No Difference in Small or Large Nerve Fiber Function Between Individuals With Normal Glucose Tolerance and Impaired Glucose Tolerance

OBJECTIVE

To assess small and large nerve fiber function in people with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2D).

RESEARCH DESIGN AND METHODS

Participants were recruited consecutively from a population-based cohort: NGT (n = 39), IGT (n = 29), and T2D (n = 51). Electrophysiological measures included nerve conduction studies and thermal thresholds. Intraepidermal nerve fiber density (IENFD) in skin biopsies was calculated.

RESULTS

There was no difference between IGT and NGT in sural nerve conduction, IENFD, and thermal thresholds. IENFD was significantly lower in T2D (median = 2.8 fibers/mm [interquartile range 1.1–4.7 fibers/mm]) than NGT individuals (4.5 fibers/mm [3.4–6.1 fibers/mm]; P < 0.05). T2D participants had poorer nerve conduction and higher heat thresholds than NGT and IGT.

CONCLUSIONS

Large and small nerve function in people with IGT did not differ from those with NGT. Our finding does not support the existence of neuropathy in a prediabetic stage.A high prevalence of impaired glucose tolerance (IGT) in individuals with idiopathic neuropathy has been reported (1), but whether neuropathy already exists in the prediabetic stage, i.e., IGT, is unknown (2,3). In a population-based study, neuropathy was marginally more common in IGT than in normoglycemic controls (4), but others reported no difference in measures of neuropathy between IGT and normal glucose tolerance (NGT) (5,6).When addressing the question of whether “IGT neuropathy” truly exists, objective measures of nerve dysfunction are frequently crude and focused on large nerve fibers, and small nerve fiber dysfunction is often overlooked (1,4,6).Thus, our aim was to study measures of both small and large nerve function in well-characterized normoglycemic, IGT, and type 2 diabetic (T2D) individuals.     

Corneal Confocal Microscopy Detects Neuropathy in Subjects With Impaired Glucose Tolerance

OBJECTIVE

Impaired glucose tolerance (IGT) represents one of the earliest stages of glucose dysregulation and is associated with macrovascular disease, retinopathy, and microalbuminuria, but whether IGT causes neuropathy is unclear.

RESEARCH DESIGN AND METHODS

Thirty-seven subjects with IGT and 20 age-matched control subjects underwent a comprehensive evaluation of neuropathy by assessing symptoms, neurological deficits, nerve conduction studies, quantitative sensory testing, heart rate variability deep breathing (HRVdb), skin biopsy, and corneal confocal microscopy (CCM).

RESULTS

Subjects with IGT had a significantly increased neuropathy symptom profile (P < 0.001), McGill pain index (P < 0.001), neuropathy disability score (P = 0.001), vibration perception threshold (P = 0.002), warm threshold (P = 0.006), and cool threshold (P = 0.03), with a reduction in intraepidermal nerve fiber density (P = 0.03), corneal nerve fiber density (P < 0.001), corneal nerve branch density (P = 0.002), and corneal nerve fiber length (P = 0.05). No significant difference was found in sensory and motor nerve amplitude and conduction velocity or HRVdb.

CONCLUSIONS

Subjects with IGT have evidence of neuropathy, particularly small-fiber damage, which can be detected using skin biopsy and CCM.     

Corneal Confocal Microscopy: A novel noninvasive test to diagnose and stratify the severity of human diabetic neuropathy

OBJECTIVE

The accurate quantification of human diabetic neuropathy is important to define at-risk patients, anticipate deterioration, and assess new therapies.

RESEARCH DESIGN AND METHODS

A total of 101 diabetic patients and 17 age-matched control subjects underwent neurological evaluation, neurophysiology tests, quantitative sensory testing, and evaluation of corneal sensation and corneal nerve morphology using corneal confocal microscopy (CCM).

RESULTS

Corneal sensation decreased significantly (P = 0.0001) with increasing neuropathic severity and correlated with the neuropathy disability score (NDS) (r = 0.441, P < 0.0001). Corneal nerve fiber density (NFD) (P < 0.0001), nerve fiber length (NFL), (P < 0.0001), and nerve branch density (NBD) (P < 0.0001) decreased significantly with increasing neuropathic severity and correlated with NDS (NFD r = −0.475, P < 0.0001; NBD r = −0.511, P < 0.0001; and NFL r = −0.581, P < 0.0001). NBD and NFL demonstrated a significant and progressive reduction with worsening heat pain thresholds (P = 0.01). Receiver operating characteristic curve analysis for the diagnosis of neuropathy (NDS >3) defined an NFD of <27.8/mm² with a sensitivity of 0.82 (95% CI 0.68–0.92) and specificity of 0.52 (0.40–0.64) and for detecting patients at risk of foot ulceration (NDS >6) defined a NFD cutoff of <20.8/mm² with a sensitivity of 0.71 (0.42–0.92) and specificity of 0.64 (0.54–0.74).

