Luigi Uccioli

Visual electrophysiological responses in persons with type 1 diabetes

Persons with type 1 diabetes show electrophysiological abnormalities of the visual system which are revealed by methods such as flash electroretinogram (FERG), oscillatory potentials (OPs), pattern electroretinogram (PERG), focal electroretinogram (focal ERG), visual evoked potentials (VEP) in basal condition and after photostress. This review reports the changes in electrophysiological responses of the different structures composing the visual system observed in persons with type 1 diabetes before the development of the overt clinical retinopathy. In persons with type 1 diabetes without retinopathy (IDD), the earlier abnormal electrophysiological responses are recorded from the innermost retinal layers and postretinal visual pathways, as suggested by impaired PERGs and delayed retinocortical time (RCT). These are observed in IDD persons with a disease duration shorter than 6 months. Further electrophysiological changes are recorded from the macula (abnormal focal ERG and VEP after photostress) in IDD persons with disease duration greater than 1 year. Additional electrophysiological changes are recorded from the middle and outer retinal layers (impaired FERG and OPs) in IDD persons with a disease duration greater than 10 years. All the electrophysiological tests show a greater degree of abnormal responses in persons with type 1 diabetes when a background retinopathy is present. Copyright

Long-Term Outcomes of Diabetic Patients With Critical Limb Ischemia Followed in a Tertiary Referral Diabetic Foot Clinic

OBJECTIVE We describe the long-term outcomes of 510 diabetic patients with critical limb ischemia (CLI) and an active foot ulcer or gangrene, seen at the University Hospital of Rome Tor Vergata, a tertiary care clinic. RESEARCH DESIGN AND METHODS These patients were seen between November 2002 and November 2007 (mean follow-up 20 ± 13 months [range 1–66 months]). The Texas Wound Classification was used to grade these wounds that were either class C (ischemia) and D (ischemia+infection) and grade 2–3 (deep–very deep). This comprehensive treatment protocol includes rapid and extensive initial debridement, aggressive use of peripheral percutaneous angioplasty, empirical intravenous antibiotic therapy, and strict follow-up. RESULTS The protocol was totally applied (with percutaneous angioplasty [PA+]) in 456 (89.4%) patients and partially (without percutaneous angioplasty [PA−]) in 54 (10.6%) patients. Outcomes for the whole group and PA+ and PA− patients are, respectively: healing, n = 310 (60.8%), n = 284 (62.3%), and n = 26 (48.1%); major amputation, n = 80 (15.7%), n = 67 (14.7%), and n = 13 (24.1%); death, n = 83 (16.25%), n = 68 (14.9%), and n = 15 (27.8%); and nonhealing, n = 37 (7.25%), n = 37 (8.1%), and n = 0 (0%) (χ2 <0.0009). Predicting variables at multivariate analysis were the following: for healing, ulcer dimension, infection, and ischemic heart disease; and for major amputation, ulcer dimension, number of minor amputations, and age. Additional predicting variables for PA+ patients were the following: for healing, transcutaneous oxygen tension [ΔTcPo2]; and for major amputation, basal TcPo2, basal A1C, ΔTcPo2, and percutaneous angioplasty technical failure. CONCLUSIONS Early diagnosis of CLI, aggressive treatment of infection, and extensive use of percutaneous angioplasty in ischemic affected ulcers offers improved outcome for many previously at-risk limbs. Ulcer size >5 cm2 indicates a reduced chance of healing and increased risk of major amputation. It was thought that all ulcers warrant aggressive treatment including percutaneous angioplasty and that treatment should be considered even for small ischemic ulcers.

Proinflammatory modulation of the surface and cytokine phenotype of monocytes in patients with acute Charcot foot.

