Absence of high-risk human papilloma virus in p16 positive inverted sinonasal papilloma.

OBJECTIVES: Sinonasal inverted papilloma (SIP) is a relatively rare disease, and its etiology is not understood. It is characterized by locally aggressive growth and a strong tendency to recur despite its benign histology. AIMS: The aim of this study was to identify the presence of human papilloma virus (HPV) and its surrogate marker p16 in SIP tissue samples from a regional cohort. MATERIAL AND METHODS: Subjects were identified from our regional center cohort of 88 SIP patients treated between 1984-2014. From these subjects, 54 were included in this study. Of these, 53 biopsies were analyzed with PCR, and 54 samples were immunohistochemically stained for p16. DNA was extracted from histopathologically verified SIP. Genotype screening for 13 high risk-, 5 oncogenic and 6 low risk HPV types was performed using the PapilloCheck® HPV-screening test. RESULTS: HPV analysis was successful for 38 of 53 samples. Of the 38 successfully analyzed samples, only 2 samples were positive for HPV 11. Notably, p16 was present in the epithelia in all samples, and in the papilloma lesions in 37 samples. CONCLUSION: Since only 2 out of 38 SIPs were positive for HPV (type 11), and at the same time p16 was positive in epithelia in all samples and in 37 of 38 papilloma lesions of the samples, it is concluded that p16 cannot be used as a surrogate marker for high-risk HPV-infection in SIP. We are currently planning a prospective, multicenter study in order to increase the study power and in order to be able to better evaluate the clinical implications of HPV-and p16 in SIP.

Acoustic formation of multicellular tumor spheroids enabling on-chip functional and structural imaging.

Understanding the complex 3D tumor microenvironment is important in cancer research. This microenvironment can be modelled in vitro by culturing multicellular tumor spheroids (MCTS). Key challenges when using MCTS in applications such as high-throughput drug screening are overcoming imaging and analytical issues encountered during functional and structural investigations. To address these challenges, we use an ultrasonic standing wave (USW) based MCTS culture platform for parallel formation, staining and imaging of 100 whole MCTS. A protein repellent amphiphilic polymer coating enables flexible production of high quality and unanchored MCTS. This enables high-content multimode analysis based on flow cytometry and in situ optical microscopy. We use HepG2 hepatocellular carcinoma, A498 and ACHN renal carcinoma, and LUTC-2 thyroid carcinoma cell lines to demonstrate (i) the importance of the ultrasound-coating combination, (ii) bright field image based automatic characterization of MTCS, (iii) detailed deep tissue confocal imaging of whole MCTS mounted in a refractive index matching solution, and (iv) single cell functional analysis through flow cytometry of single cell suspensions of disintegrated MTCS. The USW MCTS culture platform is customizable and holds great potential for detailed multimode MCTS analysis in a high-content manner.

Mortality and extent of coronary artery disease in 2776 patients with type 1 diabetes undergoing coronary angiography: A nationwide study.

Background In a modern perspective there is limited information on mortality by affected coronary vessels assessed by coronary angiography in patients with type 1 diabetes. The aim of the present study was to characterise distribution of coronary artery disease and impact on long-term mortality in patients with type 1 diabetes undergoing coronary angiography. Design The design of this research was a nationwide population-based cohort study. Methods Individuals ( n = 2776) with type 1 diabetes undergoing coronary angiography 2001-2013 included in the Swedish National Diabetes Registry and Swedish Coronary Angiography and Angioplasty Registry were followed for mortality until 31 December 2013 (mean 7.1 years). In 79% the indication was stable or acute coronary artery disease. Coronary artery disease was categorised into normal (21%), one- (23%), two- (18%), three- (29%) and left main-vessel disease (8%). Results Mean age was 57 years and 58% were male. Mean diabetes duration was 35 years, glycated haemoglobin was 67 mmol/mol and 44% had normal or one-vessel disease. In multivariate Cox proportional analyses hazard ratio for mortality compared with normal findings was 1.09 (95% confidence interval 0.80-1.48) for one, 1.43 (1.05-1.94) for two, 1.47 (1.10-1.96) for three and 1.90 (1.35-2.68) for left main-vessel disease. Renal failure 2.29 (1.77-2.96) and previous heart failure 1.76 (1.46-2.13) were highly associated with mortality. Standard mortality ratio the first year was 5.55 (4.65-6.56) and decreased to 2.80 (2.18-3.54) after five years. Conclusions In patients with type 1 diabetes referred for coronary angiography mortality is influenced by numbers of affected coronary vessels. The overall mortality rate was higher compared with the general population. These results support early intensive prevention of coronary artery disease in this population.

