Cerebral necrosis after 25Gy radiotherapy in childhood followed 28 years later by 54Gy radiotherapy

The development of brain necrosis is life-long risk of repeat radiation therapy, even after a long time interval and a moderate radiation dose. We report on a 34-year-old patient who had prophylactic cranial irradiation with 25Gy and adjuvant chemotherapy in childhood for leukaemia and in adulthood, 28 years later, therapeutic radiotherapy with 54Gy for an atypical (WHO grade II) meningioma. About 2 years later he developed a contrast-enhancing lesion on MRI-scan that was indicative of a tumor according to a thallium-201 ((201)Tl) SPECT scan. Histopathology of the operated contrast-enhancing lesion showed extensive radionecrosis. Radiation necrosis is a small but serious risk after repeat radiation therapy, even after a very long-term interval, the delivery of small fractions and an average cumulative total dose. Patients undergoing repeat radiotherapy therefore need to be followed life-long for potential late radiation toxicity.     

Skin autofluorescence as a noninvasive marker of vascular damage in patients with type 2 diabetes

OBJECTIVE: Advanced glycation end products (AGEs) are thought to have a role in the pathogenesis of diabetes complications. We recently reported the association between skin autofluorescence, as a measure of tissue AGE accumulation, and diabetic neuropathy in a selected diabetic population. In this study, we investigated the relation between skin autofluorescence and clinical variables including micro- and macrovascular complications in a type 2 diabetes primary care population. RESEARCH DESIGN AND METHODS: Clinical data and skin autofluorescence were obtained in the type 2 diabetes group (n = 973) and in a control group (n = 231). Skin autofluorescence was assessed by illumination of the lower arm with a fluorescent tube (peak intensity approximately 370 nm). RESULTS: Skin autofluorescence was significantly higher in type 2 diabetic patients compared with control subjects in each age category. Multiple regression analysis showed significant correlation of skin autofluorescence with age, sex, diabetes duration, BMI, smoking, HbA1c, plasma creatinine, HDL cholesterol, and albumin-to-creatinine ratio in the type 2 diabetes group (R2 = 25%) and with age and smoking in the control group (R2 = 46%). Skin autofluorescence was significantly higher in the type 2 diabetes group, with both micro- and macrovascular disease, compared with the group without complications and the group with only microvascular complications. CONCLUSIONS: This study confirms in a large group of type 2 diabetic patients that skin autofluorescence is higher compared with age-matched control subjects and is associated with the severity of diabetes-related complications. Skin autofluorescence reflecting vascular damage might be a rapid and helpful tool in the diabetes outpatient clinic for identifying diabetic patients who are at risk for developing complications.     

Anti-T-cell antibodies for the treatment of acute rejection after renal transplantation

INTRODUCTION: Given the central role of T cells in the alloimmune response, anti-T-cell antibodies retain a prominent place in the treatment of renal allograft rejection. During the past decades, many anti-T-cell antibodies have emerged and subsequently left the field of solid organ transplantation, but rabbit-antithymocyte globulin (ATG) and the humanized anti-CD52 monoclonal rat antibody alemtuzumab have remained. AREAS COVERED: This article reviews the literature about the use of ATG and alemtuzumab for the treatment of acute rejection after renal transplantation. Furthermore, it discusses possible side effects, including infusion reactions. A literature search using PubMed and Embase databases was undertaken using search words alemtuzumab, antithymocyte globulin, rejection, kidney and renal transplantation. EXPERT OPINION: Treatment of severe or steroid-resistant renal allograft rejections with ATG is very effective, but is also associated with frequent infusion reactions and an increased incidence of infections and posttransplant lymphoproliferative disease. Alemtuzumab may prove to be an attractive alternative. It can be administered easily, is relatively cheap and nearly devoid of acute side effects, but the long-term efficacy and safety as anti-rejection treatment are currently difficult to judge. The increasing knowledge about lymphocyte subsets and their plasticity will drive the development of new, specific immunosuppression that lacks side effects of ATG and alemtuzumab. TOL101, a monoclonal antibody specifically directed against the human αβ T cell receptor, might be of potential value.     

