Excess of DD homozygotes in haemodialysed patients with type II diabetes. The Diabetic Nephropathy Study Group

The role of the insertion/deletion polymorphism of the angiotensin- converting enzyme (ACE) gene in the genesis of diabetic nephropathy has been controversial. It has recently been proposed that progression occurs more rapidly in individuals with diabetic and non-diabetic renal disease who are homozygous for the D allele. We studied 658 patients with type II diabetes, 347 without diabetic nephropathy and 311 with various stages of diabetic nephropathy, and determined the I/D polymorphism of the ACE gene. Patients at the extremes of renal risk, i.e. normotensive patients without antihypertensive treatment and without nephropathy (n = 144), vs patients on dialysis (n = 61), differed with respect to genotype (DD 36.8% vs 57.4%; P = 0.007) and allele frequencies (D 0.59 vs 0.76; P < 0.001). In contrast, patients with and without presumed nephropathy as assessed by albuminuria did not differ with respect to DD genotype. In conclusion, in this study, which was limited by sample size, patients with the highest renal risk more frequently had the DD genotype. This would be compatible with a greater risk of (or rate of) progression to end-stage renal failure.      

Angiotensinogen gene M235T polymorphism is not associated with diabetic nephropathy

BACKGROUND.: There is agreement that a family history of hypertension (HT),is a predictor for the risk of diabetic nephropathy (DN) inpatients with type 2 diabetes, and possibly also type 1 diabetes.It follows that genes related to the risk of hypertension mustalso be considered candidate genes for DN. The 235T allele ofthe angiotensinogen gene was found to be related to primaryHT. METHODS.: To examine whether it is predictive for DN as well, we examinedthe angiotensinogen gene polymorphism in 230 healthy local controls,423 patients with type 1 diabetes (n=180 with DN; n=243 withoutDN) and 663 patients with type 2 diabetes (n=310 with DN; n=353without DN). The angiotensinogen gene M235T polymorphism wasdetermined using PCR amplification. RESULTS.: The following results were obtained (i) no significant differenceof genotype distribution (type 1: MM/MT/TT(%) 27.6/57.2/15.2vs. 27.2/56.1/16.7 (P=0.92); type 2: MM/MT/TT (%) 31.7/48.2/20.1vs. 32.9/46.8/20.3 (P=0.93)) or allele frequencies (type 1:M 0.56 vs. 0.55 (P=0.795); type 2: M 0.56 vs. 0.56 (P=0.86))was found, between diabetic patients with or without DN, (ii)no difference was found between normotensive and hypertensivediabetic patients. CONCLUSION.: The data argue against a role of the angiotensinogen gene M235Tpolymorphism in the manifestation of diabetic nephropathy orhypertension in diabetic patients.     

Evaluation of three substitutes for Percoll in sperm isolation by density gradient centrifugation

Silane-coated silica particle solutions (ISolate(TM) and PureSperm)TM)) and iodixanol (OptiPrep(TM)) were compared to polyvinylpyrrolidone (PVP)-coated silica particles (Percoll(TM)) in their efficacy to recover spermatozoa by gradient centrifugation for use in assisted reproductive procedures. Efficacy was assessed in terms of percentages of sperm recovery, sperm vitality and motility, normal sperm morphology and normal sperm chromatin condensation. No significant difference was found in the recovery of spermatozoa for men with both normal sperm counts and oligozoospermia, between PVP-coated and silane-coated particle solutions. Iodixanol had significantly lower sperm recovery compared to the other products. Sperm vitality, progressive motility, normal morphology and normal chromatin condensation did not differ significantly between any of the sperm isolation products.      

Protective cytotoxic T lymphocyte responses against paramyxoviruses induced by epitope-based DNA vaccines: involvement of IFN-gamma

Plasmid DNA vectors have been constructed with minigenes encoding a single cytotoxic T lymphocyte (CTL) epitope from either the M2 protein of respiratory syncytial virus (RSV) or from the nucleoprotein of measles virus (MV) with or without a signal sequence (also called secretory or leader sequence). Following intradermal immunization, plasmids in which the CTL epitopes were expressed in-frame with the signal sequence were more effective at inducing peptide- and virus- specific CTL responses than plasmids expressing CTL epitopes without the signal sequence. This immunization resulted in protection against MV-induced encephalitis and a significant reduction in viral load following RSV challenge. The reduction of viral load following RSV challenge was abrogated by prior injection with anti-IFN-gamma antibodies. These results highlight the ability of epitope-based DNA immunization to induce protective immune responses to well-defined epitopes and indicate the potential of this approach for the development of vaccines against infectious diseases.      

Enhancement of excitability and inhibitory processes in hippocampal dentate gyrus by noradrenaline: a pharmacological study in awake, freely moving rats.