CONCLUSIONS

CCM is a noninvasive clinical technique that may be used to detect early nerve damage and stratify diabetic patients with increasing neuropathic severity.Established diabetic neuropathy leads to pain and foot ulceration. Detecting neuropathy early may allow intervention with treatments to slow or reverse this condition (1). Recent studies suggested that small unmyelinated C-fibers are damaged early in diabetic neuropathy (2–4) but can only be detected using invasive procedures such as sural nerve biopsy (4,5) or skin-punch biopsy (6–8). Our studies have shown that corneal confocal microscopy (CCM) can identify early small nerve fiber damage and accurately quantify the severity of diabetic neuropathy (9–11). We have also shown that CCM relates to intraepidermal nerve fiber loss (12) and a reduction in corneal sensitivity (13) and detects early nerve fiber regeneration after pancreas transplantation (14). Recently we have also shown that CCM detects nerve fiber damage in patients with Fabry disease (15) and idiopathic small fiber neuropathy (16) when results of electrophysiology tests and quantitative sensory testing (QST) are normal.In this study we assessed corneal sensitivity and corneal nerve morphology using CCM in diabetic patients stratified for the severity of diabetic neuropathy using neurological evaluation, electrophysiology tests, and QST. This enabled us to compare CCM and corneal esthesiometry with established tests of diabetic neuropathy and define their sensitivity and specificity to detect diabetic patients with early neuropathy and those at risk of foot ulceration.     

Diagnosis of Neuropathy and Risk Factors for Corneal Nerve Loss in Type 1 and Type 2 Diabetes: A Corneal Confocal Microscopy Study

OBJECTIVETo assess the diagnostic utility of corneal confocal microscopy (CCM) for diabetic peripheral neuropathy (DPN) and the risk factors for corneal nerve loss.RESEARCH DESIGN AND METHODSA total of 490 participants, including 72 healthy control subjects, 149 with type 1 diabetes, and 269 with type 2 diabetes, underwent detailed assessment of peripheral neuropathy and CCM in relation to risk factors.RESULTSCorneal nerve fiber density (CNFD) (P < 0.0001 and P < 0.0001), corneal nerve fiber branch density (CNBD) (P < 0.0001 and P < 0.0001), and corneal nerve fiber length (CNFL) (P < 0.0001 and P = 0.02) were significantly lower in patients with type 1 and type 2 diabetes compared with control subjects. CNFD (P < 0.0001), CNBD (P < 0.0001), and CNFL (P < 0.0001) were lower in type 1 diabetes compared with type 2 diabetes. Receiver operating characteristic curve analysis for the diagnosis of DPN demonstrated a good area under the curve for CNFD of 0.81, CNBD of 0.74, and CNFL of 0.73. Multivariable regression analysis showed a significant association among reduced CNFL with age (β = −0.27, P = 0.007), HbA_1c (β = −1.1; P = 0.01), and weight (β = −0.14; P = 0.03) in patients with type 2 diabetes and with duration of diabetes (β = −0.13; P = 0.02), LDL cholesterol (β = 1.8, P = 0.04), and triglycerides (β = −2.87; P = 0.009) in patients with type 1 diabetes.CONCLUSIONSCCM identifies more severe corneal nerve loss in patients with type 1 diabetes compared with type 2 diabetes and shows good diagnostic accuracy for DPN. Furthermore, the risk factors for a reduction in corneal nerve fiber length differ between type 1 and type 2 diabetes.     

Diabetes and Vascular Disease in Different Arterial Territories

OBJECTIVE

The aim of this study was to investigate the relationship between diabetes and different phenotypes of peripheral vascular disease (lower extremity peripheral artery disease [PAD], carotid artery stenosis [CAS], and abdominal aortic aneurysm [AAA]).

RESEARCH DESIGN AND METHODS

Prevalence of vascular disease was evaluated in 3,696,778 participants of the Life Line Screening survey between 2003 and 2008. PAD was defined as ankle-brachial pressure index <0.90 or prior revascularization, CAS as ≥50% stenosis or prior revascularization, and AAA as infrarenal aortic diameter ≥3 cm or prior repair. Odds ratios (ORs) and 95% CIs were assessed using logistic regression modeling.

