Painless stress fractures in diabetic neuropathic feet.

We describe two patients with diabetes mellitus and associated neuropathy, who presented with painless foot swelling and no history of trauma. X-Rays revealed recent underlying fractures-in one of a metatarsus, and the other of a proximal phalanx. These were assumed to be ''stress'' fractures unassociated with pain because of the severe sensory neuropathy. Though spontaneous fractures in neuropathic feet have been previously described, they almost always occur in association with Charcot joints, and are usually painful. The differential diagnosis of acute swelling in the foot of a diabetic patient with sensory neuropathy should include stress fracture.     

Nanoarchitectures for efficient IgE cross-linking on effector cells to study amoxicillin allergy

Background

Amoxicillin (AX) is nowadays the β-lactam that more frequently induces immediate allergic reactions. Nevertheless, diagnosis of AX allergy is occasionally challenging due to risky in vivo tests and non-optimal sensitivity of in vitro tests. AX requires protein haptenation to form multivalent conjugates with increased size to be immunogenic. Knowing adduct structural features for promoting effector cell activation would help to improve in vitro tests. We aimed to identify the optimal structural requirement in specific cellular degranulation to AX using well-precised nanoarchitectures of different lengths.

Method

We constructed eight Bidendron Antigens (BiAns) based on polyethylene glycol (PEG) linkers of different lengths (600–12,000 Da), end-coupled with polyamidoamine dendrons that were terminally multi-functionalized with amoxicilloyl (AXO). In vitro IgE recognition was studied by competitive radioallergosorbent test (RAST) and antibody–nanoarchitecture complexes by transmission electron microscopy (TEM). Their allergenic activity was evaluated using bone marrow-derived mast cells (MCs) passively sensitized with mouse monoclonal IgE against AX and humanized RBL-2H3 cells sensitized with polyclonal antibodies from sera of AX-allergic patients.

Results

All BiAns were recognized by AX-sIgE. Dose-dependent activation responses were observed in both cellular assays, only with longer structures, containing spacers in the range of PEG 6000–12,000 Da. Consistently, greater proportion of immunocomplexes and number of antibodies per complex for longer BiAns were visualized by TEM.

Conclusions

BiAns are valuable platforms to study the mechanism of effector cell activation. These nanomolecular tools have demonstrated the importance of the adduct size to promote effector cell activation in AX allergy, which will impact for improving in vitro diagnostics.

     

Vitamin B12 Supplementation in Diabetic Neuropathy: A 1-Year,Randomized, Double-Blind,Placebo-Controlled Trial

Aim: To investigate the effect of normalizing vitamin B12 (B12) levels with oral B12 (methylcobalamin) 1000 μg/day for one year in patients with diabetic neuropathy (DN). Patients and methods: In this prospective, double-blind, placebo-controlled trial, 90 patients with type 2 diabetes on metformin for at least four years and both peripheral and autonomic DN were randomized to an active treatment group (n = 44) receiving B12 and a control group (n = 46) receiving a placebo. All patients had B12 levels less than 400 pmol/L. Subjects underwent measurements of sural nerve conduction velocity (SNCV), sural nerve action potential (amplitude) (SNAP), and vibration perception threshold (VPT), and they performed cardiovascular autonomic reflex tests (CARTs: mean circular resultant (MCR), Valsalva test, postural index, and orthostatic hypotension). Sudomotor function was assessed with the SUDOSCAN that measures electrochemical skin conductance in hands and feet (ESCH and ESCF, respectively). We also used the Michigan Neuropathy Screening Instrument Questionnaire and Examination (MNSIQ and MNSIE, respectively) and questionnaires to evaluate quality of life (QoL) and level of pain (pain score). Results: B12 levels increased from 232.0 ± 71.8 at baseline to 776.7 ± 242.3 pmol/L at follow-up, p < 0.0001, in the active group but not in the control group. VPT, MNSIQ, QoL, pain score, SNCV, SNAP, and ESCF significantly improved in the active group (p < 0.001, p = 0.002, p < 0.0001, p < 0.000, p < 0.0001, p < 0.0001, and p = 0.014, respectively), whereas CARTS and MNSIE improved but not significantly. MCR, MNSIQ, SNCV, SNAP, and pain score significantly deteriorated in the control group (p = 0.025, p = 0.017, p = 0.045, p < 0.0001, and p < 0.0001, respectively). Conclusions: The treatment of patients with DN with 1 mg of oral methylcobalamin for twelve months increased plasma B12 levels and improved all neurophysiological parameters, sudomotor function, pain score, and QoL, but it did not improve CARTS and MNSIE.     

