The roles of ATF3 in glucose homeostasis. A transgenic mouse model with liver dysfunction and defects in endocrine pancreas.

Activating transcription factor 3 (ATF3) is a member of the ATF/cAMP-response element-binding protein family of transcription factors. It is a transcriptional repressor, and the expression of its corresponding gene is induced by stress signals in a variety of tissues, including the liver. In this report, we demonstrate that ATF3 is induced in the pancreas by partial pancreatectomy, streptozotocin treatment, and ischemia coupled with reperfusion. Furthermore, ATF3 is induced in cultured islet cells by oxidative stress. Interestingly, transgenic mice expressing ATF3 in the liver and pancreas under the control of the transthyretin promoter have defects in glucose homeostasis and perinatal lethality. We present evidence that expression of ATF3 in the liver represses the expression of genes encoding gluconeogenic enzymes. Furthermore, expression of ATF3 in the pancreas leads to abnormal endocrine pancreas and reduced numbers of hormone-producing cells. Analyses of embryos indicated that the ATF3 transgene is expressed in the ductal epithelium in the developing pancreas, and the transgenic pancreas has fewer mitotic cells than the non-transgenic counterpart, providing a potential explanation for the reduction of endocrine cells. Because ATF3 is a stress-inducible gene, these mice may represent a model to investigate the molecular mechanisms for some stress-associated diseases.

Use of magnesium hydroxide and low magnesium dialysate does not permit reduction of aluminum hydroxide during continuous ambulatory peritoneal dialysis.

In an effort to reduce the ingestion of aluminum in phosphate-binding antacids, we treated seven patients on continuous ambulatory peritoneal dialysis (CAPD) with low magnesium dialysate and phosphate binders containing both aluminum and magnesium hydroxide. The total amount of phosphate binders prescribed was adjusted to maintain the serum phosphorus at normal levels. The dose of magnesium hydroxide was limited by intolerable gastrointestinal side effects in six of the seven patients. One patient also developed symptomatic hypermagnesemia. When magnesium hydroxide was prescribed in tolerable doses, the mean aluminum dose was not significantly decreased compared with the dose when taking aluminum hydroxide alone. We conclude that substitution of magnesium hydroxide for aluminum hydroxide as a phosphate binder fails to reduce the dose of aluminum in most patients on CAPD.

Drug-induced hyperkalemia.

After reviewing the available data on drug-induced hyperkalemia, we conclude that the situation has not improved since Lawson quantitatively documented the substantial risks of potassium chloride over a decade ago (90). As discussed, the risk of developing hyperkalemia in hospital remains at least at the range of 1 to 2% and can reach 10%, depending on the definition used (Table 2). Potassium chloride supplements and potassium-sparing diuretics remain the major culprits but they have been joined by a host of new actors, e.g., salt substitutes, beta-blockers, converting enzyme inhibitors, nonsteroidal antiinflammatory agents, and heparin, among others. Readily identifiable risk factors (other than drugs) for developing hyperkalemia are well-known but seem to be consistently ignored, even in teaching hospitals. The presence of diabetes mellitus, renal insufficiency, hypoaldosteronism, and age greater than 60 years results in a substantial increase in the risk of hyperkalemia from the use of any of the drugs we have reviewed. If prevention of hyperkalemia is the goal, as it should be, the current widespread and indiscriminate use of potassium supplements and potassium-sparing diuretics will need to end. We remain intrigued by Burchell's prescient pronouncement of over a decade ago that "more lives have been lost than saved by potassium therapy" (28).

Amoxapine-associated acute renal failure.

Acute renal failure, a brief seizure, and mild rhabdomyolysis developed in a 27-year-old man following overdosage with the tricyclic antidepressant, amoxapine. Renal function returned to normal approximately ten days following drug ingestion. Strikingly, of 111 cases of amoxapine overdosage reported to the manufacturer, acute renal failure has occurred in 12. Of these 12 patients, seizures were documented in seven, and presumptive or definitive evidence of rhabdomyolysis or myoglobinuria was documented in eight. Three possible mechanisms of the renal failure are (1) acute tubular necrosis secondary to nontraumatic rhabdomyolysis; (2) hypotension-induced acute tubular necrosis; and (3) direct nephrotoxic reaction from amoxapine. Rapid hydration with intravenously administered saline is proposed as a means of reducing the substantial incidence of acute renal failure following amoxapine overdosage.

Measurement and scaling of workload in complex performance.

Two groups of paid male volunteers (Groups I, N = 51, tested with identical schedules on two successive days; Group II, N = 43, tested on one day only) performed over nine intervals on various combinations of the six tasks of the CAMI Multiple Task Performance Battery. Two of the tasks involved monitoring static (lights) and dynamic (meters) processes, and four more-active tasks involved mental arithmetic, elementary problem solving, pattern identification, two-dimensional compensatory tracking. Five of the nine intervals provided different complex tasks consisting of concurrent monitoring tasks and two of the active tasks. Other trials provided data on the single active tasks as well as the combined monitoring tasks. The results indicated that all performance measures--a total of 12 for the six tasks--varied significantly as a function of the different task-combination conditions. A standard psychological scaling technique (Thurstone Case V) was applied to the monitoring data (response times for green and red lights, and for meter monitoring) to develop an index of workload for the five complex task combinations. Since better performance was presumed to indicate a lower workload, workload was inferred to increase as performance declined across conditions. The best performances, which were assigned scale values of 0, were found to be associated with single-task performances, as expected. Scale values for the complex task-combination conditions were found to be consistent between groups and between the two days of testing of Group I (r's of 0.947 to 0.993). Although the scale values are specific to the task and task-combination conditions employed, the scaling-procedure application shows promise for cases in which quantitative measures of performance can be acquired with moderately large samples of subjects (N's greater than 50).

