PIB is a non-specific imaging marker of amyloid-beta (Aβ) peptide-related cerebral amyloidosis

The in vivo imaging probe [11C]-PIB (Pittsburgh Compound B, N-methyl[11C]2-(4′-methylaminophenyl-6-hydroxybenzathiazole) is under evaluation as a key imaging tool in Alzheimer's disease (AD) and to date has been assumed to bind with high affinity and specificity to the amyloid structures associated with classical plaques (CPs), one of the pathological hallmarks of the disease. However, no studies have systematically investigated PIB binding to human neuropathological brain specimens at the tracer concentrations achieved during in vivo imaging scans. Using a combination of autoradiography and histochemical techniques, we demonstrate that PIB, in addition to binding CPs clearly delineates diffuse plaques and cerebrovascular amyloid angiopathy (CAA). The interaction of PIB with CAA was not fully displaceable and this may be linked to the apolipoprotein E-ε4 allele. PIB was also found to label neurofibrillary tangles, although the overall intensity of this binding was markedly lower than that associated with the amyloid-beta (Aβ) pathology. The data provide a molecular explanation for PIB's limited specificity in diagnosing and monitoring disease progression in AD and instead indicate that the ligand is primarily a non-specific marker of Aβ-peptide related cerebral amyloidosi

Understanding the factors that determine workplace coaching effectiveness: a systematic literature review

Meta-analytic results have established that workplace coaching is effective, however, little is known about the determinants of coaching effectiveness. This paper reports an inclusive systematic literature review, covering the quantitative and qualitative research on workplace coaching. We focus on seven promising areas in the current workplace coaching literature that emerged by the synthesis of 117 empirical studies: self-efficacy, coaching motivation, goal orientation, trust, interpersonal attraction, feedback intervention, and supervisory support. The major contribution of our paper is the systematic integration of well-established theoretical constructs in the workplace coaching context and the new insights we provide in the synthesis of these literatures. Based on our review we provide specific recommendations to be addressed in future research, including recommended research methodologies, which we propose will significantly progress the field of workplace coaching theory and practice

Metal Hydrides Form Halogen Bonds: Measurement of Energetics of Binding

The formation of halogen bonds from iodopentafluorobenzene and 1-iodoperfluorohexane to a series of bis(η5-cyclopentadienyl)metal hydrides (Cp2TaH3, 1; Cp2MH2, M = Mo, 2, M = W, 3; Cp2ReH, 4; Cp2Ta(H)CO, 5; Cp = η5-cyclopentadienyl) is demonstrated by 1H NMR spectroscopy. Interaction enthalpies and entropies for complex 1 with C6F5I and C6F13I are reported (ΔH° = −10.9 ± 0.4 and −11.8 ± 0.3 kJ/mol; ΔS° = −38 ± 2 and −34 ± 2 J/(mol·K), respectively) and found to be stronger than those for 1 with the hydrogen-bond donor indole (ΔH° = −7.3 ± 0.1 kJ/mol, ΔS° = −24 ± 1 J/(mol·K)). For the more reactive complexes 2–5, measurements are limited to determination of their low-temperature (212 K) association constants with C6F5I as 2.9 ± 0.2, 2.5 ± 0.1, <1.5, and 12.5 ± 0.3 M–1, respectively

Safety profile of the newest antiepileptic drugs: a curated literature review

BACKGROUND: Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remain unsatisfactory. In addition, whilst several antiepileptic drugs (AEDs) have been approved and consequently marketed in recent years, little is known about their long-term safety and tolerability. Availability of the newest AEDs, characterized by improved pharmacokinetic profiles, has positively impacted the treatment approach for patients with partial seizures in clinical practice. However, the main cause of treatment failure is still poor patient compliance due to the occurrence of adverse drug reactions (ADRs) that lead to treatment withdrawal in about 25% of cases before achieving maximal efficacy, and is associated with increasing health care costs. METHODS: In this Review, we conducted an online database search using Medline, PubMed, Embase, and the Cochrane Online Library to review the available studies highlighting the clinical relevance of side effects, pharmacological interactions, safety and tolerability of the newest AEDs: Brivaracetam (BRV), Cannabidiol (CBD), Eslicarbazepine acetate (ESL), Lacosamide (LCM), and Perampanel (PER). RESULTS: The principal benefit of the newest AEDs, in addition to reduced frequency and seizure severity, is the low number and severity of ADRs reported compared to more historic drugs. CONCLUSION: Early detection of ADRs could lead to an improvement in patients' quality of life, therefore it is important to monitor ADRs and to adequately perform post marketing surveillance in the clinical practice setting

