Excess all-cause mortality before age 30 in childhood onset type 1 diabetes: data from the Brecon Group Cohort in Wales.

BACKGROUND: Long-term outcomes in young people with type 1 diabetes continue to be of interest, and may help evaluate the effects of changes to the clinical care of children that have occurred in recent decades. AIMS: To identify mortality and its causes before age 30 years in patients developing type 1 diabetes before age 15 years. METHODS: Since 1995, paediatricians in Wales have compiled a prospective register of incident cases of type 1 diabetes occurring before age 15 years in Wales (the Brecon Cohort). Their subsequent mortality rates were compared with mortality in the general populations of Wales and England using the patient-years exposure method. Causes of death were ascertained from death certificates and from clinicians. RESULTS: The standardised mortality ratio for young people with type 1 diabetes in Wales was 2.91 with no clear evidence of improvement or worsening of mortality risk over time. Most deaths occurred between ages 15 and 30 years although at a slightly younger age than in the general population. There were more deaths with increasing age at diagnosis of diabetes. Ketoacidosis remains the most common cause of death before age 30 years. Hypoglycaemia was difficult to ascertain with certainty but also caused some deaths. In this age group, chronic complications of diabetes were not a cause of mortality. CONCLUSIONS: Despite the developments in clinical care in recent years, the mortality risk for people developing type 1 diabetes in childhood remains high in young adult life before the onset of chronic complications.

Determining diabetic retinopathy screening interval based on time from no retinopathy to laser therapy.

Objectives To determine the necessary screening interval for retinopathy in diabetic patients with no retinopathy based on time to laser therapy and to assess long-term visual outcome following screening. Methods In a population-based community screening programme in North Wales, 2917 patients were followed until death or for approximately 12 years. At screening, 2493 had no retinopathy; 424 had mostly minor degrees of non-proliferative retinopathy. Data on timing of first laser therapy and visual outcome following screening were obtained from local hospitals and ophthalmology units. Results Survival analysis showed that very few of the no retinopathy at screening group required laser therapy in the early years compared with the non-proliferative retinopathy group ( p < 0.001). After two years, <0.1% of the no retinopathy at screening group required laser therapy, and at three years 0.2% (cumulative), lower rates of treatment than have been suggested by analyses of sight-threatening retinopathy determined photographically. At follow-up (mean 7.8 ± 4.6 years), mild to moderate visual impairment in one or both eyes due to diabetic retinopathy was more common in those with retinopathy at screening (26% vs. 5%, p < 0.001), but blindness due to diabetes occurred in only 1 in 1000. Conclusions Optimum screening intervals should be determined from time to active treatment. Based on requirement for laser therapy, the screening interval for diabetic patients with no retinopathy can be extended to two to three years. Patients who attend for retinal screening and treatment who have no or non-proliferative retinopathy now have a very low risk of eventual blindness from diabetes.

Inflammatory Adipokines Decrease Expression of Two High Molecular Weight Isoforms of Tropomyosin Similar to the Change in Type 2 Diabetic Patients.

Cardiovascular disease and cancer are increased in Type 2 diabetes. TPM1 and TPM4 genes encode proteins associated with cardiovascular and neoplastic disease. High (HMW) and low (LMW) molecular weight isoforms from TPM1 and TPM4 are altered in several cancer cells and the 3'UTR of TPM1 mRNA is tumour suppressive. Leukocytes influence cardiovascular and neoplastic disease by immunosurveillance for cancer and by chronic inflammation in Type 2 diabetes and cardiovascular disease. The aim was to determine changes in expression of isoforms from TPM1 and TPM4 genes in leukocytes from Type 2 diabetic patients and to use the leukocyte cell line THP1 to identify possible mediators of changes in the patients. Gene expression was determined by RT-qPCR. In diabetes, expression of HMW isoforms from TPM1 were markedly decreased (0.55 v 1.00; p = 0.019) but HMW isoforms from TPM4 were not significantly different (0.76 v 1.00; p = 0.205). Within individual variance in expression of HMW isoforms was very high. The change in expression in HMW isoforms from TPM1 and TPM4 was replicated in THP1 cells treated with 1 ng/ml TNFα (0.10 and 0.12 v 1.00 respectively) or 10 ng/ml IL-1α (0.17 and 0.14 v 1.00 respectively). Increased insulin or glucose concentrations had no substantial effects on TPM1 or TPM4 expression. Decreased TPM1 mRNA resulted in decreases in HMW protein levels. Expression of HMW isoforms from TPM1 is decreased in Type 2 diabetes. This is probably due to increased levels of inflammatory cytokines TNFα and IL-1α in Type 2 diabetes. Lower levels of TPM1 mRNA reduce tumour suppression and could contribute to increased cancer risk in Type 2 diabetes. Decreased HMW tropomyosin isoforms are associated with cancer. Decreased HMW isoforms give rise to cells that are more plastic, motile, invasive and prone to dedifferentiation resulting in leukocytes that are more invasive but less functionally effective.

