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Abstract SPR1NT (NCT03505099) was a Phase III, multicenter, single-arm study to investigate the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated at ≤6 weeks of life. Here, we report final results for 14 children with two copies of SMN2, expected to develop spinal muscular atrophy (SMA) type 1. Efficacy was compared with a matched Pediatric Neuromuscular Clinical Research natural-history cohort (n = 23). All 14 enrolled infants sat independently for ≥30 seconds at any visit ≤18 months (Bayley-III item #26; P

Most children with biallelic SMN1 deletions and three SMN2 copies develop spinal muscular atrophy (SMA) type 2. SPR1NT (NCT03505099), a Phase III, multicenter, single-arm trial, investigated the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated within six postnatal weeks. Of 15 children with three SMN2 copies treated before symptom onset, all stood independently before 24 months (P P

Lakes and reservoirs globally are experiencing unprecedented changes in land use and climate, depleting dissolved oxygen (DO) in the bottom waters (hypolimnia) of these ecosystems. Because DO is the most energetically favorable terminal electron acceptor (TEA) for organic carbon mineralization, its availability controls the onset of alternate TEA pathways (for example, denitrification, manganese reduction, iron reduction, sulfate reduction, methanogenesis). Low DO concentrations can trigger organic carbon mineralization via alternate TEA pathways in the water column and sediments, which has important implications for greenhouse gas production [carbon dioxide (CO2) and methane (CH4)]. In this study, we experimentally injected supersaturated DO into the hypolimnion of a eutrophic reservoir and measured concentrations of TEAs and terminal electron products (TEPs) in the experimental reservoir and an upstream reference reservoir. We calculated the electron equivalents yielded from each TEA pathway and estimated the contributions of each TEA pathway to organic carbon processing in both reservoirs. DO additions to the hypolimnion of the experimental reservoir promoted aerobic respiration, suppressing most alternate TEA pathways and resulting in elevated CO2 accumulation. In comparison, organic carbon mineralization in the reference reservoir’s anoxic hypolimnion was dominated by alternate TEA pathways, resulting in both CH4 and CO2 accumulation. Our ecosystem-scale experiments demonstrate that the alternate TEA pathways that succeed aerobic respiration in lakes and reservoirs can be manipulated at the ecosystem scale. Moreover, changes in the DO dynamics of freshwater lakes and reservoirs may result in concomitant changes in the redox reactions in the water column that control organic carbon mineralization and greenhouse gas accumulation.

Procrastination takes a considerable toll on people's lives, the economy and society at large. Procrastination is often a consequence of people's propensity to prioritize their immediate experiences over the long-term consequences of their actions. This suggests that aligning immediate rewards with long-term values could be a promising way to help people make more future-minded decisions and overcome procrastination. Here we develop an approach to decision support that leverages artificial intelligence and game elements to restructure challenging sequential decision problems in such a way that it becomes easier for people to take the right course of action. A series of four increasingly realistic experiments suggests that this approach can enable people to make better decisions faster, procrastinate less, complete their work on time and waste less time on unimportant tasks. These findings suggest that our method is a promising step towards developing cognitive prostheses that help people achieve their goals.

The probiotic effect of Enterococcus faecalis-1 (isolated from healthy chickens) on growth performance, immune response, and modulation of the intestinal microbiota of broilers was assessed with a total of 100-day-old commercial Cobb chicks. The chicks were randomly divided into two equal groups. The control group received a basal diet, while the test group received a basal diet and was orally supplied with E. faecalis at a dose of 108 CFU/bird/day. Results showed that E. faecalis-1 supplement significantly (P

Reputation Quotients (RQs®) produced by Harris Interactive, Inc. are a presumed credible measure of corporate reputation that assesses corporate reputations employing six drivers, which are correlated with 20 attributes. Reputations appear to be an important characteristic of a firm, which transcends a company’s current production and financial statements to set a path for future performance. Although many years and multiple factors go into creating a reputation, this study found that past share price performance was unrelated to company reputation. However, reputation does appear to provide insight into future firm performance. Firms with the worst reputations often seem to have trouble providing a return sufficient to cover risk, especially in the absence of dividends. By comparison, firms with the best reputations tend to have lower risk, whether measured in terms of systematic risk or total risk, and therefore generate significantly higher risk-adjusted rates of return.

