Celia Emery

Endothelial control of the pulmonary circulation in normal and chronically hypoxic rats.

1. The effect of blockade of nitric oxide synthesis in pulmonary endothelium by two L‐arginine analogues was tested in isolated blood‐perfused lungs of normal rats and rats exposed chronically to 10% O2. 2. In both groups of rats the analogues (N‐monomethyl‐L‐arginine (L‐NMMA) and N‐nitro‐L‐arginine methyl ester (L‐NAME)) enhanced hypoxic vasoconstriction. In normal rats, with rare exceptions, these analogues had little or no effect on pulmonary artery pressure (Ppa) at constant blood flow during normoxia. However, chronically hypoxic rats have pulmonary hypertension and in these rats the analogues always raised Ppa; the rise in Ppa after L‐NMMA but not L‐NAME could be partially reversed by L‐arginine. L‐NAME was more potent than L‐NMMA. 3. To see whether the difference between rat groups was due to the high Ppa in chronically hypoxic rats, in control rats we raised Ppa passively by lung inflation to values higher than found in chronically hypoxic rats. L‐NAME did not alter the effects of lung inflation on Ppa. 4. Ppa was also raised passively by plotting pressure‐flow lines up to high flow rates; the lines were changed minimally by both analogues in control rats but in chronically hypoxic rats the lines were raised to higher pressures and steepened substantially. 5. In control rats, during vasoconstriction caused by hypoxia, endothelin 1 and almitrine, L‐NAME caused further rises in pressure. We conclude that a stimulus for nitric oxide release in control rats is the narrowing of vessels caused by vasoconstriction rather than passive increases in intravascular pressure. 6. In chronically hypoxic rats arterioles are narrowed by growth of new muscle and there is some muscle tone even in normoxia. Thus narrowing of the vascular lumen is the stimulus common to both groups of rats which leads to nitric oxide synthesis and attenuation of Ppa by a negative feedback process. Narrowing is associated with a large increase in shear stress due to two factors; the pressure drop along a vessel segment is increased and the surface area of the lining of the affected segment is decreased. 7. Atrial natriuretic peptide caused dose‐dependent pulmonary vasodilation in both rat groups but had a greater effect in chronically hypoxic rats. The action persisted and was enhanced after blockade of NO synthesis.

Randomized Placebo-Controlled Double-Blind Clinical Trial of Cannabis-Based Medicinal Product (Sativex) in Painful Diabetic Neuropathy Depression is a major confounding factor

OBJECTIVE To assess the efficacy of Sativex, a cannabis-based medicinal extract, as adjuvant treatment in painful diabetic peripheral neuropathy (DPN). RESEARCH DESIGN AND METHODS In this randomized controlled trial, 30 subjects with painful DPN received daily Sativex or placebo. The primary outcome measure was change in mean daily pain scores, and secondary outcome measures included quality-of-life assessments. RESULTS There was significant improvement in pain scores in both groups, but mean change between groups was not significant. There were no significant differences in secondary outcome measures. Patients with depression had significantly greater baseline pain scores that improved regardless of intervention. CONCLUSIONS This first-ever trial assessing the efficacy of cannabis has shown it to be no more efficacious than placebo in painful DPN. Depression was a major confounder and may have important implications for future trials on painful DPN.

Painful Diabetic Neuropathy Is Associated With Greater Autonomic Dysfunction Than Painless Diabetic Neuropathy

OBJECTIVE Although a clear link between diabetic peripheral neuropathy (DPN) and autonomic neuropathy is recognized, the relationship of autonomic neuropathy with subtypes of DPN is less clear. This study aimed to investigate the relationship of autonomic neuropathy with painless and painful DPN. RESEARCH DESIGN AND METHODS Eighty subjects (20 healthy volunteers, 20 with no DPN, 20 with painful DPN, 20 with painless DPN) underwent detailed neurophysiological investigations (including conventional autonomic function tests [AFTs]) and spectral analysis of short-term heart rate variability (HRV), which assesses sympathovagal modulation of the heart rate. Various frequency-domain (including low frequency [LF], high frequency [HF], and total power [TP]) and time-domain (standard deviation of all normal-to-normal R-R intervals [SDNN] and root mean square of successive differences [RMSSD]) parameters were assessed. RESULTS HRV analysis revealed significant differences across the groups in LF, HF, TP, SDNN, and RMSSD (ANOVA P < 0.001). Subgroup analysis showed that compared with painless DPN, painful DPN had significantly lower HF (3.59 ± 1.08 [means ± SD] vs. 2.67 ± 1.56), TP (5.73 ± 1.28 vs. 4.79 ± 1.51), and SDNN (2.91 ± 0.65 vs. 1.62 ± 3.5), P < 0.05. No significant differences were seen between painless DPN and painful DPN using an AFT. CONCLUSIONS This study shows that painful DPN is associated with significantly greater autonomic dysfunction than painless DPN. These changes are only detected using spectral analysis of HRV (a simple test based on a 5-min electrocardiogram recording), suggesting that it is a more sensitive tool to detect autonomic dysfunction, which is still under-detected in people with diabetes. The greater autonomic dysfunction seen in painful DPN may reflect more predominant small fiber involvement and adds to the growing evidence of its role in the pathophysiology of painful DPN.