RESULTS

Diabetes mellitus was present in 10.8% of participants (n = 399,884). Prevalence of PAD, CAS, and AAA was significantly higher (P < 0.0001) in participants with compared with those without diabetes. After multivariate adjustment for baseline demographics and clinical risk factors, a significant interaction existed between diabetes and vascular disease phenotype (P < 0.0001). Diabetes was associated with increased odds of PAD (OR 1.42 [95% CI 1.41–1.4]; P < 0.0001) and CAS (1.45 [1.43–1.47]; P < 0.0001) but decreased odds of AAA (0.86 [0.84–0.88]; P < 0.0001). The strength of association increased with increasing severity of disease in each vascular phenotype, and this association persisted in the population with asymptomatic vascular disease.

CONCLUSIONS

In a large population-based study, the association between diabetes and vascular disease differed according to vascular phenotype. Future studies exploring the mechanism for these vascular-specific differences are needed.     

Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis

Introduction

The incidence of death among patients admitted for severe sepsis or septic shock is high. Adrenomedullin (ADM) plays a central role in initiating the hyperdynamic response during the early stages of sepsis. Pilot studies indicate an association of plasma ADM with the severity of the disease. In the present study we utilized a novel sandwich immunoassay of bioactive plasma ADM in patients hospitalized with sepsis in order to assess the clinical utility.

Methods

We enrolled 101 consecutive patients admitted to the emergency department with suspected sepsis in this study. Sepsis was defined by fulfillment of at least two systemic inflammatory response syndrome (SIRS) criteria plus clinical suspicion of infection. Plasma samples for ADM measurement were obtained on admission and for the next four days. The 28-day mortality rate was recorded.

Results

ADM at admission was associated with severity of disease (correlation with Acute Physiology and Chronic Health Evaluation II (APACHE II) score: r = 0.46; P <0.0001). ADM was also associated with 28-day mortality (ADM median (IQR): survivors: 50 (31 to 77) pg/mL; non-survivors: 84 (48 to 232) pg/mL; P <0.001) and was independent from and additive to APACHE II (P = 0.02). Cox regression analysis revealed an additive value of serial measurement of ADM over baseline assessment for prediction of 28-day mortality (P < 0.01). ADM was negatively correlated with mean arterial pressure (r = -0.39; P <0.0001), and it strongly discriminated those patients requiring vasopressor therapy from the others (ADM median (IQR): no vasopressors 48 (32 to 75) pg/mL; with vasopressors 129 (83 to 264) pg/mL, P <0.0001).

Conclusions

In patients admitted with sepsis, severe sepsis or septic shock plasma ADM is strongly associated with severity of disease, vasopressor requirement and 28-day mortality.     

Prevalence of Diabetes Among Hispanics/Latinos From Diverse Backgrounds: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL)

OBJECTIVE

We examine differences in prevalence of diabetes and rates of awareness and control among adults from diverse Hispanic/Latino backgrounds in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

RESEARCH DESIGN AND METHODS

The HCHS/SOL, a prospective, multicenter, population-based study, enrolled from four U.S. metropolitan areas from 2008 to 2011 16,415 18–74-year-old people of Hispanic/Latino descent. Diabetes was defined by either fasting plasma glucose, impaired glucose tolerance 2 h after a glucose load, glycosylated hemoglobin (A1C), or documented use of hypoglycemic agents (scanned medications).

RESULTS

Diabetes prevalence varied from 10.2% in South Americans and 13.4% in Cubans to 17.7% in Central Americans, 18.0% in Dominicans and Puerto Ricans, and 18.3% in Mexicans (P < 0.0001). Prevalence related positively to age (P < 0.0001), BMI (P < 0.0001), and years living in the U.S. (P = 0.0010) but was negatively related to education (P = 0.0005) and household income (P = 0.0043). Rate of diabetes awareness was 58.7%, adequate glycemic control (A1C <7%, 53 mmol/mol) was 48.0%, and having health insurance among those with diabetes was 52.4%.

CONCLUSIONS

Present findings indicate a high prevalence of diabetes but considerable diversity as a function of Hispanic background. The low rates of diabetes awareness, diabetes control, and health insurance in conjunction with the negative associations between diabetes prevalence and both household income and education among Hispanics/Latinos in the U.S. have important implications for public health policies.     

Corneal Confocal Microscopy Identifies Small-Fiber Neuropathy in Subjects With Impaired Glucose Tolerance Who Develop Type 2 Diabetes