LDL cholesterol is not a good marker of cardiovascular risk in Type 1 diabetes.

AIM: LDL cholesterol (LDL-C) is considered an important cardiovascular disease (CVD) risk factor. Less is known in Type 1 diabetes. We assessed LDL-C and total cholesterol to HDL cholesterol ratio (TC/HDL-C) as predictors of CVD in Type 1 diabetes. METHODS: The study monitored 30 778 people with Type 1 diabetes, baseline 2003-2006, to 31 December 2011. Cox regression analyses were performed with LDL-C and TC/HDL-C as predictors of fatal/non-fatal CVD. Models were adjusted for traditional CVD risk factors. RESULTS: Hazard ratios (HR) (with 95% CI) per 1 mmol/l increase in LDL-C for CVD were 1.09 (1.01-1.18) in people without lipid-lowering medication and 1.02 (0.95-1.09) in people with lipid-lowering medication (P = 0.02 and 0.65). In people aged 40 years or older having a CVD risk factor, and in people with a history of CVD, HR was 1.07 (0.99-1.16) and 1.02 (0.92-1.13) (P = 0.07 and 0.66). HR per 1 unit increase in TC/HDL-C was 1.12 (1.05-1.20) in people without lipid-lowering medication and 1.08 (1.02-1.15) in people with lipid-lowering medication (P < 0.001 and 0.01). For people aged 40 or older and people with a history of CVD, HR was 1.16 (1.09-1.24) and 1.04 (0.95-1.14) (P < 0.001 and 0.43). Broken down into octiles, LDL-C was not a significant predictor of CVD in any group. Higher octiles of TC/HDL-C were significant predictors for CVD in people without lipid-lowering medication and in those aged 40 years or older. CONCLUSION: In this study of people with Type 1 diabetes in clinical practice, LDL-C was not a good predictor of CVD. We found no support for an LDL-C cut-off point < 2.6 mmol/l. TC/HDL-C seems more reliable as a marker for CVD risk when considering primary prevention.

Expression of p16 in squamous cell carcinoma of the mobile tongue is independent of HPV infection despite presence of the HPV-receptor syndecan-1.

BACKGROUND: Tongue squamous cell carcinoma (TSCC) is increasing in incidence, especially among young patients and preferably females. Infection with human papilloma virus (HPV) has been suggested as a cause of SCC in the head and neck, and the proportion of oropharyngeal cancers caused by HPV has steadily increased. METHODS: Samples from 109 patients with primary TSCC were analysed for the presence of HPV16 by in situ hybridisation and for expression of its surrogate marker p16 and the HPV receptor syndecan-1 by immunhistochemistry. RESULTS: No evidence of HPV16 DNA was observed in the tumours, although one-third showed p16 staining. There was no difference in the expression of the primary HPV receptor, syndecan-1, between TSCC and a group of tonsil SCC. CONCLUSION: Whereas p16 is expressed in some TSCCs, HPV16 is undetectable, therefore, p16 cannot be used as a surrogate marker for high-risk HPV-infection in this tumour. Despite presence of the HPV-receptor syndecan-1 in TSCC, HPV prefers the tonsillar environment. Lack of p16 associates with worse prognosis primarily in patients aged ⩽40 years with tongue SCC. The improved prognosis seen in p16-positive TSCC can be due to induction of a senescent phenotype or an inherent radiosensitivity due to the ability of p16 to inhibit homologous recombination repair.

Glycaemic control of Type 1 diabetes in clinical practice early in the 21st century: an international comparison.