"Diabetes of the elderly" and type 2 diabetes in younger patients: possible role of the biological clock

The increased prevalence of type 2 diabetes in the aged has been recognized for a long time. Within the last decades, a growing number of younger subjects and even children are prone to develop type 2 diabetes. In both groups, aged and young, the biological clock, located in the suprachiasmatic nucleus of the hypothalamus (SCN) is malfunctioning as evidenced by disturbed sleep cycles and altered circadian rhythms. While elderly patients have an impaired function of the SCN due to the degeneration of neurons, we propose that in younger subjects the clock loses its "feeling" for internal and external rhythms caused by the modern lifestyle. Sleeping late and less coupled with constant metabolic excess alter both internal and external environmental stimuli to the brain. In response to these alterations, the rhythm of the biological clock is disrupted which may lead to the metabolic syndrome and type 2 diabetes.     

A 12-month randomized crossover study on the effects of lanreotide Autogel and octreotide long-acting repeatable on GH and IGF-l in patients with acromegaly

Background Somatostatin analogues have been used successfully for the treatment of acromegaly but no randomized studies have compared the effects of lanreotide Autogel (LAN) and octreotide acetate long‐acting repeatable (OCT). Objective To compare the effect of LAN and OCT for the treatment of acromegaly in a randomized study design. Material and methods Twelve acromegalic patients were included and 10 patients completed treatment with LAN or OCT for 6 months and were then switched to the opposite treatment modality for 6 months without a washout period in a randomized crossover design. GH and IGF‐I profiles, clinical and biochemical evaluations were performed at 0, 4, 6, 10 and 12 months. Results After 6 months of treatment, five patients had GH levels < 0·38 µg/l during both therapies. The remaining patients had GH levels > 0·38 µg/l during both LAN and OCT treatment. Four patients had normalized IGF‐I levels during both treatment regimes. Two patients on LAN and one on OCT had normalized IGF‐I levels during one treatment and not during the other. In three patients, IGF‐I levels were elevated during both therapies. Four patients developed palpable nodules, two patients on LAN and two patients on OCT. Gastrointestinal complaints were seen in three patients during both therapies, in three patients only during LAN, and in one patient only during OCT. Two patients were withdrawn from the study because of serious adverse effects during LAN. After the study period, four patients preferred LAN and six patients preferred OCT treatment. Conclusion The effects of LAN and OCT therapy on GH and IGF‐I levels were comparable, but 3/10 patients had different treatment efficacies and 6/10 had different side‐effect profiles during the LAN and OCT treatment. These results indicate that a change from LAN to OCT or vice versa may be beneficial in some patients with treatment failure or side‐effects.     

The Effect of Aggressive Versus Conventional Lipid-lowering Therapy on Markers of Inflammatory and Oxidative Stress

Purpose Recent trial results are in favor of aggressive lipid lowering using high dose statins in patients needing secondary prevention. It is unclear whether these effects are solely due to more extensive lipid lowering or the result of the potentially anti-inflammatory properties of statins. We aimed to determine whether aggressive compared with conventional statin therapy is more effective in reducing systemic markers of inflammation and oxidative stress. Materials and methods This was a multi-centre, double-blind, placebo-controlled trial. Patients with previous cardiovascular disease, who did not achieve low density lipoprotein (LDL) cholesterol levels <2.6 mmol/l on conventional statin therapy (simvastatin 40 mg) were randomized to continue with simvastatin 40 mg or to receive atorvastatin 40 mg for 8 weeks and thereafter atorvastatin 80 mg for the final 8 weeks (aggressive treatment). Lipids, C-reactive protein, soluble cellular adhesion molecules, neopterin, von Willebrand Factor, and antibodies against oxidized LDL were measured at baseline and after 16 weeks. Results Lipid levels decreased significantly in the aggressive treatment group (LDL-C reduction 20.8%; P < 0.001), whereas a slight increase was observed in the conventional group (LDL-C increase 3.7%; P = 0.037). A significant reduction in antibodies against oxidized LDL was seen in the aggressive (13.4%; P < 0.001) and the conventional (26.8%; P < 0.001) group, but there was no difference between groups (P = 0.25). Furthermore, no significant differences in change in other biomarkers was observed between both groups. Conclusions This study does not support the hypothesis that a more profound reduction in inflammatory and oxidative stress contributes to the benefits of aggressive statin therapy.     

