Dual mechanisms of regulation of type I iodothyronine 5''-deiodinase in the rat kidney, liver, and thyroid gland. Implications for the treatment of hyperthyroidism with radiographic contrast agents.

Alterations in thyroid hormone status and the administration of radiographic contrast agents can markedly influence iodothyronine metabolism and, in particular, the activity of type I 5'-deiodinase (5'DI). In the present studies, the mechanisms responsible for these effects have been reassessed. As previously reported, the addition of iopanoic acid (IOP) to broken cell preparations resulted in a competitive pattern of 5'DI inhibition. However, the in vivo administration to rats of IOP or 3,3',5'-triiodothyronine (rT3) resulted in a noncompetitive pattern of inhibition of 5'DI in the liver, kidney, and thyroid gland, whereby marked decreases in maximal enzyme velocity (V max) were noted, with no change in the value of the Michaelis-Menten constant. In rats rendered hyperthyroid by the injection of 3,5,3'-triiodothyronine (T3), 5'DI activity was significantly increased in the liver and the kidney. The administration of IOP to these thyrotoxic animals resulted in a rapid loss of enzyme activity characterized by an approximate 80% decrease in 5'DI V max values in both tissues. Furthermore, this inhibitory effect persisted for longer than 60 h after a single IOP injection. IOP administration also decreased 5'DI V max levels in the thyroid gland by 52%. In other experiments, treatment of intact Reuber FAO hepatoma cells with IOP or rT3 induced a rapid decrease in 5'DI V max levels. In cells treated with cycloheximide, these agents enhanced the rate of disappearance of enzyme activity by greater than 12-fold, indicating a predominant effect on accelerating the rate of enzyme inactivation and/or degradation. These studies demonstrate that iodothyronines and other iodinated compounds have complex regulatory effects on 5'DI that entail alterations in the rates of both enzyme activation and inactivation. The previously accepted concept that rT3 and IOP impair thyroxine (T4) to T3 conversion in vivo by acting as competitive inhibitors is an oversimplification. Rather, the clinically beneficial effects of administering these agents to patients with hyperthyroidism may result primarily from the rapid and prolonged inactivation of 5'DI which occurs in the thyroid gland and peripheral tissues.     

Uninformed Decisionmaking The Case of Surrogate Research Consent

A New York court recently struck down state Office of Mental Health regulations governing research involving subjects with impaired decisionmaking capacity. The court held that neither incapacitated adults nor minors could participate in any research protocol that contained a nontherapeutic element, irrespective of possible benefits to the subject or the importance of the knowledge to be gained. Although the decision rested on a technical point of law and dealt only with psychiatric research, the court's holding has significantly broader implications.     

Relocation mortality in dementia: The effects of a new hospital

Relocation mortality has been cited as an important factor when considering the placement of elderly patients. This study describes the fate of dementia patients relocated to facilitate the move to a new hospital. Some wards were moved as intact units—that is, the patients were kept together and there was little change in the nursing or medical staff. Two other wards were closed, and these patients were dispersed to several existing and new wards and experienced changes of nursing and medical staff. All patients underwent prerelocation and postrelocation orientation programmes. The mortality figures for the total patient group before and after the relocation do not show any statistically significant increase in mortality postrelocation. However, for wards that were closed and where the patients suffered maximum disruption to patient group and nursing staff, there was a significant increase in mortality rates.     

Erotomania in a brain-damaged male

A 31-year-old male presented to a neuropsychiatric service for the first time with an erotomatic delusion among other symptoms. He had suffered significant brain damage several times in the past and experienced a recent loss. After extensive evaluation, a trial of haloperidol resulted in some improvement. However, the erotomanic delusion remained unchanged.     

Complement Activation and Cytokine Generation After Modified Fontan Procedure

Background. The modified Fontan procedure separates the systemic and pulmonary circulations in patients born with a functional single ventricle. Delayed recovery is frequently observed after this procedure. It was our hypothesis that complement activation or cytokine generation may contribute to the pathophysiology of this problem.

