA-I (2.66%), and pAA (7.45%). Of the 188 E. coli field isolates examined, 25.53% were found to be pathogenic ETEC, having both fimbriae and enterotoxins. However, the ratio increased to 44.68% when the presence of other adhesins was considered as criteria for virulence. Among the adherence factors, F1 was found to be the most prevalent. AIDA-I and pAA were also found with similar ratio as compared with other virulence factors. In addition, virulence patterns carrying these alternate adhesive genes with enterotoxins were detected with significant ratio. Therefore, it is desirable that alternate adhesins be considered as markers for diagnosis of ETEC.


Mammography interval and breast cancer mortality in women over the age of 75.
The purpose of this study is to evaluate the relationship between mammography interval and breast cancer mortality among older women with breast cancer. The study population included 1,914 women diagnosed with invasive breast cancer at age 75 or later during their participation in the Women's health initiative, with an average follow-up of 4.4 years (3.1 SD). Cause of death was based on medical record review. Mammography interval was defined as the time between the last self-reported mammogram 7 or more months prior to diagnosis, and the date of diagnosis. Multivariable adjusted hazard ratios (HR) and 95 % confidence intervals (CIs) for breast cancer mortality and all-cause mortality were computed from Cox proportional hazards analyses. Prior mammograms were reported by 73.0 % of women from 7 months to ≤2 year of diagnosis (referent group), 19.4 % (>2 to <5 years), and 7.5 % (≥5 years or no prior mammogram). Women with the longest versus shortest intervals had more poorly differentiated (28.5 % vs. 22.7 %), advanced stage (25.7 % vs. 22.9 %), and estrogen receptor negative tumors (20.9 % vs. 13.1 %). Compared to the referent group, women with intervals of >2 to <5 years or ≥5 years had an increased risk of breast cancer mortality (HR 1.62, 95 % CI 1.03-2.54) and (HR 2.80, 95 % CI 1.57-5.00), respectively, p trend = 0.0002. There was no significant relationship between mammography interval and other causes of death. These results suggest a continued role for screening mammography among women 75 years of age and older.


Dual inhibition of PI3K and mTOR mitigates compensatory AKT activation and improves tamoxifen response in breast cancer.
Everolimus, an mTOR inhibitor, showed great clinical efficacy in combination with tamoxifen, letrozole, or exemestane for the treatment of estrogen receptor-positive (ER+) breast cancer. However, its antitumor activity was shown to be compromised by a compensatory process involving AKT activation. Here, it was determined whether combining an additional PI3K inhibitor can reverse this phenomenon and improve treatment efficacy. In breast cancer cells (MCF-7 and BT474), everolimus inhibited the mTOR downstream activity by limiting phosphorylation of p70S6K and 4EBP1, which resulted in p-Ser473-AKT activation. However, addition of a LY294002, a PI3K inhibitor, to tamoxifen and everolimus treatment improved the antitumor effect compared with tamoxifen alone or the other two agents in combination. Moreover, LY294002 suppressed the activity of the PI3K/AKT/mTOR axis and mitigated the p-Ser473-AKT activation feedback loop in both cell lines. Critically, this combination scheme also significantly inhibited the expression of HIF-1a, an angiogenesis marker, under hypoxic conditions and reduced blood vessel sprout formation in vitro. Finally, it was shown that the three-agent cocktail had the greatest efficacy in inhibiting MCF-7 xenograft tumor growth and angiogenesis. Taken together, these results suggest that inhibition of PI3K and mTOR may further improve therapy in ER(+) breast cancer cells. Combinatorial inhibition of the PI3K/AKT/mTOR signaling axis may enhance endocrine-based therapy in breast cancer.


Ticks and tick-borne disease in Guatemalan cattle and horses.
Blood samples and ticks were collected from 48 cattle and 74 horses from seven sites in the Peten region of Guatemala. Data on body condition, mucous membrane capillary refill time and tick infestation levels were recorded for each animal in the study. Horses had significantly higher levels of tick infestation than cattle, as well as poorer body condition scores. Seroprevalence of Babesia spp. was 95.8% for B. bovis in cattle, 89.6% for B. bigemina in cattle, and 92.7% for B. equi in horses. Seroprevalence of Anaplasma marginale in cattle was 87.5%, similar to reports in animals from other regions of Central America. This is the first time that A. phagocytophilum has been reported in animals from this region, with overall PCR-prevalence of 27.6% in cattle and horses, and seroprevalence of 28.4% (52% in cattle and 13% in horses). An agent was identified with serological cross-reactivity and close genetic relatedness to Ehrlichia ruminantium, but further testing confirmed that the agent in Guatemalan cows was not the agent of heartwater. Ticks were identified to species with the predominant species identified on cattle as Boophilus microplus and Amblyomma cajennense, while Anocentor nitens and A. cajennense were most commonly found on horses. Prevalence of infection, tick infestation levels, host factors and environmental data were analyzed for association; A. nitens was significantly associated with A. phagocytophilum prevalence by village.


In vitro isolation from Amblyomma ovale (Acari: Ixodidae) and ecological aspects of the Atlantic rainforest Rickettsia, the causative agent of a novel spotted fever rickettsiosis in Brazil.
Recently, a novel human rickettsiosis, namely Atlantic rainforest spotted fever, was described in Brazil. We herein report results of a survey led around the index case in an Atlantic rainforest reserve in Peruibe municipality, southeastern Brazil. A Rickettsia parkeri-like agent (Rickettsia sp. Atlantic rainforest genotype) and Ricketsia bellii were isolated from adult Amblyomma ovale ticks collected from dogs. Molecular evidence of infection with strain Atlantic rainforest was obtained for 30 (12.9%) of 232 A. ovale adult ticks collected from dogs. As many as 88.6% of the 35 examined dogs had anti-Rickettsia antibodies, with endpoint titres at their highest to R. parkeri. High correlation among antibody titres in dogs, A. ovale infestations, and access to rainforest was observed. Amblyomma ovale subadults were found predominantly on a rodent species (Euryoryzomys russatus). From 17 E. russatus tested, 6 (35.3%) displayed anti-Rickettsia antibodies, with endpoint titres highest to R. parkeri. It is concluded that Atlantic rainforest genotype circulates in this Atlantic rainforest area at relatively high levels. Dogs get infected when bitten by A. ovale ticks in the forest, and carry infected ticks to households. The role of E. russatus as an amplifier host of Rickettsia to A. ovale ticks deserves investigation.


Registration of myocardial PET and SPECT for viability assessment using mutual information.
The combination of sequentially acquired cardiac PET and SPECT data integrating metabolic and perfusion information allows the assessment of myocardial viability, a relevant clinical parameter for the management of patients who have suffered myocardial infarction and are now candidates for complex and cost intensive therapies such as bypass surgery. However, registration of cardiac functional datasets acquired on different imaging systems is limited by the difficulty to define anatomical landmarks and by the relatively poor inherent spatial resolution. In this article, the authors sought to evaluate whether it is possible to automatically register FDG-PET and sestamibi-SPECT cardiac data. Automatic rigid registration was implemented with the ITK framework using Mattes mutual information as the similarity measure and a quaternion to represent the rotational component. The goodness of the alignment was evaluated by computing the mean target registration error (mTRE) at the myocardial wall. The registration parameters were optimized for robustness and speed using the data from 11 cardiac patients undergoing both PET and SPECT examinations (training datasets). The optimized algorithm was applied on the PET and SPECT data from 11 further patients (evaluation datasets). Quantitative (mTRE calculation) and visual (scoring method) comparisons were performed between automatic and manual registrations. Moreover, the automatic registration was also compared to the registration implicitly defined in the standard clinical analysis. The registration parameters were successfully optimized and resulted in a mean mTRE of 1.13 mm and 1.2 s average runtime on standard computer hardware for the training datasets. Automatic registration in the 11 validation datasets resulted in an average mTRE of 2.3 mm, with 7.5 mm mTRE in the worst case and an average runtime of 1.6 s. Automatic registration outperformed manual registrations both for the mTRE and for the visual assessment. Automatic registration also resulted in higher accuracy and better visual assessment as compared to the registration implicitly performed in the standard clinical analysis. The results demonstrate the possibility to successfully perform mutual information based registration of PET and SPECT cardiac data, allowing an improved workflow for the sequentially acquired cardiac datasets, in general, and specifically for the assessment of myocardial viability.


