Neonatal hyperoxia induces alterations in neurotrophin gene expression.

Each year in the United States, nearly 500,000 infants a year are born prematurely. Babies born before 35 weeks gestation are often placed on ventilators and/or given supplemental oxygen. This increase in oxygen, while critical for survival, can cause long-term damage to lungs, retinas and brains. In particular, hyperoxia causes apoptosis in neurons and alters glial activity. Brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) are members of the neurotrophin family of proteins that function to promote the growth, differentiation and development of the nervous system. We hypothesized that hyperoxia can alter the regulation of these genes and by doing so adversely affect the development of the brain. We predicted that mice exposed to hyperoxic conditions would have differences in BDNF and GDNF mRNA expression and relative level of methylated promoter regions coinciding with differences in the relative levels of DNMT1 and DNMT3a mRNA expression. To test this hypothesis, newborn C57Bl/6 mice and their littermates were placed in hyperoxic or normoxic conditions from postnatal day 7 to 12. There were significant decreases in BDNF mRNA expression in the prefrontal cortex following hyperoxia, but a significant increase in the isocortex. GDNF mRNA expression was significantly increased in both the isocortex and prefrontal cortex following hyperoxia. DNMT1 mRNA expression was significantly decreased in the isocortex but significantly increased in the prefrontal following hyperoxia. Together these data suggest that short-term exposure to hyperoxic conditions can affect the regulation and expression of BDNF and GDNF potentially leading to alterations in neural development.

Personality type and success among female naval academy midshipmen.

There are relatively few studies regarding factors that predict success among female midshipmen at the U.S. Naval Academy (USNA). This study examined the personality characteristics of 1,568 women admitted to USNA between 1988 and 1996 to evaluate whether personality type was predictive of success vs. attrition. Participants completed the Myers-Briggs Type Indicator as well as a demographic questionnaire upon admission. Indicators of performance were gathered at graduation. Results indicated that most women at USNA are extroverts. Extroverted-Sensing-Thinking-Judging types were more likely to graduate, whereas Feeling and Perceiving themes were associated with dropping out. Previous military service and higher Scholastic Aptitude Test Math scores were also predictive of success at USNA. In general, the Myers-Briggs Type Indicator was not a good predictor of academic or military success at USNA. Among women who graduate, Scholastic Aptitude Test (Verbal and Math) scores appear to be the best predictors of both academic and military ratings.

Etanercept in juvenile rheumatoid arthritis.

OBJECTIVE: To review the classification, pathophysiology, safety, and efficacy of treatment options for juvenile rheumatoid arthritis (JRA). Etanercept, the agent most recently approved by the Food and Drug Administration for use in JRA, is featured. DATA SOURCES: Articles were identified from a search of the MEDLINE database (1966 to January 2000) and through secondary sources. Meeting abstracts and posters were also evaluated. STUDY SELECTION AND DATA EXTRACTION: Articles identified and retrieved from data sources were evaluated and, if determined to be relevant, were included in this review. DATA SYNTHESIS: JRA represents a major cause of functional disability in children. In contrast to traditional therapeutic agents for JRA, which act through generalized antiinflammatory activity or generalized immunosuppression, new therapeutic modalities have been developed that target specific molecules involved in the pathophysiology of JRA. Etanercept inhibits the activity of tumor necrosis factor and lymphotoxin-alpha. In a clinical trial of patients with polyarticular-course JRA, etanercept-treated patients experienced less pain and swelling in their joints, decreased incidence of disease activity, less frequent flare, and a longer time to flare than patients receiving placebo. Treatment with etanercept was generally well-tolerated. CONCLUSIONS: Etanercept represents an exciting new therapeutic option for the treatment of JRA. The positioning of etanercept among other therapeutic options for JRA will be more clearly established as additional safety and efficacy data are made available.

Recombinant human tumor necrosis factor receptor (p75) Fc fusion protein (TNFR:Fc) in rheumatoid arthritis.