Idazoxan (IDA), an alpha 2 receptor antagonist which increases firing rate of noradrenergic neurons in the locus coeruleus (LC) and release of noradrenaline (NA) in target structures, was used to study the neuromodulatory effects of NA in the hippocampus in awake rats. After IDA the population spike in the dentate gyrus (DG), evoked by a single pulse to the perforant path, was greatly enhanced with no effect of the drug on excitatory postsynaptic potentials (EPSPs). Paired pulses with short interpulse intervals (25-30 ms) produced inhibition of the response to the second pulse which was increased by IDA. This drug effect was independent of its effect on the amplitude of the first spike, since the increase in inhibition was seen at stimulation intensities which did not increase the response amplitude to the initial pulse. Thus both excitability and inhibitory processes can be enhanced in the same population of neurons by an alpha 2 adrenoceptor antagonist.     

Anicteric hepatoxicity: a potential health risk of occupational exposures in Nigerian petroleum oil refining and distribution industry

Background

Literature abounds linking one’s job to certain unpalatable health outcomes. Since exposures to hazardous conditions in industrial environments often results in sundry health effects among workers, we embarked on this study to investigate the hepatic health effects of occupational activities in the petroleum refining and distribution industry.

Method

Biochemical markers of liver functions were assayed in plasma, using Reflotron dry chemistry spectrophotometric system. The study was conducted on randomly selected workers of Port Harcourt Refining Company (PHRC) and Pipelines and Petroleum Product Marketing Company (PPMC) both in Alesa-Eleme near Port Harcourt, Nigeria, as well as non-oil work civil servants serving as control subjects.

Result and conclusion

Results showed that, bilirubin ranged 0.3-1.6 mg/dl with a mean of 0.66±0.20mg/dl among the oil workers as against 0.5-1.00mg/dl with a mean of 0.58±0.13mg/dl in non-oil workers, Alkaline phosphatase ranged 50.00-296.00u/l (mean: 126.21±39.49u/l) in oil workers as against 40.20-111u/l (mean: 66.83±18.54u/l) for non-oil workers, Aspartic transaminases (AST) ranged 5.80-140.20u/l (mean: 21.81±11.49u/l) in oil workers against 18.00-44.00u/l (mean: 26.89±6.99u/l) for non-oil workers, while Alanine transaminases (ALT) ranged 4.90-86.00u/l (mean: 22.14±11.28u/l) in oil workers as against 10.00-86.60u/l (mean: 22.30±10.22u/l) for the non-oil workers. A close study of the results revealed that although the mean values for all the studied parameters were still within the parametric reference ranges, however, relative to the referents, there were significant increases (P<0.05) in plasma bilirubin (though anicteric) and alkaline phosphatase that was not matched with a corresponding increase in the plasma transaminases, suggesting a possibility that toxic anicteric hepatoxicity is part of the potential health effects of sundry exposures in the Nigeria petroleum oil refining and distribution industry. Gender differentiation data showed that though the mean values for the parameters were higher in males than females, the increases were not significant in most cases (P>0.05), whereas data for age and exposure period classifications revealed that irrespective of the age of the worker, the effects are likely to start after the first five years, manifesting fully after the first decade of occupational exposures. Thus, an update of industrial/occupational health measures is necessary for a safer and healthier work environment.     

Analysis of the relationship between age and treatment response in migraine

In migraine, headache severity varies with age. As a consequence, the effectiveness of medication may also depend on a patient's age. The purpose of this study was to assess the combined effect of age and drug treatment on headache characteristics. Using data from clinical trials of sumatriptan in adolescents and adults, we show how the interaction between age and drug exposure can be parameterised as a covariate on a Markov model that describes the decline of headache severity over three clinically defined stages (no relief, relief and pain-free status). The model explains important clinical observations: (i) the rates at which the pain relief and pain-free status were attained were found to be inversely related to age; (ii) in placebo-treated patients, the mean transit time from 'no relief' to 'relief' is 3 h for young adolescents and increases to 6 h for patients aged ≥ 30 years; and (iii) sumatriptan reduces the transit time to 2 h, irrespective of age. These findings indicate that the therapeutic gain over placebo increases with age. Prospective studies of antimigraine drugs should take this relationship into account when extrapolating efficacy data from adults to adolescents.     

A randomized double-blind placebo-controlled crossover study of subcutaneous sumatriptan in general practice

Objective. To evaluate the therapeutic response to sumatriptan in the acute migraine attack. Material and methods. Two hundred and thirty migraineurs diagnosed by their general practitioners in accordance with their usual practice were included in the study. The patients treated two migraine attacks at home by subcutaneous injection of sumatriptan or placebo for the first attack and the alternative medication, i.e. placebo or sumatriptan, for the second attack (crossover). Following treatment, a neurology resident interviewed and examined the patients, Results. When sumatriptan was compared to placebo, significantly more of the 209 evaluable patients reported headache relief at I h (56% vs 8%, p < 0.001) and 2 h (62% vs 15%, p < 0.001) after the first injection. Resolution of nausea, photophobia, and phonophobia was significantly more common in patients on sumatriptan than in those on placebo ( p < 0.001 for all comparisons). The adverse events were usually transient and of mild or moderate severity; however, three patients withdrew due to adverse events. Ninety-five percent of patients evaluated by a neurology resident met the IHS criteria for migraine. Conclusion. In general practice, sumatriptan taken subcutaneously using an autoinjector at home was an effective and well tolerated acute treatment for migraine.     