The role of complement in the localization of pneumococci in the splanchnic reticuloendothelial system during experimental bacteremia.
Pneumococci activate the alternative complement (C) pathway in the absence of demonstrable antibody in normal guinea pig serum. They also activate the classical C pathway in the presence of type-specific antibody and perhaps through other mechanisms as well. A quantitative examination was undertaken of the roles of these 2 pathways of C activation in the splanchnic sequestration of 125I-labeled pneumococci, using a-guinea pig model of pneumococcal bacteremia. Normal unimmunized guinea pigs (NIH-GP) localized more than 3 times as many pneumococci to the liver as the spleen during a period when exponential bloodstream clearance was occurring. C4-deficient guinea pigs (C4D-GP) and cobra venom factor-treated guinea pigs (CVF-GP) showed progressively fewer pneumococci cleared by the liver with concomitant increases in the extent of splenic uptake, demonstrating the important role of C in the clearance of bacteria in the unimmunized animal. Immunization of guinea pigs brought about an increase in pneumococcal sequestration by the liver in NIH and C4D-GP but did not affect the localization pattern of CVF-GP. A comparison of reticuloendothelial system (RES) localization patterns with the rate of removal of bacteria from the bloodstream showed a highly significant correlation between increases in splenic sequestration and persistence of bacteremia. Thus, opsonization by C is an important determinant of the RES clearance of pneumococci. Unlike RBC clearance, where C plus IgM leads to hepatic localization, and C plus IgG tends to produce splenic localization, C in the presence or absence of type-specific antibody tends to cause hepatic localization of pneumococci. When C-mediated opsonic activity is less than optimal, the slower clearance of bacteremia that results is accompanied by an increased dependence on splenic sequestration of pneumococci.


A prospective study of cytomegalovirus and herpes simplex virus disease in renal transplant recipients.
A prospective study of 84 renal graft recipients demonstrated cytomegalovirus (CMV) disease after transplantation in 37% of patients. Reactivation infection was found in 20 of 44 patients (46%) who were seropositive for CMV prior to transplant and primary CMV disease occurred in 11 of 40 (28%) initially seronegative patients. Nearly all cases of primary disease (91%) were associated with symptoms and in these cases CMV was probably acquired via the donated kidneys. Only 35% of the reactivation infections were associated with clinical symptoms. Actuarial life tables indicated that CMV disease did not reduce the length of graft survival. Herpes simplex virus (HSV) infections were diagnosed in 44 (52%) of the patients and included a fatal case of disseminated disease associated with hepatitis.


Flightin is a myosin rod binding protein.
The assembly of striated muscle myosin into thick filaments of precise and regular length requires the assistance of accessory proteins. Drosophila indirect flight muscle (IFM) contain flightin, a 20-kDa protein that has been shown to be essential for flight, for maintenance of sarcomeric integrity in active muscle, and informative in length determination of thick filaments during IFM development. Additionally, a point mutation in the myosin rod (Mhc(13)) negates flightin accumulation in the IFM in vivo. The manner in which flightin interacts with thick filaments is not known. Here, two different solid-state binding assays demonstrate that flightin binds to myosin and to a recombinant fragment of the myosin rod that include the COOH-terminal 600 amino acids (zone 19 to tail piece). The interaction of flightin and myosin is abolished by the single amino acid substitution in Mhc(13) at position 1e of zone 27 of the rod (residue 1554). The molar ratio of flightin to myosin is approx 1 : 1 to 1 : 2. Thus, the instability of thick filaments seen in vivo in the absence of flightin suggests that the flightin myosin interaction is critical for maintaining sarcomere integrity in active muscle.


The mechanism of potentiation of horseradish peroxidase-catalysed oxidation of NADPH by porphyrins.
Several porphyrins, including HpD (haematoporphyrin derivative), potentiate the oxidation of NADPH by horseradish peroxidase/H2O2. To elucidate the mechanism of potentiation, the following observations are relevant. During peroxidase-catalysed NADPH oxidation, O2-.(superoxide radical) is generated, as judged from superoxide dismutase-inhibitable cytochrome c reduction. This generation of O2-. is suppressed by HpD. Peroxidase-catalysed NADPH oxidation is stimulated by superoxide dismutase and by anaerobic conditions. Under anaerobic conditions HpD has no influence on peroxide-catalysed NADPH oxidation. Previous studies have shown that horseradish peroxidase is inhibited by O2-.. Thus the experimental results indicate that the potentiating effect of HpD can be explained by its ability to inhibit O2-. generation in the horseradish peroxidase/H2O2/NADPH system.


Isoform- and cell cycle-dependent substrate degradation by the Fbw7 ubiquitin ligase.
The SCF(FBW7) ubiquitin ligase degrades proteins involved in cell division, growth, and differentiation and is commonly mutated in cancers. The Fbw7 locus encodes three protein isoforms that occupy distinct subcellular localizations, suggesting that each has unique functions. We used gene targeting to create isoform-specific Fbw7-null mutations in human cells and found that the nucleoplasmic Fbw7alpha isoform accounts for almost all Fbw7 activity toward cyclin E, c-Myc, and sterol regulatory element binding protein 1. Cyclin E sensitivity to Fbw7 varies during the cell cycle, and this correlates with changes in cyclin E-cyclin-dependent kinase 2 (CDK2)-specific activity, cyclin E autophosphorylation, and CDK2 inhibitory phosphorylation. These data suggest that oscillations in cyclin E-CDK2-specific activity during the cell cycle regulate the timing of cyclin E degradation. Moreover, they highlight the utility of adeno-associated virus-mediated gene targeting in functional analyses of complex loci.


Vertebrobasilar insufficiency. Part 1: Microsurgical treatment of extracranial vertebrobasilar disease.
Extracranial vertebrobasilar artery thrombo-occlusive disease may cause repetitive transient ischemic episodes and, less frequently, brain-stem or cerebellar infarction. This report describes 40 patients who experienced repetitive vertebrobasilar ischemic symptoms despite maximal medical therapy. The natural history, pathogenesis, and treatment options for each causative lesion are reviewed. The operative approaches to symptomatic disease of the proximal vertebral arteries, arterial compression by cervical osteophytes, traumatic lesions of the vertebral arteries, and thrombo-occlusive pathology of the distal extracranial vertebral arteries are outlined. Specific anesthetic and surgical techniques that have proved successful while achieving zero operative mortality and low perioperative morbidity rates are reported.


Phase transformations and indications for acoustic mode softening in Tb-Gd orthophosphate.
At ambient conditions the anhydrous rare earth orthophosphates assume either the xenotime (zircon) or the monazite structure, with the latter favored for the heavier rare earths and by increasing pressure. Tb0.5Gd0.5PO4 assumes the xenotime structure at ambient conditions but is at the border between the xenotime and monazite structures. Here we show that, at high pressure, Tb0.5Gd0.5PO4 does not transform directly to monazite but through an intermediate anhydrite-type structure. Axial deformation of the unit cell near the anhydrite- to monazite-type transition indicates softening of the (c1133 + c1313) combined elastic moduli. Stress response of rare-earth orthophosphate ceramics can be affected by both formation of the anhydrite-type phase and the elastic softening in the vicinity of the monazite-phase. We report the first structural data for an anhydrite-type rare earth orthophosphate.


The Functions of Bursal Hexapeptide (BHP) on Immune Response and the Molecular Mechanism on Immature B Cell.
The bursa of Fabricius (BF) is an acknowledged central immune organ, and is important to B cell differentiation. Bursal hexapeptide (BHP) is the recently reported bursalderived peptide, while its inducing function on immune response is uncertain. The main objective of this study was to analyze the immune responses to JEV vaccine in mice induced by BHP plus JEV vaccine, and to detect the signal and biological functions of BHP on immature B cells. Mice were immunized with Japanese encephalitis virus (JEV) vaccine and BHP from 0.01 mg/mL to 0.25 mg/mL to detect antibody response and cellular immune response, respectively. The production of IgG, IgG1 and IgG2a specific to JEV in serum from immunized mice were measured by ELISA, and T cell subpopulation from immunized mice were detected with using fluorochrome conjugated mAbs of the corresponding PE-Cys/FITC/PE by flow cytometry. Spleen cells from all immunized mice were harvested after one week of second immunization for lymphocyte proliferation assay. Mouse immature B cell WEHI-231 cell was treated with 0.01μg/mL BHP for 4h, and analyzed the involved biological function and pathway of differentially expressed genes with gene microarray. BHP co-immunization with JEV vaccine generated significant increased antibody levels, neutralizing antibody titers and spleen lymphocyte viability, compared to that of vaccine control. The subpopulations of T cells in spleen lymphocytes were significantly modified in the mice coimmunized with JEV vaccine and BHP. The analysis results of gene expression profiles of WEHI- 231 mouse immature B cells with BHP treatment showed that the regulated genes with BHP treatment were involved various immune related biological functions, including proliferation and activation of lymphocyte and T cell, T cell mediated immunity and regulation of adaptive immune response. Furthermore, BHP stimulated three significant enriched pathways, including amphetamine addiction, long-term potentiation, and RIG-I-like receptor signaling pathway. Our results indicated BHP induced significant humoral and cellular immunity to JEV vaccine, and regulated various biological processes and signalling related to immune activation in immature B cells. These results proposed the immunomodulatory function and mechanism of BHP on immune induction, which provided the novel insight on the candidate reagent for immune improvement.


