The impact of cardiovascular co-morbidities and duration of diabetes on the association between microvascular function and glycaemic control.

BACKGROUND: Good glycaemic control in type 2 diabetes (T2DM) protects the microcirculation. Current guidelines suggest glycaemic targets be relaxed in advanced diabetes. We explored whether disease duration or pre-existing macrovascular complications attenuated the association between hyperglycaemia and microvascular function. METHODS: 743 participants with T2DM (n = 222), cardiovascular disease (CVD = 183), both (n = 177) or neither (controls = 161) from two centres in the UK, underwent standard clinical measures and endothelial dependent (ACh) and independent (SNP) microvascular function assessment using laser Doppler imaging. RESULTS: People with T2DM and CVD had attenuated ACh and SNP responses compared to controls. This was additive in those with both (ANOVA p < 0.001). In regression models, cardiovascular risk factors accounted for attenuated ACh and SNP responses in CVD, whereas HbA1c accounted for the effects of T2DM. HbA1c was associated with ACh and SNP response after adjustment for cardiovascular risk factors (adjusted standardised beta (ß) -0.096, p = <0.008 and -0.135, p < 0.001, respectively). Pre-existing CVD did not modify this association (ß -0.099; p = 0.006 and -0.138; p < 0.001, respectively). Duration of diabetes accounted for the association between HbA1c and ACh (ß -0.043; p = 0.3), but not between HbA1c and SNP (ß -0.105; p = 0.02). CONCLUSIONS: In those with T2DM and CVD, good glycaemic control is still associated with better microvascular function, whereas in those with prolonged disease this association is lost. This suggests duration of diabetes may be a better surrogate for "advanced disease" than concomitant CVD, although this requires prospective validation.

Ru-catalysed C-H silylation of unprotected gramines, tryptamines and their congeners.

Selective Ru-catalysed C2-H silylation of heteroarenes is presented. The transformation works with or without directing group assistance and requires no protecting groups. Gramines and tryptamines may be converted efficiently whilst avoiding deleterious elimination side-reactions. Mechanistic studies reveal an unusual activation of the indole C4-H bond by an electron-rich metal.

Exercise intensity and the protection from postprandial vascular dysfunction in adolescents.

Acute exercise transiently improves endothelial function and protects the vasculature from the deleterious effects of a high-fat meal (HFM). We sought to identify whether this response is dependent on exercise intensity in adolescents. Twenty adolescents (10 male, 14.3 ± 0.3 yr) completed three 1-day trials: 1) rest (CON); 2) 8 × 1 min cycling at 90% peak power with 75 s recovery [high-intensity interval exercise (HIIE)]; and 3) cycling at 90% of the gas exchange threshold [moderate-intensity exercise (MIE)] 1 h before consuming a HFM (1.50 g/kg fat). Macrovascular and microvascular endothelial function was assessed before and immediately after exercise and 3 h after the HFM by flow-mediated dilation (FMD) and laser Doppler imaging [peak reactive hyperemia (PRH)]. FMD and PRH increased 1 h after HIIE [P < 0.001, effect size (ES) = 1.20 and P = 0.048, ES = 0.56] but were unchanged after MIE. FMD and PRH were attenuated 3 h after the HFM in CON (P < 0.001, ES = 1.78 and P = 0.02, ES = 0.59). FMD remained greater 3 h after the HFM in HIIE compared with MIE (P < 0.001, ES = 1.47) and CON (P < 0.001, ES = 2.54), and in MIE compared with CON (P < 0.001, ES = 1.40). Compared with CON, PRH was greater 3 h after the HFM in HIIE (P = 0.02, ES = 0.71) and MIE (P = 0.02, ES = 0.84), with no differences between HIIE and MIE (P = 0.72, ES = 0.16). Plasma triacylglycerol concentration and total antioxidant status concentration were not different between trials. We conclude that exercise intensity plays an important role in protecting the vasculature from the deleterious effects of a HFM. Performing HIIE may provide superior vascular benefits than MIE in adolescent groups.

Measures of atherosclerotic burden are associated with clinically manifest cardiovascular disease in type 2 diabetes: a European cross-sectional study.