AIMS: Improving glycaemic control in people with Type 1 diabetes is known to reduce complications. Our aim was to compare glycaemic control among people with Type 1 diabetes using data gathered in regional or national registries. METHODS: Data were obtained for children and/or adults with Type 1 diabetes from the following countries (or regions): Western Australia, Austria, Denmark, England, Champagne-Ardenne (France), Germany, Epirus, Thessaly and Thessaloniki (Greece), Galway (Ireland), several Italian regions, Latvia, Rotterdam (The Netherlands), Otago (New Zealand), Norway, Northern Ireland, Scotland, Sweden, Volyn (Ukraine), USA and Wales) from population or clinic-based registries. The sample size with available data varied from 355 to 173 880. Proportions with HbA1c < 58 mmol/mol (< 7.5%) and ≥ 75 mmol/mol (≥ 9.0%) were compared by age and sex. RESULTS: Data were available for 324 501 people. The proportions with HbA1c 58 mmol/mol (< 7.5%) varied from 15.7% to 46.4% among 44 058 people aged < 15 years, from 8.9% to 49.5% among 50 766 people aged 15-24 years and from 20.5% to 53.6% among 229 677 people aged ≥ 25 years. Sex differences in glycaemic control were small. Proportions of people using insulin pumps varied between the 12 sources with data available. CONCLUSION: These results suggest that there are substantial variations in glycaemic control among people with Type 1 diabetes between the data sources and that there is room for improvement in all populations, especially in young adults.

Word-level intelligibility after caudal zona incerta stimulation for Parkinson's disease.

OBJECTIVES: To investigate the effect of caudal zona incerta-deep brain stimulation (cZi-DBS) on word-level speech intelligibility in patients with Parkinson's disease, under both an optimal listening condition and a simulated more naturalistic listening condition. MATERIALS AND METHODS: Spoken single words were extracted from read samples collected from 10 bilaterally implanted patients with PD pre- and post-cZi-DBS. Intelligibility was assessed through a transcription task performed by 32 naive listeners under two listening conditions: (i) with low-amplitude conversational speech added as background and (ii) with no added background noise. The listeners' responses were scored in terms of agreement with the intended words. RESULTS: Post-operatively, the total intelligibility score was significantly lower when cZi stimulation was switched on compared with off, for both listening conditions (with and without added background noise). Intelligibility was also significantly lower on stimulation compared with preoperative recordings, but only when assessed in the listening condition without background noise. The listening condition with added background noise resulted in significantly lower intelligibility scores compared with the no added noise condition for all stimulation conditions. CONCLUSIONS: The results of this study indicate that cZi-DBS in patients with PD can be detrimental to word-level speech intelligibility.

LDL-cholesterol versus non-HDL-to-HDL-cholesterol ratio and risk for coronary heart disease in type 2 diabetes.

AIMS: We assessed the association between different blood lipid measures and risk of fatal/nonfatal coronary heart disease (CHD), which has been less analysed previously in type 2 diabetes. DESIGN, METHODS: Observational study of 46,786 patients with type 2 diabetes, aged 30-70 years, from the Swedish National Diabetes Register, followed for a mean of 5.8 years until 2009. Baseline and updated mean low-density lipoprotein (LDL)-, high-density lipoprotein (HDL)-, non-HDL-cholesterol, and non-HDL-to-HDL-cholesterol ratio were measured. RESULTS: Hazard ratios (HR) for CHD with quartiles 2-4 of baseline lipid measures, with lowest quartile 1 as reference: 1.03-1.29-1.63 for LDL; 1.23-1.41-1.95 for non-HDL; 1.29-1.39-1.57 for HDL; and 1.31-1.67-2.01 for non-HDL:HDL, all p < 0.001 except for quartile 2 of LDL, when adjusted for clinical characteristics and nonlipid risk factors. A similar picture was seen with updated mean values. Splines with absolute 6-year CHD rates in a Cox model showed decreasing rates only down to around 3 mmol/l for LDL, with linearly decreasing rates to the lowest level of non-HDL:HDL. Non-HDL and HDL were independent additive risk factors for CHD risk. HRs per 1 SD continuous decrease in baseline or updated mean HDL were 1.14-1.17 when fully adjusted as above, and 1.08-1.13 when also adjusted for non-HDL (p < 0.001). HRs were 1.13-1.16 adjusted for LDL, and 1.22-1.26 adjusted for total cholesterol and triglycerides (p < 0.001). Splines showed progressively increasing 6-year CHD rates with lower HDL down to 0.5 mmol/l. CONCLUSIONS: This study suggests that lower levels of non-HDL:HDL are a better risk marker for CHD than LDL-cholesterol below 3 mmol/l.