Molecular mechanisms of sodium transport inhibition in proximal tubule during acute hypertension.
Acute hypertension provokes a rapid decrease in proximal tubule salt and water reabsorption that increases the levels of sodium chloride at the macula densa, the error signal to increase arteriolar resistance to autoregulate renal blood flow and glomerular filtration rate, and contributes to pressure natriuresis. The molecular mechanisms responsible for this critical homeostatic adjustment are beginning to be dissected: apical sodium transporters in the proximal tubule are redistributed out of the brush border to intermicrovillar and endosomal stores and sodium pump activity is inhibited. These responses are strikingly similar to the cellular responses to parathyroid hormone, and are mediated by similar signalling pathways.


Evaluating Prevalence and Patterns of Prescribing Medications for Depression for Patients With Obesity Using Large Primary Care Data (Canadian Primary Care Sentinel Surveillance Network).
Introduction: Depression is a serious disorder that brings a tremendous health and economic burden. Many antidepressants (AD) have obesogenic effects, increasing the population of obese patients at increased risk for a more severe disease course and poor treatment response. In addition, obese patients with depression may not be receiving the recommended standard of care due to "obesity bias." It is important to evaluate prescribing pharmacological treatment of depression in patients with obesity. Objectives: To describe the prevalence and patterns of AD prescribing for patients with depression and comorbid obesity compared with normal weight patients, and to examine the association of prescribing prevalence with obesity class. Methods: Study sample of adult patients (>18 years old) with depression was extracted from the national Canadian Primary Care Sentinel Surveillance Network (CPCSSN) Electronic Medical Records database for 2011-2016. Measures were prescribing of at least one AD (outcome) and body mass index (BMI) to categorize patients into weight categories (exposure). Data were analyzed cross-sectionally using descriptive statistics and mixed effects logistic regression model with clustering on CPCSSN networks and adjusting for age, sex, and the comorbidities. Results: Of 120,381 patients with depression, 63,830 patients had complete data on studied variables (complete cases analysis). Compared with normal weight patients, obese patients were more likely to receive an AD prescription (adjusted Odds Ratio [aOR] = 1.17; 95% Confidence Interval [CI]: 1.12-1.22). Patients with obesity classes II and III were 8% (95% CI: 1.00, 1.16) and 6% (95% CI: 0.98, 1.16) more likely, respectively, to receive AD. After imputing missing data using Multiple Imputations by Chained Equations, the results remained unchanged. The prevalence of prescribing >3 AD types was higher in obese category (7.27%, [95% CI: 6.84, 7.73]) than in normal weight category (5.6%; [95% CI: 5.24, 5.99]). Conclusion: The association between obesity and high prevalence of AD prescribing and prescribing high number of different AD to obese patients, consistent across geographical regions, raises a public health concern. Study results warrant qualitative studies to explore reasons behind the difference in prescribing, and quantitative longitudinal studies evaluating the association of AD prescribing patterns for obese patients with health outcomes.


Posttraumatic stress in survivors 1 month to 19 years after an airliner emergency landing.
Posttraumatic stress (PTS) is common in survivors from life-threatening events. Little is known, however, about the course of PTS after life threat in the absence of collateral stressors (e.g., bereavement, social stigma, property loss) and there is a scarcity of studies about PTS in the long term. This study assessed the short- and long-term course of PTS, and the influence of gender, education and age on the level and course of PTS, in survivors from a non-fatal airliner emergency landing caused by engine failure at an altitude of 1 km. There were 129 persons on board. A survey including the Impact of Event Scale was distributed to 106 subjects after 1 month, 4 months, 14 months, and 25 months, and to 95 subjects after 19 years (response rates 64-83%). There were initially high levels of PTS. The majority of changes in PTS occurred from 1 to 4 months after the event. There were small changes from 4 to 25 months but further decrease in PTS thereafter. Female gender was associated with higher levels of PTS whereas gender was unrelated to the slope of the short- and long-term trajectories. Higher education was related to a quicker recovery although not to initial or long-term PTS. Age was not associated with PTS. The present findings suggest that a life-threatening experience without collateral stressors may produce high levels of acute posttraumatic stress, yet with a benign prognosis. The findings further implicate that gender is unrelated to trajectories of recovery in the context of highly similar exposure and few collateral stressors.


A comparative study of two methods for the isolation of human leucocytes for DNA extraction.
The 'Dextran' and the 'Buffy-coat' methods for isolation of human leucocytes for DNA extraction were compared on the basis of DNA yield from the same amounts (10 ml) of blood. Human leucocytes from a total of 11 samples were isolated using both methods for each sample after which DNA was extracted. Extracted DNA samples were treated with ribonucleases and proteinase K after which the yields were quantitated by measuring absorbance at 260 nm. The 'Buffy-coat' method yielded a mean concentration of DNA of 476.7 micrograms/ml (range: 212 to 700 micrograms/ml) while the 'Dextran' method yielded 188.4 micrograms/ml (range: 64 to 340 micrograms/ml). The difference was confirmed by subjecting the extracted DNA samples to agarose gel electrophoresis.


Dial-in flow cytometry data analysis.
As listmode data files continue to grow larger, access via any kind of network connections becomes more and more trouble because of the enormous traffic generated. The limited speed of transmission via modem makes analysis almost impossible. This unit presents a solution to these problems, one that involves installation at the central storage facility of a small computer program called a Web servlet. Operating in concert with a Web server, the servlet assists the analysis by extracting the display array from the data file and organizing its transmission over the network to a remote client program that creates the data display. The author discusses a recent implementation of this solution and the results for model transmission of two typical data files. The system greatly speeds access to remotely stored data yet retains the flexibility of manipulation expected with local access.


Human papillomavirus as a single infection in pregnant women from Northeastern Mexico: Cross-sectional study.
The role of human papillomavirus (HPV) as single or multiple infections in pregnant women would be relevant to determine the time to progression and/or the time to regression of cervical lesions. In this preliminary study, we determined the prevalence of HPV as single or multiple infections in pregnant women from Northeastern Mexico. Samples from 31 pregnant and 62 nonpregnant women were examined between January 2015 and November 2015 at UMAE-23 of the Instituto Mexicano del Seguro Social (IMSS). The samples of cervicovaginal exudate were obtained for HPV DNA detection using the INNO-LiPA test, and HPV infections were analyzed as single or multiple infections. Participants completed a questionnaire on sociodemographic, gynecological, obstetric, and sexual behavior characteristics. The mean age of the pregnant women was 25.7 ± 4.8 yr, with an average time of pregnancy of 6 ± 1 months at the time of the study. With respect to age, parity, smoking history, or oral contraceptive use no statistically significant differences between the two studied groups was observed. The HPV infection was 2.7 times higher in pregnant women (35%) than in the control group (13%). In total, 78% of the pregnant women who were HPV-positive presented with single infections compared with 28% of the nonpregnant women. A higher prevalence of HPV as a single infection was found in this sample of pregnant Mexican women. Follow-up is necessary to evaluate the persistence or regression of the infection.


Variation in human T cell receptor V beta and J beta repertoire: analysis using anchor polymerase chain reaction.
Anchor polymerase chain reaction has been applied to the study of human T cell receptor beta chain repertoire in peripheral blood. The use of this technique has demonstrated that considerable variation in V beta and J beta usage exists, both within and between individuals. Particular V beta families, including V beta 6, V beta 4 and V beta 12 are commonly utilized, while families such as V beta 10, V beta 11 and V beta 15 are rare in all individuals studied. Marked interindividual variation in V beta usage was detected for V beta 12 and V beta 4. Biased usage of J beta elements is a prominent feature of peripheral repertoire, while there is no evidence for preferential V beta-J beta recombination events. Biased J beta usage in expressed V beta-D beta-J beta-C beta transcripts, subject to selection, was the same as that in aberrant, unselected D beta-J beta-C beta transcripts, implying that bias resulted from events relating to rearrangement itself, in the absence of selection. N-region diversity showed some evidence for preferential insertion of deoxyguanosine, consistent with the action of terminal deoxytransferase. No P-nucleotide incorporation was seen in association with intact J beta elements. These data provide evidence of some of the variation in human T cell receptor beta chain repertoire and provide a basis for comparisons with sequences which may be obtained in autoimmune and superantigen-mediated diseases.


TLR-Stimulated Neutrophils Instruct NK Cells To Trigger Dendritic Cell Maturation and Promote Adaptive T Cell Responses.
Polymorphonuclear neutrophils (PMNs) are innate effector cells with pivotal roles in pathogen recognition, phagocytosis, and eradication. However, their role in the development of subsequent immune responses is incompletely understood. This study aimed to identify mechanisms of relevance to the cross talk between human neutrophils and NK cells and its potential role in promoting adaptive immunity. TLR-stimulated PMNs were found to release soluble mediators to attract and activate NK cells in vitro. PMN-conditioned NK cells displayed enhanced cytotoxicity and cytokine production, and responded vigorously to ensuing stimulation with exogenous and endogenous IL-12. The neutrophil-induced activation of NK cells was prevented by caspase-1 inhibitors and by natural antagonists to IL-1 and IL-18, suggesting a role for the NOD-like receptor family pyrin domain containing-3 inflammasome. In addition, PMN-conditioned NK cells triggered the maturation of monocyte-derived dendritic cells, which promoted T cell proliferation and IFN-γ production. These data imply that neutrophils attract NK cells to sites of infection to convert these cells into an active state, which drives adaptive immune responses via maturation of dendritic cells. Our results add to a growing body of evidence that suggests a sophisticated role for neutrophils in orchestrating the immune response to pathogens.


