Clinical and instrumental evaluation of Botulinum Toxin type A safety profile in post stroke spasticity rehabilitation treatment

Post stroke spasticity (PSS) occurs approximately in 30% of stroke survivors. Spasticity varies from a subtle neurological sign to a gross increase in tone causing immobility of joints. PSS is associated with several complications, increasing care needs and utilisation of healthcare resources. Botulinum toxin type A (BoNT-A) has been considered as an effective and safe treatment for focal spasticity in stroke survivors, with low prevalence of complications, reversibility of effect, and efficacy in reducing spastic hypertonia. Recent studies estimated that a significant percentage of patients affected by PSS could benefit from higher doses than those permitted by current country directives. However, at present time, there is no general consensus on the maximum dose of BoNT-A in terms of safety and clinical interchangeability among the three commercially approved products (abobotulinumtoxinA, onabotulinumtoxinA, incobotulinumtoxinA). In light of these considerations, the aim of this thesis is to investigate the safety profile of BoNT-A high doses in the treatment of post stroke spasticity. In our research activity we investigated the clinical effect of this treatment in severely affected patients, focusing on both clinical and instrumental assessment of systemic effects of BoNT-A

ABC-F proteins mediate antibiotic resistance through ribosomal protection

Members of the ABC-F subfamily of ATP-binding cassette proteins mediate resistance to a broad array of clinically important antibiotic classes that target the ribosome of Gram positive pathogens. The mechanism by which these proteins act has been a subject of long-standing controversy, with two competing hypotheses each having gained considerable support: antibiotic efflux versus ribosomal protection. Here, we report on studies employing a combination of bacteriological and biochemical techniques to unravel the mechanism of resistance of these proteins, and provide several lines of evidence that together offer clear support to the ribosomal protection hypothesis. Of particular note, we show that addition of purified ABC-F proteins to an in vitro translation assay prompts dose-dependent rescue of translation, and demonstrate that such proteins are capable of displacing antibiotic from the ribosome in vitro. To our knowledge, these experiments constitute the first direct evidence that ABC-F proteins mediate antibiotic resistance through ribosomal protection

Quantum phase transition in a single-molecule quantum dot

Quantum criticality is the intriguing possibility offered by the laws of quantum mechanics when the wave function of a many-particle physical system is forced to evolve continuously between two distinct, competing ground states. This phenomenon, often related to a zero-temperature magnetic phase transition, can be observed in several strongly correlated materials such as heavy fermion compounds or possibly high-temperature superconductors, and is believed to govern many of their fascinating, yet still unexplained properties. In contrast to these bulk materials with very complex electronic structure, artificial nanoscale devices could offer a new and simpler vista to the comprehension of quantum phase transitions. This long-sought possibility is demonstrated by our work in a fullerene molecular junction, where gate voltage induces a crossing of singlet and triplet spin states at zero magnetic field. Electronic tunneling from metallic contacts into the $\rm{C_{60}}$ quantum dot provides here the necessary many-body correlations to observe a true quantum critical behavior.Comment: 8 pages, 5 figure

Hypersensitive K303R oestrogen receptor-α variant not found in invasive carcinomas

INTRODUCTION: Genetic abnormalities or mutations in premalignant breast lesions may have a role in progression toward malignancy or influence the behaviour of subsequent disease. The A908G (Lys303→Arg) change in the gene encoding oestrogen receptor-α (ER-α) creates a hypersensitivity to oestradiol and would have significant consequences if present in breast carcinoma, especially those treated with endocrine therapy. We have therefore examined a panel of endocrine-treated invasive carcinomas for the presence of this mutation. METHODS: Sequencing of control DNA was shown to detect mutation present in as little as 15% of the starting material. Enrichment for the mutation by using MboII restriction digestion allowed the detection of mutant present at 1% or less. We applied these techniques to genomic DNA and cDNA from 136 invasive breast carcinomas. RESULTS: No evidence of the A908G mutation was found with either technique. The incidence of this mutation in our panel of tumours is therefore significantly less than previously reported. CONCLUSION: The fact that the mutation was not found leads us to believe that this mutation is absent from most cells in invasive carcinomas and furthermore that the major expression product of the ER-α gene in cancers does not contain the K303R mutation. It is therefore unlikely to influence the effectiveness of endocrine treatment