BACKGROUND: Tumor necrosis factor (TNF) is the dominant mediator of the cytokine cascade that causes inflammation and joint destruction in rheumatoid arthritis. A new class of agents under investigation, the biologic TNF inhibitors, inhibits the activity of TNF. Recombinant human TNF receptor p75 Fc fusion protein (TNFR:Fc; Enbrel) blocks the activity of the cytokine TNF. The preclinical, Phase I, and Phase II data of TNFR:Fc in rheumatoid arthritis are reviewed in this article. METHODS: All available data on TNFR:Fc in rheumatoid arthritis were reviewed. These data included published literature and data on file at the manufacturer. RESULTS: TNFR:Fc has been effective in many models of inflammation, including animal models of rheumatoid arthritis and in clinical rheumatoid arthritis trials. Conclusions from a study with TNFR "knockout" mice (genetically altered mice incapable of producing TNFR proteins) demonstrated that p75 TNFR is a natural antagonist of TNF-mediated inflammation. A placebo-controlled, dose-escalation, Phase I trial evaluated the safety and efficacy of TNFR:Fc in patients with rheumatoid arthritis. There were no serious adverse effects reported. A Phase II, randomized, double-blind, placebo-controlled trial evaluated 180 patients with active rheumatoid arthritis whose previous therapy had failed. A dose-response relationship was observed in the number of tender and swollen joints; patients who received the highest dose (16 mg/m2) of TNFR:Fc had the greatest improvement. Treatment was generally well tolerated. TNFR:Fc is nonimmunogenic; no antibodies to TNFR:Fc have been detected thus far in human studies. CONCLUSIONS: Preliminary data indicate that TNFR:Fc is an excellent candidate for future long-term studies in the treatment of rheumatoid arthritis.

Stability of thiotepa (lyophilized) in 0.9% sodium chloride injection.

The stability of thiotepa in a new formulation of the drug was studied. Vials of Thioplex (Immunex), a relatively new lyophilized formulation of thiotepa, were reconstituted with sterile water and diluted with 0.9% sodium chloride injection in polyvinyl chloride infusion bags to thiotepa concentrations of 0.5, 1, and 3 mg/mL. The solutions were stored at 8 and 25 degrees C in ambient light and analyzed at 0, 8, 24, and in most cases 48 hours for thiotepa concentration and chloro-adduct formation by stability-indicating high-performance liquid chromatography. Thiotepa 1 and 3 mg/mL was stable for 48 hours at 8 degrees C and for 24 hours at 25 degrees C. Thiotepa 0.5 mg/mL was not stable at either temperature. Storage at 8 degrees C slowed but did not prevent chloro-adduct formation and loss of potency. The pH tended to increase with time; turbidity remained low. Thiotepa (lyophilized) 1 and 3 mg/mL in 0.9% sodium chloride injection was stable for 48 hours at 8 degrees C and for 24 hours at 25 degrees C; the drug was unstable when diluted to 0.5 mg/mL and stored under the same conditions.

Corticosteroids in tuberculosis.

OBJECTIVE: To examine the effects of corticosteroids used for concomitant disease states in patients with latent or active tuberculosis (TB). The role of corticosteroids in the treatment of extrapulmonary TB is also discussed. DATA SOURCES: A MEDLINE search was conducted for the years 1953-1995. The International Pharmaceutical Abstracts service was also used to conduct an extensive literature review. In addition, relevant articles were cross-referenced to screen for additional information. STUDY SELECTION/DATA EXTRACTION: During the literature review, emphasis was placed on human studies and individual case reports. DATA SYNTHESIS: The resurgence of TB in this decade has affected many populations, especially immunocompromised patients. These patients may need corticosteroid therapy for various concomitant diseases that might predispose a patient to develop primary TB infection or reactivate latent TB infection. In appropriate patients, prophylaxis with isoniazid is recommended. Corticosteroid therapy may benefit patients with some forms of extrapulmonary TB. After steroid therapy, improved survival and more rapid reduction of tuberculous symptoms have been noted in cases of tuberculous pleurisy, endobronchial TB, tuberculous meningitis, and tuberculous pericarditis. Corticosteroids may also be useful in controlling both fever and hypersensitivity reactions in pulmonary and extrapulmonary TB, although not routinely used for this purpose. CONCLUSIONS: Corticosteroids may play an important role in TB infection by promoting reactivation of latent infection. Corticosteroids may modify symptoms of some forms of extrapulmonary TB, although randomized, placebo-controlled studies are needed before corticosteroids will have a definitive place in the standard therapy of TB.

Spontaneous regression of a giant pulmonary bulla.

