Benefits of a simple glycaemic protocol in an orthopaedic surgery ward: a randomized prospective study.

BACKGROUND: Hyperglycaemia and diabetes mellitus are common in patients hospitalized in the orthopaedic surgery ward. However, glycaemic control obtained during hospitalization is often suboptimal. No method for achieving adequate glycaemic control in this population has been validated in an in-hospital setting. INTERVENTION: An intervention including an intensive subcutaneous insulin protocol in the orthopaedic department. METHODS: All diabetic patients admitted to the Department of Orthopaedic Surgery were prospectively randomized during a 6-month period. One group (n = 30) received standard care with sliding scale insulin and the other group (n = 35) received the intervention protocol. During the intervention period, the staff was briefed on the importance of glucose monitoring and control. An intensive multiple-injection protocol consisting of four daily regular/neutral protamine hagedorn (NPH) insulin injections was initiated in diabetic patients. The programme was followed up by a consulting diabetologist. RESULTS: Mean blood glucose levels throughout the hospitalization were 161.48 ± 3.8 mg/dL in the intervention group versus 175.29 ± 2.3 mg/dL in the control group (p < 0.0005). Hospitalization was shorter by 2 days in the intervention group (p < 0.05). The number of severe hyperglycaemic events (blood glucose level above 400 mg%) was significantly lower (p < 0.05) in the intervention group. There was no significant difference in the number of hypoglycaemic events. CONCLUSIONS: The suggested four-step intervention regimen improved glycaemic control of hospitalized patients in the orthopaedic department and simplified the 'in-house' treatment of the diabetic patient. Hospital stays were reduced on average by two days (p < 0.05).

Open-label study to assess the safety and pharmacodynamics of five oral insulin formulations in healthy subjects.

AIM: Orally delivered insulin is predicted to bear therapeutic advantages in diabetes management when compared to injectable insulin, because of its ability to mimic the natural route of endogenous insulin secreted by the pancreas into the portal vein and directly to the liver. Oramed Pharmaceuticals is developing an oral insulin product which consists of unmodified recombinant human insulin combined with adjuvants that protect it from enzymatic degradation in the gastrointestinal tract and promote its absorption from the gut. The aim was to determine the optimal adjuvants to insulin ratio which can provide for the best pharmacodynamic profile, while maintaining the safety of the product. METHODS: Eight healthy, male volunteers participated in this open-label study which included five independent visits. During each visit, subjects were administered one of the five encapsulated oral insulin formulations which contained equal amounts of insulin but varying proportions of adjuvants. Parameters measured included safety, C(max) and T(max) for insulin and C(min), T(min) and area under the curve (AUC) for glucose and c-peptide. Comparisons were made between formulations and between post-treatment time periods within each visit. RESULTS: All five oral insulin formulations were well tolerated and no serious adverse events were reported. All formulations resulted in a significant response in the response period (60-300 min) in comparison to baseline (0-60 min); this was captured both in the c-peptide response and the glucose response (all five formulations p < 0.05). However, none of the formulations turned out significantly different in response over the other. Formulation 5 showed the most profound reduction in c-peptide when AUC(0-60) (baseline) was compared to AUC(60-300) (p < 0.007). CONCLUSIONS: All five oral insulin formulations resulted in glucose and c-peptide reductions, where formulation 5 demonstrated the most pronounced effect on c-peptide concentration reduction. This formulation was deemed the lead formulation to be advanced to future clinical studies. This study also reinforces the notion that oral insulin can maintain its biological activity after delivery, suggesting a potential role for this product in management of diabetes.

Treatment of new-onset type 1 diabetes with peptide DiaPep277 is safe and associated with preserved beta-cell function: extension of a randomized, double-blind, phase II trial.