Level of physical activity associated with risk of cardiovascular diseases and mortality in patients with type-2 diabetes: report from the Swedish National Diabetes Register.

AIMS: To estimate risks of coronary heart disease (CHD), cardiovascular disease (CVD), and total mortality with low or higher levels of physical activity (PA) assessed with questionnaire, in an observational study of patients with type-2 diabetes from the Swedish National Diabetes Register. SUBJECTS AND METHODS: A total of 15,462 patients (60 years), were followed for 5 years from baseline in 2004 until 2009, with 760 CVD events and 427 total mortality events based on 54,344 person-years. RESULTS: Comparing 6963 patients with low baseline PA (never or 1-2 times/week for 30 min) and 8499 patients with higher baseline PA (regular 3 times/week or more), hazard ratios for fatal/nonfatal CHD, fatal/nonfatal CVD, fatal CVD, and total mortality were 1.25 (95% CI 1.05-1.48; p = 0.01), 1.26 (95% CI 1.09-1.45; p = 0.002), 1.69 (95% CI 1.18-2.41; p = 0.004), and 1.48 (95% CI 1.22-1.79; p < 0.001), adjusting for age, sex, diabetes duration, diabetes treatment, and smoking (model 1). Adjusting also for HbA1c, systolic blood pressure, low- and high-density lipoprotein cholesterol, triglycerides, body mass index, and albuminuria (model 2), HRs were 1.19 (95% CI 1.00-1.42; p = 0.049), 1.18 (95% CI 1.02-1.36; p = 0.04), 1.54 (95% CI 1.07-2.22; p = 0.02), and 1.41 (95% CI 1.16-1.72; p < 0.001), respectively. Corresponding results (model 2), comparing 4166 patients having low PA both baseline and at follow up with all other 11,296 patients were 1.68 (95% CI 1.41-2.01), 1.68 (95% CI 1.45-1.96), 2.12 (95% CI 1.48-3.03), and 2.03 (95% CI 1.66-2.48) (all p < 0.001) and compared to 2797 patients with low baseline PA and higher PA at follow up were 2.51 (95% CI 1.87-3.38), 2.54 (95% CI 1.98-3.27), 3.26 (95% CI 1.74-6.10), and 2.91 (95% CI 2.08-4.07) (all p < 0.001). CONCLUSIONS: This large observational study of patients with type-2 diabetes showed considerably increased risks for CVD and mortality with low PA.

Deep brain stimulation - effects on swallowing function in Parkinson's disease.

OBJECTIVE: In patients with Parkinson's disease (PD), deep brain stimulation of the subthalamic nucleus (STN DBS) is well recognized in improving limb function, but the outcome on swallowing function has rarely been studied. The aim of this work was to evaluate the effect of STN DBS on pharyngeal swallowing function in patients with PD using self-estimation and fiberoptic endoscopic evaluation of swallowing. METHODS: Eleven patients (aged 41-72, median 61 years) were evaluated preoperatively and at 6 and 12 months after STN DBS surgery. All patients were evaluated with self-estimation on a visual analogue scale, and eight of them with a fiberoptic endoscopic examination with a predefined swallowing protocol including Rosenbek's Penetration-Aspiration Scale, Secretion Severity Scale, preswallow spillage, pharyngeal residue, and pharyngeal clearance. RESULTS: The self-assessments of swallowing function revealed a subjective improvement with STN DBS stimulation, whereas the data from the swallowing protocol did not show any significant effect of the STN DBS treatment itself. The prevalence of aspiration was not affected by the surgery. CONCLUSIONS: The results show that swallowing function was not negatively affected by STN DBS and the risk of aspiration did not increase. Self-estimation of swallowing function showed a subjective improvement due to stimulation.

Expression of tlr4, md2 and cd14 in equine blood leukocytes during endotoxin infusion and in intestinal tissues from healthy horses.