OBJECTIVE Despite increased information on the importance of an inappropriate inflammatory response in the acute Charcot process, there has been no previous attempt to define the specific pathways that mediate its pathogenesis. Here, the role played by monocytes was analyzed. RESEARCH DESIGN AND METHODS The immune phenotype of peripheral monocytes was studied by fluorescence-activated cell sorter analysis comparing patients with acute Charcot (n = 10) in both the active and recovered phase, diabetic patients with neuropathy (with or without osteomyelitis), and normal control subjects. RESULTS When compared with diabetic control subjects and healthy subjects, monocytes from acute Charcot patients showed a proinflammatory immune phenotype characterized by increased production of proinflammatory cytokines, reduced secretion of anti-inflammatory cytokines, increased expression of surface costimulatory molecules, and increased resistance to serum withdrawal-induced apoptosis. In addition, the pattern of circulating cytokines confirmed activation of proinflammatory cytokines. No modulation of the monocyte phenotype was documented in diabetic control subjects and healthy subjects, thus indicating that the proinflammatory alterations of monocytes are specific and causative of acute Charcot. CONCLUSIONS Together, these data provide evidence for the role of proinflammatory changes in the immune phenotype of monocytes in the pathogenesis of acute Charcot. These alterations may explain the abnormally intense and prolonged inflammatory response that characterizes this disorder and may represent a potential therapeutic target for specific pharmacological interventions.

Muscle performance and ankle joint mobility in long-term patients with diabetes

BackgroundLong-term patients with diabetes and peripheral neuropathy show altered foot biomechanics and abnormal foot loading. This study aimed at assessing muscle performance and ankle mobility in such patients under controlled conditions.MethodsForty six long-term diabetes patients with (DN) and without (D) peripheral neuropathy, and 21 controls (C) were examined. Lower leg muscle performance and ankle mobility were assessed by means of a dedicated equipment, with the patient seated and the examined limb unloaded. 3D active ranges of motion and moments of force were recorded, the latter during maximal isometric contractions, with the foot blocked in different positions.ResultsAll patients showed reduced ankle mobility. In the sagittal and transversal planes reduction vs C was 11% and 20% for D, 20% and 21% for DN, respectively.Dorsal-flexing moments were significantly reduced in all patients and foot positions, the highest reduction being 28% for D and 37% for DN. Reductions of plantar-flexing moments were in the range 12–15% for D (only with the foot blocked in neutral and in dorsal-flexed position), and in the range 10–24% for DN. In all patients, reductions in the frontal and transversal planes ranged 14–41%.ConclusionThe investigation revealed ankle functional impairments in patients with diabetes, with or without neuropathy, thus suggesting that other mechanisms besides neuropathy might contribute to alter foot-ankle biomechanics. Such impairments may then play a role in the development of abnormal gait and in the onset of plantar ulcers.

Lower limb arterio-venous shunts, autonomic neuropathy and diabetic foot

We have quantitatively assessed the percentage of lower limb arterio-venous (a-v) shunting using a radioisotopic technique and correlated it with autonomic neuropathy evaluated by cardiovascular tests. We have studied three groups of diabetic patients: Group A, 12 non-neuropathic subjects without foot lesions; Group B, 12 neuropathic subjects without foot lesions; Group C, 12 neuropathic subjects with recurrent foot ulcers. Shunting was higher in Group C (10.4 +/- 2.7%) than in Group B (6.8 +/- 2.3%, P less than 0.01) and Group A (3.8 +/- 1.2%, P less than 0.001). Shunts in Group B were higher than in Group A (P less than 0.05). All the tests exploring autonomic function were more impaired in Groups B and C than in Group A, with no difference between Groups B and C. A direct correlation was found between a-v shunting and the following cardiovascular tests: postural hypotension (PH) (r = 0.41, P less than 0.02), sustained handgrip (SH) (r = 0.56, P less than 0.001), deep breathing (DB) (r = 0.40, P less than 0.005) and lying to standing (LS) (r = 0.44, P less than 0.01). A positive correlation was also found between a-v shunts and duration of the disease (r = 0.62, P less than 0.001). Arterio-venous shunting was found to be directly related to autonomic neuropathy even if the higher shunting found in the patients with foot ulcers was not related to a higher degree of autonomic involvement; in addition, this group of patients was characterized by having a more advanced sensory and motor neuropathy. In conclusion, autonomic neuropathy, through its influence on a-v shunts, may play a role in the pathogenesis of diabetic foot, but peripheral neuropathy probably plays a key role in conditioning the development of the overt clinical manifestations of diabetic foot.