Regulation of microRNA biogenesis and turnover by animals and their viruses

Item does not contain fulltextMicroRNAs (miRNAs) are a ubiquitous component of gene regulatory networks that modulate the precise amounts of proteins expressed in a cell. Despite their small size, miRNA genes contain various recognition elements that enable specificity in when, where and to what extent they are expressed. The importance of precise control of miRNA expression is underscored by functional studies in model organisms and by the association between miRNA mis-expression and disease. In the last decade, identification of the pathways by which miRNAs are produced, matured and turned-over has revealed many aspects of their biogenesis that are subject to regulation. Studies in viral systems have revealed a range of mechanisms by which viruses target these pathways through viral proteins or non-coding RNAs in order to regulate cellular gene expression. In parallel, a field of study has evolved around the activation and suppression of antiviral RNA interference (RNAi) by viruses. Virus encoded suppressors of RNAi can impact miRNA biogenesis in cases where miRNA and small interfering RNA pathways converge. Here we review the literature on the mechanisms by which miRNA biogenesis and turnover are regulated in animals and the diverse strategies that viruses use to subvert or inhibit these processes

New understandings of the genetic basis of isolated idiopathic central hypogonadism

Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network

Buffered memory: a hypothesis for the maintenance of functional, virus-specific CD8(+) T cells during cytomegalovirus infection.

Chronic infections have been a major topic of investigation in recent years, but the mechanisms that dictate whether or not a pathogen is successfully controlled are incompletely understood. Cytomegalovirus (CMV) is a herpesvirus that establishes a persistent infection in the majority of people in the world. Like other herpesviruses, CMV is well controlled by an effective immune response and induces little, if any, pathology in healthy individuals. However, controlling CMV requires continuous immune surveillance, and thus, CMV is a significant cause of morbidity and death in immune-compromised individuals. T cells in particular play an important role in controlling CMV and both CD4(+) and CD8(+) CMV-specific T cells are essential. These virus-specific T cells persist in exceptionally large numbers during the infection, traffic into peripheral tissues and remain functional, making CMV an attractive vaccine vector for driving CMV-like T cell responses against recombinant antigens of choice. However, the mechanisms by which these T cells persist and differentiate while remaining functional are still poorly understood, and we have no means to promote their development in immune-compromised patients at risk for CMV disease. In this review, I will briefly summarize our current knowledge of CMV-specific CD8(+) T cells and propose a mechanism that may explain their maintenance and preservation of function during chronic infection

Disclosure of plasma p-tau217 measure improves diagnostic confidence in patients with Alzheimer's disease versus syndromes associated with frontotemporal lobar degeneration

Introduction: Further research is needed to understand the performance of plasma phosphorylated tau (p-tau)217 in the diagnostic thinking at the individual patient level. We evaluated the incremental diagnostic value of plasma p-tau217, expressed in terms of diagnostic confidence of Alzheimer's disease (DCAD; range 0-100). Methods: Two hundred thirty-two patients with dementia were included and scored in terms of DCAD in a three-step consecutive assessment: (1) clinical work-up, (2) clinical work-up plus plasma p-tau217, and (3) clinical work-up, plasma p-tau217, plus conventional amyloid markers. Two blinded neurologists were asked to review DCAD at each step. Results: DCAD accuracy, expressed as area under the curve, significantly increased from 0.93 with clinical work-up alone, to 0.97 with clinical work-up plus plasma p-tau217 (P = 0.01), with no further increase with the addition of conventional amyloid markers (0.99, P = 0.13). Discussion: Plasma p-tau217 in addition to routine assessment significantly enhances diagnostic confidence that is comparable to well-established amyloidosis biomarkers. Highlights: Plasma phosphorylated tau (p-tau)217 measurements increase diagnostic confidence of Alzheimer's disease. Plasma p-tau217 increases diagnostic confidence comparable to traditional markers. Plasma p-tau217 dosage may be helpful in addition to routine assessment

New understandings of the genetic basis of isolated idiopathic central hypogonadism

Idiopathic hypogonadotropic hypogonadism is a rare disease that is characterized by delayed/absent puberty and/or infertility due to an insufficient stimulation of an otherwise normal pituitary-gonadal axis by gonadotrophin-releasing hormone (GnRH) action. Because reduced or normal luteinizing hormone (LH)/follicle-stimulating hormone (FSH) levels may be observed in the affected patients, the term idiopathic central hypogonadism (ICH) appears to be more appropriate. This disease should be distinguished from central hypogonadism that is combined with other pituitary deficiencies. Isolated ICH has a complex pathogenesis and is fivefold more prevalent in males. ICH frequently appears in a sporadic form, but several familial cases have also been reported. This finding, in conjunction with the description of numerous pathogenetic gene variants and the generation of several knockout models, supports the existence of a strong genetic component. ICH may be associated with several morphogenetic abnormalities, which include osmic defects that, with ICH, constitute the cardinal manifestations of Kallmann syndrome (KS). KS accounts for approximately 40% of the total ICH cases and has been generally considered to be a distinct subgroup. However, the description of several pedigrees, which include relatives who are affected either with isolated osmic defects, KS, or normo-osmic ICH (nICH), justifies the emerging idea that ICH is a complex genetic disease that is characterized by variable expressivity and penetrance. In this context, either multiple gene variants or environmental factors and epigenetic modifications may contribute to the variable disease manifestations. We review the genetic mechanisms that are presently known to be involved in ICH pathogenesis and provide a clinical overview of the 227 cases that have been collected by the collaborating centres of the Italian ICH Network