Evidence for a persistent, major excess in all cause admissions to hospital in children with type-1 diabetes: results from a large Welsh national matched community cohort study.

OBJECTIVES: To estimate the excess in admissions associated with type1 diabetes in childhood. DESIGN: Matched-cohort study using anonymously linked hospital admission data. SETTING: Brecon Group Register of new cases of childhood diabetes in Wales linked to hospital admissions data within the Secure Anonymised Information Linkage Databank. POPULATION: 1577 Welsh children (aged between 0 and 15 years) from the Brecon Group Register with newly-diagnosed type-1 diabetes between 1999-2009 and 7800 population controls matched on age, sex, county, and deprivation, randomly selected from the local population. MAIN OUTCOME MEASURES: Difference in all-cause hospital admission rates, 30-days post-diagnosis until 31 May 2012, between participants and controls. RESULTS: Children with type-1 diabetes were followed up for a total of 12,102 person years and were at 480% (incidence rate ratios, IRR 5.789, (95% CI 5.34 to 6.723), p<0.0001) increased risk of hospital admission in comparison to matched controls. The highest absolute excess of admission was in the age group of 0-5 years, with a 15.4% (IRR 0.846, (95% CI 0.744 to 0.965), p=0.0061) reduction in hospital admissions for every 5-year increase in age at diagnosis. A trend of increasing admission rates in lower socioeconomic status groups was also observed, but there was no evidence of a differential rate of admissions between men and women when adjusted for background risk. Those receiving outpatient care at large centres had a 16.1% (IRR 0.839, (95% CI 0.709 to 0.990), p=0.0189) reduction in hospital admissions compared with those treated at small centres. CONCLUSIONS: There is a large excess of hospital admissions in paediatric patients with type-1 diabetes. Rates are highest in the youngest children with low socioeconomic status. Factors influencing higher admission rates in smaller centres (eg, "out of hours resources") need to be explored with the aim of targeting modifiable influences on admission rates.

Psychosocial interventions for the diabetic patient.

Diabetes usually requires substantial life-long self-management by the patient. Psychological factors and the patient's health beliefs are important determinants of self-care behavior. Education has a modest influence on generating better self-care, but psychologically based interventions are clearly more effective. This review gives an overview of these interventions with some discussion of their basis in psychological theory. Some labels such as cognitive behavioral therapy and family therapy include a wide range of approaches. Randomized trials have generally produced improvement in measures of psychological well-being, but improved glycemic control has been more elusive. The influence on behavior can be very dependent on the individual therapist. Only a few trials have managed to sustain improvement in glycosylated hemoglobin beyond a year. Not all patients are prepared to engage and accept these forms of therapeutic intervention. We are still some way from moving psychological management from the trial situation into the diabetic clinic.

Changes in Coping Behavior and the Relationship to Personality, Health Threat Communication and Illness Perceptions from the Diagnosis of Diabetes: A 2-year Prospective Longitudinal Study.