BACKGROUND: There is a need to develop and validate surrogate markers of cardiovascular disease (CVD) in subjects with diabetes. The macrovascular changes associated with diabetes include aggravated atherosclerosis, increased arterial stiffness and endothelial dysfunction. The aim of this study was to determine which of these factors is most strongly associated with clinically manifest cardiovascular events. METHODS: Vascular changes were measured in a cohort of 458 subjects with type 2 diabetes (T2D) and CVD (myocardial infarction, stroke or lower extremity arterial disease), 527 subjects with T2D but without clinically manifest CVD and 515 subjects without T2D and with or without CVD. RESULTS: Carotid intima-media thickness (IMT) and ankle-brachial pressure index were independently associated with the presence of CVD in subjects with T2D, whereas pulse wave velocity and endothelial function provided limited independent additive information. Measurement of IMT in the carotid bulb provided better discrimination of the presence of CVD in subjects with T2D than measurement of IMT in the common carotid artery. The factors most significantly associated with increased carotid IMT in T2D were age, disease duration, systolic blood pressure, impaired renal function and increased arterial stiffness, whereas there were no or weak independent associations with metabolic factors and endothelial dysfunction. CONCLUSIONS: Measures of atherosclerotic burden are associated with clinically manifest CVD in subjects with T2D. In addition, vascular changes that are not directly related to known metabolic risk factors are important in the development of both atherosclerosis and CVD in T2D. A better understanding of the mechanisms involved is crucial for enabling better identification of CVD risk in T2D.

Randomized controlled trial assessing participation and quality of life in a supported speed treadmill training exercise program vs. a strengthening program for children with cerebral palsy.

OBJECTIVE: A multi-site Randomized-Controlled Trial compared a home-based Supported Speed Treadmill Training Exercise Program (SSTTEP) with a strengthening exercise program in children with cerebral palsy (CP) on the following categories; Participation, quality of life (QOL), self-concept, goal attainment, and satisfaction. DESIGN: Twenty-six children with spastic cerebral palsy were assigned by site-based block randomization to the SSTTEP (n=14) or strengthening exercise (n=12) group. Both groups participated in a two week clinic-based induction period and continued the intervention at home for ten weeks. Data were collected at baseline, post-intervention (12 weeks), and follow-up (16 weeks). Assessments included the Canadian Occupational Performance Measure, Children's Assessment of Participation and Enjoyment Scale, Pediatric Quality of Life Cerebral Palsy Module, and Piers-Harris Children's Self-Concept Scale. Evaluators were blinded to group assignment at two sites. RESULTS: Satisfaction and performance on individual goals, participation, and parent-reported QOL improved in both groups with improvement maintained for four weeks post intervention. CONCLUSION: The hypothesis that the SSTTEP group would have better outcomes than the exercise group was not supported. However, both groups showed that children with CP can make gains in participation, individual goals, and satisfaction following a 12-week intensive exercise intervention, and these findings persisted for four weeks post intervention.

Alendronate for the treatment of pediatric osteogenesis imperfecta: a randomized placebo-controlled study.

CONTEXT: Information on the use of oral bisphosphonate agents to treat pediatric osteogenesis imperfecta (OI) is limited. OBJECTIVE: The objective of the investigation was to study the efficacy and safety of daily oral alendronate (ALN) in children with OI. DESIGN AND PARTICIPANTS: We conducted a multicenter, double-blind, randomized, placebo-controlled study. One hundred thirty-nine children (aged 4-19 yr) with type I, III, or IV OI were randomized to either placebo (n = 30) or ALN (n = 109) for 2 yr. ALN doses were 5 mg/d in children less than 40 kg and 10 mg/d for those 40 kg and greater. MAIN OUTCOME MEASURES: Spine areal bone mineral density (BMD) z-score, urinary N-telopeptide of collagen type I, extremity fracture incidence, vertebral area, iliac cortical width, bone pain, physical activity, and safety parameters were measured. RESULTS: ALN increased spine areal BMD by 51% vs. a 12% increase with placebo (P < 0.001); the mean spine areal BMD z-score increased significantly from -4.6 to -3.3 (P < 0.001) with ALN, whereas the change in the placebo group (from -4.6 to -4.5) was insignificant. Urinary N-telopeptide of collagen type I decreased by 62% in the ALN-treated group, compared with 32% with placebo (P < 0.001). Long-bone fracture incidence, average midline vertebral height, iliac cortical width, bone pain, and physical activity were similar between groups. The incidences of clinical and laboratory adverse experiences were also similar between the treatment and placebo groups. CONCLUSIONS: Oral ALN for 2 yr in pediatric patients with OI significantly decreased bone turnover and increased spine areal BMD but was not associated with improved fracture outcomes.

