Effects of beta non-selective and beta 1 selective adrenergic blocking agents on glucagon secretion from isolated perfused rat pancreas

To characterize beta-receptors which affect pancreatic A-cell activity, the effects of propranolol (beta non-selective blockade) and metoprolol (beta 1 selective blockade) were evaluated on epinephrine modulated insulin (IRI) and glucagon (IRG) release both in basal state and during metabolic stimulus (arginine 20 mM). The isolated perfused rat pancreas model with the exclusion of stomach and duodenum was used. Epinephrine infusion (at 10(-7) M) caused a prompt and sustained increase in basal IRG secretion and significantly potentiated glucagon release in response to metabolic stimulus. Insulin secretion was markedly suppressed by epinephrine both in basal conditions and during metabolic stimulus. Propranolol (at 10(-7) M) and metoprolol (at 10(-7) M) infusion clearly and similarly counteracted epinephrine stimulatory effects on IRG secretion but failed to elicit any significant effect on the epinephrine inhibited IRI release either in basal state or during the metabolic stimulus. These results suggest that, at least in the rat, the adrenergic stimulation of IRG release is mediated through a beta 1 receptor.     

An Immunological Investigation of Hemophilia B with a Tentative Classification of the Disease into Five Variants1

Abstract. 23 patients with hemophilia B have been investigated by means of several immunological methods. 16 patients (69.9%) had no detectable factor XI antigen. Five had a normal factor IX antigen and the electrophoretic mobility of this abnormal factor IX was similar to that of its normal counterpart. One of these five patients had hemophilia BW, since ox brain thromboplastin clotting time was severely prolonged. The remaining two patients had reduced or decreased factor IX antigen. Several patients showed a slight prolongation of ox brain thromboplastin time due to an associated slight factor VII deficiency. On the basis of these results, a tentative classification of hemophilia B into five variants is proposed, namely: hemophilia B, or with no factor IX antigen; hemophilia Bt, or with normal factor IX antigen; hemophilia BRA, or with reduced factor IX antigen; hemophilia BM, or with normal factor TX antigen and severely prolonged ox brain thromboplastin; hemophilia B, usually B-, with associated mild factor VII defect. A complete evaluation of the hemophilia B patients is feasible only by means of a battery of tests, namely: factor TX activity assay, factor IX antigen determination, ox brain thromboplastin clotting time, factor VII activity assay.     

Low serum bioactive luteinizing hormone in nonorganic male impotence: possible relationship with altered gonadotropin-releasing hormone pulsatility

We determined the biological activity of serum LH in 23 men, aged 25-50 yr, complaining of nonorganic impotence of at least 1-yr duration and 20 normal men. All of the impotent men had normal general physical examinations, penile Doppler tests, psychological tests, and peripheral nerve conduction. Serum PRL, FSH, LH, and thyroid hormone concentrations were normal as were the results of provocative tests of TSH, gonadotropin, and PRL secretion. The mean serum immunoreactive LH (I-LH) levels, measured in each impotent and normal man in three samples taken at 15-min intervals, were similar [7.2 +/- 0.5 (+/-SE) vs. 6.4 +/- 0.5 mIU/mL (IU/L)]. In contrast, the mean serum bioactive LH (B-LH) level was significantly lower in the impotent men than in the normal men [15.9 +/- 2.1 (+/-SE) vs. 33.0 +/- 2.8 mIU/mL (IU/L); P less than 0.05], as was the LH bio- to immunoactive (B/I) ratio (2.1 +/- 0.2 vs. 5.6 +/- 0.5; P less than 0.02). The mean serum testosterone level in the impotent men, although all individual values were within the range of normal for our laboratory [200-900 ng/100 mL (693-3120 nmol/L)], was 25% lower than that in the normal men [347 +/- 23 vs. 450 +/- 26 ng/100 mL; P less than 0.05 (1204 +/- 81 vs. 1560 +/- 91 nmol/L)]. In addition, a significant positive correlation was found between serum testosterone levels and LH B/I ratios in the impotent men (r = 0.45; P = 0.029). Pulsatile LH secretion, measured in six impotent and four normal men in blood samples collected every 15 min for 6 h, was similar in the two groups. The mean serum I-LH levels were similar [7.5 +/- 1.1 (+/-SE) vs. 5.1 +/- 1.0 mIU/mL (IU/L)], while the mean serum B-LH level as well as the LH B/I ratio was significantly lower in the impotent men throughout the observation period [11.4 +/- 2.0 (+/-SE) vs. 26.0 +/- 3.2 mIU/mL (IU/L) and 1.4 +/- 0.2 vs. 5.4 +/- 0.6; P less than 0.05 and P less than 0.02, respectively]. The B-LH pulse amplitude in the impotent men was reduced [mean peak LH, 8.6 +/- 0.3 vs. 25.3 +/- 4.0 mIU/mL (IU/L); P less than 0.05], while the LH pulse frequency was similar in the two groups. The median intrapulse LH B/I ratios were significantly higher than the median interpulse ratios in both impotent (P = 0.02) and normal men (P = 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)     

A plaster combining diclofenac and heparin: microcirculatory evaluation in 2 models of high-perfusion microangiopathy