Methods. We measured activated complement C3, thromboxane B₂, interleukin-6, and tumor necrosis factor- levels by immunoassay in 16 patients undergoing Fontan procedure. Patient plasma samples were obtained preoperatively, on initiation of cardiopulmonary bypass, after administration of protamine, and 1, 4, 8, and 24 hours postoperatively.

Results. There was no early or late mortality in this cohort of patients. Low cardiac output developed in 3 of 16 patients, and pleural effusions developed in 5. The median length of hospital stay was 9 days. Activated complement C3 levels increased from a baseline of 1,486 ± 564 to 4,600 ± 454 ng/mL after cardiopulmonary bypass and administration of protamine, and returned to baseline by 24 hours. The level of interleukin-6 increased from 42 ± 32 to 176 ± 22 pg/mL and at 24 hours remained elevated at 71 ± 15 pg/mL. Neither thromboxane B₂ nor tumor necrosis factor- levels increased significantly.

Conclusions. The data demonstrate threefold to fourfold increases in activated complement C3 and interleukin-6, indicating that both humoral and cellular systems are affected. It is our conclusion that complement and cytokine activation may contribute to the delayed recovery observed after Fontan procedure.     

Improving immunization coverage

A study was made on the causes of unsatisfactory progress in immunization coverage in an area of Tamil Nadu, southern India. The findings led to the appointment of additional community health workers (CHW), improvement in supervision, the enhancement of accessibility to services through an increase in the number of peripheral clinics and the organizing of temporary clinics, and the concentration of effort on underprivileged groups. As a result, immunization coverage was more than doubled. The Community Health and Development Project, a primary health care program serving 68 villages since 1981 with a population of about 80,000 was the site of the study which was conducted by discussions with staff and various members of the community. Issues explored were nonacceptance or dropout reasons, and specific factors affecting immunization coverage. A special effort was made to obtain the views of staff working at the periphery, particularly CHWS. The service area was divided into 4 sectors and the CHWS, auxiliary nurse midwives, community health nurses and other development staff in each were brought together for discussions. Views were also solicited from mothers' clubs and youth groups and in meetings with village leaders. Issues raised were further considered by supervisory staff. Statistical studies and other studies were done to clarify doubtful issues and test hypotheses emerging from the discussion. Poor immunization coverage was linked to inadequate supervision of CHWs, scattered communities (village with houses clustered together had better acceptance rates), difficulty of access to health services (distance factors), and low economic and educational status. In light of the study findings, community health workers were increased from 42 in 1984 to 57 in 1987 to cover all the villages, with modifications in selection method to make the worker acceptable to all sections of the villages; abolishment of the auxiliary nurse midwife and addition of a new category, health aide, to link the CHW and the community health nurse, increase of peripheral clinics from 37 to 75 and holding of more temporary clinics, more efforts to reach all socioeconomic groups and increased health education through film shows, drama, and work with village groups.     

Ecology of a Southern Ohio stream receiving fly ash pond discharge: Changes from acid mine drainage conditions

Prior to 1975, Stingy Run was a third-order tributary of Kyger Creek, which empties into the Ohio River at Mile 260 (Gallia County, Ohio). Both streams drained strip mine refuse areas and physicochemical measurements indicated acidicmine drainage conditions (e.g., low pH). A depauperate macroinvertebrate community, dominated by a few acid-tolerant taxa, was found in both streams and no fishes were collected. In 1974, Stingy Run was impounded to form a fly ash pond which contains fly ash sluiced from Ohio Power Company's General James M. Gavin coal-fired power plant. Physicochemical and biological sampling during 1975–1986 indicated marked changes in the aquatic ecology of Stingy Run between 1) pre-impoundment and post-impoundment conditions; and 2) effluent pH control treatments after impoundment. Fly ash discharge eliminated acidicmine drainage characteristics in Stingy Run and lower Kyger Creek. After impoundment, net spinning caddisflies and a few dipteran taxa dominated the Stingy Run benthic community, reflecting changes in functional niches likely due to improved habitat and greater food availability. Replacement of acid feed by CO₂ injection for effluent pH control and changes in ash pond chemistry occurred concomitant with elimination of a substrate floc; increased species richness and densities of invertebrates were subsequently observed. In Stingy Run, species richness and diversity of fishes increased from 1983 to 1986, reflecting improved water quality and increased benthic production after impoundment. Many of these fishes are opportunistic feeders on drifting insects.     