The expression of tlr4, md2 and cd14 was studied in equine blood leukocytes and in intestinal samples using real time PCR. The stability of three commonly used reference genes, glyceraldehyde-3P-dehydrogenase (GAPDH), hypoxantine ribosyltransferase (HPRT) and succinate dehydrogenase complex subunit A (SDHA), was evaluated using qbase(PLUS). The equine peripheral blood mononuclear cells (eqPBMC) examined were either stimulated in vitro with Phorbol 12-myristate 13-acetate (PMA) and ionomycin or with the CpG oligodeoxynuclotide 2216 (CpG-ODN 2216) or obtained from horses before, during and after infusion of endotoxin. Intestinal tissue from healthy horses was sampled at ileum, right dorsal colon and rectum. Ranking of the three reference genes used for normalisation identified the combination HPRT/SDHA as most suitable both when determined ex vivo in leukocytes obtained from experimentally induced endotoxaemia and in eqPBMC activated in vitro while HPRT/GAPDH were most appropriate for the intestinal samples. The relative amounts of mRNA for TLR4 and MD-2 increased threefold during in vitro activation of the cells with CpG-ODN 2216 but was decreased in cultures stimulated with PMA/ionomycin. A transient elevation in the transcription of tlr4 and md2 was also evident for equine blood leukocytes following endotoxaemia. The levels of mRNA for CD14 on the other hand remained unaffected both during the induction of endotoxaemia and in the in vitro stimulated PBMCs. A low steady expression of TLR4, MD-2 and CD14 mRNA was demonstrated for the intestinal samples with no variation between the intestinal segments analysed. Thus, the foundation for real time PCR based levels of analysis of mRNA for all three components in the equine LPS receptor complex in different intestinal segments was set, making it possible to carry out future expression studies on clinical material.

Long-term mortality in patients with type 2 diabetes undergoing coronary angiography: the impact of glucose-lowering treatment.

AIMS/HYPOTHESIS: The aim of this study was to analyse whether the increased mortality rates observed in insulin-treated patients with type 2 diabetes and coronary artery disease are explained by comorbidities and complications. METHODS: A retrospective analysis of data from two Swedish registries of type 2 diabetic patients (n = 12,515) undergoing coronary angiography between the years 2001 and 2009 was conducted. The association between glucose-lowering treatment and long-term mortality was studied after extensive adjustment for cardiovascular- and diabetes-related confounders. Patients were classified into four groups, according to glucose-lowering treatment: diet alone; oral therapy alone; insulin in combination with oral therapy; and insulin alone. RESULTS: After a mean follow-up time of 4.14 years, absolute mortality rates for patients treated with diet alone, oral therapy alone, insulin in combination with oral therapy and insulin alone were 19.2%, 17.4%, 22.9% and 28.1%, respectively. Compared with diet alone, insulin in combination with oral therapy (HR 1.27; 95% CI 1.12, 1.43) and insulin alone (HR 1.62; 95% CI 1.44, 1.83) were associated with higher mortality rates. After adjustment for baseline differences, insulin in combination with oral glucose-lowering treatment (HR 1.22; 95% CI 1.06, 1.40; p < 0.005) and treatment with insulin only (HR 1.17; 95% CI 1.02, 1.35; p < 0.01) remained independent predictors for long-term mortality. CONCLUSIONS/INTERPRETATION: Type 2 diabetes patients treated with insulin and undergoing coronary angiography have a higher long-term mortality risk after adjustment for measured confounders. Further research is needed to evaluate the optimal glucose-lowering treatment for these high-risk patients.

Swallowing function in Parkinson's patients following Zona Incerta deep brain stimulation.

OBJECTIVE: The purpose of the present study was to examine whether there was a negative effect of caudal Zona Incerta deep brain stimulation (cZI DBS) on pharyngeal swallowing function in Parkinson's patients (PD). There are no former reports including swallowing and cZI DBS. METHODS: Eight patients (aged 49-71 years; median 62) were evaluated pre- and post-operatively, at 6 and 12 months after DBS surgery. Evaluation tools were fiberoptic endoscopic evaluation of swallowing examinations and patients' self-assessments of their swallowing function including a visual analog scale and quality-of-life-related questions. The swallowing protocol included Rosenbek's Penetration-Aspiration Scale, Secretion Severity Scale and parameters for preswallow spillage, pharyngeal residue, and pharyngeal clearance. RESULTS: There was no clear-cut effect of neurostimulation post-operatively at 6 and 12 months on any of the swallowing parameters except for the preswallow spillage that was slightly worsened in the stimulation on condition 12 months post-operatively. The answers to the self assessment questions did not vary significantly. CONCLUSIONS: The effect of the stimulation on the swallowing function varied among individuals, but the overall outcome was that cZI DBS did not seem to have a negative influence on swallowing function in the eight patients studied.