Early biochemical effects of an organic mercury fungicide on infants: "dose makes the poison".
Phenylmercury absorbed through the skin from contaminated diapers affected urinary excretion in infants in Buenos Aires. The effects were reversible and quantitatively related to the concentration of urinary mercury. Excretion of gamma-glutamyl transpeptidase, an enzyme in the brush borders of renal tubular cells, increased in a dose-dependent manner when mercury excretion exceeded a "threshold" value. Urine volume also increased but at a higher threshold with respect to mercury. The results support the threshold concept of the systemic toxicity of metals. gamma-Glutamyl transpeptidase is a useful and sensitive marker for preclinical effects of toxic metals.


Phosphorylation of the Nicotiana benthamiana WRKY8 transcription factor by MAPK functions in the defense response.
Mitogen-activated protein kinase (MAPK) cascades have pivotal roles in plant innate immunity. However, downstream signaling of plant defense-related MAPKs is not well understood. Here, we provide evidence that the Nicotiana benthamiana WRKY8 transcription factor is a physiological substrate of SIPK, NTF4, and WIPK. Clustered Pro-directed Ser residues (SP cluster), which are conserved in group I WRKY proteins, in the N-terminal region of WRKY8 were phosphorylated by these MAPKs in vitro. Antiphosphopeptide antibodies indicated that Ser residues in the SP cluster of WRKY8 are phosphorylated by SIPK, NTF4, and WIPK in vivo. The interaction of WRKY8 with MAPKs depended on its D domain, which is a MAPK-interacting motif, and this interaction was required for effective phosphorylation of WRKY8 in plants. Phosphorylation of WRKY8 increased its DNA binding activity to the cognate W-box sequence. The phospho-mimicking mutant of WRKY8 showed higher transactivation activity, and its ectopic expression induced defense-related genes, such as 3-hydroxy-3-methylglutaryl CoA reductase 2 and NADP-malic enzyme. By contrast, silencing of WRKY8 decreased the expression of defense-related genes and increased disease susceptibility to the pathogens Phytophthora infestans and Colletotrichum orbiculare. Thus, MAPK-mediated phosphorylation of WRKY8 has an important role in the defense response through activation of downstream genes.


[Effects of 5-HT1 and 5-HT2 serotonin receptors on anxiety- and depression-like behavior in female rats].
The influence of the chronic (14-day) administration of 5-HT1A receptor agonist 8-OH-DPAT (0.05 mg/kg, s.c.) and 5-HT2B/2C receptor agonist m-CPP (0.5 mg/kg, i.p.) on the anxiety- and depression-like behavior has been studied in adult female rats during key phases of the ovarian cycle. The chronic administration of m-CPP at the estrous phase produced an anxiolytic effect, while at the proestrous phase, the same drug produced an anxiogenic effect. At the same time, both 8-OH-DPAT and m-CPP exhibited pronounced antidepressant effect irrespective of the ovarian cycle phase.


Poly(ADP-ribose) polymerase inhibition prevents both apoptotic-like delayed neuronal death and necrosis after H(2)O(2) injury.
Toxic reactive oxygen species (ROS) such as hydrogen peroxide, nitric oxide, superoxide, and the hydroxyl radical are generated in a variety of neuropathological conditions and cause significant DNA damage. We determined the effects of 3-aminobenzamide (AB), an inhibitor of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP), on cell death in differentiated PC12 cells, a model of sympathetic neurons, after H(2) O(2) injury. Exposure to 0.5 mm H(2) O(2) resulted in a significant decrease in intracellular NAD(H), NADP(H), and ATP levels. This injury resulted in the death of 90% of the cells with significant necrosis early (2 h) after injury and increased apoptosis (12-24 h after injury), as measured by PS exposure and the presence of cytoplasmic oligonucleosomal fragments. Treatment with 2.5 mm AB restored pyridine nucleotide and ATP levels and ameliorated cell death (65% versus 90%) by decreasing the extent of both necrosis and apoptosis. Interestingly, we observed that H(2) O(2) -induced injury caused a delayed cell death exhibiting features of apoptosis but in which caspase-3 like activity was absent. Moreover, pretreatment with AB restored caspase-3-like activity. Our results suggest that apoptosis and necrosis are both triggered by PARP overactivation, and that maintenance of cellular energy levels after injury by inhibiting PARP shifts cell death from necrosis to apoptosis.


Portal Venous Interventions: How to Recognize, Avoid, or Get Out of Trouble in Transjugular Intrahepatic Portosystemic Shunt (TIPS), Balloon Occlusion Sclerosis (ie, BRTO), and Portal Vein Embolization (PVE).
Portal venous interventions comprise a large portion of many Interventional Radiology practices today, and remain some of the more technically challenging cases in one's repertoire of procedures. The patients upon whom these procedures are performed are often critically ill, have decompensated disease, or are burdened with comorbid conditions such that they are poor surgical candidates. This leaves them with few options outside the care of Interventional Radiology. Some portal venous interventions, such as transjugular intrahepatic portosystemic shunt, have an established history of excellent clinical success with numerous technical advancements over the years helping to improve outcomes. Others, like balloon occlusion sclerotherapy or portal venous recanalization, are less well established but are nonetheless invaluable in the treatment of portal venous diseases. The goal of this article is to help dispel some of the anxiety experienced by individuals performing the three main procedures of the portal venous system, namely transjugular intrahepatic portosystemic shunt, balloon-occlusion retrograde transvenous obliteration, and portal vein embolization.


Identification of differential gene expression by high throughput analysis.
High throughput analysis of differential gene expression is a powerful tool that can be applied to many areas in molecular cell biology, including differentiation, development, physiology, and pharmacology. In recent years, a variety of techniques have been developed to analyze differential gene expression, including comparative expressed sequence tag sequencing, differential display, representational difference analysis, cDNA or oligonucleotide arrays, and serial analysis of gene expression. This review explains the technologies, their scopes, impact on science, as well as their costs and possible limitations. The application of differential display is presented as a tool to identify genes induced by darkness or yellowing process in rice leaves.


Relevance of oxidative and carbonyl stress to long-term uremic complications.
Oxidative stress is a disturbance of balance between oxidants and antioxidant species. The existence of an increased oxidative stress in chronic renal failure is supported by evidence of increased lipid, carbohydrate, and protein oxidation products in plasma and cell membrane. Recent studies have implicated the oxidative stress in the nonenzymatic biochemistry leading to irreversible protein modifications. Reactive oxygen species may directly alter proteins with the eventual formation of oxidized amino acids. Alternatively, reactive carbonyl compounds formed by the oxidation of carbohydrates and lipids may indirectly lead to advanced glycation or lipoxidation of proteins. Chronic uremia is associated with increased modification of protein caused by reactive carbonyl compounds derived from both carbohydrates and lipids. Increased carbonyl modification of proteins subsequently results in the rise of plasma and tissue contents of advanced glycation end products and advanced lipoxidation end products, in which the deleterious biological effects have been revealed. This article focuses on the irreversible nonenzymatic modification of proteins, which might, at least in part, contribute to the development of complications associated with chronic renal failure and long-term dialysis, such as atherosclerosis and dialysis-related amyloidosis.


Single-cell RNA-Seq of human esophageal epithelium in homeostasis and allergic inflammation.
Inflammation of the esophageal epithelium is a hallmark of eosinophilic esophagitis (EoE), an emerging chronic allergic disease. Herein, we probed human esophageal epithelial cells at single-cell resolution during homeostasis and EoE. During allergic inflammation, the epithelial differentiation program was blocked, leading to loss of KRT6hi differentiated populations and expansion of TOP2hi proliferating, DSPhi transitioning, and SERPINB3hi transitioning populations; however, there was stability of the stem cell-enriched PDPNhi basal epithelial compartment. This differentiation program blockade was associated with dysregulation of transcription factors, including nuclear receptor signalers, in the most differentiated epithelial cells and altered NOTCH-related cell-to-cell communication. Each epithelial population expressed genes with allergic disease risk variants, supporting their functional interplay. The esophageal epithelium differed notably between EoE in histologic remission and controls, indicating that remission is a transitory state poised to relapse. Collectively, our data uncover the dynamic nature of the inflamed human esophageal epithelium and provide a framework to better understand esophageal health and disease.