Venous Irritation Related to Intravenous Administration of Phenytoin versus Fosphenytoin

Study Objective . To compare the frequency, severity, and time course of venous irritation after administration of a single intravenous dose of phenytoin with an equimolar dose of fosphenytoin, a water-soluble phenytoin prodrug. Design . Randomized, double-blind, two-period, crossover study. Setting . University hospital clinical research unit. Patients . Twelve healthy volunteers within 15% of ideal body weight and with no clinically significant abnormalities on physical examination, medical history, or laboratory assessment. Interventions . Volunteers randomly received a 30-minute infusion of phenytoin sodium 250 mg (250 mg/5 ml) or an equimolar dose of fosphenytoin 375 mg (375 mg/5 ml). Subjects returned for the crossover treatment 14–21 days later. Measurements and Main Results . Subjects assessed venous irritation (pain, burning, itching), and investigators evaluated phlebitis (erythema, swelling, tenderness), induration, exudation, and cording. Phenytoin was associated with a significantly higher degree of pain at the infusion site in all subjects and a significant degree of phlebitis in eight subjects (p<0.05); cording occurred in six subjects. The time course of phenytoin-induced phlebitis was bimodal. Erythema and tenderness were prominent at the end of the infusion and again at 24 hours. Cording was first noted between 24 hours and 1 week after infusion. In contrast, fosphenytoin was associated with mild pain in two subjects, one incident of phlebitis, and no erythema or cording. Conclusions . Fosphenytoin administration resulted in significantly less venous irritation and phlebitis compared with an equimolar dose of phenytoin. The clinical use of this water-soluble phenytoin prodrug should minimize the frequency and severity of infusion-site reactions and should allow convenient, rapid, intravenous administration of drug, undiluted or admixed with intravenous solutions.     

Comparison of Ampicillin-Sulbactam and Ticarcillin-Clavulanic Acid in Patients With Chronic Renal Failure: Effects of Differential Pharmacokinetics on Serum Bactericidal Activity

Study Objectives . To evaluate the pharmacodynamic antibacterial activity of ticarcillin-clavulanic acid (T-C) and ampicillin-sulbactam (A-S) combinations against reference bacterial strains in patients with end-stage renal disease maintained on long-term hemodialysis. Design . Randomized, crossover, controlled study. Setting . National Institutes of Health-funded general clinical research unit in a Veterans Administration Medical Center. Patients . Nine adult men with end-stage renal disease maintained on long-term hemodialysis. Two subjects did not complete the study due to problems of vascular access, and another withdrew for personal reasons. Interventions . On a nondialysis day, each subject was randomly administered either T-C 3.1 g or A-S 3 g as a slow intravenous infusion over 30 minutes. Serial blood samples were collected for measurement of antibiotic serum concentrations and determination of serum bactericidal titers. Following a washout period, the study was repeated with the alternative antibiotic combination. Measurements and Main Results . The mean observed apparent β-half-life of clavulanic acid was substantially shorter than that for the other three drugs. The bactericidal activity of both A-S and T-C against non-β-lactamase-producing (Nβ-LP) strains of S. aureus and E. coli was consistently high, as indicated by geometric mean SBTs of at least 1:5 at 24 hours. Against β-lactamase-producing (β-LP) S. aureus, the geometric mean SBTs for A-S were at least 1:25 throughout the study period, while the geometric mean SBTs for T-C decreased over 24 hours from 1:29 to 1:6. Against β-LP E. coli, the bactericidal activities for both A-S and T-C were poor, with geometric mean peak SBTs of only 1:6 and 1:3, respectively. The geometric mean SBT for T-C against this E. coli strain had declined to 1:1 at 6 hrs. Conclusion . Increasing the dosing interval for T-C in patients with end-stage renal disease may lead to periods of insufficient clavulanic acid to protect ticarcillin from β-lactamase degradation.