Can we know the immunization status of healthcare workers? Results of a feasibility study in hospital trusts, England, 2008.

In England, there is no surveillance system for vaccines offered to healthcare workers apart from that in place annually for the seasonal influenza vaccine. To inform the feasibility of a general vaccine uptake surveillance system and to understand which policies are currently in place, we conducted a survey in the 162 National Health Service Foundation and Acute Hospital trusts in England, by submitting a questionnaire to their occupational health departments on immunization policies and methods of storing vaccine uptake data. In total, 104 hospital trusts (64.2%) responded. All responders offer hepatitis B, tuberculosis, measles-mumps-rubella, and influenza vaccines to healthcare workers; 0.9% reported not offering varicella and 13.5% not offering tetanus-diphtheria-polio; 66.4% record staff eligible for immunizations and 68.2% record staff they have immunized. Our study suggests that setting up a surveillance system to monitor vaccine uptake in healthcare workers is possible but would be challenging, given the variation in current systems.

Could exercise be a new strategy to revert some patients with atrial fibrillation?

BACKGROUND: This study is the result of the anecdotal observation that a number of patients with atrial fibrillation (AF) had noted reversion to sinus rhythm (SR) with exercise.We aimed to evaluate the potential role of exercise stress test (EST) for the reversion of AF. METHODS: Patients with AF who were scheduled to undergo electrical cardioversion (DCR) underwent EST using a modified Bruce protocol. RESULTS: Eighteen patients (16 male); aged 36-74 years (mean 58 years) were studied. Five patients (27.7%) had successful reversion with exercise (group 1). Thirteen patients remained in AF (group 2). No patient who failed to revert with exercise did so spontaneously before DCR 3 h to 7 months later (median 20 days). Comparison between group 1 and group 2 did not reveal any significant difference CONCLUSION: This small preliminary study suggests that in some patients it may be possible to revert AF to SR with exercise and avoid DCR and concomitant general anaesthesia. The authors suggest that a larger multicentre randomized trial is warranted to confirm or refute these initial results and if correct identify those who might benefit.

Pilot scheme for monitoring sickness absence in schools during the 2006/07 winter in England: can these data be used as a proxy for influenza activity?

During influenza epidemics, school-aged children are amongst the first affected patients. They frequently then spread the virus within their families. Recognising influenza activity in schools may therefore be an important indicator of early activity in the wider community. During 2005/06, influenza B was associated with high levels of morbidity in school-children and over 600 schools outbreaks were reported to the Health Protection Agency by local Health Protection Units. While it is not possible to directly monitor influenza in schools, the feasibility and validity of using sentinel school absenteeism data, as a proxy for influenza in the community can be investigated. From week 02/07 to 20/07, eight primary and three secondary schools from five HPA regions were able, via the Department of Health-funded Health Protection Informatics website, to report daily electronic registration data, relating to absenteeism due to illness. Aggregated absenteeism data due to illness peaked the same week as indices for the age group comparable to that used by the Royal College for General Practitioners and NHS Direct schemes. When illness-defined absenteeism data was stratified into primary and secondary schools, absence in primary schools peaked one week before that in secondary schools and the established schemes for all ages. The start time of the study meant that initial increases in activity could not be measured. These encouraging results justify expanding this sentinel scheme to collect more rigorous evidence of the usefulness of absenteeism as a proxy for influenza activity and a tool to inform policy and trigger local responses.

The electronic, 'paperless' medical office; has it arrived?

