Agmatine, a bioactive metabolite of arginine. Production, degradation, and functional effects in the kidney of the rat.

Until recently, conversion of arginine to agmatine by arginine decarboxylase (ADC) was considered important only in plants and bacteria. In the following, we demonstrate ADC activity in the membrane-enriched fraction of brain, liver, and kidney cortex and medulla by radiochemical assay. Diamine oxidase, an enzyme shown here to metabolize agmatine, was localized by immunohistochemistry in kidney glomeruli and other nonrenal cells. Production of labeled agmatine, citrulline, and ornithine from [3H]arginine was demonstrated and endogenous agmatine levels (10(-6)M) in plasma ultrafiltrate and kidney were measured by HPLC. Microperfusion of agmatine into renal interstitium and into the urinary space of surface glomeruli of Wistar-Frömter rats produced reversible increases in nephron filtration rate (SNGFR) and absolute proximal reabsorption (APR). Renal denervation did not alter SNGFR effects but prevented APR changes. Yohimbine (an alpha 2 antagonist) microperfusion into the urinary space produced opposite effects to that of agmatine. Microperfusion of urinary space with BU-224 (microM), a synthetic imidazoline2 (I2) agonist, duplicated agmatine effects on SNGFR but not APR whereas an I1 agonist had no effect. Agmatine effects on SNGFR and APR are not only dissociable but appear to be mediated by different mechanisms. The production and degradation of this biologically active substance derived from arginine constitutes a novel endogenous regulatory system in the kidney.     

A prospective study of patient assaults on nurses in a provincial psychiatric hospital in Canada

A 27-month prospective study was conducted of patient assaults on nurses in a Canadian psychiatric hospital. Rates were low (4% of the patients committing an assault) and the injuries mostly trivial. Schizophrenics accounted for 43% of attacks, but when allowance was made for the disproportionate number of patients in the hospital with this diagnosis, individuals with mental retardation or dementia were approximately twice as likely to be assaultive as schizophrenics. Repeat assaulters (greater than 4 attacks) were more likely to be suffering from paranoid schizophrenia.     

Sampling bias in an international internet survey of diversion programs in the criminal justice system

Despite advances in the storage and retrieval of information within health care systems, health researchers conducting surveys for evaluations still face technical barriers that may lead to sampling bias. The authors describe their experience in administering a Web-based, international survey to English-speaking countries. Identifying the sample was a multistage effort involving (a) searching for published e-mail addresses, (b) conducting Web searches for publicly funded agencies, and (c) performing literature searches, personal contacts, and extensive Internet searches for individuals. After pretesting, the survey was converted into an electronic format accessible by multiple Web browsers. Sampling bias arose from (a) system incompatibility, which did not allow potential respondents to open the survey, (b) varying institutional gate-keeping policies that "recognized" the unsolicited survey as spam, (c) culturally unique program terminology, which confused some respondents, and (d) incomplete sampling frames. Solutions are offered to the first three problems, and the authors note that sampling bias remains a crucial problem.     

Inhibition of constitutive nitric oxide synthase (NOS) by nitric oxide generated by inducible NOS after lipopolysaccharide administration provokes renal dysfunction in rats.

Excess NO generation plays a major role in the hypotension and systemic vasodilatation characteristic of sepsis. Yet the kidney response to sepsis is characterized by vasoconstriction resulting in renal dysfunction. We have examined the roles of inducible nitric oxide synthase (iNOS) and endothelial NOS (eNOS) on the renal effects of lipopolysaccharide administration by comparing the effects of specific iNOS inhibition, -N6-(1-iminoethyl)lysine (L-NIL), and 2,4-diamino6-hydroxy-pyrimidine vs. nonspecific NOS inhibitors (nitro- -arginine-methylester). cGMP responses to carbamylcholine (CCh) (stimulated, basal) and sodium nitroprusside in isolated glomeruli were used as indices of eNOS and guanylate cyclase (GC) activity, respectively. LPS significantly decreased blood pressure and GFR (112+/-4 vs. 83+/-4 mmHg; 2.66+/-0.29 vs. 0. 96+/-0.22 ml/min, P < 0.05) and inhibited the cGMP response to CCh. GC activity was reciprocally increased. L-NIL and 2, 4-diamino-6-hydroxy-pyrimidine administration prevented the decrease in GFR (2.71+/-0.28 and 3.16+/-0.18 ml/min, respectively), restored the normal response to CCh, and GC activity was normalized. In vitro application of L-NIL also restored CCh responses in LPS glomeruli. Neuronal NOS inhibitors verified that CCh responses reflected eNOS activity. L-NAME, a nonspecific inhibitor, worsened GFR (0.41+/-0.15 ml/min), a reduction that was functional and not related to glomerular thrombosis, and eliminated the CCh response. No differences were observed in eNOS mRNA expression among the experimental groups. Selective iNOS inhibition prevents reductions in GFR, whereas nonselective inhibition of NOS further decreases GFR. These findings suggest that the decrease in GFR after LPS is due to local inhibition of eNOS by iNOS, possibly via NO autoinhibition.     

Deletion mapping of chromosome 17 in benign and malignant adrenocortical tumors associated with the Arg337His mutation of the p53 tumor suppressor protein

The human p53 tumor suppressor gene is located at the short arm of chromosome 17. A germinative mutation (Arg337His) in the tetramerization domain of p53 has been frequently identified in Brazilian children with sporadic adrenocortical tumors. Loss of heterozygosity at this region was demonstrated in the majority of the cases. In the present study, we performed deletion mapping of chromosome 17 in 30 adrenocortical tumors from 29 Brazilian patients (15 children and 14 adults). One boy had bilateral adrenocortical tumor. Sixteen patients had the germinative Arg337His mutation. Loss of heterozygosity analysis using six polymorphic microsatellite markers disclosed loss of the entire chromosome 17 in 18 tumors (10 adenomas and eight carcinomas) from 17 patients. The Arg337His mutation was present in 13 of them. Chromosomal instability involving chromosomes 2, 9, and 11 was also found in 47, 47, and 70% of the 17 patients who exhibited chromosome 17 losses, respectively. The concomitant loss of chromosomes 2, 9, 11, and 17 was evidenced exclusively in malignant tumors. Therefore, chromosomal instability involving three or more chromosomes may contribute to define the malignant adrenocortical lesions. In conclusion, we demonstrated a high frequency of biallelic inactivation of p53 derived from two distinct events, the germinative Arg337His mutation and the acquired loss of the entire chromosome 17. In addition, the isolated loss of the entire chromosome 17 did not correlate with aggressive tumor behavior in these patients with adrenocortical tumors.