BACKGROUND: Treatment with DiaPep277, a peptide derived from HSP60, has been shown to preserve beta-cell function in non-obese diabetic mouse (NOD) mice and in a trial with newly diagnosed human patients with type 1 diabetes treated over a 10-month period. This article extends the clinical trial observations to a total of 20 months of treatment to determine the safety and the effects of repeated doses of DiaPep277 on endogenous insulin secretion, metabolic control, and exogenous insulin requirements. METHODS: Thirty-five male patients (aged 16-58) with a basal C-peptide greater than 0.1 nmol/L were assigned to periodic treatment with DiaPep277 (1 mg) or placebo for a 12-month treatment and 18-month observation protocol, later extended to an additional year of treatment. Stimulated C-peptide, HbA1c, and an exogenous insulin dose were the clinical endpoints. RESULTS: At 18 months, stimulated C-peptide concentrations had fallen in the placebo group (p = 0.0005) but were maintained in the DiaPep277 group. The need for exogenous insulin was higher in the placebo group than in the DiaPep277 group. Mean HbA1c concentrations were similar in both groups. After extension of the study, patients continuing treatment with DiaPep277 and those switched from placebo to DiaPep277 manifested a trend towards a greater preservation of beta-cell function compared to patients maintained on or switched to placebo. The safety profile of DiaPep277 was similar between the treatment and placebo groups, and no drug-related adverse events occurred. CONCLUSIONS: Periodic treatment of subjects with DiaPep277 over 2 years was safe and associated preservation of endogenous insulin secretion up to 18 months was observed.

Lymphocytic interstitial pneumonia associated with common variable immunodeficiency resolved with intravenous immunoglobulins.

Lymphocytic interstitial pneumonia (LIP) is a rare form of interstitial lung disease. A few case reports have described an association with common variable immunodeficiency (CVID). Corticosteroids are usually used to treat symptomatic patients but their efficacy has never been studied in a controlled trial. We describe a patient with LIP and CVID who was treated monthly with intravenous immunoglobulins (IVIG) without steroids. The patient improved dramatically. We believe that, in selected cases of LIP and immunodeficiency, IVIG given monthly should be considered as the only treatment without adding steroids.

Conditional and specific NF-kappaB blockade protects pancreatic beta cells from diabetogenic agents.

Type 1 diabetes is characterized by the infiltration of inflammatory cells into pancreatic islets of Langerhans, followed by the selective and progressive destruction of insulin-secreting beta cells. Islet-infiltrating leukocytes secrete cytokines such as IL-1beta and IFN-gamma, which contribute to beta cell death. In vitro evidence suggests that cytokine-induced activation of the transcription factor NF-kappaB is an important component of the signal triggering beta cell apoptosis. To study the in vivo role of NF-kappaB in beta cell death, we generated a transgenic mouse line expressing a degradation-resistant NF-kappaB protein inhibitor (DeltaNIkappaBalpha), acting specifically in beta cells, in an inducible and reversible manner, by using the tet-on regulation system. In vitro, islets expressing the DeltaNIkappaBalpha protein were resistant to the deleterious effects of IL-1beta and IFN-gamma, as assessed by reduced NO production and beta-cell apoptosis. This effect was even more striking in vivo, where nearly complete protection against multiple low-dose streptozocin-induced diabetes was observed, with reduced intraislet lymphocytic infiltration. Our results show in vivo that beta cell-specific activation of NF-kappaB is a key event in the progressive loss of beta cells in diabetes. Inhibition of this process could be a potential effective strategy for beta-cell protection.

New and experimental approaches to treatment of diabetic foot ulcers: a comprehensive review of emerging treatment strategies.

Diabetic foot ulcers occur in up to 15% of all diabetic patients and are a leading cause of nontraumatic amputation worldwide. Neuropathy, abnormal foot biomechanics, peripheral vascular disease and external trauma are the major contributors to the development of a foot ulcer in the diabetic patient. Therapy today includes repeated debridement, offloading, and dressings, for lower grade ulcers, and broad spectrum antibiotics and occasionally limited or complete amputation for higher grades, requiring a team effort of health care workers from various specialties. The large population affected by diabetic foot ulcers and the high rates of failure ending with amputation even with the best therapeutic regimens, have resulted in the development of new therapies and are the focus of this review. These include new off loading techniques, dressings from various materials, methods to promote wound closure using artificial skin grafts, different growth factors or wound bed modulators and methods of debridement. These new techniques are promising but still mostly unproven and traditional approaches cannot be replaced. New and generally more expensive therapies should be seen as adding to traditional approaches.