OBJECTIVEImpaired glucose tolerance (IGT) through to type 2 diabetes is thought to confer a continuum of risk for neuropathy. Identification of subjects at high risk of developing type 2 diabetes and, hence, worsening neuropathy would allow identification and risk stratification for more aggressive management.RESULTSTen subjects who developed type 2 diabetes had a significantly lower CNFD (P = 0.003), CNBD (P = 0.04), and CNFL (P = 0.04) compared with control subjects at baseline and a further reduction in CNFL (P = 0.006), intraepidermal nerve fiber density (IENFD) (P = 0.02), and mean dendritic length (MDL) (P = 0.02) over 3 years. Fifteen subjects who remained IGT and 5 subjects who returned to normal glucose tolerance had no significant baseline abnormality on CCM or IENFD but had a lower MDL (P < 0.0001) compared with control subjects. The IGT subjects showed a significant decrease in IENFD (P = 0.02) but no change in MDL or CCM over 3 years. Those who returned to NGT showed an increase in CNFD (P = 0.05), CNBD (P = 0.04), and CNFL (P = 0.05), but a decrease in IENFD (P = 0.02), over 3 years.CONCLUSIONSCCM and skin biopsy detect a small-fiber neuropathy in subjects with IGT who develop type 2 diabetes and also show a dynamic worsening or improvement in corneal and intraepidermal nerve morphology in relation to change in glucose tolerance status.     

Polyendocrinopathy in Children, Adolescents, and Young Adults With Type 1 Diabetes: A multicenter analysis of 28,671 patients from the German/Austrian DPV-Wiss database

OBJECTIVE

To investigate diabetes-specific autoantibodies and additional autoimmune phenomena in a large cohort of young patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Data from 28,671 patients <30 years with type 1 diabetes from 242 specialized centers in Germany and Austria were analyzed.

RESULTS

At least one β-cell antibody was present in 81.6% of patients. β-cell–Ab-negative patients were significantly younger at diabetes onset (P < 0.0001). A total of 19.6% had positive thyroid antibodies with female predominance (62%, P < 0.0001). Antibodies to tissue transglutaminase were present in 10.7%, with a significantly longer duration of diabetes (P < 0.0001). Parietal cell antibodies were found in 283 patients, associated with older age (P < 0.001), and adrenal antibodies were present in 94 patients. In 575 patients, at least three different autoimmune phenomena were present.

CONCLUSIONS

Thyroid autoimmunity and antibodies suggestive for celiac disease are the most prevalent additional immune phenomena in type 1 diabetes. Parietal/adrenal antibodies are rare.Additional autoimmune phenomena such as Hashimoto thyroiditis or celiac disease are a frequent observation in type 1 diabetes (1,2). The appearance of autoantibodies is often the first detectable sign of autoimmune diseases (3). The aim of this study was to investigate screening frequency and prevalence of autoimmune phenomena in a large cohort of children, adolescents, and young adults with type 1 diabetes.     

Platelet mitochondrial membrane depolarization reflects disease severity in patients with sepsis and correlates with clinical outcome

Introduction

Sepsis is still a leading cause of morbidity and mortality, even in modern times, and thrombocytopenia has been closely associated with unfavorable disease outcome. Decreases in mitochondrial membrane potential (depolarization) were found in different tissues during sepsis. Previous work suggests that mitochondrial dysfunction of platelets correlates with clinical disease activity in sepsis. However, platelet mitochondrial membrane potential (Mmp) has not been investigated in a clinical follow-up design and not with regard to disease outcome.

Methods

In this study, platelet mitochondrial membrane depolarization was assessed by means of a fluorescent Mmp-Index with flow cytometry in 26 patients with sepsis compared with control patients. Platelet Mmp-Index on admission was correlated with the clinical disease scores Acute Physiology and Chronic Health Evaluation Score II (APACHE II), Sequential Organ Failure Score (SOFA), and Simplified Acute Physiology Score II (SAPS II). Finally, platelet Mmp-Index on admission and follow-up were compared in the group of sepsis survivors and nonsurvivors. Expression of the prosurvival protein Bcl-xL in platelets was quantified by immunoblotting.

Results

Platelet mitochondrial membrane depolarization correlated significantly with the simultaneously assessed clinical disease severity by APACHE II (r = -0.867; P < 0.0001), SOFA (r = -0.857; P <0.0001), and SAPS II score (r = -0.839; P < 0.0001). Patients with severe sepsis showed a significant reduction in platelet Mmp-Index compared with sepsis without organ failure (0.18 (0.12 to 0.25) versus 0.79 (0.49 to 0.85), P < 0.0006) or with the control group (0.18 (0.12 to 0.25) versus 0.89 (0.68 to 1.00), P < 0.0001). Platelet Mmp-Index remained persistently low in sepsis nonsurvivors (0.269 (0.230 to 0.305)), whereas we observed recovery of platelet Mmp-Index in the survivor group (0.9 (0.713 to 1.017)). Furthermore, the level of prosurvival protein Bcl-xL decreased in platelets during severe sepsis.

Conclusion

In this study, we demonstrated that mitochondrial membrane depolarization in platelets correlates with clinical disease severity in patients with sepsis during the disease course and may be a valuable adjunct parameter to aid in the assessment of disease severity, risk stratification, and clinical outcome.     