LARGE-FIBER DYSFUNCTION IN DIABETIC PERIPHERAL NEUROPATHY IS PREDICTED BY CARDIOVASCULAR RISK FACTORS

OBJECTIVE Diabetic large–nerve fiber dysfunction, as measured by vibration perception threshold (VPT), predicts foot ulceration, amputation, and mortality. Thus, determination of modifiable risk factors is of great clinical importance. RESEARCH DESIGN AND METHODS We assessed 1,407 patients with type 1 diabetes and a normal VPT participating in the EURODIAB Prospective Complications Study, at baseline mean ± SD age of 32.7 ± 10.2 years with diabetes duration of 14.7 ± 9.3 years and follow-up of 7.3 ± 0.6 years. VPT was measured using biothesiometry on the right big toe and medial malleolus. An abnormal result was defined as >2 SD from the predicted mean for the patient s age. RESULTS An abnormal VPT was associated with an increased incidence of gangrene, amputation, foot ulceration, leg bypass or angioplasty, and mortality (P ≤ 0.02). The incidence of abnormal VPT was 24% over the 7.3-year follow-up. Duration of diabetes and A1C significantly influenced the incidence of abnormal VPT (P < 0.0001). After correction for these, established risk factors for cardiovascular disease (CVD), including male sex (P = 0.0004), hypertension (P < 0.0001), total cholesterol (P = 0.002), LDL cholesterol (P = 0.01), smoking (P < 0.0001), weight (P < 0.0001), and diabetes complications (retinopathy [P = 0.0001], nephropathy [P = 0.01], and autonomic neuropathy [P = 0.001]), were all found to be significant risk factors. A previous history of CVD doubled the incidence of abnormal VPT. CONCLUSIONS This prospective study indicates that cardiovascular risk factors predict development of large-fiber dysfunction, which may account for the high mortality rate in patients with an abnormal VPT, and emphasizes the importance of early determination of VPT to detect subclinical neuropathy and to address cardiovascular risk factors.

Frequency of biochemical hypoglycaemia in adults with Type 1 diabetes with and without impaired awareness of hypoglycaemia: no identifiable differences using continuous glucose monitoring.

Diabet. Med. 27, 666–672 (2010)

Thalamic neuronal dysfunction and chronic sensorimotor distal symmetrical polyneuropathy in patients with type 1 diabetes mellitus

Aims/hypothesisAlthough clear peripheral nerve pathological abnormalities have been demonstrated in diabetic peripheral neuropathy (DPN), there is little information with regard to brain involvement. Our aim was to use in vivo proton magnetic resonance specroscopy (H-MRS) in patients with DPN in order to assess the neuro-chemical status of the thalamus, which acts as the gateway to the brain for somatosensory information.MethodsParticipants included 18 type 1 diabetic men (eight without DPN, ten with DPN) and six non-diabetic healthy volunteers, who all underwent detailed clinical and neurophysiological assessments yielding a Neuropathy Composite Score (NCS) derived from Neuropathy Impairment Score of the Lower Limbs plus seven tests of nerve function prior to investigation via a single-voxel H-MRS technique, which was used to sample ventral posterior thalamic parenchyma. Spectroscopic resonances including those due to N-acetyl aspartate (NAA) were assessed at both short and long echo-time, providing putative indicators of neuronal function and integrity, respectively.ResultsAt long echo-time we observed significantly lower NAA:creatine (p = 0.04) and NAA:choline (p = 0.02) ratios in DPN patients than in the other groups. No group differences were detected at short echo-time. We found a significant positive association between both sural amplitude (ρ = 0.61, p = 0.004) and nerve conduction velocity (r = 0.58, p = 0.006) and NAA:creatine signal among participants with diabetes. Vibration detection threshold (ρ = −0.70, p = 0.004) was significantly related to NAA:choline ratio. Heart rate variability with deep breathing (ρ = −0.46, p = 0.05) and NCS (ρ = −0.53, p = 0.03) were significantly related to NAA:creatine ratio.Conclusions/interpretationThe significantly lower NAA:creatine ratio in DPN is suggestive of thalamic neuronal dysfunction, while the lack of difference in short echo-time between the groups does not suggest neuronal loss. Taken together with the observed correlations between NAA and neurophysiological assessments, these findings provide evidence for thalamic neuronal involvement in DPN.

