Case Series of Post-Thrombolysis Patients Undergoing Hemicraniectomy for Malignant Anterior Circulation Ischaemic Stroke

While ischaemic stroke remains a leading cause of death and disability, there have been recent advancements in treatment modalities including thrombolysis and decompressive hemicraniectomy. A retrospective review of patients treated in our NHS teaching hospital, in Plymouth (UK), over a 2 year period identified 17 thrombolysed patients, of whom two had undergone subsequent decompressive hemicraniectomy. These were non-dominant hemisphere strokes in young patients, aged 51 and 57. Initial NIHSS scores were 16 and 17, and they received thrombolysis at 2 hrs 42 min and 5 hrs 10 min post onset of symptoms respectively. CT imaging demonstrated cerebral swelling with significant midline shift in both cases, and decompressive hemicraniectomy was undertaken at 29 hrs 8 min and 27 hrs 30 min post-thrombolysis. We found no significant intra-operative complications attributable to prior use of thrombolytics. Both patients have had acceptable psychological and physical outcomes, with Barthel Index scores of 40 and 25, and MMSE scores of 29/30 and 27/30. We conclude that the use of thrombolytic therapy does not contra-indicate subsequent decompressive hemicraniectomy in well selected patients with non-dominant hemisphere strokes. More research in this field is required to elucidate factors which would facilitate recognition of stroke patients who will benefit most from aggressive medical and neurosurgical intervention

Cerebrospinal fluid opening pressure: The effect of body mass index and body composition

Objectives: Idiopathic intracranial hypertension (IIH) is strongly related to obesity. The relationship between intracranial pressure, body mass index (BMI), percentage body fat and distribution of body fat in non-IIH patients remains less clear. The aim of this study was to examine the relationship between intracranial pressure and body type in non-IIH patients. Patients and Methods: Lumbar puncture manometry was used to measure cerebrospinal fluid opening pressure (CSFOP). BMI, in addition to neck, waist and hip circumferences were Journal Pre-proof calculated. Air displacement plethysmography (BODPOD) was used to assess body composition. Results: Data was collected from 100 subjects. 11 subjects with conditions known to cause raised intracranial pressure were excluded from analysis. According to Pearson correlation factors displaying a significant relationship with CSFOP included: BMI (R = 0.635, p<0.0001); waist circumference (R = 0.498, p<0.0001), hip circumference (R = 0.513, p<0.0001) and percentage body fat (R = 0.435, p<0.001). Multivariate analysis indicated that BMI was the only independent factor which predicted CSFOP. Sub-analysis according to gender indicated that BMI was predictive in females and percentage body fat was predictive in males. We did not identify any differences in BMI, percentage body fat or distribution of body fat in 7 IIH patients and 7 weight-matched non-IIH patients. Conclusion: BMI and %body fat both positively correlated with CSFOP, but BMI was more predictive in women and %body fat was more predictive in men. We did not find a relationship between distribution of body fat and CSFOP

The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Toward a Therapeutic Approach

The Third International Meeting on Genetic Disorders in the RAS/MAPK Pathway: Towards a Therapeutic Approach was held at the Renaissance Orlando at SeaWorld Hotel (August 2-4, 2013). Seventy-one physicians and scientists attended the meeting, and parallel meetings were held by patient advocacy groups (CFC International, Costello Syndrome Family Network, NF Network and Noonan Syndrome Foundation). Parent and patient advocates opened the meeting with a panel discussion to set the stage regarding their hopes and expectations for therapeutic advances. In keeping with the theme on therapeutic development, the sessions followed a progression from description of the phenotype and definition of therapeutic endpoints, to definition of genomic changes, to identification of therapeutic targets in the RAS/MAPK pathway, to preclinical drug development and testing, to clinical trials. These proceedings will review the major points of discussion

Design and in vitro studies of a needle-type glucose sensor for subcutaneous monitoring

International audienceA new miniaturized glucose oxidase based needle-type glu¬ cose mlcrosensor has been developed for subcutaneous glu¬ cose monitoring. The sensor Is equivalent In shape and size to a 26-gauge needle (0.45-mm o.d.) and can be Implanted with ease without any Incision. The novel configuration greatly facilitates the deposition of enzyme and polymer films so that sensors with characteristics suitable for In vivo use (upper limit of linear range > 15 mM, response time 60%). The sensor response is largely Independent of ox¬ ygen tension In the normal physiological range. It also ex¬ hibits good selectivity against common interferences except for the exogenous drug acetaminophen

Overcoming Wnt–β-catenin dependent anticancer therapy resistance in leukaemia stem cells

Leukaemia stem cells (LSCs) underlie cancer therapy resistance but targeting these cells remains difficult. The Wnt–β-catenin and PI3K–Akt pathways cooperate to promote tumorigenesis and resistance to therapy. In a mouse model in which both pathways are activated in stem and progenitor cells, LSCs expanded under chemotherapy-induced stress. Since Akt can activate β-catenin, inhibiting this interaction might target therapy-resistant LSCs. High-throughput screening identified doxorubicin (DXR) as an inhibitor of the Akt–β-catenin interaction at low doses. Here we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. Targeted DXR reduced Akt-activated β-catenin levels in chemoresistant LSCs and reduced LSC tumorigenic activity. Mechanistically, β-catenin binds multiple immune-checkpoint gene loci, and targeted DXR treatment inhibited expression of multiple immune checkpoints specifically in LSCs, including PD-L1, TIM3 and CD24. Overall, LSCs exhibit distinct properties of immune resistance that are reduced by inhibiting Akt-activated β-catenin. These findings suggest a strategy for overcoming cancer therapy resistance and immune escape

Covalent enzyme coupling on cellulose acetate membranes for glucose sensor development

International audienceMethods for immobilizing glucose oxidase (GOx) on cellulose acetate (CA) membranes are compared. The optimal method involves covalent coupling of bovine serum albumin (BSA) to CA membrane and a subsequent reaction of the membrane with GOx, which has previously been activated with an excess of p-benzoquinone. This coupling procedure is fairly reproducible and allows the preparation of thin membranes (5-20 µm) showing high surface activities (1-3 U/cm2) which are stable over a period of 1-3 months. Electrochemical and radiolabeling experiments show that enzyme inactivation as a result of immobilization is negligible. A good correlation between surface activity of membranes and their GOx load is observed

The concept of "compartment allergy": prilocaine injected into different skin layers

We herein present a patient with delayed-type allergic hypersensitivity against prilocaine leading to spreading eczematous dermatitis after subcutaneous injections for local anesthesia with prilocaine. Prilocaine allergy was proven by positive skin testing and subcutaneous provocation, whereas the evaluation of other local anesthetics - among them lidocaine, articaine and mepivacaine - did not exhibit any evidence for cross-reactivity

Screening out irrelevant cell-based models of disease

The common and persistent failures to translate promising preclinical drug candidates into clinical success highlight the limited effectiveness of disease models currently used in drug discovery. An apparent reluctance to explore and adopt alternative cell-and tissue-based model systems, coupled with a detachment from clinical practice during assay validation, contributes to ineffective translational research. To help address these issues and stimulate debate, here we propose a set of principles to facilitate the definition and development of disease-relevant assays, and we discuss new opportunities for exploiting the latest advances in cell-based assay technologies in drug discovery, including induced pluripotent stem cells, three-dimensional (3D) co-culture and organ-on-a-chip systems, complemented by advances in single-cell imaging and gene editing technologies. Funding to support precompetitive, multidisciplinary collaborations to develop novel preclinical models and cell-based screening technologies could have a key role in improving their clinical relevance, and ultimately increase clinical success rates