Preclinical efficacy of a PARP-1 targeted Auger-emitting radionuclide in prostate cancer

There is an unmet need for better therapeutic strategies for advanced prostate cancer. Poly (ADP-ribose) polymerase-1 (PARP-1) is a chromatin-binding DNA repair enzyme overexpressed in prostate cancer. This study evaluates whether PARP-1, on account of its proximity to the cell\u27s DNA, would be a good target for delivering high-linear energy transfer Auger radiation to induce lethal DNA damage in prostate cancer cells. We analyzed the correlation between PARP-1 expression and Gleason score in a prostate cancer tissue microarray. A radio-brominated Auger emitting inhibitor (

Functional network disorganization and cognitive decline following fractionated whole-brain radiation in mice

Cognitive dysfunction following radiotherapy (RT) is one of the most common complications associated with RT delivered to the brain, but the precise mechanisms behind this dysfunction are not well understood, and to date, there are no preventative measures or effective treatments. To improve patient outcomes, a better understanding of the effects of radiation on the brain\u27s functional systems is required. Functional magnetic resonance imaging (fMRI) has shown promise in this regard, however, compared to neural activity, hemodynamic measures of brain function are slow and indirect. Understanding how RT acutely and chronically affects functional brain organization requires more direct examination of temporally evolving neural dynamics as they relate to cerebral hemodynamics for bridging with human studies. In order to adequately study the underlying mechanisms of RT-induced cognitive dysfunction, the development of clinically mimetic RT protocols in animal models is needed. To address these challenges, we developed a fractionated whole-brain RT protocol (3Gy/day for 10 days) and applied longitudinal wide field optical imaging (WFOI) of neural and hemodynamic brain activity at 1, 2, and 3 months post RT. At each time point, mice were subject to repeated behavioral testing across a variety of sensorimotor and cognitive domains. Disruptions in cortical neuronal and hemodynamic activity observed 1 month post RT were significantly worsened by 3 months. While broad changes were observed in functional brain organization post RT, brain regions most impacted by RT occurred within those overlapping with the mouse default mode network and other association areas similar to prior reports in human subjects. Further, significant cognitive deficits were observed following tests of novel object investigation and responses to auditory and contextual cues after fear conditioning. Our results fill a much-needed gap in understanding the effects of whole-brain RT on systems level brain organization and how RT affects neuronal versus hemodynamic signaling in the cortex. Having established a clinically-relevant injury model, future studies can examine therapeutic interventions designed to reduce neuroinflammation-based injury following RT. Given the overlap of sequelae that occur following RT with and without chemotherapy, these tools can also be easily incorporated to examine chemotherapy-related cognitive impairment

Issues in onfarm experimentation at Gandajika, Zaire

Farming systems research (FSR) at Gandajika, Zaire, is conducted by the national Legume Program (Programme National Legumineuses-PNL), which is part of the Applied Research and Extension Project (Projet de Recherche Agronomique Appliquee et Vulgarisation-RAV) of the department of Agriculture of Zaïre. RAV has a mandate for crop improvement. FSR and extension in cassava, maize and four grain legume crops

Effect of the addition of simple sugars to mixed meals on the glycemic control of insulin treated diabetic patients.

In order to evaluate the long term effects of a daily intake of simple sugars upon the glycemic control, 10 insulin treated diabetic outpatients received, according to a randomized cross over design, a conventional or a sucrose-enriched isocaloric, isoglucidic diet (about 20 g sucrose per day, given as desserts and/or soft drinks during or after mixed meals) for 3 months each. The daily insulin doses remained identical during both diets: 0.58 +/- 0.07 vs 0.58 +/- 0.06 U/kg body weight (mean +/- SEM) after conventional and sugar-enriched diet, respectively. The percentages of short acting insulin were also similar: 50 +/- 4 vs 49 +/- 4%. The mean glycemic profiles after lunch and dinner were comparable with both regimens. Moreover, glycosylated hemoglobin levels were 10.0 +/- 0.3 vs 9.9 +/- 0.4% after conventional and sucrose enriched diet, respectively. Plasma cholesterol and triglycerides remained unchanged. In conclusion, a relatively small daily intake of sucrose for 3 months has no clinical and/or metabolic side effects. Therefore, it seems no longer justified to completely ban sucrose from the diet of diabetic patients

Treatment of systemic hypertension in insulin-treated diabetes mellitus with rilmenidine.