Lowering of postprandial lipids in individuals with type 2 diabetes treated with alogliptin and/or pioglitazone: a randomised double-blind placebo-controlled study.

AIMS/HYPOTHESIS: Pharmacological augmentation of glucagon-like peptide 1 receptor signalling by dipeptidyl peptidase 4 (DPP-4) inhibition reduced intestinal lipoprotein secretion in experimental studies, suggesting that DPP-4 inhibitors may ameliorate dyslipidaemia and thus reduce cardiovascular risk in patients with type 2 diabetes. We assessed the effects of alogliptin (Alo) and Alo co-administered with pioglitazone (Pio) vs placebo (Pbo) on triacylglycerol (TG)-rich lipoproteins in type 2 diabetes before and following a high-fat meal. METHODS: Seventy-one patients (age 18-70 years), who did not reach HbA(1c) 6.5% (48 mmol/mol) with lifestyle and/or metformin, sulfonylurea or glinide therapy, participated in this 16 week, double-centre (university hospitals) Pbo-controlled parallel-group study. All participants, people doing measurements or examinations, and people assessing the outcomes were blinded to group assignment. Fasting TG 1.7-5.0 mmol/l was among the entry criteria. Patients received a high-fat mixed meal before and 4 and 16 weeks after randomisation (allocation by central office) to Alo (n = 25), Alo/Pio (n = 22) or Pbo (n = 24). Blood was sampled at pre-specified intervals, starting at 15 min before and ending 8 h after meal ingestion. RESULTS: At week 16, Alo (n = 25) and Alo/Pio (n = 21) vs Pbo (n = 24) produced similar significant reductions in total postprandial TG response (incremental AUC [iAUC]; p < 0.001), as well as in chylomicron TG (p < 0.001) and VLDL1 TG iAUCs (p < 0.001 and p = 0.012, respectively). Postprandial chylomicron apolipoprotein B-48 iAUC showed a significant decrease after Alo treatment (p = 0.028), and a non-significant trend towards a decrease with Alo/Pio (p = 0.213). The incidence of adverse events was low and consistent with previous studies. CONCLUSIONS/INTERPRETATION: Treatment with Alo and Alo/Pio produced significant reductions in postprandial TG and TG-rich lipoproteins, contributing to an improved overall cardiometabolic risk profile in type 2 diabetes. The data support the concept that incretins not only modulate glucose metabolism but also influence chylomicron metabolism in intestinal cells. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00655863.

A new model for 5-year risk of cardiovascular disease in Type 1 diabetes; from the Swedish National Diabetes Register (NDR).

AIMS: We assessed the association between risk factors and cardiovascular disease in an observational study of patients with Type 1 diabetes from the Swedish National Diabetes Register. METHODS: A derivation sample of 3661 patients, aged 30-65 years, 6.1% with previous cardiovascular disease, baseline 2002, and 197 cardiovascular disease events when followed for 5 years until 2007. A separate validation data set of 4484 patients, baseline 2003, 201 cardiovascular disease events when followed for 4 years. RESULTS: Adjusted hazard ratios at Cox regression for fatal/non-fatal cardiovascular disease were: diabetes duration 2.76 (2.21-3.44); onset age 1.47 (1.21-1.78); log ratio total cholesterol:HDL cholesterol 1.26 (1.09-1.45); log HbA(1c) 1.19 (1.03-1.38); log systolic blood pressure 1.17 (1.01-1.34) (1 SD increase in continuous variables); smoker 1.76 (1.27-2.46); macroalbuminuria (> 200 µg/min) 1.52 (1.10-2.10); previous cardiovascular disease 3.51 (2.54-4.84). All eight variables were used to elaborate a risk equation for 5-year cardiovascular disease risk. Regarding calibration in the derivation data set, ratio predicted 5-year risk (mean 5.4 ± 7.9%) to observed event rate was 1.0. Discrimination was sufficient, with C-statistic 0.83, sensitivity and specificity 72 and 77%, respectively, for the top quartile of predicted risk. Similarly, calibration and discrimination were adequate in the validation data set: ratio of predicted 4-year risk/observed rate 0.94, C-statistic 0.80, sensitivity and specificity 62 and 77%, respectively, for the top quartile. CONCLUSIONS: This 5-year cardiovascular disease risk model from a large observational study of patients with Type 1 diabetes in routine care showed adequate calibration and discrimination and can be useful for clinical practice. It should also be tested in patients with Type 1 diabetes from other countries.

