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Newsletter for Boston University School of Medicine alumni

Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder

Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy

Primates in peril: The world's 25 most endangered primates, 2006-2008

From first paragraph: Here we report on the fourth iteration of the biennial listing of a consensus of 25 primate species considered to be amongst the most endangered worldwide and the most in need of urgent conservation measures. The first was drawn up in 2000 by the IUCN/SSC Primate Specialist Group, together with Conservation International (Mittermeier et al. 2000). The list was subsequently reviewed and updated in 2002 during an open meeting held during the 19th Congress of the International Primatological Society (IPS) in Beijing, China (Mittermeier et al. 2002). That occasion provided for debate among primatologists working in the field who had first-hand knowledge of the causes of threats to primates, both in general and in particular with the species or communities they study

Primates in Peril: The world's 25 most endangered primates 2008-2010

Introduction Here we report on the fifth iteration of the biennial listing of a consensus of 25 primate species considered to be amongst the most endangered worldwide and the most in need of urgent conservation measures. The first was drawn up in 2000 by the IUCN/SSC Primate Specialist Group, together with Conservation International (Mittermeier et al. 2000). The list was subsequently reviewed and updated in 2002 during an open meeting held during the 19th Congress of the International Primatological Society (IPS) in Beijing, China (Mittermeier et al. 2002). That occasion provided for debate among primatologists working in the field who had first-hand knowledge of the causes of threats to primates, both in general and in particular with the species or communities they study. The meeting and the review of the list of the World’s 25 Most Endangered Primates resulted in its official endorsement by the IPS, and became as such a combined endeavor of the Primate Specialist Group, the IPS, and Conservation International. A third revision was carried out at a meeting in August 2004, at the 20th Congress of the IPS in Torino, Italy (Mittermeier et al. 2006). The fourth, covering the biennium 2006–2008, was the result of a meeting held during the 21st Congress of the International Primatological Society (IPS), in Entebbe, Uganda, 26–30 June 2006 (Mittermeier et al. 2007)

Dissociation of tau pathology and neuronal hypometabolism within the ATN framework of Alzheimer’s disease

Alzheimer’s disease (AD) is defined by amyloid (A) and tau (T) pathologies, with T better correlated to neurodegeneration (N). However, T and N have complex regional relationships in part related to non-AD factors that influence N. With machine learning, we assessed heterogeneity in 18F-flortaucipir vs. 18F-fluorodeoxyglucose positron emission tomography as markers of T and neuronal hypometabolism (NM) in 289 symptomatic patients from the Alzheimer’s Disease Neuroimaging Initiative. We identified six T/NM clusters with differing limbic and cortical patterns. The canonical group was defined as the T/NM pattern with lowest regression residuals. Groups resilient to T had less hypometabolism than expected relative to T and displayed better cognition than the canonical group. Groups susceptible to T had more hypometabolism than expected given T and exhibited worse cognitive decline, with imaging and clinical measures concordant with non-AD copathologies. Together, T/NM mismatch reveals distinct imaging signatures with pathobiological and prognostic implications for AD

An \u3cem\u3eIL1RL1\u3c/em\u3e genetic variant lowers soluble ST2 levels and the risk effects of \u3cem\u3eAPOE\u3c/em\u3e-ε4 in female patients with Alzheimer’s disease

Changes in the levels of circulating proteins are associated with Alzheimer’s disease (AD), whereas their pathogenic roles in AD are unclear. Here, we identified soluble ST2 (sST2), a decoy receptor of interleukin-33–ST2 signaling, as a new disease-causing factor in AD. Increased circulating sST2 level is associated with more severe pathological changes in female individuals with AD. Genome-wide association analysis and CRISPR–Cas9 genome editing identified rs1921622, a genetic variant in an enhancer element of IL1RL1, which downregulates gene and protein levels of sST2. Mendelian randomization analysis using genetic variants, including rs1921622, demonstrated that decreased sST2 levels lower AD risk and related endophenotypes in females carrying the Apolipoprotein E (APOE)-ε4 genotype; the association is stronger in Chinese than in European-descent populations. Human and mouse transcriptome and immunohistochemical studies showed that rs1921622/sST2 regulates amyloid-beta (Aβ) pathology through the modulation of microglial activation and Aβ clearance. These findings demonstrate how sST2 level is modulated by a genetic variation and plays a disease-causing role in females with AD

Swallowing, nutrition and patient-rated functional outcomes at 6 months following two non-surgical treatments for T1-T3 oropharyngeal cancer

Altered fractionation radiotherapy with concomitant boost (AFRT-CB) may be considered an alternative treatment for patients not appropriate for chemoradiation (CRT). As functional outcomes following AFRT-CB have been minimally reported, this exploratory paper describes the outcomes of patients managed with AFRT-CB or CRT at 6 months post-treatment