The effects of a new alpha 2 agonist (S 3341 or rilmenidine) on blood pressure (BP), glycemic control, lipid metabolism and renal function were investigated during a 16-week open study in 29 insulin-treated diabetic patients with mild to moderate hypertension. There were 17 men and 12 women aged 50.9 +/- 2.2 years (mean +/- standard error of the mean). Duration of diabetes and insulin therapy was 218 +/- 24 and 143 +/- 30 months. After 2 weeks of placebo, systolic and diastolic BP was 165 +/- 3 and 97 +/- 0.5 mm Hg, respectively (supine). Rilmenidine (S 3341) given alone at daily doses of 1 or 2 mg according to the clinical response led to a prompt and sustained decrease of systolic and diastolic BP (159 +/- 4 and 88 +/- 1 mm Hg after 2 weeks; 149 +/- 3 and 85 +/- 1 mm Hg after 12 weeks; p less than 0.01). Seventeen patients (59%) had normal BP (systolic BP less than 160; diastolic BP less than 90 mm Hg, supine) after 12 weeks of S 3341. Diuretics were associated with S 3341 for the nonresponders at week 12; this led to normalization of BP in 90% of the patients at the end of the study. Glycemic control was assessed by home glucose monitoring (5 determinations/1 day per week), 24-hour glucosuria and postprandial plasma glucose at the outpatient clinic (n = 7) as well as by the measurement of the glycosylated hemoglobin. None of these parameters was significantly affected by S 3341.(ABSTRACT TRUNCATED AT 250 WORDS

Treatment of hypertension in diabetic patients.

Hypertension, common in diabetic patients, worsens not only the risk of cardiovascular complications, but also that of microangiopathic complications (nephropathy, retinopathy) of diabetes mellitus. It is thus important to ensure the perfect control of even mild hypertension in diabetic patients. However, treatment sometimes becomes difficult given that certain categories of antihypertensive drugs interfere with blood glucose control and/or lipid metabolism, interfere with the symptomatology of hypoglycemia, or promote orthostatic hypotension, a complication of autonomic neuropathy. A study was undertaken to determine the effects of rilmenidine, administered for 16 weeks, in 29 diabetic patients treated with insulin and experiencing mild-to-moderate hypertension (supine diastolic blood pressure, 96.7 +/- 0.5 mmHg). Administered as single-drug therapy, rilmenidine rapidly normalized blood pressure (systolic blood pressure, less than 160 mmHg; diastolic blood pressure, no more than 90 mmHg--supine) in 17 patients; this persisted throughout the trial period. Addition of a diuretic after 12 weeks in the remaining 12 patients led to normalization of blood pressure in nine additional patients. Blood glucose control (evaluated at home by weekly blood glucose measurements and by glycosylated hemoglobin levels) was unaffected by treatment. Plasma levels of cholesterol (total, high-density lipoprotein and low-density lipoprotein), triglycerides and proteinuria (or microalbuminuria) showed no change during the course of the trial. In conclusion, rilmenidine offers an effective and safe treatment for mild-to-moderate hypertension in diabetic patients treated with insulin and does not interfere with their blood glucose control

Metabolic and psychological evolution of insulin dependent diabetic patients during a 6 months insulin-pen treatment.

The aim of the study is to assess whether an insulin pen-treatment (NovopenR) could be of interest in 10 type I insulin dependent diabetic patients (C-peptide: 0.04 +/- 0.01 pmol/ml, mean +/- SEM), with metabolic and psychological parameters being together taken into account. The daily insulin doses were comparable during the previous treatment with conventional syringes (2-3 daily injections of ActrapidR and MonotardR) and the pen therapy: 0.65 +/- 0.05 vs 0.68 +/- 0.04 U/kg b.w. The metabolic control assessed by HbA1 levels was unchanged before and after 6 months pen treatment: 10.7 +/- 0.7 vs 10.9 +/- 0.6%, respectively. However, fructosamine increased from 2.89 +/- 0.26 to 3.92 +/- 0.20 mmol/l (p less than 0.01) during pen treatment. The psychological objective variables showed no significant changes after pen treatment. In contrast, the staff ratings about the patients attitude toward illness and the spouse evaluation of subjective well-being increased from 40.2 +/- 8.4 to 49.5 +/- 7.8 (p = 0.03) and 34.8 +/- 23.4 to 51.1 +/- 21.1 (p = 0.04), respectively. In conclusion, in a limited group of patients, a multiple injection regimen by pen treatment did not lead to an improved metabolic control. However, subjective psychological tests showed that some aspects of well-being tended to improve