Diabetic autonomic neuropathy and iritis: an association suggesting an immunological cause.

Of 47 insulin requiring diabetics aged 21-40 years with autonomic neuropathy (heart rate variability less than 10), 14 had previously developed iritis. In all except two cases the iritis preceded the autonomic symptoms. The autonomic neuropathy was very severe, 10 patients having two or more characteristic symptoms. Ten of the patients with iritis were women. The association of iritis (itself an immune disorder) with severe symptomatic autonomic neuropathy raises the possibility of an underlying immunological basis for autonomic neuropathy.     

Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation: no causal relation with diabetic autonomic neuropathy.

OBJECTIVE--To examine the traditional view that unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation in insulin dependent diabetes mellitus are manifestations of autonomic neuropathy. DESIGN--Perspective assessment of unawareness of hypoglycaemia and detailed assessment of autonomic neuropathy in patients with insulin dependent diabetes according to the adequacy of their hypoglycaemic counterregulation. SETTING--One routine diabetic unit in a university teaching hospital. PATIENTS--23 Patients aged 21-52 with insulin dependent diabetes mellitus (seven with symptoms suggesting autonomic neuropathy, nine with a serious clinical problem with hypoglycaemia, and seven without symptoms of autonomic neuropathy and without problems with hypoglycaemia) and 10 controls with a similar age distribution, without a personal or family history of diabetes. MAIN OUTCOME MEASURES--Presence of autonomic neuropathy as assessed with a test of the longest sympathetic fibres (acetylcholine sweatspot test), a pupil test, and a battery of seven cardiovascular autonomic function tests; adequacy of hypoglycaemic glucose counterregulation during a 40 mU/kg/h insulin infusion test; history of unawareness of hypoglycaemia; and response of plasma pancreatic polypeptide during hypoglycaemia, which depends on an intact and responding autonomic innervation of the pancreas. RESULTS--There was little evidence of autonomic neuropathy in either the 12 diabetic patients with a history of unawareness of hypoglycaemia or the seven patients with inadequate hypoglycaemic counterregulation. By contrast, in all seven patients with clear evidence of autonomic neuropathy there was no history of unawareness of hypoglycaemia and in six out of seven there was adequate hypoglycaemic counterregulation. Unawareness of hypoglycaemia and inadequate hypoglycaemic counterregulation were significantly associated (p less than 0.01). The response of plasma pancreatic polypeptide in the diabetic patients with adequate counterregulation but without autonomic neuropathy was not significantly different from that of the controls (change in plasma pancreatic polypeptide 226.8 v 414 pmol/l). The patients with autonomic neuropathy had a negligible plasma pancreatic polypeptide response (3.7 pmol/l), but this response was also blunted in the patients with inadequate hypoglycaemic counterregulation (72.4 pmol/l) compared with that of the controls (p less than 0.05). CONCLUSIONS--Unawareness of hypoglycaemia and inadequate glucose counterregulation during hypoglycaemia are related to each other but are not due to autonomic neuropathy. The blunted plasma pancreatic polypeptide responses of the patients with inadequate hypoglycaemic counterregulation may reflect diminished autonomic activity consequent upon reduced responsiveness of a central glucoregulatory centre, rather than classical autonomic neuropathy.     

Immediate heart-rate response to standing: simple test for autonomic neuropathy in diabetes.

The immediate heart-rate response to standing was measured in 22 normal controls and 25 patients with diabetes, 15 of whom had autonomic neuropathy. The response in the controls and patients without autonomic neuropathy was characteristic and consistent, with tachycardia maximal at around the 15th beat and relative bradycardia maximal at around the 30th beat. The diabetics with autonomic neuropathy, however, showed a flat response. In three controls the response was abolished with intravenous atropine but not with propranolol, showing that it is mediated through the vagus. A simplified test using routine ECGs and measuring the R-R interval at beats 15 and 30 with a ruler is easily performed as an outpatient procedure and may be used as a measure of autonomic function in diabetes.     