Cost-effectiveness of carotid endarterectomy.
Carotid endarterectomy (CEA) reduces the risk of stroke in symptomatic patients with high-grade carotid stenosis. In this study, we evaluated the long-term, societal cost-benefit ratio of endarterectomy using a decision analysis model. We reviewed the results of 150 CEAs performed at an academic center and established a Markov model comparing cohorts of patients who experienced transient ischemic attacks and then underwent observation, aspirin therapy, or CEA. The cost-effectiveness of CEA was estimated using perioperative complication rates from our review and from the North American Symptomatic Carotid Endarterectomy Trial. Stroke and mortality rates were estimated from the literature. Cost estimates were based on medicare reimbursement data. Among the 150 CEAs reviewed, complications included major stroke (0.67%), minor stroke (1.33%), myocardial infarction (1.33%), pulmonary edema (0.67%), and wound hematoma (3.33%). There were no deaths or intracerebral hemorrhages. Using complication rates from our review, CEA produced cost savings of $5730.62 over the cost of observation and $3264.66 over the cost of aspirin treatment. CEA extended the average quality-adjusted life expectancy 15.8 months over that of observation and 13.2 months over that of aspirin. Substituting the North American Symptomatic Carotid Endarterectomy Trial results, CEA yielded savings of $2997.50 over the cost of observation and $531.54 over the cost of aspirin. Quality-adjusted life expectancy was extended 13.8 months compared with observation and 11.2 months compared with aspirin therapy. This analysis demonstrates that when performed with low perioperative morbidity and mortality rates, CEA is a highly cost-effective therapy for symptomatic carotid stenosis and results in substantial societal cost and life savings.


Proton MR Spectroscopy in Patients With Sleep-Related Hypermotor Epilepsy (SHE): Evidence of Altered Cingulate Cortex Metabolism.
To identify structural and/or metabolic alterations in patients with sleep-related hypermotor epilepsy (SHE) using magnetic resonance imaging (MRI) and proton MR spectroscopy (1H-MRS). Nineteen SHE patients (seven males; 34.7 ± 9.7 years, mean age ± standard deviation) and 17 matched healthy volunteers (seven males; 34.0 ± 8.9 years) were included in the study. In all patients, the diagnosis of SHE was confirmed by video-polysomnographic recording of seizures. Semiology, seizure frequency, and therapy were assessed for all patients. For each recruited participant, structural MRI and 1H-MRS sequences were acquired. 1H-MRS was performed on two regions of interest: the medial thalamus and the anterior cingulate gyrus. At examination, five patients were seizure free. In the remainder, seizure frequency ranged from yearly to multiple episodes per night. Brain MRI was normal in all patients but one. The ratio of N-acetyl-aspartate/Creatine (NAA/Cr) was significantly reduced in the anterior cingulate cortex in patients compared to controls (p < .05). Thalamic NAA/Cr showed no differences between patients and controls. Regression analysis showed that NAA/Cr in the anterior cingulate gyrus correlated with seizure frequency (p < .05), being lower in patients with higher seizure frequency. Given the absence of structural MR changes, our 1H-MRS data point to a functional NAA reduction in the cingulate cortex of SHE patients, more severe in those patients with higher seizure frequency and thus supporting the involvement of the anterior mesial structures in the pathophysiology of SHE.


[New-concept animal vaccines emerging in recent years].
Animal infectious diseases pose a serious and continuing threat to the animal health and cause huge economic losses throughout the world. Vaccination is one of the most effective solutions to prevent and control animal infectious diseases. With the development of biotechnologies and the need for disease prevention and control, the focus of vaccine research has been shifted to the development of safe, efficient, broad-spectrum, low-dose and marker vaccines. Novel vaccines capable of inducing high levels of both humoral and cellular immune responses are promising to provide more efficient protection against animal infectious diseases. This minireview summarizes the development, applications, advantages and disadvantages of new-concept animal vaccines emerging in recent years, including mucosal vaccines, long-acting and fast-acting vaccines, chimeric vaccines, nanoparticle vaccines, and so on. Furthermore, we discuss future directions of the vaccines, in order to provide new insights for animal vaccine development.


Alteration of seed storage protein composition in soybean [Glycine max (L.) Merrill] mutant lines induced by γ-irradiation mutagenesis.
This study investigated the alteration of seed storage proteins in soybean mutants induced by γ-irradiation. Five soybean cultivars and four landraces were irradiated with 250 Gy of γ rays to induce variability. The seed storage protein profiles of 414 genetic fixed mutants (M(12)-M(20)) having excellent agricultural traits were analyzed by SDS-PAGE. Among the 414 mutants, 58 were identifed as lacking lipoxygenase, 89 lacking the α' subunit, 113 lacking the α subunit, and 40 with an altered β subunit. One hundred and forty-nine mutants lacked the A(3) subunit of glycinin. Fifty-four mutants showed higher trypsin inhibitor (TIA) activity, whereas 139 showed lower TIA activity compared to their original cultivars. The selected mutants with low amounts of antinutritional factors such as trypsin inhibitor, lipoxygenase, and α subunit will constitute genetic resources for improving soybean protein quality.


[Learning/memory and drug dependence].
We investigated the possible mechanisms of development of latent learning and morphine dependence by the methods of behavioral pharmacology and confirmed them by using mutant mice. The heterozygous mice for the tyrosine hydroxylase (TH) gene and for the cyclic AMP (cAMP) response element binding protein (CREB) binding protein (CBP) gene showed the impairment of latent learning in the water finding task, and these mice did not develop morphine dependence. The spatial learning and hippocampal long-term potentiation (LTP) were normal in the both mutants. TH heterozygous mice showed a reduction of high K(+)-evoked noradrenaline release in the frontal cortex measured by the microdialysis technique and of cAMP content in the brain. In conclusion, the results of mutant mice suggest that the alternation of catecholamine biosynthesis and cAMP signal pathways may play a key role in development of latent learning and morphine dependence, and they furthermore show that the expression of genes mediated by phosphorylated CREB may be involved in the development of latent learning and morphine dependence.


PARROT is a flexible recurrent neural network framework for analysis of large protein datasets.
The rise of high-throughput experiments has transformed how scientists approach biological questions. The ubiquity of large-scale assays that can test thousands of samples in a day has necessitated the development of new computational approaches to interpret this data. Among these tools, machine learning approaches are increasingly being utilized due to their ability to infer complex nonlinear patterns from high-dimensional data. Despite their effectiveness, machine learning (and in particular deep learning) approaches are not always accessible or easy to implement for those with limited computational expertise. Here we present PARROT, a general framework for training and applying deep learning-based predictors on large protein datasets. Using an internal recurrent neural network architecture, PARROT is capable of tackling both classification and regression tasks while only requiring raw protein sequences as input. We showcase the potential uses of PARROT on three diverse machine learning tasks: predicting phosphorylation sites, predicting transcriptional activation function of peptides generated by high-throughput reporter assays, and predicting the fibrillization propensity of amyloid beta with data generated by deep mutational scanning. Through these examples, we demonstrate that PARROT is easy to use, performs comparably to state-of-the-art computational tools, and is applicable for a wide array of biological problems.


Role of Foxl2 in uterine maturation and function.
Foxl2 codes for a forkhead/HNF3 transcription factor essential for follicular maturation and maintenance of ovarian identity. FOXL2 mutations are associated with Blepharophimosis, Ptosis and Epicanthus inversus Syndrome (BPES) characterized by eyelid malformations (types I and II) and premature ovarian insufficiency (type I). We show that Foxl2 is not only expressed by the ovary, but also by other components of the mouse female reproductive tract, including the uterus, the cervix and the oviduct. In the uterus, Foxl2 expression is first observed in the neonatal mesenchyme and, during uterine maturation, persists in the stroma and in the deep inner myometrial layer (IML). In the adult, Foxl2 is expressed in the differentiated stromal layer, but no longer in the myometrium. Conditional deletion of Foxl2 in the postnatal (PN) uterus using Progesterone Receptor-cre (Pgr(cre/+)) mice results in infertility. During PN uterine maturation Pgr(cre/+); Foxl2(flox/flox) mice present a severely reduced thickness of the stroma layer and an hypertrophic, disorganized IML. In adult Pgr(cre/+); Foxl2(flox/flox) mice a supplementary muscular layer is present at the stroma/myometrium border and vascular smooth muscle cells fail to form a coherent layer around uterine arteries. Wnt signalling pathways play a central role in uterine maturation; in Pgr(cre/+); Foxl2(flox/flox) mice, Wnt genes are deregulated suggesting that Foxl2 acts through these signals. In humans, thickening of the IML (also called "junctional zone") is associated with reduced fertility, endometriosis and adenomyosis. Our data suggest that Foxl2 has a crucial role in PN uterine maturation and could help to understand sub-fertility predisposition in women.


