Combined thiazolidinedione-metformin treatment synergistically improves insulin signalling to insulin receptor substrate-1-dependent phosphatidylinositol 3-kinase, atypical protein kinase C and protein kinase B/Akt in human diabetic muscle.

AIMS/HYPOTHESES: Insulin-stimulated glucose transport in muscle is impaired in type 2 diabetes, presumably reflecting reduced activation of atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt). As previously shown, reductions in aPKC activation are seen at sub-maximal and maximal insulin stimulation, reductions in PKB activation are best seen at sub-maximal insulin stimulation and aPKC reductions at maximal insulin are partly improved by thiazolidinedione or metformin treatment. However, effects of combined thiazolidinedione-metformin treatment on aPKC or PKB activation by sub-maximal and maximal insulin are unknown. METHODS: Type 2 diabetic patients were examined before and 5 to 6 weeks after combined thiazolidinedione-metformin therapy for activation of muscle aPKC and PKBbeta and their upstream activators, the insulin receptor (IR) and IRS-1-associated phosphatidylinositol 3-kinase (PI3K), during euglycaemic-hyperinsulinaemic clamp studies conducted with sub-maximal (400-500 pmol/l) and maximal (1400 pmol/l) insulin concentrations. RESULTS: Following combined thiazolidinedione-metformin therapy, increases in glucose disposal and increases in sub-maximal and maximal insulin-induced activities of all four muscle signalling factors, IR, IRS-1-dependent PI3K (IRS-1/PI3K), aPKC and PKBbeta, were observed. Increases in PKBbeta enzyme activity were accompanied by increases in phosphorylation of PKB and its substrate, AS160, which is needed for glucose transport. Despite improved aPKC activity, muscle aPKC levels, which are diminished in type 2 diabetes, were not altered. CONCLUSIONS/INTERPRETATION: Combined thiazolidinedione-metformin treatment markedly improves sub-maximal and maximal insulin signalling to IR, IRS-1/PI3K, aPKC and PKBbeta in type 2 diabetic muscle. These improvements exceed those previously reported after treatment with either agent alone.

Canadian Stroke Best Practice Recommendations for Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care, 6th Edition, Update 2018.

The 2018 update of the Canadian Stroke Best Practice Recommendations for Acute Stroke Management, 6th edition, is a comprehensive summary of current evidence-based recommendations, appropriate for use by healthcare providers and system planners caring for persons with very recent symptoms of acute stroke or transient ischemic attack. The recommendations are intended for use by a interdisciplinary team of clinicians across a wide range of settings and highlight key elements involved in prehospital and Emergency Department care, acute treatments for ischemic stroke, and acute inpatient care. The most notable changes included in this 6th edition are the renaming of the module and its integration of the formerly separate modules on prehospital and emergency care and acute inpatient stroke care. The new module, Acute Stroke Management: Prehospital, Emergency Department, and Acute Inpatient Stroke Care is now a single, comprehensive module addressing the most important aspects of acute stroke care delivery. Other notable changes include the removal of two sections related to the emergency management of intracerebral hemorrhage and subarachnoid hemorrhage. These topics are covered in a new, dedicated module, to be released later this year. The most significant recommendation updates are for neuroimaging; the extension of the time window for endovascular thrombectomy treatment out to 24 h; considerations for treating a highly selected group of people with stroke of unknown time of onset; and recommendations for dual antiplatelet therapy for a limited duration after acute minor ischemic stroke and transient ischemic attack. This module also emphasizes the need for increased public and healthcare provider's recognition of the signs of stroke and immediate actions to take; the important expanding role of paramedics and all emergency medical services personnel; arriving at a stroke-enabled Emergency Department without delay; and launching local healthcare institution code stroke protocols. Revisions have also been made to the recommendations for the triage and assessment of risk of recurrent stroke after transient ischemic attack/minor stroke and suggested urgency levels for investigations and initiation of management strategies. The goal of this updated guideline is to optimize stroke care across Canada, by reducing practice variations and reducing the gap between current knowledge and clinical practice.

Discrete event simulation of patient admissions to a neurovascular unit.