Diagnostic accuracy of heart-rate recovery after exercise in the assessment of diabetic cardiac autonomic neuropathy

Diabet. Med. 29, e312-e320 (2012) ABSTRACT: Aims Poor prognosis associated with blunted post-exercise heart-rate recovery may reflect autonomic dysfunction. This study sought the accuracy of post-exercise heart-rate recovery in the diagnosis of cardiac autonomic neuropathy, which represents a serious, but often unrecognized complication of Type?2 diabetes. Methods Clinical assessment of cardiac autonomic neuropathy and maximal treadmill exercise testing for heart-rate recovery were performed in 135 patients with Type?2 diabetes and negative exercise echocardiograms. Cardiac autonomic neuropathy was defined by abnormalities in ≥?2 of 7 autonomic function markers, including four cardiac reflex tests and three indices of short-term (5-min) heart-rate variability. Heart-rate recovery was defined at 1-, 2- and 3-min post-exercise. Results Patients with cardiac autonomic neuropathy (n?=?27; 20%) had lower heart-rate recovery at 1-, 2- and 3-min post-exercise (P?相似文献   

Rheumatoid cachexia: a complication of rheumatoid arthritis moves into the 21st century

Rheumatoid cachexia, loss of muscle mass and strength and concomitant increase in fat mass, is very common in patients with rheumatoid arthritis (RA). Despite great advances in the treatment of RA, it appears that rheumatoid cachexia persists even after joint inflammation improves. Rheumatoid cachexia may be an important risk factor for cardiovascular disease and excess mortality in RA. In this issue of Arthritis Research & Therapy, Elkan and colleagues demonstrate a link between rheumatoid cachexia and metabolic syndrome, further reinforcing the need for therapy directed beyond inflammation and at the metabolic consequences of RA.     

Decreased response of epinephrine and norepinephrine to insulin-induced hypoglycemia in diabetic autonomic neuropathy

The responses of epinephrine, norepinephrine and other counter-regulatory hormones to insulin-induced hypoglycemia were investigated in 5 diabetics who showed signs of autonomic neuropathy, in 7 age-matched diabetics without autonomic neuropathy and in 7 healthy subjects. The presence of autonomic neuropathy was evaluated by decreased beat-to-beat variation in heat rates during hyperventilation or orthostatic hypotension. Catecholamines were determined by a totally automated plasma catecholamine analyzing system using a two-column system of high performance liquid chromatography. Plasma epinephrine and norepinephrine responses to hypoglycemia in diabetics with autonomic neuropathy were significantly lower than those in diabetics without autonomic neuropathy. Plasma glucagon response in diabetics was apparently attenuated compared to normal controls and there was no significant difference in glucagon response between the two patient groups. Other counter-regulatory hormone responses did not differ among the three groups. The data demonstrate that the responses of plasma epinephrine and norepinephrine to insulin-induced hypoglycemia are impaired in diabetics with autonomic neuropathy.     

Gene polymorphisms and serum levels of TL1A in patients with rheumatoid arthritis

Recent findings showed elevated expression of tumor necrosis factor (TNF)-like ligand 1A (TL1A) in rheumatoid arthritis (RA) patients and arthritis mice. However, whether TL1A gene polymorphisms may correlate with RA susceptibility needs to be discussed. This case-control study was performed on 350 RA patients and 556 healthy subjects to identify TL1A genetic variants (rs3810936, rs6478109, and rs7848647) and their possible association with TL1A levels, susceptibility to and severity of RA. Odds ratio and 95% confidence interval were calculated to represent the correlation between TL1A polymorphisms and RA. The TL1A serum levels were evaluated. Results showed that frequencies of TC, TT + TC genotypes of rs3810936, rs7848647 in RA patients were significantly lower in RA patients compared with controls. Patients with C allele showed more severe disease course (disease activity index: erythrocyte sedimentation rate, rheumatoid factor) than in carriers of T allele. However, the allele or genotype frequencies of rs6478109 were not associated with RA. In addition, TL1A genetic variants conferred higher TL1A levels in RA patients compared with controls. In conclusion, these findings indicated an association between TL1A rs3810936, rs7848647 variation and the susceptibility of RA in a sample of Chinese individuals, and TL1A may correlate with severity of RA.     

Impaired response of pancreatic polypeptide to hypoglycaemia: an early sign of autonomic neuropathy in diabetics.

The pancreatic polypeptide (PP) response to insulin-induced hypoglycaemia was studied in 18 juvenile diabetics and was calculated as the difference between the prestimulatory PP concentration and the maximal concentration measured. The response was severely impaired in patients with autonomic neuropathy (mean +/- SE of mean 22 +/- 12 pmol/l) as compared with patients without neuropathy (252 +/- 51 pmol/l). Patients whose diabetes was of only a few years'' duration showed a normal PP response to hypoglycaemia, and the response diminished significantly with increasing duration of diabetes. The decreased PP response to hypoglycaemia was significantly correlated with an increased threshold of the sense of vibration, (rs = 0.86). These results suggest that impaired, secretion of PP may serve as an early sign of autonomic neuropathy in diabetes.     