Ulceration of the oral mucosa induced by antidepressant medication: a case report

<p>Abstract</p> <p>Introduction</p> <p>Ulcers are frequent lesions of the oral mucosa. Generally, they are circumscribed round or elliptical lesions surrounded by an erythematous halo and covered with an inflammatory exudate in their central portion, and are accompanied by painful symptoms. Oral ulcers affect 20% of the population, especially adolescents and young adults. The etiopathogenesis includes immunological alterations, infections, nutritional deficiency, trauma, food and contact allergies, autoimmune diseases, neoplasms, and psychosomatic, genetic and environmental factors.</p> <p>Case presentation</p> <p>A 78-year-old Caucasian woman was referred by her dentist to our outpatient clinic with a 4-week history of an oral ulceration after using an antidepressant (sertraline hydrochloride). On the basis of the clinical findings and anamnesis, the occurrence of the lesion was attributed to the use of the drug. Exfoliative cytology was performed, to reassure the patient that it was not oral cancer, which revealed the presence of a nonspecific inflammatory reaction. The drug was replaced and resolution of symptoms was observed.</p> <p>Conclusion</p> <p>Exfoliative cytology should be the complementary examination of choice in cases of oral ulcers with a suspicion of drug interaction. Although this is a rare event in dental practice, dentists should be aware of the diagnostic possibility of drug-induced ulcers and should cooperate with the clinician to adjust the prescribed medication to resolve the symptoms.</p

The Surgical Infection Society revised guidelines on the management of intra-abdominal infection

Background: Previous evidence-based guidelines on the management of intra-abdominal infection (IAI) were published by the Surgical Infection Society (SIS) in 1992, 2002, and 2010. At the time the most recent guideline was released, the plan was to update the guideline every five years to ensure the timeliness and appropriateness of the recommendations. Methods: Based on the previous guidelines, the task force outlined a number of topics related to the treatment of patients with IAI and then developed key questions on these various topics. All questions were approached using general and specific literature searches, focusing on articles and other information published since 2008. These publications and additional materials published before 2008 were reviewed by the task force as a whole or by individual subgroups as to relevance to individual questions. Recommendations were developed by a process of iterative consensus, with all task force members voting to accept or reject each recommendation. Grading was based on the GRADE (Grades of Recommendation Assessment, Development, and Evaluation) system; the quality of the evidence was graded as high, moderate, or weak, and the strength of the recommendation was graded as strong or weak. Review of the document was performed by members of the SIS who were not on the task force. After responses were made to all critiques, the document was approved as an official guideline of the SIS by the Executive Council. Results: This guideline summarizes the current recommendations developed by the task force on the treatment of patients who have IAI. Evidence-based recommendations have been made regarding risk assessment in individual patients; source control; the timing, selection, and duration of antimicrobial therapy; and suggested approaches to patients who fail initial therapy. Additional recommendations related to the treatment of pediatric patients with IAI have been included. Summary: The current recommendations of the SIS regarding the treatment of patients with IAI are provided in this guideline

Structure of HsdS Subunit from Thermoanaerobacter tengcongensis Sheds Lights on Mechanism of Dynamic Opening and Closing of Type I Methyltransferase

Type I DNA methyltransferases contain one specificity subunit (HsdS) and two modification subunits (HsdM). The electron microscopy model of M.EcoKI-M2S1 methyltransferase shows a reasonable closed state of this clamp-like enzyme, but the structure of the open state is still unclear. The 1.95 Å crystal structure of the specificity subunit from Thermoanaerobacter tengcongensis (TTE-HsdS) shows an unreported open form inter-domain orientation of this subunit. Based on the crystal structure of TTE-HsdS and the closed state model of M.EcoKI-M2S1, we constructed a potential open state model of type I methyltransferase. Mutational studies indicated that two α-helices (aa30-59 and aa466-495) of the TTE-HsdM subunit are important inter-subunit interaction sites in the TTE-M2S1 complex. DNA binding assays also highlighted the importance of the C-terminal region of TTE-HsdM for DNA binding by the TTE-M2S1 complex. On the basis of structural analysis, biochemical experiments and previous studies, we propose a dynamic opening and closing mechanism for type I methyltransferase

