Although typically identified in early childhood, the social communication symptoms and adaptive behavior deficits that are characteristic of autism spectrum disorder (ASD) persist throughout the ...lifespan. Despite this persistence, even individuals without cooccurring intellectual disability show substantial heterogeneity in outcomes. Previous studies have found various behavioral assessments such as intelligence quotient (IQ), early language ability, and baseline autistic traits and adaptive behavior scores to be predictive of outcome, but most of the variance in functioning remains unexplained by such factors. In this study, we investigated to what extent functional brain connectivity measures obtained from resting-state functional connectivity MRI (rs-fcMRI) could predict the variance left unexplained by age and behavior (follow-up latency and baseline autistic traits and adaptive behavior scores) in two measures of outcome—adaptive behaviors and autistic traits at least 1 y postscan (mean follow-up latency = 2 y, 10 mo). We found that connectivity involving the so-called salience network (SN), default-mode network (DMN), and frontoparietal task control network (FPTCN) was highly predictive of future autistic traits and the change in autistic traits and adaptive behavior over the same time period. Furthermore, functional connectivity involving the SN, which is predominantly composed of the anterior insula and the dorsal anterior cingulate, predicted reliable improvement in adaptive behaviors with 100% sensitivity and 70.59% precision. From rs-fcMRI data, our study successfully predicted heterogeneity in outcomes for individuals with ASD that was unaccounted for by simple behavioral metrics and provides unique evidence for networks underlying long-term symptom abatement.
Hydrogen sulfide (H2S) is a gaseous meditator that has various physiological and pathophysiological roles in the body. It has been shown to be an important mediator of gastrointestinal (GI) mucosal ...defense and contributes significantly to repair of damage and resolution of inflammation. Synthesis of H2S increases markedly after mucosal injury, and inhibition of H2S in such circumstances leads to delayed healing and exacerbated inflammation. The beneficial effects of H2S may be attributable to its ability to elevate mucosal blood flow, prevent leukocyte-endothelial adhesion, reduce oxidative stress, and stimulate angiogenesis. The use of H2S-donating agents and inhibitors of the key enzymes contributing to H2S synthesis have provided strong evidence for the importance of H2S in enhancing mucosal resistance to damage, as well as modulating inflammation and repair. In recent years, significant evidence has been generated to support the notion that these positive aspects of H2S can be exploited in drug design, particularly for arthritis, inflammatory bowel disease, and colon cancer chemoprevention. Thus novel H2S-based therapies have been shown to be effective anti-inflammatories that can promote the resolution of inflammation and accelerate the healing of GI ulcers. Encouraging results have already been seen experimentally with a mesalamine derivative and with H2S-releasing derivatives of nonsteroidal anti-inflammatory drugs.
Hydrogen sulfide (H₂S) is produced throughout the gastrointestinal tract, and it contributes to maintenance of mucosal integrity, resolution of inflammation, and repair of damaged tissue. H₂S ...synthesis is elevated in inflamed and damaged colonic tissue, but the enzymatic sources of that synthesis are not completely understood. In the present study, the contributions of three enzymatic pathways to colonic H₂S synthesis were determined, with tissues taken from healthy rats and rats with colitis. The ability of the colonic tissue to inactivate H₂S was also determined. Colonic tissue from rats with hapten-induced colitis produced significantly more H₂S than tissue from healthy controls. The largest source of the H₂S synthesis was the pathway involving cysteine amino transferase and 3-mercaptopyruvate sulfurtransferase (an α-ketoglutarate-dependent pathway). Elevated H₂S synthesis occurred specifically at sites of mucosal ulceration, and was not related to the extent of granulocyte infiltration into the tissue. Inactivation of H₂S by colonic tissue occurred rapidly, and was significantly reduced at sites of mucosal ulceration. This correlated with a marked decrease in the expression of sulfide quinone reductase in these regions. Together, the increased production and decreased inactivation of H₂S at sites of mucosal ulceration would result in higher H₂S levels at these sites, which promotes of resolution of inflammation and repair of damaged tissue.
