Role of cyclic GMP-inhibitable phosphodiesterase and nitric oxide in the beta adrenoceptor control of renin secretion

We have reported that inhibition of nitric oxide synthesis with N(G)-nitro-L-arginine methyl ester (L-NAME) attenuates the renin secretory response to beta adrenoceptor stimulation. We proposed that the attenuation results from disinhibition of the cyclic GMP-inhibitable isoform of phosphodiesterase (PDE III) with a resultant increase in cyclic AMP hydrolysis in the juxtaglomerular cells. In our investigation, experiments were performed in conscious rabbits to test the effects of the specific PDE III inhibitor milrinone on resting renin secretion and on the renin responses to isoproterenol and L-NAME. In the first series of experiments, infusion of milrinone increased plasma renin activity from 5.4 +/- 0.6 to 10.2 +/- 1.4 ng/ml/2 hr (P < .01). Heart rate increased markedly, but arterial pressure did not change. In the second series, infusion of isoproterenol increased plasma renin activity from 6.3 +/- 1.1 to 15.0 +/- 1.0 ng/ml/2 hr (P < .01). The renin response to isoproterenol was increased (P < .01) in the presence of milrinone (15.3 +/- 3.7 to 38.4 +/- 6.2 ng/ml/2 hr, P < .01). In the third series, L-NAME alone decreased plasma renin activity from 5.0 +/- 1.0 to 3.3 +/- 1.0 ng/ml/2 hr (P < .01). Milrinone again increased plasma renin activity and prevented the suppression of plasma renin activity by L-NAME. By contrast, milrinone did not alter the suppression of plasma renin activity produced by infusion of phenylephrine. In addition, a PDE IV inhibitor failed to prevent the suppression of PRA by L-NAME. Finally, administration of milrinone completely reversed the L-NAME-induced suppression of the renin response to isoproterenol. These results provide evidence that PDE III participates in the regulation of renin secretion, and support the proposal that the L-NAME-induced reductions in renin secretion and in the renin response to beta adrenoceptor stimulation result from disinhibition of PDE III and increased hydrolysis of cyclic AMP in the juxtaglomerular cells.     

Lucigenin as a substrate of microsomal NAD(P)H-oxidoreductases

In various genetic disorders it has been observed that the severity of illness increases and the age at onset decreases in successive generations. This phenomenon is termed anticipation. We sampled 15 families, totalling 123 individuals with at least one person affected by a disease of the schizophrenia spectrum in the index generation in each family (IG; n = 33 affected out of a total of 67 individuals) and in the parental generation (PG; n = 16 affected out of a total of 56 individuals). The pedigrees had originally been identified for linkage studies in schizophrenia. We found a significant difference between IG and PG regarding severity of illness as defined by Kendler et al's hierarchical model of categories of the schizophrenia spectrum (p = 0.001). Age at onset was significantly earlier in the IG (21.6 +/- 6.6 years) than in the PG (40.2 +/- 9.2 years) (p = 0.0001). We excluded a potential birth cohort effect by investigating a control sample consisting of two non-overlapping birth cohorts of patients with schizophrenia. Age at onset between the two groups of the control sample did not differ. Anticipation is an important aspect in the investigation of a possible genetic basis, at least for the familial form of schizophrenia. Active research on a molecular level with special emphasis on trinucleotide repeats might be able to shed further light on this phenomenon.     

Mycophenolate mofetil: therapeutic applications in kidney transplantation and immune-mediated renal disease

The inhibition of arylamine N-acetyltransferase (NAT) activity by ibuprofen was determined in a human colon tumour (adenocarcinoma) cell line. Two assay systems were employed, one with cellular cytosols (9000 g supernatant) and the other with intact colon tumour cell suspensions. The NAT activity in a human colon tumour cell line was inhibited by ibuprofen in a dose-dependent manner in both systems, i.e. the greater the concentration of ibuprofen in the reaction, the greater the inhibition of NAT activities in both systems. The data also indicated that ibuprofen decreases the apparent Km and Vmax of NAT enzyme from human colon tumour cells in both systems examined. This report is the first demonstration to show that ibuprofen affects human colon tumour cell NAT activity.     