Esophageal disorders in diabetes mellitus.

Esophageal motility disturbances are common in diabetics in general and are most prevalent in these with peripheral neuropathy or autonomic neuropathy. The usual findings are a decrease in the amplitude of esophageal contractions in the smooth muscle portion of the body, frequent absence of primary peristalsis, simultaneous or repetitive body contractions, and a decrease in the velocity of peristalsis. Radiographically, this may be manifest as delayed esophageal emptying. These changes do not produce symptoms. Dysphagia and chest pain should be thoroughly evaluated and not ascribed to the diabetes. Candidiasis may be more common in diabetics.     

Thermal biofeedback and lower extremity blood flow in adults with diabetes: is neuropathy a limiting factor?

Thermal biofeedback may be a useful adjunctive technique for enhancing cutaneous blood flow in patients with lower-extremity vascular complications of diabetes. However, autonomic, sensory, and/or motor neuropathies may impair vasomotion and limit the ability to alter blood flow and achieve significant foot warming with thermal biofeedback. We examined nerve function associated with four common types of diabetic neuropathy (sympathetic–autonomic, vagal–autonomic, sensory, and motor), hypothesizing that both sympathetic–autonomic and sensory neuropathies would limit the acquisition of biofeedback-mediated foot warming. Twenty-four participants with diabetes mellitus (19 with type II and 5 with type I) received a nerve conduction study and neurological evaluation of the upper and lower extremities. Hand temperature, foot temperature, and electrodermal gradient at the toes were monitored across six thermal biofeedback sessions. Participants were able to significantly raise p < .01) foot temperatures across sessions, an average of 2.2°F. Consistent with our hypotheses, 41% of the variance in foot warming was explained by lower-extremity sympathetic–autonomic and sensory nerve function tests. This study demonstrated that a general diabetic population, including patients with mild-to-moderate neuropathy, can increase skin perfusion with thermal biofeedback. As hypothesized, lower-extremity sympathetic–autonomic and sensory neuropathies interfered with foot warming.     

Can anti-cyclic citrullinated peptide antibody-negative RA be subdivided into clinical subphenotypes?

Introduction  

Studies investigating genetic risk factors for susceptibility to rheumatoid arthritis (RA) studied anti-citrullinated peptide antibody (CCP)-positive RA more frequently than anti-CCP-negative RA. One of the reasons for this is the perception that anti-CCP-negative RA may include patients that fulfilled criteria for RA but belong to a wide range of diagnoses. We aimed to evaluate the validity of this notion and explored whether clinical subphenotypes can be discerned within anti-CCP-negative RA.     

Plasma levels of immunoreactive atrial natriuretic hormone in patients with diabetes mellitus

In order to determine whether atrial natriuretic hormone (ANH) secretion is altered in diabetic patients with autonomic neuropathy, plasma immunoreactive ANH (IR-ANH) levels were measured in 23 patients with insulin-dependent diabetes mellitus, 12 of whom had definite cardiac autonomic neuropathy determined by noninvasive maneuvers. Levels were also measured in 31 healthy control subjects. Whereas only one of the 11 diabetics without cardiac autonomic neuropathy had elevated IR-ANH levels, four of the 12 diabetics with cardiac autonomic neuropathy had elevated IR-ANH levels (P = 0.03 compared to control subjects). 24-h urinary sodium excetion was not different among the groups. There was no significant correlation between IR-ANH levels and diabetes control and any of the parameters of autonomic nervous system activity nor between IR-ANH levels and plasma norepinephrine or epinephrine levels. Furthermore, no relationship was observed in the diabetic subjects between IR-ANH levels and left ventricular ejection fraction determined by radionuclide ventriculography. Thus, elevated IR-ANH levels occur with greater frequency in diabetic patients with autonomic neuropathy. These elevations do not appear to be due to alterations in dietary sodium intake or left ventricular dysfunction.     

Using dynamic pupillometry as a simple screening tool to detect autonomic neuropathy in patients with diabetes: a pilot study

Background  

Autonomic neuropathy is a common and serious complication of diabetes. Early detection is essential to enable appropriate interventional therapy and management. Dynamic pupillometry has been proposed as a simpler and more sensitive tool to detect subclinical autonomic dysfunction. The aim of this study was to investigate pupil responsiveness in diabetic subjects with and without cardiovascular autonomic neuropathy (CAN) using dynamic pupillometry in two sets of experiments.     