AbstractHuman papillomavirus (HPV) vaccines are currently utilised globally in national immunisation programmes. In July 2017, a national HPV vaccine programme for men who have sex with men (MSM) was ...initiated across Scotland with vaccine being offered in the sexual health clinic setting. During the first year of this targeted vaccination programme, there were 5905 individuals who received at least one dose of HPV vaccine, representing 63.7% of eligible MSM attendees in this period. Vaccine uptake was relatively stable across all age groups (range 49.8–55.5%). The vaccination programme appears to have dovetailed well with pre-existing sexual health services and appears to be popular with MSM attending the service. The MSM HPV vaccine programme is a robust adjunct to the national girls programme but gender-neutral immunisation will reduce stigma and inequality in HPV-driven disease.
Modern-day science is under great pressure. A potent mix of increasing expectations, limited resources, tensions between competition and cooperation, and the need for evidence-based funding is ...creating major change in how science is conducted and perceived. Amidst this ‘perfect storm’ is the allure of ‘research excellence’, a concept that drives decisions made by universities and funders, and defines scientists’ research strategies and career trajectories. But what is ‘excellent’ science? And how to recognise it? After decades of inquiry and debate there is still no satisfactory answer. Are we asking the wrong question? Is reality more complex, and ‘excellence in science’ more elusive, than many are willing to admit? And how should excellence be defined in different parts of the world, particularly in lower-income countries of the ‘Global South’ where science is expected to contribute to pressing development issues, despite often scarce resources? Many wonder whether the Global South is importing, with or without consenting, the flawed tools for research evaluation from North America and Europe that are not fit for purpose. This book takes a critical view of these issues, touching on conceptual issues and practical problems that inevitably emerge when ‘excellence’ is at the center of science systems. Emerging from the capacity-building work of the Science Granting Councils Initiative in sub-Saharan Africa, it speaks to scholars, as well as to managers and funders of research around the world. Confronting sticky problems and uncomfortable truths, the chapters contain insights and recommendations that point towards new solutions – both for the Global South and the Global North.
c-MET (MET) receptor activation is associated with poor prognosis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance in non-small-cell lung cancer (NSCLC). This ...global, randomized phase II trial examined erlotinib plus tivantinib (ARQ 197; ArQule, Woburn, MA), a novel MET inhibitor.
Previously treated patients with EGFR TKI-naive advanced NSCLC were randomly assigned to receive oral erlotinib (150 mg daily) plus oral tivantinib (360 mg twice daily) or erlotinib plus placebo (EP). The primary end point was progression-free survival (PFS). At the time of progression, cross-over from EP to erlotinib plus tivantinib (ET) was permitted. Archival tumor tissue specimens were required.
One hundred sixty-seven patients were randomly assigned to ET (n = 84) and to EP (n = 83). Median PFS was 3.8 months for ET and 2.3 months for EP (hazard ratio HR, 0.81; 95% CI, 0.57 to 1.16; P = .24). Exploratory analysis revealed that the small cohort with KRAS mutations achieved a PFS HR of 0.18 (95% CI, 0.05 to 0.70; interaction P = .006). Objective responses were seen in 10% of patients on ET, 7% of patients on EP, and in two patients who crossed over from EP to ET, including one with EGFR mutation and MET gene copy number greater than 5. There were no significant differences in adverse events between study arms.
The combination of the MET inhibitor tivantinib and erlotinib is well-tolerated. Although the study did not meet its primary end point, evidence of activity was demonstrated, especially among patients with KRAS mutations. Additional study of tivantinib and erlotinib in patients with NSCLC is planned.