Identification of features of electronic prescribing systems to support quality and safety in primary care using a modified Delphi process

<p>Abstract</p> <p>Background</p> <p>Electronic prescribing is increasingly being used in primary care and in hospitals. Studies on the effects of e-prescribing systems have found evidence for both benefit and harm. The aim of this study was to identify features of e-prescribing software systems that support patient safety and quality of care and that are useful to the clinician and the patient, with a focus on improving the quality use of medicines.</p> <p>Methods</p> <p>Software features were identified by a literature review, key informants and an expert group. A modified Delphi process was used with a 12-member multidisciplinary expert group to reach consensus on the expected impact of the features in four domains: patient safety, quality of care, usefulness to the clinician and usefulness to the patient. The setting was electronic prescribing in general practice in Australia.</p> <p>Results</p> <p>A list of 114 software features was developed. Most of the features relate to the recording and use of patient data, the medication selection process, prescribing decision support, monitoring drug therapy and clinical reports. The expert group rated 78 of the features (68%) as likely to have a high positive impact in at least one domain, 36 features (32%) as medium impact, and none as low or negative impact. Twenty seven features were rated as high positive impact across 3 or 4 domains including patient safety and quality of care. Ten features were considered "aspirational" because of a lack of agreed standards and/or suitable knowledge bases.</p> <p>Conclusions</p> <p>This study defines features of e-prescribing software systems that are expected to support safety and quality, especially in relation to prescribing and use of medicines in general practice. The features could be used to develop software standards, and could be adapted if necessary for use in other settings and countries.</p

The Cow: Discovery of a Luminous, Hot, and Rapidly Evolving Transient

We present the ATLAS discovery and initial analysis of the first 18 days of the unusual transient event, ATLAS18qqn/AT2018cow. It is characterized by a high peak luminosity (~1.7 × 1044 erg s−1), rapidly evolving light curves (>5 mag rise to peak in ~3.5 days), and hot blackbody spectra, peaking at ~27,000 K that are relatively featureless and unchanging over the first two weeks. The bolometric light curve cannot be powered by radioactive decay under realistic assumptions. The detection of high-energy emission may suggest a central engine as the powering source. Using a magnetar model, we estimated an ejected mass of 0.1–0.4 M ${}_{\odot }$, which lies between that of low-energy core-collapse events and the kilonova, AT2017gfo. The spectra cooled rapidly from 27,000 to 15,000 K in just over two weeks but remained smooth and featureless. Broad and shallow emission lines appear after about 20 days, and we tentatively identify them as He i although they would be redshifted from their rest wavelengths. We rule out that there are any features in the spectra due to intermediate mass elements up to and including the Fe group. The presence of r-process elements cannot be ruled out. If these lines are due to He, then we suggest a low-mass star with residual He as a potential progenitor. Alternatively, models of magnetars formed in neutron star mergers, or accretion onto a central compact object, give plausible matches to the data

The Keele community knee pain forum: action research to engage with stakeholders about the prevention of knee pain and disability

<p>Abstract</p> <p>Background</p> <p>Involvement of users in health care research is central to UK health care policy, and guidelines for involvement exist. However, there are limited examples in rheumatology research. The aim of this study was to establish a community knee pain forum aimed at engaging stakeholders in design, dissemination and prioritisation of knee pain research.</p> <p>Methods</p> <p>Ten people were recruited to the forum representing a wide range of agencies. These included Weight Watchers, the leisure industry, Beth Johnson Foundation, health and social care professionals and the public. Three two-hour meetings over a two-year period were held. Experienced qualitative researchers facilitated each meeting. Written feedback after each meeting was elicited, and a short evaluation form was mailed to all members after the final meeting.</p> <p>Results</p> <p>Establishing and maintaining a forum of mixed members required careful preparation and ongoing support. Meetings had to be well-structured in order to allow for balanced participation of lay and professional users. Users contributed to the design of methods, provided ideas for dissemination and set priorities for further research. Clear documentation of meetings ensured that users' contributions to the research cycle were transparent.</p> <p>Conclusion</p> <p>Our knee pain forum illustrates that community engagement can have a positive impact on the development, dissemination and implementation of health research. Engaging with non-academic partners enables mutual learning and this enhances the quality of NHS research.</p