Membrane estrogen signaling in female reproduction and motivation.
Estrogen receptors were initially identified in the uterus, and later throughout the brain and body as intracellular, ligand-regulated transcription factors that affect genomic change upon ligand binding. However, rapid estrogen receptor signaling initiated outside of the nucleus was also known to occur via mechanisms that were less clear. Recent studies indicate that these traditional receptors, estrogen receptor-α and estrogen receptor-β, can also be trafficked to act at the surface membrane. Signaling cascades from these membrane-bound estrogen receptors (mERs) not only rapidly effect cellular excitability, but can and do ultimately affect gene expression, as seen through the phosphorylation of CREB. A principal mechanism of neuronal mER action is through glutamate-independent transactivation of metabotropic glutamate receptors (mGluRs), which elicits multiple signaling outcomes. The interaction of mERs with mGluRs has been shown to be important in many diverse functions in females, including, but not limited to, reproduction and motivation. Here we review membrane-initiated estrogen receptor signaling in females, with a focus on the interactions between these mERs and mGluRs.


A combined top-down and bottom-up LC-HRMS/MS method for the quantification of human growth hormone in plasma and serum.
The precise and accurate quantification of human growth hormone (GH) in plasma/ serum is crucial for the diagnosis and treatment of diseases like GH deficiency or acromegaly. However, the ligand-binding assays (LBAs) currently used for routine testing show considerable methodological variability. Here, we present a complementary, combined top-down and bottom-up LC-MS-based method to quantify (intact) GH in plasma and serum, which concurrently provides a basis for a MS-based analysis of GH in doping controls. Extraction of GH from plasma/ serum was accomplished by protein precipitation, followed by an immunocapture step using protein A-coupled magnetic beads and a polyclonal anti-GH antibody. The intact protein was subsequently analyzed top-down on a 2D-LC-HRMS/MS system. In addition, sample extracts were digested with trypsin and analyzed for signal peptides corresponding to 'total', 22 kDa and 20 kDa GH (bottom-up). Both assays were validated according to current guidelines and compared to the GH isoform differential immunoassay used in routine doping control analysis. GH concentrations in serum samples of healthy adults, patients with acromegaly, and in samples obtained after administration of recombinant GH were analyzed as proof-of-principle. The intact monomeric 22 kDa isoform of GH was selectively quantified in a representative working range of 0.5 to 10 ng/ml by top-down LC-HRMS/MS. Subsequent bottom-up analysis provided additional data on 'total' and 20 kDa GH. Top-down and bottom-up assay results for the 22 kDa isoform correlated well with the corresponding immunoassay results (R2 > 0.95). For a possible application of the method in an anti-doping context, the ratio between 22 kDa and 'total' GH was evaluated, indicating differences between the various donor groups, but only with limited significance. The top-down and bottom-up LC-HRMS/MS method developed here presents a valuable tool for the quantification of GH in plasma/ serum complementary to established LBAs used at present in clinical measurements. Albeit the examination of the GH isoform proportions by the LC-MS method does not yet allow for the assessment of GH abuse, the obtained findings provide an important basis to enable LC-MS-based GH analysis of doping control samples in the future.


Hypnotizability in patients with anorexia nervosa and bulimia.
Hypnotizability was assessed with the use of three standardized hypnosis scales in 86 patients with eating disorders. All diagnoses were made according to DSM-III criteria. Sixty-five patients had anorexia nervosa and 21 had bulimia. The anorectic patients were divided into subgroups of 19 abstainers and 46 vomiters and purgers. Bulimic patients were highly hypnotizable, significantly more so than the patients with anorexia nervosa and age-matched populations. There was also a trend for the purging subgroup of anorectics to have higher hypnotic capacity than abstaining anorectics.


Utility and the limit of motor evoked potential monitoring for preventing complications in surgery for cerebral arteriovenous malformation.
To evaluate the usefulness of motor evoked potential (MEP) monitoring and mapping in arteriovenous malformation surgery. Intraoperative MEP monitoring was performed in 21 patients whose AVMs were located near the motor area or fed by arteries related to the corticospinal tract to detect blood flow insufficiency and/or direct injury to the corticospinal tract and/or to map the motor area. In 4 of 16 patients monitored for blood flow insufficiency, the MEP changed intraoperatively. In 2 patients, the changes were attributable to temporary occlusion of the feeding artery (anterior choroidal or lenticulostriate artery): 1 patient had a venous infarction around the internal capsule caused by thrombosis of the draining vein and the other bled intraoperatively from the nidus. In 17 patients, the MEP was monitored to rule out direct injury. In 1 patient, the MEP changed on coagulation of fragile vessels around the nidus in the precentral gyrus; it recovered after coagulation was discontinued. In 1 of 5 patients with MEP changes, the MEP did not recover; permanent hemiparesis developed in this patient because of venous infarction. In 1 of 11 patients subjected to MEP mapping of the motor area, we found translocation to the postcentral sulcus. In arteriovenous malformation surgery, MEP monitoring facilitates the detection of blood flow insufficiency and/or direct injury of the corticospinal tract and mapping of the motor area. It contributes to reducing the incidence of postoperative motor paresis.


Pharmacological interventions for stroke: failures and future.
Given the few options currently available for patients following ischaemic stroke, the recent disappointing failures of several large-scale Phase III clinical trials has made the search for novel therapeutic approaches even more critical. Experimental evidence has suggested that the majority of stroke patients have a slow evolution of brain injury which can occur over several hours. Progressive microcirculatory failure following the initial onset of ischaemia may contribute to the expansion of brain injury. Included among the pathophysiological changes that are speculated to occur as a secondary response to the initial ischaemia are free radical production, excitotoxicity (for example, glutamate) disruption of ionic homeostasis (for example, sodium and calcium influx), enzymatic changes, stimulation of the inflammatory process, endothelin release, activation of platelets and leukocytes, delayed coagulation and endothelial dysfunction. All of these pathophysiological reactions could contribute to an increase in local vascular resistance and therefore cause progressive hypoperfusion of the brain following the onset of stroke. The scope of this review will focus on recent clinical failures in addition to agents currently in clinical development, comparing vascular targets to the common neuroprotective strategies.


Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic.
We conducted a genome-wide association study to identify novel genes influencing diastolic blood pressure (BP) response to hydrochlorothiazide, a commonly prescribed thiazide diuretic preferred for the treatment of high BP. Affymetrix GeneChip Human Mapping 100K Arrays were used to measure single nucleotide polymorphisms across the 22 autosomes in 194 non-Hispanic black subjects and 195 non-Hispanic white subjects with essential hypertension selected from opposite tertiles of the race- and sex-specific distributions of age-adjusted diastolic BP response to hydrochlorothiazide (25 mg daily, PO, for 4 weeks). The black sample consisted of 97 "good" responders (diastolic BP response [mean+/-SD]=-18.3+/-4.2 mm Hg; age=47.1+/-6.1 years; 51.5% women) and 97 "poor" responders (diastolic BP response=-0.18+/-4.3; age=47.4+/-6.5 years; 51.5% women). Haplotype trend regression identified a region of chromosome 12q15 in which haplotypes constructed from 3 successive single nucleotide polymorphisms (rs317689, rs315135, and rs7297610) in proximity to lysozyme (LYZ), YEATS domain containing 4 (YEATS4), and fibroblast growth receptor substrate 2 (FRS2) were significantly associated with diastolic BP response (nominal P=2.39 x 10(-7); Bonferroni corrected P=0.024; simulated experiment-wise P=0.040). Genotyping of 35 additional single nucleotide polymorphisms selected to "tag" linkage disequilibrium blocks in these genes provided corroboration that variation in LYZ and YEATS4 was associated with diastolic BP response in a statistically independent data set of 291 black subjects and in the sample of 294 white subjects. These results support the use of genome-wide association analyses to identify novel genes influencing antihypertensive drug responses.


Heterogeneous population effects of an alcohol excise tax increase on sexually transmitted infections morbidity.
Alcohol taxes reduce population-level excessive alcohol use and alcohol-related morbidity and mortality, yet little is known about the distribution of the effects of alcohol taxation across race/ethnicity and age subgroups. We examined the race/ethnicity- and age group-specific effects of an excise alcohol tax increase on a common and routinely collected alcohol-related morbidity indicator, sexually transmitted infections. We used an interrupted time series design to examine the effect of a 2009 alcohol tax increase in Illinois, USA on new cases of two common sexually transmitted infections (chlamydia and gonorrhea) reported to the US National Notifiable Disease Surveillance System from January 2003 to December 2011 (n = 108 repeated monthly observations). We estimated the effects of the tax increase on infection rates in the general population and within specific race/ethnicity and age subgroups using mixed models accounting for temporal trends and median income. Following the Illinois alcohol tax increase, state-wide rates of gonorrhea decreased 21% [95% confidence Interval (CI) = -25.7, -16.7] and chlamydia decreased 11% [95% CI = -17.8, -4.4], resulting in an estimated 3506 fewer gonorrhea infections and 5844 fewer chlamydia infections annually. The null hypothesis of homogenous effects by race/ethnicity and age was rejected (P < 0.0001). Significant reductions were observed among non-Hispanic blacks: gonorrhea rates decreased 25.6% (95% CI = -30.0, -21.0) and chlamydia rates decreased 14.7% (95% CI = -20.9, -8.0). Among non-Hispanics, point estimates suggest decreases were highest among 25-29-year-olds. Increased alcohol taxes appear to reduce sexually transmitted infections, especially among subpopulations with high disease burdens, such as non-Hispanic blacks.


