Cataract-associated P23T γ 3D-crystallin retains a native-like fold in amorphous-looking aggregates formed at physiological pH

Cataracts cause vision loss through the large-scale aggregation of eye lens proteins as a result of ageing or congenital mutations. The development of new treatments is hindered by uncertainty about the nature of the aggregates and their mechanism of formation. We describe the structure and morphology of aggregates formed by the P23T human Î 3D-crystallin mutant associated with congenital cataracts. At physiological pH, the protein forms aggregates that look amorphous and disordered by electron microscopy, reminiscent of the reported formation of amorphous deposits by other crystallin mutants. Surprisingly, solid-state NMR reveals that these amorphous deposits have a high degree of structural homogeneity at the atomic level and that the aggregated protein retains a native-like conformation, with no evidence for large-scale misfolding. Non-physiological destabilizing conditions used in many in vitro aggregation studies are shown to yield qualitatively different, highly misfolded amyloid-like fibrils

A successfully treated case of herpes simplex encephalitis complicated by subarachnoid bleeding: a case report

<p>Abstract</p> <p>Introduction</p> <p>Histopathologically, herpes simplex virus type 1 causes hemorrhagic necrosis. Overt hemorrhage is infrequent in herpes simplex virus encephalitis but can lead to poor outcomes. This report describes a successfully treated case of herpes simplex virus encephalitis associated with subarachnoid bleeding in which real-time polymerase chain reaction was useful for diagnosis.</p> <p>Case presentation</p> <p>A 30-year-old previously healthy Japanese woman who had fever and headache for five days presented with disorganised speech, unusual behavior and delusional thinking. Real-time polymerase chain reaction amplification of herpes simplex virus type 1 in cerebrospinal fluid was positive (38,000 copies/mL) and antivirus treatment was started. During the course of her illness, the level of her consciousness decreased in association with desaturation and tachycardia. Thrombosis of the right pulmonary artery trunk with pulmonary embolism was evident on enhanced chest computed tomography. In addition, cranial computed tomography revealed subarachnoid and intraventricular bleeding. Intravenous heparin (12,000 U/day) was started and the dose was adjusted according to the activated partial thromboplastin time for about a month (maximum dose of heparin, 20,400 U/day). After the treatments, her Glasgow coma score increased and the thrombosis of the pulmonary artery trunk had disappeared.</p> <p>Conclusions</p> <p>The present case raises the question of whether anticoagulant treatment is safe in patients with herpes simplex virus encephalitis complicated by subarachnoid bleeding.</p

Do pediatricians manage influenza differently than internists?

<p>Abstract</p> <p>Background</p> <p>Little is known about how pediatricians or internists manage influenza symptoms. Recent guidelines on antiviral prescribing by the Centers for Disease Control and Prevention (CDC) make almost no distinction between adults and children. Our objective was to describe how pediatricians in two large academic medical institutions manage influenza and compare them to internists.</p> <p>Methods</p> <p>At the end of the 2003–4 influenza season, we conducted a cross sectional on-line survey of physician knowledge, attitudes and practices regarding rapid diagnostic testing and use of antiviral therapy for influenza at two large academic medical centers, one in Massachusetts and the other in Texas. We collected data on self-reported demographics, test use, prescribing practices, and beliefs about influenza and anti-influenza drugs.</p> <p>Results</p> <p>A total of 107 pediatricians and 103 internists completed the survey (response rate of 53%). Compared to internists, pediatricians were more likely to perform rapid testing (74% vs. 47%, p < 0.0001), to use amantadine (88% vs. 48%, p < 0.0001), to restrict their prescribing to high-risk patients (86% vs. 53%, p < 0.0001), and to believe that antiviral therapy could decrease mortality (38% vs. 22%, p = 0.01). Other beliefs about antiviral therapy did not differ statistically between the specialties. Internists were more likely to be unfamiliar with rapid testing or not to have it available.</p> <p>Conclusion</p> <p>Pediatricians and internists manage influenza differently. Evidence-based guidelines addressing the specific concerns of each group would be helpful.</p

Structure and Dynamics of the G121V Dihydrofolate Reductase Mutant: Lessons from a Transition-State Inhibitor Complex

It is well known that enzyme flexibility is critical for function. This is due to the observation that the rates of intramolecular enzyme motions are often matched to the rates of intermolecular events such as substrate binding and product release. Beyond this role in progression through the reaction cycle, it has been suggested that enzyme dynamics may also promote the chemical step itself. Dihydrofolate reductase (DHFR) is a model enzyme for which dynamics have been proposed to aid in both substrate flux and catalysis. The G121V mutant of DHFR is a well studied form that exhibits a severe reduction in the rate of hydride transfer yet there remains dispute as to whether this defect is caused by altered structure, dynamics, or both. Here we address this by presenting an NMR study of the G121V mutant bound to reduced cofactor and the transition state inhibitor, methotrexate. NMR chemical shift markers demonstrate that this form predominantly adopts the closed conformation thereby allowing us to provide the first glimpse into the dynamics of a catalytically relevant complex. Based on 15N and 2H NMR spin relaxation, we find that the mutant complex has modest changes in ps-ns flexibility with most affected residues residing in the distal adenosine binding domain rather than the active site. Thus, aberrant ps-ns dynamics are likely not the main contributor to the decreased catalytic rate. The most dramatic effect of the mutation involves changes in µs-ms dynamics of the F-G and Met20 loops. Whereas loop motion is quenched in the wild type transition state inhibitor complex, the F-G and Met20 loops undergo excursions from the closed conformation in the mutant complex. These excursions serve to decrease the population of conformers having the correct active site configuration, thus providing an explanation for the G121V catalytic defect

