Diabetic neuropathic cachexia and acute bilateral cataract formation following rapid glycaemic control in a newly diagnosed type 1 diabetic patient.

In patients with Type 1 diabetes mellitus (DM), the development of complications within the first few years of diagnosis is very unusual and the development of complications within weeks of commencement of insulin therapy is exceptional. Diabetic neuropathic cachexia, unlike the other more common neuropathies associated with diabetes, is a rare form of peripheral neuropathy characterized by profound weight loss, painful dysaesthesias over the limbs and trunk with spontaneous resolution usually occurring within a year. The morphologically distinct diabetic or metabolic cataract in patients with newly diagnosed Type 1 DM is also a rare complication. We describe the first case of a young man with newly diagnosed Type 1 DM who developed these two rare complications within 3 months of diagnosis and insulin therapy commencement. Rapid development of complications in this patient raises two possibilities, i.e. a probable link between the pathophysiology of these two complications following rapid glycaemic control, and a subset of patients with unusual susceptibility to complications. We re-emphasize the need for vigilant monitoring of complications in young diabetic patients, even in the first few years of their disease. In particular, young patients with visual impairment should be evaluated carefully for evidence of treatable eye complications.     

Characterization of the cytolytic activity of CD4+ and CD8+ tumor-infiltrating lymphocytes in human renal cell carcinoma

Previously we showed that IL2 expanded tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma mediated non-major histocompatibility complex-restricted cytotoxicity. Phenotypic analysis showed that cultured TILs were composed mostly of T-lymphocytes with varying numbers of CD4+, CD8+, and CD56+ (Leu19+) populations. Here we compared the cytolytic activity of the two predominant TIL subsets, CD3+CD4+ and CD3+CD8+, to that of the CD56+ populations. Using magnetic beads coated with antibodies to either CD4 or CD8, CD3+CD4+, and CD3+CD8+ TILs were isolated in a highly enriched form (greater than 92%) and could be expanded for over 40 days in vitro with 1000 units/ml IL2. In a 4-h 51Cr release assay the CD4+ and CD8+ TILs showed minimal lytic activity, whereas unseparated cells exhibited significant levels of non-major histocompatibility complex-restricted cytotoxicity. The lytic activity seen in the 4-h assay with unseparated TILs appeared to be related to the presence of CD56+ populations. With one exception none of the purified CD4+ or CD8+ TILs expressed any significant levels of CD56, while the unseparated TILs contained varying numbers of CD3+CD56+ and CD3-CD56+ populations. Cell-sorting experiments verified that the CD56+ populations were responsible for most of the lytic activity in 4 h even though CD3+CD56- cells represented the predominant cell type. Although CD3+CD56- TILs were minimally lytic in 4 h, we show here that both CD3+CD4+ and CD3+CD8+ subsets displayed substantial cytotoxicity in long-term assays. In the 18-h 51Cr release assay 5 of 6 CD4+ and 2 of 3 CD8+ TILs were lytic for the autologous tumor. In two cases, restimulation with the autologous tumor induced augmented cytolytic activity of TIL subsets and in one case induced lytic activity in 4 h. The cytotoxic activity of TIL subsets was further examined using a 72-h assay in which TILs were cocultured with a confluent layer of tumor cells. The degree of cytotoxicity was quantitated by measuring the amount of crystal violet dye that was incorporated by tumor cells which remained after the incubation period. CD4+ and CD8+ TILs typically caused greater than a 50% reduction of tumor cells in 3 days and the level of reduction was increased when IL2 was added to the cultures. All the CD4+ and CD8+ subset preparations were cytotoxic in the 3-day assay even though some were not lytic for certain targets in the 18-h 51Cr release assay.(ABSTRACT TRUNCATED AT 400 WORDS)     

C‐fiber function assessed by the laser doppler imager flare technique and acetylcholine iontophoresis

Vasodilation induced by both acetylcholine iontophoresis (ACh Ionto) and the laser Doppler flare technique (LDIFT) can be used to measure small‐fiber function. The aim of this study was to compare the neurogenic nature of these methods. ACh Ionto and the LDIFT were performed on 10 controls, with and without local anesthetic cream. The local anesthetic cream blocks the axon reflex; thus, by determining the ratio of hyperemic area to stimulus area before and after anesthesia, the neurogenic nature of the hyperemia can be determined. The ratio of hyperemic area to stimulus area was significantly reduced by local anesthesia in the LDIFT [ratio (mean ± SD): 2.33 ± 0.67 with local anesthesia; 6.84 ± 1.33 without local anesthesia; P < 0.0001], whereas this ratio was unaffected by local anesthesia in the ACh Ionto group (2.61 ± 0.57 with local anesthesia; 2.67 ± 1.27 without local anesthesia). This study confirms that the LDIFT measures small‐fiber function. In contrast, hyperemia elicited by ACh Ionto outside the capsule is not blocked by local anesthesia and is thus non‐neurogenic. Muscle Nerve, 2009     