Coping behavior is of critical importance in diabetes because of its impact upon self-care and hence eventual medical outcome. We examined how coping behavior and its relationship to personality, diabetes health threat communication (DHTC) and illness representations changes after diagnosis of diabetes. Newly diagnosed diabetic patients were assessed after diagnosis and at 6, 12 and 24 months using the DHTC, Illness Perceptions and Coping inventory questionnaires. Personality traits were assessed at baseline. Active coping, planning, positive reinterpretation and growth (PRG), seeking emotional and instrumental (social) support decreased over the 2 years from diagnosis while passive acceptance increased. Openness/intellect and conscientiousness traits were associated with active coping and seeking instrumental support. Openness/intellect also associated with planning and PRG. These relationships did not vary over time. Perceived threat and serious consequences were associated with active coping but the effect diminished over time. Illness coherence (understanding of diabetes), personal and treatment control were associated with active coping, planning and seeking instrumental support and did not change over time. The coping strategies most commonly employed by diabetic patients are adaptive. Coping behavior changes over the 2 years from diagnosis. Promoting better understanding of diabetes, perceptions of personal control and treatment effectiveness are more likely than perception of health threat to sustain adaptive problem focused coping behavior.

Functional structure of the promoter regions for the predominant low molecular weight isoforms of tropomyosin in human kidney cells.

High and low molecular weight (LMW) tropomyosin isoforms, by regulation of actin filaments, have a major role in the regulation of cell behaviour. They affect malignant transformation, motility, differentiation, metastasis and cell membrane protein presentation. Expression of LMW isoforms from the TPM1 and TPM3 genes have an important role in these effects but the regulation of their expression is unknown. Luciferase assays on a progressively truncated 1.7 kb fragment upstream of the exon 1b translation start site in the TPM1 and TPM3 genes in HEK-293 cells showed upstream activation sequences in TPM1 between -152 and -139 bp and in TPM3 between -154 and -102 bp. The effect of mutating candidate transcription factor binding sites identified an AML1-like transcription factor binding site in TPM1 and a cAMP response element in TPM3. Downstream from the primary activation sequence in TPM1 was a repressor region corresponding to two Sp/KLF family binding GC boxes. Band shift assays confirmed that deletion of these sites altered transcription factor binding and ChIP assays confirmed the presence of AML1 and CREB at the TPM1 and TPM3 activation sequences in the respective promoters. Expression of LMW isoforms from TPM1 and TPM3 genes is regulated very differently. This facilitates regulation of the many cell processes involving these proteins. In situations where these proteins have a critical role, such as cancer metastasis, it also facilitates specific intervention.

Deterministic nonlinear features of cutaneous perfusion are lost in diabetic subjects with neuropathy.

The aim of this study was to analyze and compare the deterministic nonlinear structure of cutaneous laser Doppler flowmetry signals obtained from the forearm and foot of normal subjects and diabetic patients without neuropathy (D), with peripheral neuropathy (DPN) and with combined autonomic and peripheral neuropathy (DAN). Flow oscillations were evaluated under baseline conditions, after local warming of the skin to 44 °C and after warming plus iontophoresis of phenylephrine. The presence of nonlinearity was investigated by three complementary approaches: (i) attractor reconstruction, (ii) calculation of largest Lyapunov exponents (LLEs), and (iii) correlation dimension analysis. Conclusions were validated against surrogate stochastic time series generated by randomizing the Fourier phase of the raw data. In the control and D groups, the combination of phenylephrine and warming unmasked flowmotion with a prominent component at 0.1 Hz. Attractor reconstruction revealed toroidal structure and estimated LLEs were positive. LLEs decreased to zero and dimension estimates increased for surrogate data, consistent with loss of determinism. In diabetic subjects with neuropathy estimates of LLE were not significantly different from zero and dimensions were unaffected by phase randomization. Evidence for nonlinear structure was also obtained under baseline conditions in normal and D subjects, but was lost on warming alone. We conclude that deterministic control mechanisms contribute to cutaneous flowmotion, particularly when pseudo-quasiperiodic behavior is enhanced by phenylephrine. Nonlinear analysis of laser Doppler signals may provide previously unrecognized insights into the effects of diabetic neuropathy on perfusion because it can identify loss of complexity independently of the amplitude of the signals recorded.

Glycemic control in children with type 1 diabetes in wales: influence of the pediatric diabetes specialist nurse.