Additive effects of glycaemia and dyslipidaemia on risk of cardiovascular diseases in type 2 diabetes: an observational study from the Swedish National Diabetes Register.

AIMS/HYPOTHESIS: The study aimed to assess the relative importance of the control of HbA(1c) and total cholesterol/HDL-cholesterol ratio (TC/HDL) on risk of cardiovascular disease (CVD). METHODS: In 22,135 participants with type 2 diabetes (age 30-75 years, 15% with previous CVD) followed for 5 years, baseline and annually updated mean HbA(1c) and TC/HDL were analysed and also categorised in combinations of quartiles. Outcomes were fatal/non-fatal CHD, stroke, CVD and total mortality. RESULTS: In all participants, HRs per 1 SD increase in updated mean HbA(1c) or TC/HDL using Cox regression analysis were 1.13 (95% CI 1.07, 1.19) and 1.31 (1.25, 1.37) for CHD, 1.15 (1.06, 1.24) and 1.25 (1.17, 1.34) for stroke, 1.13 (1.08, 1.18) and 1.29 (1.24, 1.34) for CVD (all p < 0.001), and 1.07 (1.02, 1-13; p = 0.01) and 1.18 (1.12, 1.24; p < 0.001) for total mortality, respectively, adjusted for clinical characteristics and traditional risk factors. The p value for the interaction between HbA(1c) and TC/HDL was 0.02 for CHD, 0.6 for stroke and 0.1 for CVD. Adjusted mean 5-year event rates in a Cox model, in combinations of quartiles of updated mean TC/HDL and HbA(1c) (lowest <3.1 mmol/l and 5.0-6.4% [31-46 mmol/mol]; <3.1 mmol/l and ≥7.8% [≥62 mmol/mol]; ≥4.6 mmol/l and 5.0-6.4% 31-46 mmol/mol; and highest ≥4.6 mmol/l and ≥7.8% [≥62 mmol/mol]), were 4.8%, 7.0%, 9.1% and 14.5% for CHD, and 7.1%, 9.9%, 12.8% and 19.4% for CVD, respectively. Adjusted HRs for highest vs lowest combinations were 2.24 (1.58-3.18) for CHD and 2.43 (1.79-3.29) for CVD (p < 0.001). CONCLUSIONS/INTERPRETATION: Hyperglycaemia and hyperlipidaemia were less than additive for CHD and additive for other endpoints, with the lowest risk at lowest combination levels and a considerable increase in absolute risk at high combination levels.

Reference values for F wave parameters in healthy 3-20 year old subjects.

OBJECTIVE: To create a reference value database for F wave parameters from healthy subjects aged 3-20 yr. METHODS: We studied the following parameters: minimum F wave latency minus distal motor latency (FMINLAT), number of F waves/20 stimuli (FNUMBER) and F wave dispersion (FDISP). The median, ulnar, peroneal and tibial nerves were studied. All four nerves were not analyzed in all subjects, the number of subjects varied from 78 to 118 in each nerve. RESULTS: Age explained 71-87% of the variability of FLATMIN while height explained 80-95% of the variability. The FMINLAT increases by 0.12 ms/cm of height in the upper limb nerves and by 0.28 ms/cm in the lower limb nerves. Gender did not influence the FMINLAT. FDISP was not related with age, height or gender. FNUMBER was not related with age or height, it was somewhat larger in males than females but the difference was not significant in all nerves. CONCLUSIONS: The best model for FMINLAT was a linear regression model with height as an independent variable. FDISP and FNUMBER are not related to age, height or gender between the ages of 3 and 20 yr. SIGNIFICANCE: We have constructed clinically useful reference values for F wave parameters in healthy subjects aged 3-20 yr for the main motor nerves commonly studied.