Circadian Patterns of ST Elevation Myocardial Infarction in the New Millennium

Objective

Nearly four decades ago, a circadian pattern of acute myocardial infarction (AMI) with a peak in the early morning waking hours was described. The goal of the present study was to determine whether major changes in lifestyle and significant advances in medical therapy have altered this pattern in the intervening years.

Design

Retrospective chart review.

Setting

Tertiary care hospital in central Wisconsin.

Methods

We examined circadian patterns of ST elevation myocardial infarction (STEMI) in 519 patients diagnosed with STEMI over a 5-year period. Time of symptom onset was obtained from patient self-reports in the medical record and was recorded over 24 hours.

Results

We observed a circadian pattern of STEMI occurrence with a morning peak at approximately 11:30 AM. This pattern was highly significant in patients who were not using beta-blockers (P <0.0001) and had no history of diabetes (P <0.0001), but was otherwise absent. The circadian pattern appeared to be attenuated in patients of a younger age, female gender, or who used statins or aspirin. Peak STEMI occurrence was earlier in smokers than non-smokers.

Conclusions

Despite significant lifestyle changes and medical advances in the nearly four decades since a circadian pattern of AMI occurrence was first described, patients with STEMI had a circadian pattern of symptom onset with a morning peak. Use of beta-blockers and a history of diabetes mellitus abolished this pattern. Other modifying factors, including medications, age, and gender attenuated, but did not abolish, the circadian pattern.     

Identifying predictive morphologic features of malignancy in eyelid lesions: The LUI triage key

Objective

To determine features of eyelid lesions most predictive of malignancy, and to design a key to assist general practitioners in the triaging of such lesions.

Design

Prospective observational study.

Setting

Department of Ophthalmology at Queen’s University in Kingston, Ont.

Participants

A total of 199 consecutive periocular lesions requiring biopsy or excision were included.

Main outcome measures

First, potential features suggestive of malignancy for eyelid lesions were identified based on a survey sent to Canadian oculoplastic surgeons. The sensitivity, specificity, and odds ratios (ORs) of these features were then determined using 199 consecutive photographed eyelid lesions of patients who presented to the Department of Ophthalmology and underwent biopsy or excision. A triage key was then created based on the features with the highest ORs, and it was pilot-tested by a group of medical students.

Results

Of the 199 lesions included, 161 (80.9%) were benign and 38 (19.1%) were malignant. The 3 features with the highest ORs in predicting malignancy were infiltration (OR = 18.2, P < .01), ulceration (OR = 14.7, P < .01), and loss of eyelashes (OR = 6.0, P < .01). The acronym LUI (loss of eyelashes, ulceration, infiltration) was created to assist in memory recall. After watching a video describing the LUI triage key, the mean total score of a group of medical students for correctly identifying malignant lesions increased from 46% to 70% (P < .001).

Conclusion

Differentiating benign from malignant eyelid lesions can be difficult even for experienced physicians. The LUI triage key provides physicians with an evidence-based, easy-to-remember system for assisting in the triaging of these lesions.     

Adoption of the chronic care model to improve HIV care: In a marginalized,largely aboriginal population

Objective

To measure the effectiveness of implementing the chronic care model (CCM) in improving HIV clinical outcomes.

Design

Multisite, prospective, interventional cohort study.

Setting

Two urban community health centres in Vancouver and Prince George, BC.

Participants

Two hundred sixty-nine HIV-positive patients (18 years of age or older) who received primary care at either of the study sites.

Intervention

Systematic implementation of the CCM during an 18-month period.

Main outcome measures

Documented pneumococcal vaccination, documented syphilis screening, documented tuberculosis screening, antiretroviral treatment (ART) status, ART status with undetectable viral load, CD4 cell count of less than 200 cells/mL, and CD4 cell count of less than 200 cells/mL while not taking ART compared during a 36-month period.

Results

Overall, 35% of participants were women and 59% were aboriginal persons. The mean age was 45 years and most participants had a history of injection drug use that was the presumed route of HIV transmission. During the study follow-up period, 39 people died, and 11 transferred to alternate care providers. Compared with their baseline clinical status, study participants showed statistically significant (P < .001 for all) increases in pneumococcal immunization (54% vs 84%), syphilis screening (56% vs 91%), tuberculosis screening (23% vs 38%), and antiretroviral uptake (47% vs 77%), as well as increased viral load suppression rates among those receiving ART (72% vs 90%). Stable housing at baseline was associated with a 4-fold increased probability of survival. Aboriginal ethnicity was not associated with better or worse outcomes at baseline or at follow-up.