Two-step autologous grafting using HYAFF scaffolds in treating difficult diabetic foot ulcers: results of a multicenter, randomized controlled clinical trial with long-term follow-up

This study evaluated the efficacy and tolerability of an autologous tissue-engineered graft—a 2-step HYAFF autograft—in the treatment of diabetic foot ulcers compared with standard care. In all, 180 patients with dorsal or plantar diabetic foot ulcers (unhealed for ≥1 month) were randomized to receive Hyalograft-3D autograft first and then Laserskin autograft after 2 weeks (n = 90; treatment group) or nonadherent paraffin gauze (n = 90; control group). Efficacy and adverse events were assessed weekly for 12 weeks, at 20 weeks, and at 18 months. The primary efficacy outcome was complete ulcer healing at 12 weeks. Wound debridement, adequate pressure relief, and infection control were provided to both groups. At 12 weeks, complete ulcer healing was similar in both groups (24% of treated vs 21% controls). A 50% reduction in ulcer area was achieved significantly faster in the treatment group (mean 40 vs 50 days; P = .018). Weekly percentage ulcer reduction was consistently higher in the treatment group. At 20 weeks, ulcer healing was achieved in 50% of the treated group as compared with 43% of controls. Dorsal ulcers had a 2.17-fold better chance of wound healing per unit time following autograft treatment (P = .047). In a subgroup with hard-to-heal ulcers, there was a 3.65-fold better chance of wound healing following autograft treatment of dorsal ulcers ( P = .035). Adverse events were similar in both groups. The study results demonstrated the potential of this bioengineered substitutes to manage hard-to-heal dorsal foot ulcers.

Autonomic Neuropathy Influences Great Toe Blood Pressure

OBJECTIVE To assess the influence of autonomic neuropathy on toe blood pressure (TBP), a parameter used currently as an ischemic index. RESEARCH DESIGN AND METHODS The age-matched study subjects included 20 non-insulin-dependent diabetes mellitus (NIDDM) patients with autonomic neuropathy (DN) and 10 NIDDM patients without autonomic neuropathy (D), assessedby standard cardiovascular tests and galvanic skin response, and 8 control subjects (C). None of the subjects had peripheral vascular disease (PVD) (ankle/brachial index 0.9–1.1. RESULTS The TBP and toe/brachial index (TBI) were significantly lower in DN than in C and D (P < 0.01). The saturation index (SI), the ratiobetween foot venous and arterial partial pressure of oxygen (PO2), was significantly higher in DN than in C and D (P < 0.05). An inverse relationship was found between TBI and SI (r = 0.554, P = 0.001). CONCLUSIONS The autonomic nervous system directly influences peripheral circulation. In diabetic patients without PVD, a failure of sympathetic fibers caused by autonomic neuropathy could lead to a reduction of TBP. Therefore, TBP cannot be used as an ischemic index in diabetic patients.

Visual evoked potentials after photostress in insulin-dependent diabetic patients with or without retinopathy

Visual evoked potentials (VEPs) were assessed under basal conditions and after photostress in normal control subjects, in insulin-dependent diabetic patients with retinopathy (IDDPWR) and in insulin-dependent diabetic patients without retinopathy (IDDP). The VEPs recorded under basal conditions showed a P100 latency significantly higher in IDDP and IDDPWR eyes than in control eyes and in IDDPWR than in IDDP eyes (P<0.01). N75-P100 amplitude was significantly lower in IDDP and IDDPWR eyes than in control eyes (P<0.01). No difference was recorded in the N75-P100 amplitudes between IDDP and IDDPWR eyes. In all eyes, the VEPs recorded after photostress showed an increase in latency and a decrease in amplitude. In both IDDPWR eyes and IDDP eyes VEPs recorded at 20, 40 and 60 s after photostress showed higher mean increments in P100 latency than in C control eyes, and IDDPWR eyes showed higher mean increments in P100 latency than IDDP eyes (IDDP vs control P<0.01, IDDPWR vs control P<0.01, IDDPWR vs IDDP P<0.017). The mean reductions in amplitude observed at 20, 40 and 60 s after photostress in IDDP and IDDPWR eyes were lower than in control eyes (IDDP vs control P=0.01, IDDPWR vs control P<0.01, IDDPWR vs IDDP P<0.01). VEPs were superimposable on the basal VEP (recovery time) at 73.9 s in control eyes, at 88.17 s in IDDP eyes and at 113.3 s in IDDPWR eyes. VEPs after photostress in IDDP patients with normal visual acuity and no fluorangiographic signs of retinopathy may show multiple modifications. This may indicate the presence of an early functional deficiency of the central retinal layers.