Loss of the First Phase Insulin Response to Intravenous Glucose in Subjects with Persistent Impaired Glucose Tolerance

Loss of the first phase insulin response to intravenous glucose is one of the earliest detectable defects of beta cell dysfunction in Type 2 diabetes mellitus. Impaired glucose tolerance (IGT) is considered a prediabetic condition, therefore loss of first phase insulin secretion in subjects with IGT would suggest beta cell dysfunction as an early lesion in the development of Type 2 diabetes. Three groups of subjects were studied, 7 subjects with persistent IGT (classified as having IGT at two 75 g oral glucose tolerance tests (OGTT) done 6 months apart), 6 subjects with transient IGT (IGT at the first OGTT, but normal glucose tolerance at a repeat OGTT 6 months later), and 7 normal controls. First phase insulin secretion was studied using an intravenous glucose tolerance test with arterialized blood sampling. Fasting, 3, 4 and 5 min samples were assayed for glucose and insulin (specific two-site immunoradiometric assay). The fasting insulin was similar in all three groups, however the 3 min insulin response was significantly lower in those with persistent impaired glucose tolerance (p < 0.02). Thus subjects with persistent impaired glucose tolerance demonstrated loss of the first phase insulin response as an early indicator of beta cell dysfunction while subjects with transient IGT had a normal insulin response to intravenous glucose. During the OGTT, the 30 min glucose was not significantly different (p = 0.1) but the 30 min insulin to glucose ratio was significantly lower in subjects with persistent IGT (p < 0.03). In the whole group the 30 min insulin to glucose ratio during the OGTT showed a significant correlation with the peak insulin response during the IVGTT (r = 0.76, p < 0.001). This study suggests that beta cell dysfunction with impaired early insulin release is present before the development of Type 2 diabetes.     

A Novel Capillary Collection Method for Obtaining Current Glycosylated Haemoglobin Levels in Diabetic Children

A simple method for collecting capillary blood for measurement of glycosylated haemoglobin (HbA_1c) was developed that allows samples to be obtained at home and then mailed to the laboratory 2 weeks before a hospital visit. A single drop of blood is collected into a 2 ml plastic tube and sent for HbA_1c assay on the Diamat HPLC system which has inter-and intra-assay coefficients of variation < 2.6 and < 1.2%, respectively. Results of simultaneously obtained venous and capillary samples in 32 diabetic children agreed well with each other. A separate study of 25 patients was performed to determine whether transport conditions affected the samples. Posted samples were compared with venous samples; again the values were in good agreement. This method is now used routinely in the diabetic clinic. Its value was determined by questionnaire in 40 children with age range 4–17 years. No family experienced difficulty collecting samples and all samples received were suitable for analysis. Children preferred this method to blood collection in the clinic as they felt it was less traumatic and more convenient. Seventy-nine percent of them understood its value in the long-term control of diabetes. In 40.5% of visits changes to management were made at the clinic due to the availability of the results.     

GM-CSF safety and effects in the management of advanced/refractory multiple myeloma patients: a phase I trial

PURPOSE: Some limitations of effective therapy in multiple myeloma include the low growth fraction of the malignant plasma cells, multi-drug resistance, and the presence of other concurrent diseases in this patient population. A phase I study was conducted to evaluate the toxicity of granulocyte macrophage colony stimulating factor (GM-CSF) in myeloma patients as well as the potential effect on the plasma cell labeling index (PCLI). Relapsed patients with multiple myeloma were eligible. METHODS: The first phase of this trial assessed the toxicity (including the effect on disease progression) of escalating doses (125-500 microg/m2 SC, days 1-5) of GM-CSF, and the effects of this cytokine on PCLI. Patients whose PCLI doubled and increased to > or = 1.7% were treated with chemotherapy including cyclophosphamide, vincristine, prednisone, and GM-CSF. Twenty-two patients were enrolled. RESULTS: The toxicity of GM-CSF was mild, and no dose-limiting side effects were seen. Twenty-five percent of patients (5/20) achieved the target PCLI, and 4/5 proceeded to receive chemotherapy. No relationship of GM-CSF dose to increases of the PCLI was noted. All patients who received chemotherapy responded. CONCLUSIONS: GM-CSF has acceptable toxicity in patients with multiple myeloma and produced increases of PCLI in selected individuals. Further studies of GM-CSF alone or in combination with chemotherapy are indicated.