Modern information technology offers efficiencies in medical practice, with a reduction in secretarial time in maintaining, filing and retrieving the paper medical record. Electronic requesting of investigations allows tracking of outstanding results. Less storage space is required and telephone calls from pharmacies, pathology and medical imaging service providers to clarify the hand-written request are abolished. Voice recognition software reduces secretarial typing time per letter. These combined benefits can lead to significantly reduced costs and improved patient care. The paperless office is possible, but requires commitment and training of all staff; it is preferable but not absolutely essential that at least one member of the practice has an interest and some expertise in computers. More importantly, back-up from information technology providers and back-up of the electronic data are absolutely crucial and a paperless environment should not be considered without them.

Symptomatic and asymptomatic carotid stenosis: just when we thought we had all the answers.

The management of symptomatic and asymptomatic carotid stenosis has been a hotly debated topic for decades. The publication of four randomized controlled trials of carotid endarterectomy has clarified many of the issues. Patients with symptomatic carotid stenosis >70% benefit most with an absolute risk reduction of 17% over 2 years with numbers needed to treat of 3-6, whereas in patients with asymptomatic carotid stenosis >60%, the absolute risk reduction is 1% per annum (numbers needed to treat = 14-17). There is doubt about the benefit in women >70 years of age with asymptomatic stenosis. Carotid angioplasty and stenting is in its infancy and may one day supplant carotid endarterectomy as the treatment of choice; however, currently indications for this procedure include participation in randomized controlled trials, surgically inaccessible stenosis, in patients with combined symptomatic carotid and symptomatic coronary artery disease or in patients with severe co-morbidities that preclude formal carotid endarterectomy.

Spinocerebellar ataxia type 14: study of a family with an exon 5 mutation in the PRKCG gene.

We report our observations in an Australian family with spinocerebellar ataxia type 14 (SCA 14). We describe a novel mutation in exon 5 of the PRKCG gene, altering a highly conserved cysteine to a phenylalanine at codon 150, and record the detailed clinical observations in six affected family members.

Cardiovascular toxicity is increased, but manageable, during high-dose chemotherapy and autologous peripheral blood stem cell transplantation for patients aged 60 years and older.

High-dose therapy (HDT) for non-Hodgkins lymphoma (NHL) and multiple myeloma (MM) is considered a feasible option for patients aged 60 years. This study compared the outcomes for all patients aged 60 years treated with HDT at the center to a matched cohort group aged <60 years. Results for patients who were 60 years at HDT between 1997--2002 were retrospectively analysed to assess efficacy and safety. Event-free (EFS) and overall survival (OS) rates were compared with a cohort group, matched by disease type, chemotherapy sensitivity, year of treatment and conditioning regimen. Patients with NHL were also matched by International Prognostic Index score. Forty patients aged 60 years were identified. Median age was 65 (range 60--76) with 22 MM and 18 NHL; 50% had 1 or more co-morbidity; 35% had cardiovascular co-morbidity vs. 18% of controls (p=0.075). Response rates (RR) following HDT for MM were: 4 (18%) complete responses (CR) and 18 (82%) partial responses (PR), giving an overall response rate (ORR) of 100%, vs. 77% for controls (p=0.02). For NHL patients there were: 8 CR (44%) and 4 PR (22%), giving an ORR of 67%, vs. 83% for controls (p=0.3). Transplant-related mortality was 8% compared to 5% in controls (p=0.6). Toxicities were similar with the exception of cardiac toxicity, which was significantly higher in patients aged 60 years vs. controls (50% grade 3 vs. 10%: p<0.0001). Atrial fibrillation was the most frequent cardiovascular toxicity (9 patients). At a median follow-up of 33 months, there is no significant difference between older vs. younger patients in median EFS (24 vs. 38 months: p=0.78) or OS (40 months vs. not reached: p=0.23). HDT is feasible and effective in selected patients 60 years with MM and NHL. Patients 60 years are more susceptible to cardiovascular toxicities, particularly atrial fibrillation, but have similar or better response rates following HDT and similar long-term outcomes to younger patients.

Hypothesis: could Meniere's disease be a channelopathy?

Meniere's disease is a clinical syndrome of uncertain aetiology but it is a widespread belief that it is related to endolymphatic hydrops. Clinically, it is a paroxysmal disorder with vertigo and subsequent deafness. It is responsive to acetazolamide and sensitive to the sodium content in the diet, many of the features of the channelopathies. The present paper explores the possibility that it may be related to a channelopathy.