Background Pulmonary capillary hemangiomatosis is a rare, vascular obstructive disorder that uniformly causes pulmonary arterial hypertension. Clinically, pulmonary capillary hemangiomatosis is indistinguishable from primary pulmonary arterial hypertension and histology is required for definitive diagnosis. The distinctive histologic feature of pulmonary capillary hemangiomatosis is non-malignant extensive proliferation of capillaries in the alveolar septae. Vasodilator treatment of humans with primary arterial hypertension due to pulmonary capillary hemangiomatosis can result in fatal acute pulmonary edema. Computed tomography is thus critical to discern pulmonary capillary hemangiomatosis from other causes of pulmonary arterial hypertension prior to vasodilator therapy. This is the first report of a vasoproliferative process resembling pulmonary capillary hemangiomatosis in the feline species. Case presentation A 15-year-old, male castrated, domestic shorthair cat presented for persistent labored breathing presumptively due to congestive heart failure despite treatment with diuretics for 7 days. Echocardiography showed evidence of hypertrophic cardiomyopathy with severe pulmonary hypertension; however, a normal sized left atrium was not consistent with congestive heart failure. Thoracic computed tomography was performed and showed evidence of diffuse ill-defined nodular ground glass opacities, enlarged pulmonary arteries, and filling defects consistent with pulmonary thromboembolism. The cat acutely decompensated after a single dose of sildenafil and was euthanized. Histopathology of the lungs showed severe multifocal alveolar capillary proliferation with respiratory bronchiolar infiltration, marked type II pneumocyte hyperplasia and multifocal pulmonary arterial thrombosis. Conclusion This is the first description in a cat of a vasoproliferative disorder resembling pulmonary capillary hemangiomatosis complicated by multifocal pulmonary arterial thrombosis. Inspiratory and expiratory ventilator-driven breath holds with angiography revealed lesions predominantly characterized by ground glass opacification and vascular filling defects with absence of air trapping. The results from this report suggest that, as in humans, the cat can develop a pulmonary capillary hemangiomatosis-like disease in which vasodilator therapy to address pulmonary hypertension may lead to fatal pulmonary edema.

Tumor necrosis factor alpha (TNF), interleukin-1 beta (IL1), and other cytokines are involved in non-rapid eye movement sleep (NREM) regulation under physiological and inflammatory conditions. Brain levels of IL1 and TNF increase with prolonged wakefulness. Injection of exogenous IL1 or TNF, mimicking sleep loss, induces sleepiness, excess sleep, fatigue, poor cognition, and enhanced sensitivity to pain. These symptoms characterize the syndrome associated with sleep loss. Extracellular ATP released during neuro- and glio-transmission, acting via purine P2 receptors on glia, releases IL1 and TNF. This extracellular ATP mechanism may provide an index of activity used by the brain to keep track of prior wakefulness. Prolonged wakefulness is associated with enhanced neuronal activity. TNF and IL1, in turn, act on neurons to change their intrinsic properties and sensitivities to neurotransmitters and neuromodulators such as adenosine and glutamate. Such actions change network input–output properties (i.e. state shift). State oscillations, for instance, occur within cortical columns and are responsive to TNF. Sleep is thus viewed as a local usedependent process regulated in part by cytokines. Further, state oscillations are viewed as a fundamental process of any neuronal/glia network. To investigate these hypotheses we developed an in vitro neuronal/glia culture system exhibiting field potential oscillations and have mathematically modeled the local use-dependent view of sleep initiation. These views have profound implications for sleep pathologies and function.