OBJECTIVE: To determine whether glycemic control is improving in diabetic children in Wales and to identify factors associated with improvement. RESEARCH DESIGN AND METHODS: Data were collected in 2001 and 2006. RESULTS: Over time A1C was reduced from 9.08 +/- 1.66 to 8.88 +/- 1.63% (P = 0.012). There were differences among centers (P < 0.001) and differential changes over time (interaction P < 0.001). Since 2001 five centers had appointed a pediatric diabetes specialist nurse (PDSN). A1C improved in these centers from 9.59 +/- 1.88 to 8.72 +/- 1.61% (P < 0.001). Glycemic control was worse in children aged >10 years compared with younger patients (P < 0.001). Improvement occurred in those aged >10 years. Age (P = 0.003) and insulin dose (P < 0.001) were positively and independently associated with A1C. Thus, any influence of PDSNs was not achieved through increased insulin prescription. CONCLUSIONS: Improvement in glycemic control has occurred. Worse control is associated with greater prescribed insulin dose in older children. Appointment of PDSNs was associated with improved glycemic control among adolescents.

Polymorphisms in the tropomyosin TPM1 short isoform promoter alter gene expression and are associated with increased risk of metabolic syndrome.

BACKGROUND: Inflammation contributes to the development of atherosclerotic lesions in the metabolic syndrome. Tropomyosin isoform expression is altered in this disease and has a role in inflammatory cell plasticity, motility, and insulin sensitivity. We determined the frequency of haplotype carriage of three single-nucleotide polymorphisms (SNPs) in the short isoform promoter of the TPM1 gene in 300 normal controls and 500 metabolic syndrome patients. The effect of each haplotype on tropomyosin gene expression was assessed. METHODS: PCR-restriction fragment length polymorphism assays were developed for each polymorphism. Promoter activity was measured using luciferase assays in the insulin-sensitive human embryonic kidney (HEK) 293 and the monocyte THP-1 lines. RESULTS: The SNPs -111(T/C), -426(T/C), and -491(A/G), relative to the TPM1 short isoform transcription start site, occurred in haplotypes ATT, GCT, GTT, and GTC, and were in strong linkage disequilibrium. ATT had a frequency of 66%. The presence of -491G, which conforms to a predicted binding site for transcription factor AML-1, caused a decrease in gene expression of 24% in the HEK 293 cells. In the THP-1 cells, haplotypes GTC and GTT gave 24% lower expression, whereas haplotype GCT gave expression at wild-type levels. The carriage of a -491G allele gave an odds ratio of 1.4 (95% CI 1.02-1.8) for the metabolic syndrome (P < 0.03). CONCLUSIONS: A polymorphism in the TPM1 short isoform promoter region is predicted to alter transcription factor binding, alters gene expression and is associated with the metabolic syndrome. This could affect inflammatory cells and cytoskeleton-mediated insulin signaling.

Update on treatments for neuropathic pain.

Pharmacotherapy for which there is evidence of efficacy in neuropathic pain management is described. The role of opioids is discussed in the context of recent controlled trials. Evidence to support combination pharmacotherapy for neuropathic pain management is presented.

Alpha adrenoceptor agonist-induced microcirculatory oscillations are reduced in diabetic neuropathy.

In diabetic patients small fiber neuropathy has been associated with impairment of 0.1 Hz microvascular vasomotion. The aim of this study was (1) to investigate whether vasoconstriction-induced microvascular oscillations in the skin are reduced in diabetic patients with peripheral and/or autonomic neuropathy, and (2) whether this method could be used as a non-invasive surrogate marker to assess diabetic small fiber neuropathy. Four matched groups were studied: diabetic patients without neuropathy (D), with peripheral neuropathy (DPN), with peripheral and autonomic neuropathy (DAN), and non-diabetic controls (Ctrl). All participants were evaluated for peripheral and autonomic neuropathy, microvascular endothelial function, and metabolic syndrome indicators. Laser Doppler flowmetry was used to measure oscillations after iontophoresis of the alpha one selective agonist phenylephrine. approximately 0.1-Hz oscillations recorded at the foot were significantly attenuated in diabetic patients with peripheral and/or autonomic neuropathy (DPN and DAN groups) compared to diabetic patients without neuropathy or non-diabetic controls. In the forearm, microvascular oscillations were significantly reduced only in patients with autonomic neuropathy (DAN). Oscillation measures correlated significantly (P<0.001) with all markers of peripheral neuropathy but not with markers of measurements of microvascular endothelial function, or metabolic syndrome markers. In a logistic regression model, reduced microvascular oscillations at the foot were a strong predictor for the presence of peripheral neuropathy. The measurement of phenylephrine-induced approxiamtely 0.1-Hz microvascular oscillation may represent a useful non-invasive tool with which to study the effects of treatment strategies on the diabetic small fiber neuropathy.