New aspects of HbA1c as a risk factor for cardiovascular diseases in type 2 diabetes: an observational study from the Swedish National Diabetes Register (NDR).

AIMS: To analyse the association between glycosylated haemoglobin A1c (HbA1c) and cardiovascular disease (CVD) in patients with type 2 diabetes in the Swedish National Diabetes Register (NDR). METHODS: An observational study of 18 334 patients (age 30-79 years, previous CVD in 18%, baseline HbA1c 5.0-10.9%) who were followed for 6 years (mean 5.6 years) from 1997/1998 until 2003. RESULTS: Hazard ratios per 1% unit increase in baseline or updated mean HbA1c for fatal/nonfatal coronary heart disease (CHD), CVD and total mortality were 1.11-1.13, 1.10-1.11 and 1.09-1.10, respectively (all P < 0.001), adjusted for several risk factors and clinical characteristics in Cox regression. Adjusted 6-year event rates increased with higher baseline or updated mean HbA1c with no J-shaped risk curves, in all patients and also when subgrouping by shorter (mean 3 years) or longer (mean 14 years) diabetes duration, by presence or absence of previous CVD, or by treatment with oral hypoglycaemic agents (OHAs) or insulin. Risk reductions of 20% for CHD and 16% for CVD (P < 0.001) were found in patients with a baseline mean HbA1c of 6.5%, compared to those with a mean level of 7.5%. Compared to OHA-treated patients, insulin-treated patients had an increased risk of total mortality, due almost exclusively to an increased risk of non-CVD mortality, and due less to a weakly significant increased risk of fatal CVD. HbA1c was not associated with non-CVD mortality. CONCLUSIONS: This observational study showed progressively increasing risks of CHD, CVD and total mortality with higher HbA1c, and no risk increase at low HbA1c levels even with longer diabetes duration, previous CVD or treatment with either insulin or OHAs. Patients achieving HbA1c <7% showed benefits for risk reduction.

Pulse pressure strongly predicts cardiovascular disease risk in patients with type 2 diabetes from the Swedish National Diabetes Register (NDR).

OBJECTIVES: To analyze pulse pressure (PP) as a risk predictor for coronary heart disease (CHD), stroke and cardiovascular disease (CVD; CHD and/or stroke) in type 2 diabetic patients. METHODS: A total of 11,128 female and male type 2 diabetic patients with known baseline PP values and no CVD, aged 50-74 years, were followed for a mean duration of 5.6 years (1998-2003). A subgroup of 5521 patients with known mean PP values (mean values at baseline and at the end of the study) was also included. RESULTS: Hazard ratios (HRs) with 95% CI for fatal/nonfatal CHD with baseline or mean PP>or=75mmHg, compared to <75mmHg, were 1.23 (1.07-1.40; P=0.003) and 1.32 (1.07-1.62; P=0.009), respectively, after adjusting for mean blood pressure (MBP), age, gender, diabetes duration, HbA(1c), body mass index (BMI), lipid-reducing drugs, microalbuminuria > 20microg/min, antihypertensive drugs and hypoglycaemic treatment, using Cox regression analyses. Fully-adjusted respective HRs for stroke were 1.17 (0.98-1.39) and 1.21 (0.90-1.61) and, for CVD, 1.23 (1.10-1.37; P<0.001) and 1.28 (1.07-1.52; P=0.007). Fully-adjusted HRs for baseline PP increased per quartile and, CHD, stroke or CVD, were 1.09 (1.03-1.16; P=0.004), 1.14 (1.05-1.23; P=0.002) and 1.11 (1.05-1.17; P<0.001), respectively. The data suggest that, if a mean PP>or=75mmHg were to be avoided, then 15% and 17% of CHD and or CVD, cases, respectively, in such a cohort might be prevented after multivariable adjustments, with a further 10% of cases avoided if also adjusted for MBP and age. Increasing baseline MBP, age and microalbuminuria were independently and significantly associated (P<0.001) with increasing baseline or mean PP. CONCLUSION: Increased PP is a powerful independent risk predictor of CVD in type 2 diabetic patients, and lowering PP can lead to a marked reduction in risk.