Influenza pneumonitis causes severe systemic symptoms in mice, including hypothermia and excess sleep. The association of extrapulmonary virus, particularly virus in the brain, with the onset of such disease symptoms has not been investigated. Mature C57BL/6 male mice were infected intranasally with mouse-adapted human influenza viruses (PR8 or X-31) under inhalation, systemic, or no anesthesia. Core body temperatures were monitored continuously by radiotelemetry, and tissues (lung, brain, olfactory bulb, spleen, blood) were harvested at the time of onset of hypothermia (13 to 24 h post infection [PI]) or at 4 or 7 h PI. Whole RNA from all tissues was examined by one or more of three reverse transcriptase-polymerase chain reaction (RT-PCR) procedures using H1N1 nucleoprotein (NP) primers for minus polarity RNA (genomic or vRNA) or plus polarity RNA (replication intermediates). Selected cytokines were assayed at 4, 7, and 15 h in the olfactory bulb (OB). Minus and plus RNA strands were readily detected in OBs as early as 4 h PI by nested RT-PCR. Anesthesia was not required for viral invasion of the OB. Cytokine mRNAs were also significantly elevated in the OB at 7 and 15 h PI in infected mice. Controls receiving boiled virus expressed only input vRNA and that only in lung. Immunohistochemistry demonstrated localization of H1N1 and NP antigens in olfactory nerves and the glomerular layer of the OB. Therefore a mouse-adapted human influenza virus strain, not known to be neurotropic, was detected in the mouse OB within 4 h PI where it appeared to induce replication intermediates and cytokines.

Giant cell tumour (GCT) is a benign, but aggressive, primary tumour of the bone. The recurrence rate after surgical treatment has been reported to be as high as 50%. Many surgical techniques have been employed in the treatment of this tumour. More aggressive interventions, such as en bloc resection and bulk allograft or prosthetic reconstruction, are generally understood to be associated with lower rates of local recurrence. However, because of lessened morbidity, intralesional techniques have come to be favoured for this condition. In addition to curettage, various adjuvant procedures and packing materials have been advocated in order to control and reconstruct long bone defects secondary to this neoplasm. We report our experience with 40 long bone GCT patients treated with curettage, burring, bone grafting and no adjuvants between 1997 and 2002. There was a local recurrence rate of 32.5%, with most recurrences noted within the first 30 months after surgery. Minor complications were found in 18% of patients. The risk of local recurrence in this study is acceptable (within the range that has been historically reported for curettage and bone grafting). In cases where more resources are available, the addition of adjuvant therapies, as noted in the recent literature, may be beneficial. The results of this study should be considered when designing multicenteric studies in the future.

LoWacquant provides a colorful and sociologically rich account of his experiences as a boxer at the Woodlawn Boys Club, situated in an economi- cally and racially segregated neighborhood in the South Side of Chicago. His (auto)ethnographic analysis of the urban ghetto relies on years of rich fieldnotes and interviews, and tells a compelling story about becoming a boxer and a partic- ipant in the urban underclass. Although both of us enjoyed this book, differences in opinion gradually emerged through our subsequent conversations. This review fleshes out our thoughts about Body and Soul.

Mit der steigenden Zahl an elektronisch unterstutzten Funktionen und Assistenten hat sich auch die Fahrzeug-Komplexitat erhoht. Daraus ergeben sich aber auch negative Auswirkungen auf die Fahrzeug-Ausfallsicherheit. Dies bestatigen die Daten der vorliegenden Studie, die auf einer Markenuntersuchung von ADAC und dem Center Automotive Research der FH Gelsenkirchen basiert. Damit kann gefolgert werden, dass die Ausfallsicherheit im Elektrik- und Elektronik-Feld zur grosen Herausforderung fur die Fahrzeugentwickler in der nachsten Dekade wird.