Microalbuminuria in Type 2 diabetes indicates impaired microvascular vasomotion and perfusion.

Vascular oscillation (vasomotion) occurs in the microcirculation and is thought to be a significant contributor to tissue perfusion. Our aims were to assess the relationship of vasomotion to perfusion in the cutaneous microcirculation of diabetic patients, to determine the influence on it of endothelium-dependent and nonendothelium-dependent vasodilatory stimuli, and to assess the relationship to perfusion and vasomotion of various biochemical markers of vascular function (HbA1c, LDL- and HDL-cholesterol, triglycerides, insulin resistance, high sensitive C-reactive protein, L- and E-selectin, soluble ICAM, von Willebrand factor) and microalbuminuria. Perfusion and vasomotion (spectral density at low and very low frequencies) were measured by laser-Doppler flowmetry after local heat and iontophoresis of ACh and sodium nitroprusside. Perfusion responses to all stimuli were impaired in patients with Type 2 diabetes (heat: F = 28.0, P < 0.001; ACh: F = 7.11, P = 0.003; sodium nitroprusside: F = 4.0, P = 0.028). Responses to endothelium-dependent stimuli were further impaired in microalbuminuric patients (heat: P = 0.035; ACh: P = 0.034). Vasomotion responses at low frequencies after endothelium-dependent stimuli were impaired in diabetic patients compared with that shown in controls (heat: F = 5.62, P = 0.002; ACh: F = 4.32, P = 0.015). Multivariate modeling showed microalbuminuria to be the only consistent predictor of perfusion and vasomotion responses. The results suggest that microalbuminuria in Type 2 diabetes reflects a generalized disturbance of microvascular function related to endothelium-dependent mechanisms.

Development of the Diabetes Health Threat Communication Questionnaire (DHTCQ).

OBJECTIVES: (1) To develop a brief instrument, the Diabetes Health Threat Communication Questionnaire (DHTCQ) to measure diabetes patients' (type1 and type 2) perceptions of the health threat communication process (i) at time of diagnosis and (ii) since diagnosis; (2) to assess the measure' psychometric properties. METHODS: Data from a pilot study (n=110) and a prospective longitudinal study (n=158, within 3 months of diagnosis and n=147, 6 months after baseline) were examined in order to demonstrate reliability and validity of the DHTCQ. RESULTS: Principal components factor analysis revealed 2 meaningful factors (Reassurance and Threat) with satisfactory internal consistency (Cronbach' alpha) and adequate test-retest reliability. Correlational analyses supported the measure' construct validity. CONCLUSION: Initial support for the psychometric properties of the DHTCQ was shown. Perceptions of health threat communication were associated with patients' illness representations of diabetes (beliefs and feelings about diabetes and its treatment). PRACTICE IMPLICATIONS: The DHTCQ may be used to assess patient perceptions of health communication and shape subsequent communication. The findings may help to improve practitioner/patient interaction leading to more adaptive representations of diabetes.

How reliable is estimation of glomerular filtration rate at diagnosis of type 2 diabetes?