[Combined periampullary adenocarcinoma and neuroendocrine tumor in type 1 neurofibromatosis: report of one case].
Neurofibromatosis is a hereditary autosomal-dominant disease with high rates of de novo mutations, and carries a high risk of neoplasms. It affects both sexes and all races and ethnic groups. It is characterized by multiple cutaneous lesions and tumors, both benign and malignant, especially in the nervous system. We report a 52-year-old woman with a type 1 neurofibromatosis, presenting with fever, jaundice and weight loss. On physical examination, the patient was jaundiced and had "café au lait" spots in the skin. A magnetic resonance imaging showed bile duct dilation and a possible ampullar carcinoma. The patient was operated, during the exploration she presented a periampullary tumor and multiple small nodular lesions in the stomach, the tumor was resected with a pancreaticoduodenectomy and the nodular gastric lesions were biopsied. The pathological study revealed a combined adenocarcinoma and neuroendocrine duodenal tumor. The study of the stomach lesions revealed a gastrointestinal stromal tumor. Four months after surgery, the patient is in good condition.


Dietary flavanols modulate the transcription of genes associated with cardiovascular pathology without changes in their DNA methylation state.
In a recent intervention study, the daily supplementation with 200 mg monomeric and oligomeric flavanols (MOF) from grape seeds for 8 weeks revealed a vascular health benefit in male smokers. The objective of the present study was to determine the impact of MOF consumption on the gene expression profile of leukocytes and to assess changes in DNA methylation. Gene expression profiles were determined using whole genome microarrays (Agilent) and DNA methylation was assessed using HumanMethylation450 BeadChips (Illumina). MOF significantly modulated the expression of 864 genes. The majority of the affected genes are involved in chemotaxis, cell adhesion, cell infiltration or cytoskeleton organisation, suggesting lower immune cell adhesion to endothelial cells. This was corroborated by in vitro experiments showing that MOF exposure of monocytes attenuates their adhesion to TNF-α-stimulated endothelial cells. Nuclear factor kappa B (NF-κB) reporter gene assays confirmed that MOF decrease the activity of NF-κB. Strong inter-individual variability in the leukocytes' DNA methylation was observed. As a consequence, on group level, changes due to MOF supplementation could not be found. Our study revealed that an 8 week daily supplementation with 200 mg MOF modulates the expression of genes associated with cardiovascular disease pathways without major changes of their DNA methylation state. However, strong inter-individual variation in leukocyte DNA methylation may obscure the subtle epigenetic response to dietary flavanols. Despite the lack of significant changes in DNA methylation, the modulation of gene expression appears to contribute to the observed vascular health effect of MOF in humans.


PKCζ, MMP‑2 and MMP‑9 expression in lung adenocarcinoma and association with a metastatic phenotype.
The aim of the present study was to investigate protein kinase C ζ type (PKCζ), matrix metalloproteinase (MMP)‑2 and MMP‑9 expression in lung adenocarcinoma and to define their association with in vitro invasion and metastatic capacity. PKCζ, MMP‑2 and MMP‑9 expression was assessed by immunohistochemistry in 110 cases of lung adenocarcinoma. PKCζ small interfering (si)RNA was transfected into A549 cells, and western blotting was used to confirm PKCζ‑knockdown in transfected cells and to measure MMP‑2 and MMP‑9 levels. A Transwell invasion assay was used to detect in vitro invasive capacity. The rates of positive PKCζ, MMP‑2 and MMP‑9 staining in lung adenocarcinoma tissues were 52.73, 55.45 and 61.82%, respectively. PKCζ expression was increased in malignant tissues compared with adjacent normal lung tissues and was associated with lymph node metastasis (P<0.05), although it was not associated with any other clinicopathological parameters, including sex, age, tumor size, smoking status or distant metastases (all P>0.05). PKCζ, MMP‑2 and MMP‑9 expression was markedly decreased in siPKCζ‑treated A549 cells, which exhibited a significantly decreased invasive capacity in the Transwell invasion assay (P<0.05). In conclusion, PKCζ promoted lung adenocarcinoma invasion and metastasis, and its expression was associated with MMP‑2 and MMP‑9 expression. PKCζ may be a potential target for gene therapy in lung adenocarcinoma.


Four attributes of intelligence, a thousand questions.
Jeff Hawkins is one of those rare individuals who speaks the languages of both AI and neuroscience. In his recent book, "A Thousand Brains: A New Theory of Intelligence", Hawkins proposes that current learning algorithms lack four attributes which will be necessary for true machine intelligence. Here we demonstrate that a minimal learning system which satisfies all four points can be constructed using only simple, classical machine learning techniques. We illustrate that such a system falls short of biological intelligence in some important ways. We suggest that Hawkins' list is a useful model, but the "recipe" for true intelligence-if there is one-may not be so easily defined.


Investigation of the selenium metabolism in cancer cell lines.
The aim of this work was to compare different selenium species for their ability to induce cell death in different cancer cell lines, while investigating the underlying chemistry by speciation analysis. A prostate cancer cell line (PC-3), a colon cancer cell line (HT-29) and a leukaemia cell line (Jurkat E6-1) were incubated with five selenium compounds representing inorganic as well as organic Se compounds in different oxidation states. Selenomethionine (SeMet), Se-methylselenocysteine (MeSeCys), methylseleninic acid (MeSeA), selenite and selenate in the concentration range 5-100 μM were incubated with cells for 24 h and the induction of cell death was measured using flow cytometry. The amounts of total selenium in cell medium, cell lysate and the insoluble fractions was determined by ICP-MS. Speciation analysis of cellular fractions was performed by reversed phase, anion exchange and size exclusion chromatography and ICP-MS detection. The selenium compounds exhibited large differences in their ability to induce cell death in the three cell lines and the susceptibilities of the cell lines were different. Full recovery of selenium in the cellular fractions was observed for all Se compounds except MeSeA. Speciation analysis showed that MeSeA was completely transformed during the incubations, while metabolic conversion of the other Se compounds was limited. Production of volatile dimethyl diselenide was observed for MeSeA and MeSeCys. MeSeA, MeSeCys and selenite showed noticeable protein binding. Correlations between cell death induction and the Se compounds transformations could not be demonstrated.


Richard's back: death, scoliosis and myth making.
The body of a mediaeval monarch was always under scrutiny, and Richard III's was no exception. In death, however, his body became subject to new forms of examination and interpretation: stripped naked after the battle of Bosworth, his corpse was carried to Leicester and exhibited before being buried. In 2012, it was rediscovered. The revelation that Richard suffered from scoliosis prompts this article to re-evaluate the historical sources about Richard's physique and his posthumous reputation. This article argues that Richard's death and his myth as 'crookback' are inextricably linked and traces attitudes to spinal curvature in the early modern period. It also considers how Shakespeare represented Richard as deformed, and aspects of performance history which suggest physical vulnerability. It then considers Richard's scoliosis from the perspective of medical history, reviewing classical accounts of scoliosis and arguing that Richard was probably treated with a mixture of axial traction and pressure. It demonstrates from the evidence of Richard's medical household that he was well placed to receive hands-on therapies and considers in particular the role of his physician and surgeon, William Hobbes. Finally, it shows how the case of Richard III demonstrates the close relationship between politics and medicine in the period and the contorted process of historical myth making.


[Evaluation of medical care quality in cases with health damage infliction leading to unfavorable outcomes].
Discusses modern approaches to evaluation of the quality of medical care in cases when civil action is brought against medical people for inflicting damage to health leading to unfavorable outcomes. Emphasizes the need in developing a special organization model of medical care quality and efficacy control system, which should be based on universal principles, notions, and adequate tests and evaluations.


Factors controlling the dendritic arborization of retinal ganglion cells.
The effects of changing retinal ganglion cell (RGC) density and availability of presynaptic sites on the development of RGC dendritic arbor in the developing chick retina were contrasted. Visual form deprivation was used to induce ocular enlargement and expanded retinal area resulting in a 20-30% decrease in RGC density. In these retinas, RGC dendritic arbors increased in a compensatory manner to maintain the inner nuclear layer to RGC convergence ratio in a way that is consistent with simple stretching; RGC dendritic arbors become larger with increased branch lengths, but without change in the total number of branches. In the second manipulation, partial optic nerve section was used to produce areas of RGC depletion of approximately 60% in the central retina. This reduction in density is comparable to the density of locations in the normal peripheral retina. In RGC depleted retinas, dendritic arbor areas of RGCs in the central retina grow to match the size of normal peripheral arbors. In contrast to the expanded case, two measures of intrinsic arbor structure are changed in RGC-depleted retinas; the branch density of RGC dendrites is greater, and the relative areas of the two arbors of bistratified cells are altered. We discuss the potential roles of retinal growth, local RGC density, and availability of presynaptic terminals in the developmental control of RGC dendritic arbor.