Evidence exists that clinical outcomes improve for stroke patients admitted to specialized Stroke Units. The Toronto Western Hospital created a Neurovascular Unit (NVU) using beds from general internal medicine, Neurology and Neurosurgery to care for patients with stroke and acute neurovascular conditions. Using patient-level data for NVU-eligible patients, a discrete event simulation was created to study changes in patient flow and length of stay pre- and post-NVU implementation. Varying patient volumes and resources were tested to determine the ideal number of beds under various conditions. In the first year of operation, the NVU admitted 507 patients, over 66% of NVU-eligible patient volumes. With the introduction of the NVU, length of stay decreased by around 8%. Scenario testing showed that the current level of 20 beds is sufficient for accommodating the current demand and would continue to be sufficient with an increase in demand of up to 20%.

Salvage of the carotid artery with covered stent after perforation with dialysis sheath. A case report.

We present a rare case of carotid tear caused by iatrogenic erroneous insertion of a dialysis sheath into the common carotid artery (CCA). This was treated by placement of a covered stent-graft in the CCA over the puncture site. This treatment achieved hemostasis while preserving the carotid artery with good outcome. The technical details are presented and the relevant literature regarding treatment of carotid blowout syndrome is discussed. This case suggests that placement of a covered stent-graft is a good option not only for the "usual" blowout syndrome due to head and neck tumors, but also for treatment of iatrogenic injury to the carotid artery.

A 5-item prediction rule to identify severe renal dysfunction in patients with acute stroke.

BACKGROUND AND PURPOSE: Although patients with severe renal dysfunction who receive iodinated contrast are at high risk of CIN, contrast-enhanced CT scans are often obtained without prior knowledge of kidney function in patients with acute stroke. We aimed to develop a tool to identify patients with acute stroke at a high risk of CIN in the absence of a recent GFR. MATERIALS AND METHODS: We used the RCSN (9872 patients) and OSA (2544 patients) for our derivation and validation cohort, respectively. A multivariable logistic regression model was performed to develop a predictive tool to identify severe renal dysfunction (defined as a GFR < 30 mL/min/1.73 m(2)). RESULTS: The overall prevalence of severe renal dysfunction was 4.9% and 5.2% in the derivation and validation cohort, respectively. The prediction rule was designed as follows: (age in years) + (5 points for women) + (5 points for history of diabetes mellitus) + (15 points for preadmission insulin use) + (10 points for history of hypertension). The prevalence of severe renal dysfunction is negligible in patients with a total score of ≤70 (≤0.005%-0.7%) but increases with higher Renal Risk Scores (eg, scores 71-80: 2.1%-2.2%; scores 91-100: 6.6%-7.1%; scores 111-120: 15.9%-28.1%). CONCLUSIONS: The Renal Risk Score is a validated tool that helps clinicians select which patients with stroke can safely proceed to contrast-enhanced brain imaging without waiting for laboratory evidence of good renal function.

Contrasting insulin dose-dependent defects in activation of atypical protein kinase C and protein kinase B/Akt in muscles of obese diabetic humans.

AIMS/HYPOTHESIS: Insulin-stimulated glucose transport in muscle is impaired in obesity and type 2 diabetes, but alterations in levels of relevant signalling factors, i.e. atypical protein kinase C (aPKC) and protein kinase B (PKB/Akt), are still uncertain. Clamp studies using maximal insulin concentrations have revealed defects in activation of aPKC, but not PKB, in both obese non-diabetic and obese diabetic subjects. In contrast, clamp studies using submaximal insulin concentrations revealed defects in PKB activation/phosphorylation in obese non-diabetic and diabetic subjects, but changes in aPKC were not reported. The aim of this study was to test the hypothesis that dose-related effects of insulin may account for the reported differences in insulin signalling to PKB in diabetic muscle. SUBJECTS AND METHODS: We compared enzymatic activation of aPKC and PKB, and PKB phosphorylation (threonine-308 and serine-473) during hyperinsulinaemic-euglycaemic clamp studies using both submaximal (400-500 pmol/l) and maximal (1400 pmol/l) insulin levels in non-diabetic control and obese diabetic subjects. RESULTS: In lean control subjects, the submaximal insulin concentration increased aPKC activity and glucose disposal to approximately 50% of the maximal level and PKBbeta activity to 25% of the maximal level, but PKBalpha activity was not increased. In these subjects, phosphorylation of PKBalpha and PKBbeta was increased to near-maximal levels at submaximal insulin concentrations. In obese diabetic subjects, whereas aPKC activation was defective at submaximal and maximal insulin concentrations, PKBbeta activation and the phosphorylation of PKBbeta and PKBalpha were defective at submaximal, but not maximal, insulin concentrations. CONCLUSIONS/INTERPRETATIONS: Defective PKBbeta activation/phosphorylation, seen on submaximal insulin stimulation in diabetic muscle, may largely reflect impaired activation of insulin signalling factors present in concentrations greater than those needed for full PKB activation/phosphorylation. Defective aPKC activation, seen at all insulin levels, appears to reflect, at least partly, an impaired action of distal factors needed for aPKC activation, or poor aPKC responsiveness.