Impact of the interaction of R207910 with rifampin on the treatment of tuberculosis studied in the mouse model

New drugs are needed to shorten the duration of tuberculosis treatment. R207910, a diarylquinoline, is very active against Mycobacterium tuberculosis both in vitro and in mice. In healthy volunteers, the coadministration of R207910 and rifampin induced the increased metabolism of R207910, resulting in a 50% reduction in the level of R207910 exposure. We assessed the impact of reducing the dose of R207910 on its efficacy when R207910 was combined with a background regimen of isoniazid, rifampin, and pyrazinamide. Addition of 25 mg/kg of body weight or 12.5 mg/kg R207910 to the background regimen resulted in faster bacterial clearance and culture negativity. The difference in efficacy between the two doses was not statistically significant. The minimal bactericidal dose of R207910 when it was tested as part of the combination was identical to that when it was tested as monotherapy. Because of the drug-drug interaction in humans, the activity of R207910 in humans could be less than that expected from studies with mice. Our data from the mouse model demonstrate that R207910 has significant activity, even when its exposure is reduced by 50% and when it is added to a strong background regimen of isoniazid, rifampin, and pyrazinamide. In killing kinetic studies, the bactericidal effect of R207910 in mice was modest during the first week of treatment, but it increased in the following 3 weeks, while the bactericidal activity of isoniazid was limited to the first week of treatment.     

Intravenous glucose intake independently related to intensive care unit and hospital mortality: an argument for glucose toxicity in critically ill patients

OBJECTIVE: It is assumed that the toxic effects of glucose play a role in the outcome of critically ill patients. We studied the impact of the amount of infused glucose as a determinant of mortality. DESIGN: A retrospective cohort study design was used as blood glucose levels in critically ill patients are nowadays tightly controlled. PATIENTS: Long-stay critically ill patients (7-30 days). MEASUREMENTS: The association between the mean amount of glucose infusion and both intensive care unit (ICU) and hospital mortality was determined. We corrected for the mean glucose serum concentration, the mean dosage of insulin and for severity of illness, using the acute physiology and chronic health evaluation (APACHE II) score. RESULTS: Of the 2,042 admitted patients, 273 met the inclusion criteria. The mean length of stay was 14.4 days [interquartile range (IQR) 9-18]. Hospital mortality was significantly lower for patients with a mean glucose level below 8 mmol/l (30/79; 38%) compared to patients with a level above 8 mmol/l (104/194; 54%, P=0.023). Logistic stepwise multivariate regression analysis for both ICU and hospital mortality as dependent variables showed that APACHE II score and the mean daily amount of infused glucose were associated with mortality. CONCLUSION: In long-stay ICU patients without blood glucose level control, the ICU and hospital mortality was independently related to the mean amount of infused glucose. In addition, mortality in patients with a mean glucose level above 8.0 mmol/l was higher. Both these determinants of mortality can exert their effects by insulin-independent uptake of glucose with subsequent toxic intracellular effects.     

Self-measurement of blood pressure at home reduces the need for antihypertensive drugs: a randomized, controlled trial

It is still uncertain whether one can safely base treatment decisions on self-measurement of blood pressure. In the present study, we investigated whether antihypertensive treatment based on self-measurement of blood pressure leads to the use of less medication without the loss of blood pressure control. We randomly assigned 430 hypertensive patients to receive treatment either on the basis of self-measured pressures (n=216) or office pressures (OPs; n=214). During 1-year follow-up, blood pressure was measured by office measurement (10 visits), ambulatory monitoring (start and end), and self-measurement (8 times, self-pressure group only). In addition, drug use, associated costs, and degree of target organ damage (echocardiography and microalbuminuria) were assessed. The self-pressure group used less medication than the OP group (1.47 versus 2.48 drug steps; P<0.001) with lower costs ($3222 versus $4420 per 100 patients per month; P<0.001) but without significant differences in systolic and diastolic OP values (1.6/1.0 mm Hg; P=0.25/0.20), in changes in left ventricular mass index (-6.5 g/m(2) versus -5.6 g/m(2); P=0.72), or in median urinary microalbumin concentration (-1.7 versus -1.5 mg per 24 hours; P=0.87). Nevertheless, 24-hour ambulatory blood pressure values at the end of the trial were higher in the self-pressure than in the OP group: 125.9 versus 123.8 mm Hg (P<0.05) for systolic and 77.2 versus 76.1 mm Hg (P<0.05) for diastolic blood pressure. These data show that self-measurement leads to less medication use than office blood pressure measurement without leading to significant differences in OP values or target organ damage. Ambulatory values, however, remain slightly elevated for the self-pressure group.