Emotion regulation difficulties in binge eating disorder with and without the overvaluation of weight and shape.
The objective of this study was to examine the relationship between overvaluation of weight/shape ('overvaluation') and emotion regulation (ER) difficulties among women with binge eating disorder (BED) symptoms. Four groups of women were recruited from a community-based sample and compared on ER difficulties: individuals with probable BED with (n=102) and without (n=72) overvaluation, and non-binge eating obese (n=40) and healthy-weight (n=40) control participants. Data for patients with a formal diagnosis of BED receiving treatment from a previous study were included for numerical comparative purposes. Women with probable BED and overvaluation reported significantly greater ER difficulties than all other groups and had similar levels of ER difficulties to BED patients. Women with probable BED in the absence of overvaluation were comparable to the obese control group on total ER difficulties and the majority of the ER difficulties subscales. The findings provide further evidence for the clinical significance of overvaluation among individuals with BED symptomatology. BED in the absence of overvaluation does not appear to align with current models of the disorder in which ER difficulties are viewed as a core etiological mechanism. Further research is needed to elucidate the status of this presentation.


Hydrogen and Propane Production From Butyric Acid Photoreforming Over Pt-TiO2.
Photocatalysis is a promising technology from economic, energetic, and ecological points of view because it takes advantage of solar light. Hence, it is one of the investigated green routes to produce hydrogen from renewable energy resources. Butyric acid (BA) is largely present in wastewater and as an intermediate product in anaerobic digestion and therefore it is an inexpensive resource, which can be converted to valuable chemicals. In this work, photoreforming of butyric acid (BAPR) under UV light in aqueous suspensions of platinum-modified titanium dioxide-based catalysts is reported for the first time. Titania nanotubes (TNT) synthesized and calcined at different temperatures (300, 400, 500°C) and commercial TiO2 (P25), decorated with platinum nanoparticles, have been tested and characterized through different techniques including X-ray powder diffraction, UV-vis diffuse reflectance and photoluminescence spectroscopy, transmission electron microscopy, BET and porosimetry analysis. The main identified products of the BAPR were H2, propane, CO2 and several organic acids (e.g., pentanoic and 3-methylhexanoic acid). It has been found that the morphology and crystallinity of the photocatalysts affected dramatically their optical properties and, consequently, the reaction rate and the product distribution. Specifically, the highest conversion of BA (XBA) and selectivity toward H2 (SH2) was recorded with P25-Pt (XBA = 26.9%, SH2 = 47.2% after 8 h of irradiation). TNT-400-Pt showed the highest selectivity toward propane (SC3H8 = 16.1%) with XBA = 23.4% and SH2 = 36.2%. The activity results in conjunction with the characterization of the catalysts highlighted that the main factor affecting the activity in terms of XBA and generation of H2 was the crystallinity, and in particular the presence of rutile phase in TiO2, whereas SC3H8 appears to increase when the electron-holes recombination is lower.


Simultaneous determination of flubendiamide its metabolite desiodo flubendiamide residues in cabbage, tomato and pigeon pea by HPLC.
A sensitive and simple method for simultaneous analysis of flubendiamide and its metabolite desiodo flubendiamide in cabbage, tomato and pigeon pea has been developed. The residues were extracted with QuEChERS method followed by dispersive solid-phase extraction with primary secondary amine sorbent to remove co extractives, prior to analysis by HPLC coupled with UV-Vis detector. The recoveries of flubendiamide and desiodo flubendiamide were ranged from 85.1 to 98.5% and 85.9 to 97.1% respectively with relative standard deviations (RSD) less than 5% and sensitivity of 0.01 μg g(-1). The method offers a less expensive and safer alternative to the existing residue analysis methods for vegetables.


Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice.
Autoimmune regulator (AIRE) gene mutation is responsible for the development of organ-specific autoimmune disease with monogenic autosomal recessive inheritance. Although Aire has been considered to regulate the elimination of autoreactive T cells through transcriptional control of tissue-specific Ags in thymic epithelial cells, other mechanisms of AIRE-dependent tolerance remain to be investigated. We have established Aire-deficient mice and examined the mechanisms underlying the breakdown of self-tolerance. The production and/or function of immunoregulatory T cells were retained in the Aire-deficient mice. The mice developed Sjogren's syndrome-like pathologic changes in the exocrine organs, and this was associated with autoimmunity against a ubiquitous protein, alpha-fodrin. Remarkably, transcriptional expression of alpha-fodrin was retained in the Aire-deficient thymus. These results suggest that Aire regulates the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus, at least against this ubiquitous protein. Rather, Aire may regulate the processing and/or presentation of self-proteins so that the maturing T cells can recognize the self-Ags in a form capable of efficiently triggering autoreactive T cells. With the use of inbred Aire-deficient mouse strains, we also demonstrate the presence of some additional factor(s) that determine the target-organ specificity of the autoimmune disease caused by Aire deficiency.


Prognostic value of combined exercise and recovery electrocardiographic analysis.
Heart rate-adjusted ST-segment depression (ST/HR) analysis improves the diagnostic accuracy of exercise testing, but its prognostic value has not been evaluated in unselected populations. We prospectively used comparative exercise-recovery ST/HR analysis to predict outcome in a consecutive cohort of outpatients referred for exercise testing. The stress-recovery index, defined as the difference between ST/HR areas during exercise and recovery,was derived in 1163 patients (median age, 60 years; interquartile range, 54-65 years). All-cause mortality and the combination of death or nonfatal myocardial infarction were target end points. The individual effect of clinical and exercise-testing data on outcome was evaluated by Cox regression analysis using separate models for each group of variables. Model validation was performed using bootstrap methods adjusted by the degree of optimism in estimates. Survival analysis was performed with the product-limit Kaplan-Meier method. During a 33-month follow-up, 48 deaths and 72 nonfatal myocardial infarctions occurred. After adjusting for confounding variables, hypertension (hazard ratio, 1.80; 95% confidence interval, 1.26-2.59), ST/HR index (hazard ratio, 1.32; 95% confidence interval, 1.04-1.66; for interquartile difference), and stress-recovery index (hazard ratio, 0.75; 95% confidence interval, 0.65-0.86; for interquartile difference) were predictive of death or nonfatal myocardial infarction, whereas hypertension (hazard ratio, 3.67; 95% confidence interval, 2.00-6.73) and stress-recovery index (hazard ratio, 0.55; 95% confidence interval, 0.48-0.63; for interquartile difference) were predictive of all-cause mortality. In addition, stress-recovery index increased the prognostic power of the model on top of clinical and exercise-testing variables and provided significant discrimination for survival. Combined evaluation of ST/HR analysis during exercise and recovery improves the prognostic capacity of standard exercise electrocardiography.


Relation between inflammation and symptoms in asthma.
Asthma symptoms are the main reason for healthcare utilization and are a fundamental parameter for the evaluation of asthma control. Currently, asthma is defined as a chronic inflammatory disease. A French expert group studied the association between inflammation and asthma symptoms by carrying out a critical review of the international literature. Uncontrolled asthmatics have an increased number of polynuclear eosinophils in the induced sputum and an increased production of exhaled NO. Control by anti-inflammatory treatment is accompanied by a reduction in bronchial eosinophilia and exhaled NO. Asthma symptoms are the result of complex mechanisms and many factors modify their perception. Experimental data suggest that there is a relationship between the perception of symptoms and eosinophilic inflammation and that inhaled corticoid therapy improves this perception. Although they are still not applicable in routine practice, follow-up strategies based on the evaluation of inflammation are thought to be more effective in reducing exacerbations than those usually recommended based on symptoms and sequential analysis of respiratory function. Inhaled corticosteroid therapy is the reference disease-modifying therapy for persistent asthma. Recent studies demonstrated that adjustment of anti-inflammatory treatment based on symptoms is an effective strategy to prevent exacerbations and reduce the total number of doses of inhaled corticosteroids.


Developing the Nausea and Vomiting Thermometer Scale in children with cancer.
This study aimed to develop the Nausea and Vomiting Thermometer Scale (NVTS) in children with cancer. This methodological study was conducted on 250 children with cancer at the research and training university hospital in Turkey between September 2019 and January 2020. The t-test, the ROC analysis, the Diagnostic index, and the Youden index were used for determining the scale of the cutting point. The regression analysis, the intra-class correlation coefficient, and the BlandAltman analysis were used for the data analysis. The scale-level content validity index was .94, which was coherent. As a result of the ROC analysis, the cut-off point was determined as three points. The NVTS showed good reliability, with an intra-class correlation coefficient of .99. In the linear regression analysis, a model was created for chemotherapy drugs, nausea and vomiting type, vomiting status, and the number of children with cancer who vomited explained 44.9% of their nausea and vomiting status. The results of the Bland-Altman analysis showed that the correlation coefficient between the differences and the means was insignificant.