Expression of the human erythrocyte glucose transporter Glut1 in cutaneous neoplasia.

BACKGROUND: The increased glucose uptake seen in cancer cells correlates with the expression of human erythrocyte glucose transporter (Glut1) protein in certain human malignancies. OBJECTIVE: Our purpose was to determine Glut1 expression in cutaneous neoplasms. METHODS: A polyclonal anti-Glut1 antibody (MYM) and a standard ABC immunoperoxidase technique were used to determine Glut1 expression in invasive squamous cell carcinomas (SCCs), SCC in situ, basal cell carcinomas (BCCs), melanomas, actinic keratoses (AKs), seborrheic keratoses, common acquired nevi, and scars with regenerative epidermal hyperplasia. RESULTS: All of the cases of SCC in situ, 14 of 15 (93%) of the SCC, and 13 of 15 AKs (87%) showed intense membranous staining for Glut1. Glut1 staining was present in the epidermis of 8 of 15 scars (53%) but was not detected in any BCC, even in areas of focal keratinization and squamous metaplasia. Glut1 reactivity was absent in the melanomas and seborrheic keratoses. CONCLUSION: Glut1 expression in a cutaneous lesion strongly suggests a proliferative lesion of the squamous cell type.

The gene responsible for a severe form of peripheral neuropathy and agenesis of the corpus callosum maps to chromosome 15q.

Peripheral neuropathy with or without agenesis of the corpus callosum (ACCPN) is a devastating neurodegenerative disorder that is transmitted as an autosomal recessive trait. Genealogical studies in a large number of affected French Canadian individuals suggest that ACCPN results from a single founder mutation. A genomewide search using 120 microsatellite DNA markers in 14 French Canadian families allowed the mapping of the ACCPN gene to a 5-cM region on chromosome 15q13-q15 that is flanked by markers D15S1040 and D15S118. A maximum two-point LOD score of 11.1 was obtained with the marker D15S971 at a recombination fraction of 0. Haplotype analysis and linkage disequilibrium support a founder effect. These findings are the first step in the identification of the gene responsible for ACCPN, which may shed some light on the numerous conditions associated with the progressive peripheral neuropathy or agenesis of the corpus callosum.

Machado Joseph disease maps to the same region of chromosome 14 as the spinocerebellar ataxia type 3 locus.

Machado Joseph disease (MJD) is an autosomal dominantly inherited neuro-degenerative disorder primarily affecting the motor system. It can be divided into three phenotypes based on the variable combination of a range of clinical symptoms including pyramidal and extra-pyramidal features, cerebellar deficits, and distal muscle atrophy. MJD is thought to be caused by mutation of a single gene which has recently been mapped, using genetic linkage analysis, to a 29 cM region on chromosome 14q24.3-q32 in five Japanese families. A second disorder, spinocerebellar ataxia type 3 (SCA3), which has clinical symptoms similar to MJD, has also been linked to the same region of chromosome 14q in two French families. In order to narrow down the region of chromosome 14 which contains the MJD locus and to determine if this region overlaps with the predisposing locus for SCA3, we have performed genetic linkage analysis in seven MJD families, six of Portuguese/Azorean origin and one of Brazilian origin, using nine microsatellite markers mapped to 14q24.3-q32. Our results localise the MJD locus in these families to an 11 cM interval flanked by the markers D14S68 and AFM343vf1. In addition we show that this 11 cM interval maps within the 15 cM interval containing the SCA3 locus, suggesting that these diseases are allelic.