Feature extraction and classification of electrocardiogram (ECG) signals related to hypoglycaemia

Nocturnal hypoglycaemia has been implicated in the sudden deaths of young people with diabetes. Experimental hypoglycaemia has been found to prolong the ventricular repolarisation and to affect the T wave morphology. It is postulated that abnormally low blood glucose could in certain circumstances, be responsible for the development of a fatal cardiac arrhythmia. We have used automatic extraction of both time-interval and morphological features, from the electrocardiogram (ECG) to classify ECGs into normal and arrhythmic. Classification was implemented by artificial neural networks (ANN) and linear discriminant analysis (LDA). The ANN gave more accurate results. Average training accuracy of the ANN was 85.07% compared with 70.15% on unseen data. This study may lead towards the demonstration of the possible relationship between cardiac function and abnormally low blood glucose.

Hypoxia of sleep apnoea: cardiopulmonary and cerebral changes after intermittent hypoxia in rats

Sleep apnoea (SA) is common, especially in elderly people. In severe cases, arterial P(O2) may be lowered for a third or more in a night of sleep. To simulate the degree and duration of severe SA we exposed rats in a normobaric environmental chamber to 10% O(2) for 4h daily for 56 days (intermittent hypoxia: IH group) and compared them with rats continuously exposed for 8 weeks (continuous hypoxia: CH group) and control rats breathing room air (normoxic: N group). We found significant cardiopulmonary and cerebral changes. Right ventricular hypertrophy developed in IH and to a greater extent in CH. Small peripheral lung vessels developed thicker walls (assessed by a new method), which reduced their lumen, more in CH than IH. Coronal brain sections were immunostained for the glucose-transporter 1 (GLUT1) and the vascular endothelial growth factor (VEGF). The percentages of immunoreactivity in the frontal and temporal cortex, hippocampus, accumbens and putamen were determined by image-capture analysis. We noted GLUT1 immunoreactivity of the capillaries was similarly increased in all regions after CH but less so after IH. However, there was a significant linear trend in GLUT1 reactivity from N to IH to CH (R(2) = 0.73, P = 0.007) that was also confirmed by analysis of variance. The extent of VEGF-stained neurones and glial cells was significantly increased in all regions after IH but not after CH. This suggests that the signals for angiogenesis were complete or arrested after CH. Our findings have implications for the elderly subjected to hypoxic episodes during sleep apnoea.

The contributors of emotional distress in painful diabetic neuropathy

Aims: To examine the contribution of demographic, social, clinical and psychological factors to emotional distress in patients with painful diabetic neuropathy (DN). Methods: In total, 142 patients with confirmed painful DN underwent detailed clinical and self-assessment measures (Neuropathic Pain Scale, Hospital Anxiety and Depression Scale, Pain Acceptance Questionnaire and Pain Catastrophizing Scale). Results: The prevalence of emotional distress was 51.4% in this cohort. Age, sex, marital status, employment history, pain intensity, duration of diabetes and the presence of diabetic and non-diabetic complications were significantly correlated to anxiety and depressive symptom scores. Multiple regression analysis confirmed that the presence of catastrophic thinking was an independent contributor to greater symptoms of anxiety and depression. Being young, single and unemployed significantly contributed to greater anxiety symptoms. Pain-related restriction of quality of life was associated with greater depression symptom scores. Conclusions: This study found a high prevalence of emotional distress in patients with painful DN. It highlights that the differing independent contributors to anxiety and depressive symptoms are based on an individual’s circumstances and experience. We conclude by highlighting the importance of adopting a holistic approach to pain management, incorporating interventions to increase psychological flexibility alongside conventional pharmacological treatments to improve emotional distress in painful DN.

An Approach to the Assessment of Diabetic Neuropathy Based on Dynamic Pupillometry

Autonomic neuropathy (AN) is a common and serious complication of diabetes. Early detection is essential to enable appropriate interventional therapy. It has long been recognized that subjects with diabetic peripheral neuropathy (DPN) are at much greater risk of developing AN, but there is currently no simple screening tool to assess them. The aim of this study was to investigate pupil responsiveness in diabetic subjects with and without DPN using dynamic pupillometry. During the first test, one flash was administered and the pupil response recorded for 3 seconds. In the second test, twenty-five flashes at one-second intervals were administered and the pupil response recorded for 30 seconds. Several time related parameters were computed from the results. A total of 29 diabetic subjects (17 no DPN, 12 DPN) and 25 healthy volunteers took part in the study. In the first test, pupil-iris ratios in darkness, large deviation and plateau were significantly different between groups. Latency time from flash exposure to the start of constriction was significantly longer in diabetic subjects with DPN compared to healthy volunteers. There was no difference in latency times of largest deviation, plateau or duration of constriction between groups. In the second test, the pupil-iris ratios evaluated in the frame preceding the tenth and the twenty-fifth light flash were significantly greater in healthy volunteers than diabetic subjects with DPN. Latency time from the tenth and twenty-fifth flash exposure to the start of constriction was significantly shorter in healthy volunteers than in diabetic subjects with DPN. Our results show that diabetic subjects with DPN have sympathetic and parasympathetic dysfunction evidenced by diminished amplitude reflexes and significant smaller pupil diameter. Dynamic pupillometry may provide a simple, inexpensive and non-invasive tool to screen high-risk diabetic patients for diabetic autonomic neuropathy.