The aminoacceptor stem of the yeast tRNA(Lys) contains determinants of mitochondrial import selectivity

The effect of quinine, a cinchona alkaloid, was studied on gastrointestinal transit in mice. Intraperitoneal (i.p.) administration of quinine inhibited the intestinal propulsion of a charcoal suspension at a dose of 100 mg/kg, comparing favorably with 5 mg/kg morphine. In an attempt to probe into the mechanism underlying this inhibition, a possible modulation by minoxidil (1 mg/kg, p.o.) and glibenclamide (1 mg/kg, p.o.), the drugs that, respectively, open and close ATP-sensitive K+ channels was tested on gastrointestinal transit in animals treated or not with quinine or morphine. While minoxidil produced no significant change of normal transit, glibenclamide significantly increased it. However, both drugs blocked the quinine-induced reduction in gastrointestinal transit. In contrast, the inhibitory effect of morphine on gastrointestinal transit was not modified by either drug. The effects of quinine as well as of morphine on gastrointestinal transit were significantly antagonized by naloxone (2 mg/kg, s.c.), a mu-opioid receptor antagonist but not by yohimbine (1 mg/kg, i.p.), an alpha2-adrenoceptor antagonist. Furthermore, quinine at a lower dose (25 mg/kg) that showed no per se effect on gastrointestinal transit, significantly potentiated the response to 2.5 mg/kg morphine. Although the role of ATP-sensitive K+ channels in the action of quinine and morphine was not clarified by the present results, a possible involvement of endogenous opioid(s) in the quinine-induced inhibition of gastrointestinal transit can be suggested.     

Analysis of dependent events and multiple unavailabilities with particular reference to common-cause failures

Historically the concern of reliability engineers in the aircraft, nuclear and chemical industries when dealing with dependent failures in high integrity systems has been with common mode or common cause failures. Starting from this perspective the paper considers dependent events, failure definition and classification schemes. Recently these schemes have explicitly distinguished different types of multi-unavailabilities and dependent events. The CSNI and EPRI sponsored data analyses are reviewed. CCF modelling and defenses are discussed and the limitations imposed by data are shown to lead to a possible requirement to consider a structured model that enables the engineer to consider various factors explicitly which could affect the specific system being assessed. This enables judgement to be used in an explicit way in evaluating common cause failures.     

Quantitative gait analysis after bilateral total knee arthroplasty with two different systems within each subject

The functional behavior of two kinematically different knee arthroplasty systems within each subject was studied by gait analysis (three-dimensional kinematics, kinetics, dynamic electromyography) in five elderly patients, 2 to 5 years after bilateral surgery. Clinical results were good, yet gait velocity was reduced (range, 0.57-1.1 m/s), with a shortened stride length and a decreased duration of single-limb stance in all subjects. Force plate recordings revealed an undynamic gait with slow loading, reduced modulation of the vertical forces, and poor fore/aft shears. Sagittal plane knee motion during gait was reduced in all subjects, with trunk and pelvic compensation patterns for foot clearance. Muscle activity around the knee was prolonged bilaterally, with activity modulation related to the motion pattern. Although the stride parameters were quite symmetric, there was a marked asymmetry of the motion pattern, with a side-to-side difference of peak knee flexion during stance and swing phase of up to 15 degrees. This finding, however, was not clearly related to the type of prosthesis. Even within one subject, significant side-to-side variability may persist, which leads to asymmetry of the motion pattern, unrelated to the kinematic design of the implant. Other factors, such as the patella-extensor mechanism, ligament balancing, leg-length discrepancy, proprioception, continuation of a preoperative habit, or a contralateral influence, may explain part of the asymmetry seen in these subjects.     

Participation in workplace design with reference to low back pain: a case for the improvement of the police patrol car

Thirty Canadian police officers, divided into six groups, participated in the redesign of the interior of the patrol car. Three of the groups consisted of individuals having a history of low back disease. The effect of participating in a design process on the characteristics of the final design and on the perception of the low back pain was studied in a semi-experimental setting. The participants developed a strong commitment to the participatory design process, which was reflected in their productions. The differences between participants with and without a history of a low back disease was not marked. The former tended to stress posture-related elements in their analysis and design.