International Neuropathy Workshop of 2009: Introduction to the final reports

Neuropathies are amongst the most common of the long‐term complications of diabetes, affecting up to 50% of patients. Their clinical features vary immensely and patients may present with a wide spectrum of specialties, from neurology to urology, for example, or from cardiology to podiatry. Neuropathies are typically characterized by a progressive loss of nerve fibres which may affect both of the principal divisions of the peripheral nervous system. The epidemiology and natural history of the diabetic neuropathies remain poorly defined. The International Consensus Workshop in Toronto in 2009 arose from the fact that at the moment there are no clear, universally accepted guidelines regarding the definition of diabetic neuropathies. This has resulted in a massive variation in how neuropathy is diagnosed in different centres and countries. A preliminary summary report of the Toronto meeting was published in 2010. The series of papers published in this issue of Diabetes/Metabolism Research and Reviews are the detailed reports that came from each sub‐group of this Consensus panel. These reviews cover the problems with definitions and classification of neuropathy, the management of painful neuropathy and then the sub‐group of small fibre neuropathies. There are also 3 papers on the autonomic neuropathies, covering cardiovascular autonomic neuropathies, as well as other areas of the autonomic neuropathies including gastrointestinal, urogenital and pseudomotor neuropathies. This series of papers will give the reader detailed information on the diverse aspects of diabetic neuropathies, their measurement and management, and will also assist in the selection of appropriate measures of both autonomic and somatic nerve function in clinical trials. This is clearly work in progress as diagnostic criteria for diabetic neuropathies are likely to evolve with developments in the field. Copyright © 2011 John Wiley & Sons, Ltd.     

Risk factors for cardiac autonomic neuropathy in type 1 diabetes mellitus

Aims/hypothesis Cardiac autonomic neuropathy (CAN) is associated with increased morbidity and mortality in type 1 diabetes. Apart from glycaemic control, risk factors for CAN have not been extensively studied.Methods As part of the EURODIAB Prospective Complications Study, CAN—defined as either a loss of heart rate variability or postural hypotension on standing—was assessed at baseline and follow-up (7.3±0.6 years from baseline) in patients with type 1 diabetes.Results Follow-up measurements were available for 956 participants without CAN at baseline (age at baseline 31.3±8.9 years, duration of diabetes 13.5±8.3 years). During follow-up, 163 (17%) subjects developed CAN, yielding an incidence of 23.4 per 1,000 person-years. Blood pressure, weight, the presence of cardiovascular disease, albuminuria, distal symmetrical polyneuropathy (DSP) and retinopathy at baseline were associated with the incidence of CAN after adjustment for sex, duration of diabetes and HbA₁c. In a multivariate regression model, baseline factors associated with an increased risk of developing CAN were age [odds ratio (OR)=1.3 per decade, 95% CI 1.1–1.7], HbA₁c (OR=1.2 per percentage point, 95% CI 1.1–1.4), systolic blood pressure (OR=1.1 per 10 mmHg, 95% CI 1.0–1.3), feeling faint on standing (OR=2.0, 95% CI 1.2–3.2), DSP (OR=1.9, 95% CI 1.2–3.0) and retinopathy (OR=1.7, 95% CI 1.1–2.6).Conclusion/interpretation This study confirms the importance of exposure to hyperglycaemia as a risk factor for CAN. A small set of variables, including HbA₁c, hypertension, DSP and retinopathy, predict the risk of CAN. Clinical trials are needed to address the impact of intensive antihypertensive treatment on CAN in type 1 diabetes.