Despite the persistent inverse relationship between family income and mortality, no one has examined the effect of distinct income sources or income portfolios on mortality risk. We link the National Health Interview Survey to the Multiple Cause of Death file and use hazard models to examine income-related mortality across four age groups. Income from jobs, self-employment, interest, and dividends each predicts lower mortality at the younger, middle, and early old ages. Diverse income portfolios buffer against mortality risk at all ages, net of the amount of income received. These findings illuminate the various dimensions of income that shape U.S. mortality risks.

We studied the effects of intracerebroventricular and intraperitoneal injection and the in vitro effects of Nω-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, on the nitric oxide synthase activities of the cerebellum, brainstem, hypothalamus, hippocampus, and the remainder of the brain after dissections. Male rats were chronically implanted with lateral icv guide cannula. L-NAME was injected in doses of 0.2, 1, and 5 mg intracerebroventricularly, and 50 mg/kg intraperitoneally. L-NAME induced dose-dependent suppression of NOS activities in each brain region. The threshold dose was 0.2 mg; 1 mg L-NAME completely abolished brain nitric oxide synthase activity 90 min after the injection. Brain NOS activities returned to baseline level 48 h after the injection of 5 mg L-NAME. There were significant differences between the sensitivity of various regions to L-NAME after in vivo but not in vitro administration of the enzyme inhibitor. These findings indicate that intracerebroventricular injection of L-NAME is a useful tool for inhibiting brain nitric oxide synthase activities in vivo. The differences between the sensitivity of different brain regions to L-NAME as well as the relative fast recovery of nitric oxide synthase activities must be taken into account when L-NAME is administered intracerebroventricularly to rats.

Dielectric response analysis is an advanced technique, providing information about the insulation condition of the measured test object. It is typically used for power transformers, where the water content in the solid cellulosic insulation can be assessed. Water in oil-paper/pressboard insulations is decreasing the dielectric strength, accelerating the ageing and causing the bubble effect at high temperatures. Also instrument transformers are oil-paper insulated and therefore exposed to the harming effects of water. The condition assessment of the insulation system of instrument transformers has not played an important role up to now since typical measurement methods which might be used for power transformers are not applicable here. For example oil sampling is often avoided due to the small oil volume. However, the increasing age is leading to a higher risk of explosions, which can damage surrounding parts and cause high follow-up costs. This paper introduces a new approach to use the dielectric response analysis for condition assessment of instrument transformers. The measurement of the dielectric response in a wide frequency range (e.g. 100 μHz up to 5 kHz) provides information about the insulation condition and especially for oil-paper/pressboard insulations about the water content in the solid insulation. The measured curve is formed by the superposition of the dielectric response of the cellulosic material and the oil. It is reflecting the conductivity and polarization effects of each material. Due to the high content of cellulosic material, the oil has a minor impact on the dielectric response of an instrument transformer and the curve is highly determined by the behavior of the cellulosic material. The resulting curve can be used for the assessment of the insulation condition in various ways. Qualitative comparisons, e.g. between instrument transformers of the same type and age, might give general information which of these is in better condition. The dissipation factor and the capacitance trend can also deliver valuable data. Furthermore, the water content in the solid insulation can be assessed. An automatic analysis algorithm compares the measured dielectric properties of the actual instrument transformer with modeled dielectric properties to calculate the water content in the solid insulation. This paper describes the modeling in concerns of water content, oil conductivity and geometry. Furthermore, the influences of temperature and ageing products are explained. To confirm the validity of this assessment, measurements on several instrument transformers in service were performed. Dielectric response curves and the trend of the capacitances for new and aged instrument transformers with different water contents are discussed. Selected examples presented in this paper show, that the dielectric response is well-modeled and the water content can be derived. Also ageing effects can be observed. To avoid explosions of their instrument transformers, this method is now regularly used by TNB.