SSR591813, a novel selective and partial alpha4beta2 nicotinic receptor agonist with potential as an aid to smoking cessation

(5aS,8S,10aR)-5a,6,9,10-Tetrahydro,7H,11H-8,10a-methanopyrido[2',3':5,6]pyrano[2,3-d]azepine (SSR591813) is a novel compound that binds with high affinity to the rat and human alpha4beta2 nicotinic acetylcholine receptor (nAChR) subtypes (Ki = 107 and 36 nM, respectively) and displays selectivity for the alpha4beta2 nAChR (Ki, human alpha3beta4 > 1000, alpha3beta2 = 116; alpha1beta1deltagamma > 6000 nM and rat alpha7 > 6000 nM). Electrophysiological experiments indicate that SSR591813 is a partial agonist at the human alpha4beta2 nAChR subtype (EC50 = 1.3 micro M, IA =19% compared with the full agonist 1,1-dimethyl-4-phenyl-piperazinium). In vivo findings from microdialysis and drug discrimination studies confirm the partial intrinsic activity of SSR591813. The drug increases dopamine release in the nucleus accumbens shell (30 mg/kg i.p.) and generalizes to nicotine or amphetamine (10-20 mg/kg i.p.) in rats, with an efficacy approximately 2-fold lower than that of nicotine. Pretreatment with SSR591813 (10 mg/kg i.p.) reduces the dopamine-releasing and discriminative effects of nicotine. SSR591813 shows activity in animal models of nicotine dependence at doses devoid of unwanted side effects typically observed with nicotine (hypothermia and cardiovascular effects). The compound (10 mg/kg i.p.) also prevents withdrawal signs precipitated by mecamylamine in nicotine-dependent rats and partially blocks the discriminative cue of an acute precipitated withdrawal. SSR591813 (20 mg/kg i.p.) reduces i.v. nicotine self-administration and antagonizes nicotine-induced behavioral sensitization in rats. The present results confirm important role for alpha4beta2 nAChRs in mediating nicotine dependence and suggest that SSR591813, a partial agonist at this particular nAChR subtype, may have therapeutic potential in the clinical management of smoking cessation.     

Calcium transport and ultrastructure of red cells in beta-thalassemia intermedia

Reported findings of elevated total calcium (Ca) contents in erythrocytes (RBCs) from patients with beta-thalassemia intermedia (beta-TI) prompted the question of whether the state and transport of Ca in these RBCs are similar to those in sickle cell anemia (SS) RBCs where the increased Ca is compartmentalized in endocytic inside-out vesicles and extracted by exposure of the cells to the Ca ionophore A23187 and a Ca chelator (ethylene glycol tetraacetic acid) and the levels of cytoplasmic free ionized Ca [( Ca2+]i) are normal. We confirmed a high total Ca content of 51 +/- 13 mumol/L RBCs in splenectomized (SPX) beta-TI and 24 +/- 1 mumol/L RBCs in non-SPX beta- TI. Unlike SS RBCs, however, most of the increased Ca was in the lighter, presumably younger beta-TI RBCs, and about half the Ca was not ionophore mobilizable but apparently firmly bound, possibly to remnants of organelles in nucleated and other young RBCs. In the denser RBCs from non-SPX beta-TI, total and extractable Ca amounts were normal. beta-TI RBCs loaded with the Ca chelator Benz 2 showed an initial influx of 45Ca in the normal range, which indicated normal Ca permeability, and near-steady-state levels of [Ca2+]i that were normal (22 +/- 7 nmol/L RBCs in non-SPX beta-TI) or minimally increased (40 +/- 19 nmol/L RBCs in SPX beta-TI). Serial-section electron microscopy of beta-TI ghosts from the denser cell fractions showed more fully enclosed vesicles in non-SPX ghosts than were seen in normal ghosts and many large vesicles and structured, electron-dense material in SPX ghosts. A delayed extrusion of ionophore-preloaded 45Ca only by the SPX beta-TI RBCs together with normal [Ca2+]i suggested compartmentalization of the loaded Ca in these RBCs, perhaps in endocytic inside-out vesicles, and normal Ca pumps. Since beta-TI RBCs show essentially normal levels of [Ca2+]i and normal Ca influx, their high total Ca content should not be associated with any of the deleterious effects observed in vitro with increased levels of [Ca2+]i.