Neural conduction in visual pathways in newly-diagnosed IDDM patients

OBJECTIVESnVisual evoked potentials (VEPs) show abnormal responses in newly-diagnosed insulin-dependent diabetic (IDDM) patients. Electrophysiological methods allow one to dissect and explore different structures contributing to neural conduction in the visual pathways. The aim of our work was to assess whether the VEP abnormalities are due to impaired function of the retinal layers and/or a delayed conduction in the postretinal visual pathways.nnnMETHODSnSimultaneous recordings of VEP and pattern-electroretinogram (PERG) were performed at two intervals (at entry of the study and after 3 months) in 14 newly-diagnosed IDDM patients (age: 24.8+/-6.8 years; duration of disease: 3+/-1.5 months), and in 14 age-matched control subjects.nnnRESULTSnIn comparison with control subjects, IDDM patients showed: VEP P100 latencies significantly delayed (P < 0.01), a significant impairment of all PERG parameters (P < 0.01) and retinocortical time (RCT, difference between VEP P100 and PERG P50 latencies) and latency window (LW, difference between VEP N75 and PERG P50 latencies) also significantly increased (P < 0.01). All electrophysiological parameters were not significantly changed when retested after 3 months. No correlations were found between VEP P100 latency, RCT, LW and PERG parameters.nnnCONCLUSIONSnImpaired PERG indicates an involvement of the innermost retinal layers; increased values of RCT and LW represent an index of delayed neural conduction in the postretinal visual pathways. Therefore two sources, one retinal (impaired PERG) and one postretinal (delayed RCT and LW), may independently contribute in to the abnormal responses of VEP observed in newly-diagnosed IDDM patients. Three months of relatively-stable metabolic control have not normalized the VEP and PERG impairment.

non-Healing foot ulCers in diabetiC patients: general and loCal interfering Conditions and management options WitH advanCed Wound dressings

Medical knowledge about wound management has improved as recent studies have investigated the healing process and its biochemical background. Despite this, foot ulcers remain an important clinical problem, often resulting in costly, prolonged treatment. A non-healing ulcer is also a strong risk factor for major amputation. Many factors can interfere with wound healing, including the patients general health status (i.e., nutritional condition indicated by albumin levels) or drugs such as steroids that can interfere with normal healing. Diabetic complications (i.e., renal insufficiency) may delay healing and account for higher amputation rates observed in diabetic patients under dialysis treatment. Wound environment (e.g., presence of neuropathy, ischaemia, and infection) may significantly influence healing by interfering with the physiological healing cascade and adding local release of factors that may worsen the wound. The timely and well-orchestrated release of factors regulating the healing process, observed in acute wounds, is impaired in non-healing wounds that are blocked in a chronic inflammatory phase without progressing to healing. This chronic phase is characterised by elevated protease activity (EPA) of metalloproteinases (MMPs) and serine proteases (e.g., human neutrophil elastase) that interfere with collagen synthesis, as well as growth factor release and action. EPA (mainly MMP 9, MMP-8 and elastase) and inflammatory factors present in the wound bed (such as IL-1, IL-6, and TNFa) account for the catabolic state of non-healing ulcers. The availability of wound dressings that modulate EPA has added new therapeutic options for treating non-healing ulcers. The literature confirms advantages obtained by reducing protease activity in the wound bed, with better outcomes achieved by using these dressings compared with traditional ones. New technologies also allow a physician to know the status of the wound bed environment, particularly EPA, in a clinical setting. These may be helpful in guiding a clinicians options in treating very difficult-to-heal ulcers.