Effects of altitude and two decongestant-antihistamine preparations on physiological functions and performance.

Fourteen men were studied to determine the combined effects of two altitudes--388 and 3,810 m or 1,274 and 12,500 ft--and three preparations--lactose placebo, Compound A (Actified, and Compound B (Dristan). Subjects reported least attentiveness with A and greatest with placebo. Fatigue increased significantly with time while energy, interest, and attentiveness decreased. The Multiple Task Performance Battery (MTPB) showed no effects of altitude, drugs, or time on overall performance; however, performance declined with time in several tasks, while problem solving improved. Subjects enjoyed the problem-solving tasks and may have given them preference as levels of interest declined. Though the MTPB overall composite scores did not change significantly, physiological parameters and subjective evaluations indicate that type of compound and time after ingestion are important. Declines in energy and attentiveness 2.5 h after ingestion could result in neglect of important--although routine--tasks. Hypoxia might enhance this effect and consequences might be worse in subjects whose medical conditions require these drugs.

Disseminated infection by Fusarium moniliforme during treatment for malignant lymphoma.

Disseminated infection caused by Fusarium moniliforme is described in a 32-year-old granulocytopenic man with malignant lymphoma being treated with cytotoxic drugs and corticosteroids. Infected skin denuded by antecedent severe varicella-zoster infection was the probable source of fungemia. F. moniliforme grows rapidly on common mycological media as a lavender- to violet-colored mold at 25 to 37 degrees C. Its aerial hyphae produce fusoid macroconidia and characteristic fusiform microconidia in chains. The morphology of hyphae in tissue closely resembles species of Aspergillus and is not diagnostically specific. Morphological characteristics which distinguish cultures of F. moniliforme from other medically important species of Fusarium are discussed.

Factors influencing susceptibility of Nocardia species to trimethoprim-sulfamethoxazole.

Demonstration of synergism between trimethoprim and sulfamethoxazole against 10 Nocardia isolates was found to be critically dependent upon the isolate, the duration of incubation, and the trimethoprim-sulfamethoxazole ratio. Inoculum effect was not significant. The trimethoprim-sulfamethoxazole ratio in the commercial, fixed-dose combination was found to contain too little trimethoprim to be optimal for Nocardia.

Variables influencing susceptibility testing of Cryptococcus neoformans to 5-fluorocytosine.

The minimum inhibitory concentration (MIC) of 5-fluorocytosine (5-FC) was determined for 65 isolates of Cryptococcus neoformans by using a twofold serial tube dilution method. The MIC was profoundly influenced by incubation temperature, inoculum size, and duration of incubation. By using a standard set of test conditions, 100% of 49 pretreatment isolates of C. neoformans were susceptible to 10 mug of 5-FC per ml or less, and 9 (56%) of 16 isolates recovered during or after 5-FC therapy were massively drug resistant (MIC > 320 mug/ml). With the standard test conditions recommended here, the tube dilution method was found to be both accurate and reproducible, and the results correlated with the treatment status of patients.

5-fluorocytosine resistance in Cryptococcus neoformans.

Isolates of Cryptococcus neoformans from six patients were obtained before and after unsuccessful therapy with 5-fluorocytosine (5-FC). Post-therapy isolates exhibited massive and stable 5-FC resistance. The frequency of drug-resistant mutants in susceptible isolates of C. neoformans was <0.001% (70.4 +/- 17.9 per 10(7) cryptococci), whereas mutant frequencies in resistant isolates approached 100%. Non-drug-induced, spontaneously appearing 5-FC resistant mutants were documented in four susceptible isolates of C. neoformans by use of the statistical method of fluctuation analysis. Mutation rates on these same four isolates ranged from 1.2 x 10(-7) to 4.8 x 10(-7). Total intracellular uptake and incorporation of cytosine-5-(3)H (CyH(3)) and 5-fluorocytosine-2-(14)C (5-FC(14)) into a trichloroacetic acid-insoluble fraction were markedly reduced in six isolates with in vivo-acquired resistance when compared with susceptible pretreatment strains from the same patients. Five of these six isolates also had acquired massive resistance to 5-fluorouracil (5-FU), suggesting that a mutation in the uridine-5'-monophosphate pyrophosphorylase was responsible for drug resistance. The sixth isolate, which remained susceptible to 5-FU, appeared to have a defect in a cytosine-specific permease accounting for 5-FC resistance. A single isolate with in vitro-acquired 5-FC and 5-FU resistance had no reduction in uptake or incorporation of CyH(3) or 5-FC(14). The mechanism of resistance in this isolate is discussed.

Experimental therapy of cladosporiosis and sporotrichosis with 5-fluorocytosine.

Cladosporium trichoides and Sporothrix schenckii are fungi known to be pathogenic for man. No effective chemotherapy is available for cladosporiosis, and systemic sporotrichosis can be very resistant to antifungal chemotherapy. Experimental infections of mice with these fungi resembled their respective infections in man and provided a model for evaluating a new antifungal agent, 5-fluorocytosine (5-FC). Our results with four isolates of C. trichoides demonstrated a statistically significant dose-related therapeutic effect with 5-FC. Mortality was significantly reduced in all treatment groups, and survivors showed no clinical sign of disease despite positive brain cultures. Results with a single isolate of S. schenckii were less encouraging. Fatality rate was significantly decreased in all treatment groups, but no trend was noted with increasing 5-FC dosage. Survivors manifested the signs of active disease, and all liver and spleen cultures were positive for S. schenckii. These results indicated that (i) 5-FC may be the first drug useful in the treatment of cladosporiosis, and (ii) 5-FC may have only limited therapeutic benefit in systemic sporotrichosis.