Conclusion

Application of the CCM approach to HIV care in a marginalized, largely aboriginal patient population led to improved disease screening, immunization, ART uptake, and virologic suppression rates. In addition to addressing underlying social determinants of health, a paradigm shift away from an “infectious disease” approach to a “chronic disease management” approach to HIV care for marginalized populations is strongly recommended.     

Metabolomics Reveals Broad-Scale Metabolic Perturbations in Hyperglycemic Mothers During Pregnancy

OBJECTIVE

To characterize metabolites across the range of maternal glucose by comparing metabolomic profiles of mothers with high and low fasting plasma glucose (FPG).

RESEARCH DESIGN AND METHODS

We compared fasting serum from an oral glucose tolerance test at ∼28 weeks’ gestation from 67 Northern European ancestry mothers from the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study with high (>90th percentile) FPG with 50 mothers with low (<10th percentile) FPG but comparable BMI. Metabolic data from biochemical analyses of conventional clinical metabolites, targeted mass spectrometry (MS)-based measurement of amino acids, and nontargeted gas chromatography/MS were subjected to per-metabolite analyses and collective pathway analyses using Unipathway annotation.

RESULTS

High-FPG mothers had a metabolic profile consistent with insulin resistance including higher triglycerides, 3-hydroxybutyrate, and amino acids including alanine, proline, and branched-chain amino acids (false discovery rate [FDR]-adjusted P < 0.05). Lower 1,5-anhydroglucitol in high-FPG mothers suggested recent hyperglycemic excursions (FDR-adjusted P < 0.05). Pathway analyses indicated differences in amino acid degradation pathways for the two groups (FDR-adjusted P < 0.05), consistent with population-based findings in nonpregnant populations. Exploratory analyses with newborn outcomes indicated positive associations for maternal triglycerides with neonatal sum of skinfolds and cord C-peptide and a negative association between maternal glycine and cord C-peptide (P < 0.05).

CONCLUSIONS

Metabolomics reveals perturbations in metabolism of major macronutrients and amino acid degradation pathways in high- versus low-FPG mothers.     

Blood Pressure and Pulse Pressure Effects on Renal Outcomes in the Veterans Affairs Diabetes Trial (VADT)

OBJECTIVE

Blood pressure (BP) control for renal protection is essential for patients with type 2 diabetes. Our objective in this analysis of Veterans Affairs Diabetes Trial (VADT) data was to learn whether on-study systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) affected renal outcomes measured as albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR).

RESEARCH DESIGN AND METHODS

The VADT was a prospective, randomized study of 1,791 veterans with type 2 diabetes to determine whether intensive glucose control prevented major cardiovascular events. In this post hoc study, time-varying covariate survival analyses and hazard ratios (HR) were used to determine worsening of renal outcomes.

RESULTS

Compared with SBP 105–129 mmHg, the risk of ACR worsening increased significantly for SBP 130–139 mmHg (HR 1.88 [95% CI 1.28–2.77]; P = 0.001) and for SBP ≥140 mmHg (2.51 [1.66–3.78]; P < 0.0001). Compared with a PP range of 40–49 mmHg, PP <40 was associated with significantly lowered risk of worsening ACR (0.36 [0.15–0.87]; P = 0.022) and PP ≥60 with significantly increased risk (2.38 [1.58–3.59]; P < 0.0001). Analyses of BP ranges associated with eGFR worsening showed significantly increased risk with rising baseline SBP and an interaction effect between SBP ≥140 mmHg and on-study A1C. These patients were 15% more likely than those with SBP <140 mmHg to experience eGFR worsening (1.15 [1.00–1.32]; P = 0.045) for each 1% (10.9 mmol/mol) A1C increase.

CONCLUSIONS

SBP ≥130 mmHg and PP >60 mmHg were associated with worsening ACR. The results suggest that treatment of SBP to <130 mmHg may lessen ACR worsening. The interaction between SBP ≥140 mmHg and A1C suggests that the effect of glycemic control on reducing progression of renal disease may be greater in hypertensive patients.     

Effects of Intraduodenal Glutamine on Incretin Hormone and Insulin Release,the Glycemic Response to an Intraduodenal Glucose Infusion,and Antropyloroduodenal Motility in Health and Type 2 Diabetes

OBJECTIVE

Glutamine reduces postprandial glycemia when given before oral glucose. We evaluated whether this is mediated by stimulation of insulin and/or slowing of gastric emptying.

RESEARCH DESIGN AND METHODS

Ten healthy subjects were studied during intraduodenal (ID) infusion of glutamine (7.5 or 15 g) or saline over 30 min, followed by glucose (75 g over 100 min), while recording antropyloroduodenal pressures. Ten patients with type 2 diabetes mellitus (T2DM) were also studied with 15 g glutamine or saline.