Pupillary signs in diabetic autonomic neuropathy.

Pupillary function was investigated in 36 insulin-dependent diabetics and 36 controls matched for age and sex. About half of the diabetics had evidence of peripheral somatic or autonomic neuropathy, or both. The diabetic patients had abnormally small pupil diameters in the dark and less fluctuation in pupil size (hippus) during continuous illumination than the controls. They also had reduced reflex responses to light flashes of an intensity adjusted for individual retinal sensitivities. The pupillary findings were compared with results of five tests of cardiovascular function and five tests of peripheral sensory and motor nerve function. Almost all the patients with autonomic neuropathy had pupillary signs, which we therefore conclude are a common manifestation of diabetic autonomic neuropathy.     

Bmx regulates LPS-induced IL-6 and VEGF production via mRNA stability in rheumatoid synovial fibroblasts

Discordant cytokine production is characteristic of chronic inflammatory conditions like rheumatoid arthritis (RA), and anti-cytokine therapeutics are becoming routinely used to treat RA in the clinic. Fibroblasts from rheumatoid synovium have been shown to contribute to cytokine production in inflamed joints; likewise these cells also produce cytokines in response to inflammatory mediators signalling through Toll like receptors (TLRs). Tyrosine kinase activity is essential to LPS-induced cytokine production, and we have previously implicated a role for the Tec kinase, Bmx, in inflammatory cytokine production. Here we show that Bmx kinase activity in RASF is increased following LPS stimulation and that Bmx is involved in the regulation of LPS-induced IL-6 and VEGF production via mRNA stabilisation. This is an important insight into the regulation of VEGF, which is involved in a wide range of different pathologies, and may lead to more effective design of novel anti-inflammatory/angiogenic therapeutics for conditions such as RA.     

Clonally related IgM rheumatoid factors undergo affinity maturation in the rheumatoid synovial tissue.

Using hybridoma technology we established a panel of human monoclonal rheumatoid factors (RF) from the synovial tissues of two patients with rheumatoid arthritis (RA), and one patient with polyarticular juvenile RA. Nucleotide sequence analysis of the V regions of these RF indicates that two independently derived antibodies from one of the RA patients are clonally related. One of these antibodies appears to be close to germ-line configuration, whereas the other has accumulated a total of 36 substitutions in both H and L chains. Measurements of the affinity for human IgG of the two RF show that the extensively mutated RF has 100-fold higher affinity for IgG than the RF close to germline. These findings indicate that IgM RF in RA can undergo affinity maturation and suggest that certain RF may be the product of an Ag-driven immune response.     

The production of superoxide anion (O2-) by polymorphonuclear cells in patients with rheumatoid arthritis

Superoxide anion production has been determined in controls and RA patients PMNs stimulated with zymosan, rheumatoid synovial membrane, nodule and synovial fluid, rheumatoid factor, aggregated gamma-globulins, Mycoplasma and Epstein-Barr virus. Patients with RA showed an increased production of O2- after incubation with zymosan and rheumatoid tissue extracts or synovial fluid in comparison to normal controls. The findings indicate that rheumatoid PMNs become activated by different stimuli to produce an excess of O2- which can contribute to chronic inflammatory process.     

Vasculogenesis in rheumatoid arthritis

Decreased number and impaired functions of endothelial progenitor cells (EPCs) leading to impaired vasculogenesis have been associated with rheumatoid arthritis (RA). Defective vasculogenesis has also been implicated in premature atherosclerosis in RA. Recently, early-outgrowth monocytic and late-outgrowth hemangioblastic EPC subsets have been characterized. Hemangioblastic EPCs may exert increased numbers in active RA and may play a role in vascular repair underlying RA.     

Possible case of rheumatoid arthritis from Sudanese Nubia

Due to its apparent absence in archaeologically derived skeletons, rheumatoid arthritis (RA) has generally been believed to be of fairly recent origin. A growing body of evidence now demonstrates that erosive lesions typical of RA are present in archaeological populations and that the antiquity of RA may be greater than previously expected. In support of this argument, a case of erosive arthritis is reported in a skeleton from Kulubnarti, Republic of the Sudan (c. 700-1450 A.D.). Lytic, erosive lesions and subchondral cysts are present bilaterally in the carpal and metacarpal joints of a female skeleton with an estimated age at death of 50+ years. These lesions are typical of those seen in clinically diagnosed rheumatoid patients. While their expression and distribution are highly suggestive of RA, interpretation must be made with due consideration for problems of differential diagnosis of this disease in archaeological material.