A symbiosis between chemoautotrophic bacteria and the bivalve hostSolemya occidentalis Deshayes living in Caribbean coral reef sediments is described. Transmission electron microscopy revealed dense populations of cellular inclusions resembling Gram-negative bacteria in host gill filaments. The autotrophic potential of these bacteria was determined by DNA hybridization analyses, which indicated the Calvin-Benson cycle gene for ribulose-1,5-bisphosphate carboxylase/oxygenase was present in DNA recovered fromS. occidentalis gill but not in symbiontfree foot tissue. The bacterial gene coding for 16S ribosomal RNA was amplified from DNA isolated from clam gills, sequenced directly, and found to be unique toS. occidentalis. Phylogenetic analysis of this sequence shows that theS. occidentalis symbiont groups with other known sulfur-oxidizing, chemoautotrophic symbionts within the γ-subdivision of theProteobacteria. Its closest known relative is theSolemya velum symbiont. While bootstrap analyses consistently place the symbionts from the Atlantic speciesS. velum andS. occidentalis in a monophyletic group, their phylogenetic position relative to the symbiont of the Pacific host,S. reidi, and other chemoautotrophic symbionts remains unresolved.

Mit der Komplexitat der neuen Fahrzeugelektronik und ihren Stromverbrauchern sinkt die Ausfallsicherheit der Fahrzeuge rapide ab. Dies bestatigen die Daten der vorliegenden Studie, die auf einer Markenuntersuchung vom ADAC und dem Center Automotive Research (CAR) der FH Gelsenkirchen basiert. Die Folgerung der Studie lautet: Gelingt den Automobilherstellern nicht in absehbarer Zeit der Einstieg in ein stabiles elektrisches Energiemanagement, steigt der Anteil der Elektrik/Elektronik-Pannen noch vor dem Jahr 2005 auf uber 60 % aller Fahrzeugpannen. Damit sind besonders bei den Premium-Marken erheblicher Kundenarger und Imageverlust programmiert.

Mitogen-activated protein (MAP) kinases mediate the phosphorylation and activation of nuclear transcription factors that regulate cell growth. MAP kinase activation may result from stimulation of either tyrosine-kinase (RTK) receptors, which possess intrinsic tyrosine kinase activity, or G-protein-coupled receptors (GPCR). RTK-mediated mitogenic signalling involves a series of SH2- and SH3-dependent protein-protein interactions between tyrosine-phosphorylated receptor, Shc, Grb2 and Sos, resulting in Ras-dependent MAP kinase activation. The beta gamma subunits of heterotrimeric G proteins (G beta gamma) also mediate Ras-dependent MAP kinase activation by an as-yet unknown mechanism. Here we demonstrate that activation of MAP kinase by Gi-coupled receptors is preceded by the G beta gamma-mediated tyrosine phosphorylation of Shc, leading to an increased functional association between Shc, Grb2 and Sos. Moreover, disruption of the Shc-Grb2-Sos complex blocks G beta gamma-mediated MAP kinase activation, indicating that G beta gamma does not mediate MAP kinase activation by a direct interaction with Sos. These results indicate that G beta gamma-mediated MAP kinase activation is initiated by a tyrosine phosphorylation event and proceeds by a pathway common to both GPCRs and RTKs.

In this critique of Kochman and Badarinathi's study (1993) of net selectivity, mutual funds are not found to have a return distribution exhibiting limited semivariance when monthly return data are used. Several funds are overrated, however, in the sense that they have negative semivariance-adjusted excess returns, despite having positive beta-adjusted excess returns. Similar results are obtained using the Standard and Poor's 500 Index, which was employed by Kochman and Badarinathi, and the Wilshire 5000.

Prior research regarding the influence of dividends and earnings on stock prices in the insurance industry is extended through comparison across insurance industry sectors. Dividends and earnings appear to have different impacts across sectors and at the high versus low levels of the annual stock price trading range.