The impact of herpes zoster and post-herpetic neuralgia on quality-of-life

International audienceBACKGROUND: The potentially serious nature of herpes zoster (HZ) and the long-term complication post-herpetic neuralgia (PHN) are often underestimated. One in four people will contract herpes zoster in their lifetime, with this risk rising markedly after the age of 50 years, and affecting one in two in elderly individuals. Pain is the predominant symptom in all phases of HZ disease, being reported by up to 90% of patients. In the acute phase, pain is usually moderate or severe, with patients ranking HZ pain as more intense than post-surgical or labour pains. Up to 20% of patients with HZ develop PHN, which is moderate-to-severe chronic pain persisting for months or years after the acute phase. We review the available data on the effect of HZ and PHN on patients' quality-of-life. DISCUSSION: Findings show that HZ, and particularly PHN, have a major impact on patients' lives across all four health domains--physical, psychological, functional and social. There is a clear correlation between increasing severity of pain and greater interference with daily activities. Non-pain complications such as HZ ophthalmicus can increase the risk of permanent physical impairment. Some elderly individuals may experience a permanent loss of independence after an acute episode of HZ. Current challenges in the management of HZ and PHN are highlighted, including the difficulty in administering antiviral agents before pain becomes established and the limited efficacy of pain treatments in many patients. We discuss the clinical rationale for the HZ vaccine and evidence demonstrating that the vaccine reduces the burden of the disease. The Shingles Prevention Study, conducted among >38,000 people aged >or=60 years old, showed that the HZ vaccine significantly reduces the burden of illness and the incidence of both HZ and PHN. In the entire study population, zoster vaccination reduced the severity of interference of HZ and PHN with activities of daily living by two-thirds, as measured by two questionnaires specific to HZ. SUMMARY: A vaccination scheme may positively impact the incidence and course of HZ disease, thereby improving patients' quality-of-life

Convergence versus Divergence: Testing Varieties of Capitalism Perspective on the Globalization of Business Practices

This paper analyses links between intra-organizational adaptation and institutional variation across countries. Using the varieties of capitalism viewpoint, we examine strategic options open to multinational firms operating simultaneously in liberal market economies and coordinated market economies. A holistic perspective is achieved by implementing an original ‘index of institutional impact.’ Data are drawn from a survey of the subsidiaries of German firms in the UK in 2007. The results suggest that pressure towards accepting local practices for multinational firms varies across the dimensions in which firms resolve coordination problems, inciting speedy convergence in some, but allowing for maintaining distinctive practices in other

Acupuncture for the treatment of severe acute pain in Herpes Zoster: results of a nested, open-label, randomized trial in the VZV Pain Study

<p>Abstract</p> <p>Background</p> <p>Data on the potential efficacy of acupuncture (AC) in controlling intense or very intense pain in patients with Herpes Zoster (HZ) has not been so far adequately assessed in comparison with standard pharmacological treatment (ST) by a controlled trial design.</p> <p>Methods</p> <p>Within the VZV Pescara study, pain was assessed in HZ patients on a Visual Analogue Scale (VAS) and by the McGill Pain Questionnaire (MPQ) both at the beginning and at the end of treatment. Response rates, mean changes in pain intensity, differences in total pain burden with an area-under-the-curve (AUC) method over a 1-year follow-up and differences in the incidence of Post-Herpetic Neuralgia (PHN) were evaluated.</p> <p>Results</p> <p>One hundred and two patients were randomized to receive either AC (n = 52) or ST (n = 50) for 4 weeks. Groups were comparable regarding age, sex, pain intensity at presentation and missed antiviral prescription. Both interventions were largely effective. No significant differences were observed in response rates (81.6% vs 89.2%, p = 0.8), mean reduction of VAS (4.1 +/- 2.3 vs 4.9 +/- 1.9, p = 0.12) and MPQ scores (1.3 +/- 0.9 vs 1.3 +/- 0.9, p = 0.9), incidence of PHN after 3 months (48.4% vs 46.8%, p = 0.5), and mean AUC during follow-up (199 +/- 136 vs 173 +/- 141, p = 0.4). No serious treatment-related adverse event was observed in both groups.</p> <p>Conclusions</p> <p>This controlled and randomized trial provides the first evidence of a potential role of AC for the treatment of acute herpetic pain.</p> <p>Trial registration</p> <p>ChiCTR-TRC-10001146.</p

The Past and Future of Evolutionary Economics : Some Reflections Based on New Bibliometric Evidence

This document is the Accepted Manuscript version of the following article: Geoffrey M. Hodgson, and Juha-Antti Lamberg, ‘The past and future of evolutionary economics: some reflections based on new bibliometric evidence’, Evolutionary and Institutional Economics Review, first online 20 June 2016. The final publication is available at Springer via doi: http://dx.doi.org/10.1007/s40844-016-0044-3 © Japan Association for Evolutionary Economics 2016The modern wave of ‘evolutionary economics’ was launched with the classic study by Richard Nelson and Sidney Winter (1982). This paper reports a broad bibliometric analysis of ‘evolutionary’ research in the disciplines of management, business, economics, and sociology over 25 years from 1986 to 2010. It confirms that Nelson and Winter (1982) is an enduring nodal reference point for this broad field. The bibliometric evidence suggests that ‘evolutionary economics’ has benefitted from the rise of business schools and other interdisciplinary institutions, which have provided a home for evolutionary terminology, but it has failed to nurture a strong unifying core narrative or theory, which in turn could provide superior answers to important questions. This bibliometric evidence also shows that no strong cluster of general theoretical research immediately around Nelson and Winter (1982) has subsequently emerged. It identifies developmental problems in a partly successful but fragmented field. Future research in ‘evolutionary economics’ needs a more integrated research community with shared conceptual narratives and common research questions, to promote conversation and synergy between diverse clusters of research.Peer reviewedFinal Accepted Versio