A medicated plaster containing diclofenac epolamine (DHEP) and heparin has been recently proposed for the treatment of local trauma (ie, ankle sprains) accompanied by a clinically significant edema and/or hematoma formation, based on the combined antiinflammatory, hemorheologic, and antiedema properties of diclofenac and heparin. The aim of this study was therefore to compare the effects of a combined DHEP/heparin and DHEP alone in 2 clinical experimental models of microangiopathy, in order to provide a pharmacologic rationale for association of diclofenac and heparin. The microcirculation was evaluated by measuring cutaneous blood flow (laser Doppler) and transcutaneous oxygen and carbon dioxide pressures (TcPO(2) and TcPCO(2)) in 10 healthy volunteers before and after producing 2 microcirculatory models of microangiopathy: the models were based on reactive hyperemia (RH) and on local histamine injection, which both produce a significant increase in skin flux and alterations of TcPO(2) and TcPCO(2). The area of the study was the distal medial leg, treated with placebo, DHEP alone (Flector Tissugel), and DHEP/heparin (Flector Tissugel Heparin). The plasters were applied before producing the microcirculatory models to evaluate the efficacy of DHEP and DHEP/heparin in controlling and limiting vasodilatation and development of microangiopathy. A significant increase in cutaneous flux was obtained with both models. The application of DHEP partially limited the increase in flux and in TcPCO(2), as well as the decrease in TcPO(2) (which were considered signs of microangiopathy), but the combination DHEP/heparin was significantly more effective than DHEP alone. The inclusion of heparin in the plaster thus improved the control of the microcirculation achieved with diclofenac alone, when an experimental model of venous/arterial hyperemia and microangiopathy was used. In conclusion, DHEP in association with heparin modulates microcirculatory changes better than DHEP alone. It should be interesting to investigate the product in comparable clinical conditions in which it may be useful to act pharmacologically both on inflammation and microcirculatory disturbances that delay the recovery of patients.     

Three-month B vitamin supplementation in pre-school children affects folate status and homocysteine,but not cognitive performance

Background

Suboptimal vitamin B status might affect cognitive performance in early childhood. We tested the hypothesis that short-term supplementation with folic acid and selected B vitamins improves cognitive function in healthy children in a population with relatively low folate status.

Methods

We screened 1,002 kindergarten children for suboptimal folate status by assessing the total urinary para-aminobenzoylglutamate excretion. Two hundred and fifty low ranking subjects were recruited into a double blind, randomized, controlled trial to receive daily a sachet containing 220 μg folic acid, 1.1 mg vitamin B₂, 0.73 mg B₆, 1.2 μg B₁₂ and 130 mg calcium, or calcium only for 3 months. Primary outcomes were changes in verbal IQ, short-term memory and processing speed between baseline and study end. Secondary outcomes were urinary markers of folate and vitamin B₁₂ status, acetyl-para-aminobenzoylglutamate and methylmalonic acid, respectively, and, in a subgroup of 120 participants, blood folate and plasma homocysteine.

Results

Pre- and post-intervention cognitive measurements were completed by 115 children in the intervention and 122 in the control group. Compared to control, median blood folate increased by about 50 % (P for difference, P < 0.0001). Homocysteine decreased by 1.1 μmol/L compared to baseline, no change was seen in the control group (P for difference P < 0.0001) and acetyl-para-aminobenzoylglutamate was 4 nmol/mmol higher compared to control at the end of the intervention (P < 0.0001). We found no relevant differences between the groups for the cognitive measures.

Conclusion

Short-term improvement of folate and homocysteine status in healthy children does not appear to affect cognitive performance.     

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

Research in genetics of epilepsy represents an area of great interest both for clinical purposes and for understanding the basic mechanisms of epilepsy. Most mutations in epilepsies without structural brain abnormalities have been identified in ion channel genes, but an increasing number of genes involved in a diversity of functional and developmental processes are being recognized through whole exome or genome sequencing. Targeted molecular diagnosis is now available for different forms of epilepsy. The identification of epileptogenic mutations in patients before epilepsy onset and the possibility of developing therapeutic strategies tested in experimental models may facilitate experimental approaches that prevent epilepsy or decrease its severity. Functional analysis is essential for better understanding pathogenic mechanisms and gene interactions. In vitro experimental systems are either cells that usually do not express the protein of interest or neurons in primary cultures. In vivo/ex vivo systems are organisms or preparations obtained from them (e.g., brain slices), which should better model the complexity of brain circuits and actual pathophysiological conditions. Neurons differentiated from induced pluripotent stem cells generated from the skin fibroblasts of patients have recently allowed the study of mutations in human neurons having the genetic background of a given patient. However, there is remarkable complexity underlying epileptogenesis in the clinical dimension, as reflected by the fact that experimental models have not provided yet results having clinical translation and that, with a few exceptions concerning rare conditions, no new curative treatment has emerged from any genetic finding in epilepsy.     

Genetic polymorphisms and traumatic brain injury: the contribution of individual differences to recovery

Recovery after Traumatic Brain Injury (TBI) is variable, even for patients with similar severity of brain injury. Recent research has highlighted the contribution that genetic predisposition plays in determining TBI outcome. This review considers the potential for genetic polymorphisms to influence recovery of cognitive and social processes following TBI. Limitations and considerations that researchers should make when assessing the potential impact of polymorphisms on TBI outcome are also discussed. Understanding the genetic factors that support neuroplasticity will contribute to an understanding of the variation in outcome following injury and help to identify potential targets for rehabilitation.     

Incremental value of amyloid-PET versus CSF in the diagnosis of Alzheimer’s disease

European Journal of Nuclear Medicine and Molecular Imaging - To compare the incremental diagnostic value of amyloid-PET and CSF (Aβ42, tau, and phospho-tau) in AD diagnosis in patients with...