Glaucoma is the leading cause of irreversible blindness worldwide. Although most glaucoma patients are elderly, congenital glaucoma and glaucomas of childhood are also important causes of visual ...disability. Primary congenital glaucoma (PCG) is isolated, non-syndromic glaucoma that occurs in the first three years of life and is a major cause of childhood blindness. Other early-onset glaucomas may arise secondary to developmental abnormalities, such as glaucomas that occur with aniridia or as part of Axenfeld-Rieger syndrome. Congenital and childhood glaucomas have strong genetic bases and disease-causing mutations have been discovered in several genes. Mutations in three genes (CYP1B1, LTBP2, TEK) have been reported in PCG patients. Axenfeld-Rieger syndrome is caused by mutations in PITX2 or FOXC1 and aniridia is caused by PAX6 mutations. This review discusses the roles of these genes in primary congenital glaucoma and glaucomas of childhood.
Background Childhood maltreatment has been shown to significantly elevate the risk of psychiatric disorder. Previous neuroimaging studies of children exposed to maltreatment have reported atypical ...neural structure in several regions, including the prefrontal cortex and temporal lobes. These studies have exclusively investigated volumetric differences rather than focusing on genetically and developmentally distinct indices of brain structure. Methods Here we used surface-based methods to examine cortical thickness, surface area, and local gyrification in a community sample of children with documented experiences of abuse ( n = 22) and a group of carefully matched nonmaltreated peers ( n = 21). Results Reduced cortical thickness in the maltreated compared with the nonmaltreated group was observed in an extended cluster that incorporated the anterior cingulate, superior frontal gyrus, and orbitofrontal cortex. In addition, reduced cortical surface area was observed within the parcellated regions of the left middle temporal area and lingual gyrus. Local gyrification deficits within the maltreated group were located within two clusters, the lingual gyrus and the insula extending into pars opercularis. Conclusions This is the first time structural abnormalities in the anterior cingulate and lingual gyrus have been detected in children exposed to maltreatment. Surface-based methods seem to capture subtle, previously undetected, morphological abnormalities associated with maltreatment. We suggest that these approaches detect developmental precursors of brain volume differences seen in adults with histories of abuse. Because the reported regions are implicated in several clinical disorders, they might constitute biological markers of vulnerability, linking exposure to early adversity and psychiatric risk.
Transatlantic exploration took place centuries before the crossing of Columbus. Physical evidence for early European presence in the Americas can be found in Newfoundland, Canada
. However, it has ...thus far not been possible to determine when this activity took place
. Here we provide evidence that the Vikings were present in Newfoundland in AD 1021. We overcome the imprecision of previous age estimates by making use of the cosmic-ray-induced upsurge in atmospheric radiocarbon concentrations in AD 993 (ref.
). Our new date lays down a marker for European cognisance of the Americas, and represents the first known point at which humans encircled the globe. It also provides a definitive tie point for future research into the initial consequences of transatlantic activity, such as the transference of knowledge, and the potential exchange of genetic information, biota and pathologies
.
A promising drug target currently under investigation to improve cognitive deficits in neuropsychiatric and neurological disorders is the neuronal nicotinic alpha7 acetylcholine receptor (α7nAChR). ...Improving cognitive impairments in diseases such as Alzheimer's (AD) and schizophrenia remains a large unmet medical need, and the α7nAChR has many properties that make it an attractive therapeutic target. The α7nAChR is a ligand gated ion channel that has particularly high permeability to Ca
2+ and is expressed in key brain regions involved in cognitive processes (e.g., hippocampus). The α7nAChRs are localized both pre-synaptically, where they can regulate neurotransmitter release, and post-synaptically where they can activate intracellular signaling cascades and influence downstream processes involved in learning and memory. In particular, activation of the α7nAChR with small molecule agonists enhances long-term potentiation, an
in vitro model of synaptic plasticity, and improves performance across multiple cognitive domains in rodents, monkeys, and humans. Positive allosteric modulation of the α7nAChR offers an alternate approach to direct agonism that could prove to be particularly beneficial in certain disease populations where smoking nicotine is prevalent (e.g., schizophrenia) and could interfere with an orthosteric agonist approach. The current review focuses on the neurobiology of the α7nAChR, its role in cognition and the development status of some of the most promising molecules advancing for the treatment of cognitive dysfunction in disease.
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