OBJECTIVE: The Cockcroft-Gault (CG) and Modification of Diet in Renal Disease (MDRD) equations previously have been recommended to estimate glomerular filtration rate (GFR). We compared both estimates with true GFR, measured by the isotopic (51)Cr-EDTA method, in newly diagnosed, treatment-naïve subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 292 mainly normoalbuminuric (241 of 292) subjects were recruited. Subjects were classified as having mild renal impairment (group 1, GFR <90 ml/min per 1.73 m(2)) or normal renal function (group 2, GFR >/=90 ml/min per 1.73 m(2)). Estimated GFR (eGFR) was calculated by the CG and MDRD equations. Blood samples drawn at 44, 120, 180, and 240 min after administration of 1 MBq of (51)Cr-EDTA were used to measure isotopic GFR (iGFR). RESULTS: For subjects in group 1, mean (+/-SD) iGFR was 83.8 +/- 4.3 ml/min per 1.73 m(2). eGFR was 78.0 +/- 16.5 or 73.7 +/- 12.0 ml/min per 1.73 m(2) using CG and MDRD equations, respectively. Ninety-five percent CIs for method bias were -11.1 to -0.6 using CG and -14.4 to -7.0 using MDRD. Ninety-five percent limits of agreement (mean bias +/- 2 SD) were -37.2 to 25.6 and -33.1 to 11.7, respectively. In group 2, iGFR was 119.4 +/- 20.3 ml/min per 1.73 m(2). eGFR was 104.4 +/- 26.3 or 92.3 +/- 18.7 ml/min per 1.73 m(2) using CG and MDRD equations, respectively. Ninety-five percent CIs for method bias were -17.4 to -12.5 using CG and -29.1 to -25.1 using MDRD. Ninety-five percent limits of agreement were -54.4 to 24.4 and -59.5 to 5.3, respectively. CONCLUSIONS: In newly diagnosed type 2 diabetic patients, particularly those with a GFR >/=90 ml/min per 1.73 m(2), both CG and MDRD equations significantly underestimate iGFR. This highlights a limitation in the use of eGFR in the majority of diabetic subjects outside the setting of chronic kidney disease.

Adrenomyeloneuropathy in patients with 'Addison's disease': genetic case analysis.

OBJECTIVE: To review the clinical presentations and diagnostic issues in adrenomyeloneuropathy and adrenoleukodystrophy, which are different presentations of the same single gene disorder. DESIGN: Observational study. PARTICIPANTS: Three generations of an affected kindred. INTERVENTION: None. MAIN OUTCOME MEASURES: Neurological features suggestive of adrenoleukodystrophy or adrenomyeloneuropathy. Measurement of very long chain fatty acids. Molecular analysis of the adrenoleukodystrophy gene. RESULTS: Three adults presented with adrenomyeloneuropathy and two children with adrenoleukodystrophy. Circulating concentrations of long chain fatty acids were raised consistent with clinical features. A mutation in exon 6 of the adrenoleukodystrophy gene (P543L) was identified. This had not previously been identified but has subsequently been reported by other groups. CONCLUSIONS: Adrenomyeloneuropathy should be considered in the differential diagnosis in male patients presenting with adrenal failure. Early diagnosis allows genetic counselling in such families and may become more important as treatment strategies evolve.

Understanding why people with type 1 diabetes do not attend for specialist advice: a qualitative analysis of the views of people with insulin-dependent diabetes who do not attend diabetes clinic.

Attendance at diabetes clinic is associated with improved medical outcome, however, significant numbers of people with type 1 diabetes choose not to attend. In order to understand the reasons underlying this decision, qualitative interviews were carried out with 12 long-term non-attenders. Three distinct groups emerged differing in terms of their cognitive and emotional responses to diabetes and their coping strategies: (1) the 'High fear' group; (2) the 'Patient as expert' group; and (3) the 'Low motivation' group. These differences should be recognized and suitable approaches developed to ensure that all people with diabetes are able to accept appropriate specialist support.

Sonographically guided core biopsy in the assessment of thyroid nodules.

PURPOSE: This study was conducted to assess the value of sonographically guided core biopsy in the evaluation of thyroid nodules by comparison with fine-needle aspiration cytology (FNAC) performed with and without sonographic guidance. METHODS: We performed a retrospective analysis of a consecutive series of 645 thyroid samples obtained at a single center. Samples came from 422 patients who underwent FNAC (with or without sonographic guidance), sonographically guided core biopsy, or excision of thyroid tissue with or without prior frozen sectioning. Final diagnoses were obtained from surgery or clinical follow-up. Initial and final diagnoses were compared. RESULTS: Adequate samples for assessment were obtained in 87% of core biopsies, compared with 60% of cytology aspirates (p <0.001). Sonographically guided core biopsy and sonographically guided FNAC both had zero false-negative rates for the diagnosis of malignancy, compared with a 7.0% false-negative rate (95% confidence interval, 2.0-12.0%) for aspiration cytology when sonography was not used. With core biopsy, 11% of patients required surgical confirmation of the diagnosis, compared with 43% of patients following FNAC (p <0.001). There were no major complications following core biopsy. CONCLUSIONS: Sonographically guided core biopsy provides an accurate and safe alternative to FNAC in the assessment of thyroid nodules.