RESULTS

ID glutamine stimulated glucagon-like peptide 1 (GLP-1; healthy: P < 0.05; T2DM: P < 0.05), glucose-dependent insulinotropic polypeptide (GIP; P = 0.098; P < 0.05), glucagon (P < 0.01; P < 0.001), insulin (P = 0.05; P < 0.01), and phasic pyloric pressures (P < 0.05; P < 0.05), but did not lower blood glucose (P = 0.077; P = 0.5).

CONCLUSIONS

Glutamine does not lower glycemia after ID glucose, despite stimulating GLP-1, GIP, and insulin, probably due to increased glucagon. Its capacity for pyloric stimulation suggests that delayed gastric emptying is a major mechanism for lowering glycemia when glutamine is given before oral glucose.Postprandial glycemic control represents a major focus of type 2 diabetes mellitus (T2DM) management (1). The rate of gastric emptying and the release of “incretin” hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are both important determinants of postprandial glycemic excursions (2). Glucose empties from the stomach in health in the range of 1–4 kcal/min, regulated by inhibitory small-intestinal feedback via stimulation of pyloric motility and suppression of antral and duodenal contractions (3). Differences in gastric emptying account for about one-third of the variation in postprandial blood glucose levels after oral glucose (4).Glutamine reduces glucose excursions when given before oral glucose in T2DM (5), potentially by stimulating GLP-1 secretion (6) and/or slowing gastric emptying (7). The purpose of the current study was to determine whether glutamine retains its capacity to lower glycemia when glucose is delivered directly into the duodenum, thereby removing any influence of gastric emptying, while measuring antropyloroduodenal motility, gut hormones, and insulin.     

Interest of low-dose hydrocortisone therapy during brain-dead organ donor resuscitation: the CORTICOME study

Introduction

Circulatory failure during brain death organ donor resuscitation is a problem that compromises recovery of organs. Combined administration of steroid, thyroxine and vasopressin has been proposed to optimize the management of brain deceased donors before recovery of organs. However the single administration of hydrocortisone has not been rigorously evaluated in any trial.

Methods

In this prospective multicenter cluster study, 259 subjects were included. Administration of low-dose steroids composed the steroid group (n = 102).

Results

Although there were more patients in the steroid group who received norepinephrine before brain death (80% vs. 66%: P = 0.03), mean dose of vasopressor administered after brain death was significantly lower than in the control group (1.18 ± 0.92 mg/H vs. 1.49 ± 1.29 mg/H: P = 0.03), duration of vasopressor support use was shorter (874 min vs. 1160 min: P < 0.0001) and norepinephrine weaning before aortic clamping was more frequent (33.8% vs. 9.5%: P < 0.0001). Using a survival approach, probability of norepinephrine weaning was significantly different between the two groups (P < 0.0001) with a probability of weaning 4.67 times higher in the steroid group than in the control group (95% CI: 2.30 – 9.49).

Conclusions

Despite no observed benefits of the steroid administration on primary function recovery of transplanted grafts, administration of glucocorticoids should be a part of the resuscitation management of deceased donors with hemodynamic instability.     

Free breathing contrast-enhanced time-resolved magnetic resonance angiography in pediatric and adult congenital heart disease

Background

Contrast enhanced magnetic resonance angiography (MRA) is generally performed during a long breath-hold (BH), limiting its utility in infants and small children. This study proposes a free-breathing (FB) time resolved MRA (TRA) technique for use in pediatric and adult congenital heart disease (CHD).

Methods

A TRA sequence was developed by combining spiral trajectories with sensitivity encoding (SENSE, x4 kx-ky and x2 kz) and partial Fourier (75% in kz). As no temporal data sharing is used, an independent 3D data set was acquired every ~1.3s, with acceptable spatial resolution (~2.3x2.3x2.3mm). The technique was tested during FB over 50 consecutive volumes. Conventional BH-MRA and FB-TRA data was acquired in 45 adults and children with CHD. We calculated quantitative image quality for both sequences. Diagnostic accuracy was assessed in all patients from both sequences. Additionally, vessel measurements were made at the sinotubular junction (N = 43), proximal descending aorta (N = 43), descending aorta at the level of the diaphragm (N = 43), main pulmonary artery (N = 35), left pulmonary artery (N = 35) and the right pulmonary artery (N = 35). Intra and inter observer variability was assessed in a subset of 10 patients.