Reelin, intensively studied as an extracellular protein that regulates brain development, is also expressed in a variety of tissues and a circulating pool of reelin exists in adult mammals. Here we describe the methodological and biological foundation for carrying out and interpreting clinical studies of plasma reelin. Reelin in human plasma was sensitive to proteolysis, freeze-thawing and heating during long-term storage, sample preparation and electrophoresis. Reelin in plasma was a dimer under denaturing conditions. Boiling of samples resulted in laddering, suggesting that each of the 8 repeats expressed in reelin contains a heat-labile covalent bond susceptible to breakage. Urinary-type and tissue-type plasminogen activator converted reelin to a discrete 310 kDa fragment co-migrating with the major immunoreactive reelin fragment seen in plasma and also detected in brain. (In contrast, plasmin produced a spectrum of smaller unstable reelin fragments.) We examined archival plasma of 10 pairs of age-matched male individuals differing in repeat length of a CGG repeat polymorphism of the 5'-untranslated region of the reelin gene (both alleles 11 repeats). Reelin 310 kDa band content was lower in subjects having the long repeats in all 10 pairs, by 25% on average (p < 0.001). In contrast, no difference was noted for amyloid precursor protein. Our studies indicate the need for caution in measuring reelin in archival blood samples, and suggest that assays of plasma reelin should take into account three dimensions that might vary independently: a) the total amount of reelin protein; b) the relative amounts of reelin vs. its proteolytic processing products; and c) the aggregation state of the native protein. Reelin-plasminogen activator interactions may affect their roles in synaptic plasticity. Our results also suggest that the human CGG repeat polymorphism affects reelin gene expression, and may affect susceptibility to human disease.

The periparturient period of animals (and humans) is very stressful and influenced by the microecosystem of the gastrointestinal tract (GIT). Performance and productivity of animal husbandry depend on the health of animal mothers and their offspring. We investigated the influence of prebiotic amounts of lactulose in sows and their piglets. Two experimental trial sows received daily 30 ml lactulose, 71 field trial sows received daily 45 ml lactulose during their periparturient period (10 days before until 10 days after parturison). The weaners of trial sows received 15 ml lactulose per 1 kg baby food 10 days before and 10 days after weaning. The effect of lactulose was recorded by performance parameters like number of piglet born alive, losses until weaning, body mass of piglets, daily weight gain of weaners until 35 days after weaning. The effect of lactulose on GIT microflora was estimated by bacterial counts of faeces of sows (total aerobic bacteria, Gram-negative bacteria, Clostridium (C.) perfringens). In order to show a previously unknown effect of lactulose we investigated the levels of antibodies to phospholipase C (PLC) of C. perfringens in plasma of experimental sows and in colostral and ripe milk of field sows. Lactulose influenced the performance parameters of sows in a non-significant way. In case of weaners we recorded significant daily weight gains. Lactulose significantly influenced total aerobic bacterial counts, C. perfringens counts in faeces of sows 20 days after parturison. Under experimental conditions it was shown that trial sows and their piglets had higher IgG-antibody levels to C. perfringens PLCs than the control animals. Similar results were found under field conditions. Trial sows had significant higher IgG-anti LPS (J5) antibodies in milk 10 days after birth.

Two cases of sports-related two-plane fractures of the distal tibia, their operative treatment and the result of therapy after hardware removal are reported. The incidence and mechanism of this type of fracture in adolescents are shown as well as the indication for surgical reconstruction depending on the gap in the joint surface of the distal tibia.

Using transgenic mice constitutively expressing the human inducible Hsp70, we examined the role of Hsp70 on cell survival after focal cerebral ischemia. Twenty-four hours after permanent occlusion of the middle cerebral artery, no difference in infarct area was detected between Hsp70-transgenic and non-transgenic mice. In the non-transgenic mice, many pyramidal neurons of the ipsilateral hippocampus were observed to be pyknotic. However, in all Hsp70-transgenic mice, hippocampal pyramidal neurons showed normal morphology and no evidence of pyknosis. This suggests that constitutive expression of Hsp70 reduces the extent of damage following permanent middle cerebral artery occlusion. Cell Stress Chaperones