Results

BH-MRA had significantly higher homogeneity in non-contrast enhancing tissue (coefficient of variance, P <0.0001), signal-to-noise ratio (P <0.0001), contrast-to-noise ratio (P <0.0001) and relative contrast (P = 0.02) compared to the FB-TRA images. However, homogeneity in the vessels was similar in both techniques (P = 0.52) and edge sharpness was significantly (P <0.0001) higher in FB-TRA compared to BH-MRA. BH-MRA provided overall diagnostic accuracy of 82%, and FB-TRA of 87%, with no statistical difference between the two sequences (P = 0.77). Vessel diameter measurements showed excellent agreement between the two techniques (r = 0.98, P <0.05), with no bias (0.0mm, P = 0.71), and clinically acceptable limits of agreement (-2.7 to +2.8mm). Inter and intra observer reproducibility showed good agreement of vessel diameters (r>0.988, P<0.0001), with negligible biases (between -0.2 and +0.1mm) and small limits of agreement (between -2.4 and +2.5mm).

Conclusions

We have described a FB-TRA technique that is shown to enable accurate diagnosis and vessel measures compared to conventional BH-MRA. This simplifies the MRA technique and will enable angiography to be performed in children and adults whom find breath-holding difficult.

Electronic supplementary material

The online version of this article (doi:10.1186/s12968-015-0138-9) contains supplementary material, which is available to authorized users.     

Contributors to Mortality in High-Risk Diabetic Patients in the Diabetes Heart Study

OBJECTIVE

Not all individuals with type 2 diabetes and high coronary artery calcified plaque (CAC) experience the same risk for adverse outcomes. This study examined a subset of high-risk individuals based on CAC >1,000 mg (using a total mass score) and evaluated whether differences in a range of modifiable cardiovascular disease (CVD) risk factors provided further insights into risk for mortality.

RESEARCH DESIGN AND METHODS

We assessed contributors to all-cause mortality among 371 European American individuals with type 2 diabetes and CAC >1,000 from the Diabetes Heart Study (DHS) after 8.2 ± 3.0 years (mean ± SD) of follow-up. Differences in known CVD risk factors, including modifiable CVD risk factors, were compared between living (n = 218) and deceased (n = 153) participants. Cox proportional hazards regression models were used to quantify risk for all-cause mortality.

RESULTS

Deceased participants had a longer duration of type 2 diabetes (P = 0.02) and reduced use of cholesterol-lowering medications (P = 0.004). Adjusted analyses revealed that vascular calcified plaque scores were associated with increased risk for mortality (hazard ratio 1.31–1.63; 3.89 × 10⁻⁵ < P < 0.03). Higher HbA_1c, lipids, and C-reactive protein and reduced kidney function also were associated with a 1.1- to 1.5-fold increased risk for mortality (3.45 × 10⁻⁶ < P < 0.03) after adjusting for confounding factors.

CONCLUSIONS

Even in this high-risk group, vascular calcification and known CVD risk factors provide useful information for ongoing assessment. The use of cholesterol-lowering medication seemed to be protective for mortality.     

Delivering evidence-based smoking cessation treatment in primary care practice: Experience of Ontario family health teams

Objective

To report on the delivery of evidence-based smoking cessation treatments (EBSCTs) within a sample of 40 Ontario family health teams (FHTs).

Design

In each FHT, consecutive patients were screened for smoking status and eligible patients completed a questionnaire immediately following their clinic visits (index visits). Multilevel analysis was used to examine FHT-level, provider-level, and patient-level predictors of EBSCT delivery.

Setting

Forty FHTs in Ontario.

Participants

Across the 40 participating FHTs, 24 033 patients were screened and 2501 eligible patients contributed data.

Main outcome measures

Provider performance in the delivery of EBSCTs during the preceding 12 months and during the index visits was assessed.

Results

The rate of provider delivery of EBSCT for the previous 12 months was 74.0% for the advise strategy. At the index visit, rates of EBSCT strategy delivery were 56.8% for ask; 46.9% for advise; 38.7% for assist; 11.6% for prescribing pharmacotherapy; and 11.3% for arrange follow-up. Significant intra-FHT and intraprovider variability in the rates of EBSCT delivery was identified. Family health teams with a physician champion (odds ratio [OR] 2.0; 95% CI 1.1 to 3.6; P < .01) and providers who highly ranked the importance of smoking cessation (OR 1.7; 95% CI 1.1 to 2.7; P < .01) were more likely to deliver EBSCTs. Patient readiness to quit (OR 1.6; 95% CI 1.3 to 1.9; P < .001), presence of smoking-related illness (OR 1.6; 95% CI 1.2 to 2.1; P < .01), and presenting for an annual health examination (OR 2.0; 95% CI 1.6 to 2.5; P < .001) were associated with the delivery of EBSCTs.

Conclusion

Rates of smoking cessation advice were higher than previously reported for Canadian physicians; however, rates of assistance with quitting were lower. Future quality improvement initiatives should specifically target increasing the rates of screening and advising among low-performing FHTs and providers within FHTs, with a particular emphasis on doing so at all clinic appointments; and improving the rate at which assistance with quitting is delivered.