Gradual expansion of a lung bulla is common and may be associated with debilitating pulmonary symptoms. The aetiology of bulla expansion is unclear. Spontaneous regression, on the other hand, is rarely observed. The case is presented of a man in whom near complete spontaneous resolution of a giant pulmonary bulla occurred. This event was associated with dramatic improvement in the radiographic picture and pulmonary function.

The role of continuous infusion loop diuretics.

OBJECTIVE: To evaluate the role of continuous infusion loop diuretics in selected patient populations, discuss the advantages and disadvantages associated with continuous infusion, and recommend monitoring parameters for the use of continuous infusion therapy. Current dosing guidelines for continuous infusion loop diuretics have not been established, but a summary of previously studied doses is provided. DATA SOURCES: A literature search using MEDLINE, International Pharmaceutical Abstracts, as well as additional references found in pertinent articles. STUDY SELECTION AND DATA EXTRACTION: Clinical studies concerning the use of loop diuretics administered by continuous infusion were evaluated in selected patient populations. All articles and clinical studies were considered for possible inclusion in the review. Information judged to be pertinent by the authors was selected for discussion. DATA SYNTHESIS: Comparative studies in the congestive heart failure (CHF), renal-insufficient, and postcardiac surgery patient populations have shown that loop diuretics administered by continuous infusion are more beneficial than those given by intermittent bolus administration. In adult patients with CHF, furosemide 3-4 mg/h is recommended. In adult and pediatric postcardiac surgery patients, furosemide dosages of 0.05 and 0.1 mg/kg/h have produced diuresis. In patients with renal insufficiency, bumetanide 0.912 mg/h has produced diuresis. Intravenous bolus doses were used in all studies reviewed except 1. These studies have indicated that continuous infusion of the loop diuretics yields diuresis without increasing toxicity. CONCLUSIONS: The use of continuous infusion loop diuretics is a therapeutic alternative for patients requiring diuresis. This form of administration has provided more consistent urine flow, fewer alterations in fluid balances, fewer urinary losses of electrolytes as well as decreased dosage of the diuretic requirements. The disadvantages have not been fully elucidated because of the limited evaluation of this administration method. Few studies have used this method of administration; however, the few data available indicate that continuous infusion of loop diuretics is an efficacious alternative to conventional therapy.

Torsemide: a new loop diuretic.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of torsemide are reviewed. Torsemide belongs to the pyridine-sulfonylurea class of loop diuretics. Its primary site of activity is the thick ascending limb of the loop of Henle, where it blocks active reabsorption of sodium and chloride, resulting in diuresis, natriuresis, and other effects. Torsemide has high bioavailability, a relatively long half-life, and a prolonged duration of activity. It is highly protein bound. Clinical trials indicate that torsemide is effective in the treatment of hypertension and of edema and other symptoms in patients with chronic renal failure (CRF), hepatic dysfunction, or congestive heart failure (CHF). Torsemide has infrequent, mild, and transient adverse effects; among the most common are orthostatic hypotension, fatigue, dizziness, and nervousness. The recommended initial oral dosages of torsemide are 10-20 mg/day for CHF, 20 mg/day for CRF, 5 mg/day for hypertension, and 5-10 mg/day (in combination with a potassium-sparing diuretic or aldosterone antagonist) for hepatic cirrhosis. In most patients, the pharmacokinetic advantages of torsemide over other loop diuretics are unlikely to translate into a substantial edge in clinical outcomes, and in practice there may be no cost advantages. Although torsemide does not offer major advantages over other loop diuretics, it may be of benefit in patients who do not respond to or cannot tolerate other agents.

Cephalexin-induced Stevens-Johnson syndrome.

OBJECTIVE: To report a case of cephalexin-induced Stevens-Johnson syndrome (SJS), a devastating adverse drug reaction that involves the entire skin surface and mucosal areas of the body. DATA SOURCES: MEDLINE search (key terms cephalosporins, Stevens-Johnson syndrome, erythema multiforme, and systemic lupus erythematosus) and references identified from bibliographies of pertinent articles. DATA SYNTHESIS: Clinical presentation and manifestations of SJS include the skin, eyes, gastrointestinal tract, and pulmonary system. Infectious complications are the leading cause of mortality. Early intervention is important to prevent progression of SJS. The case described is consistent with the features of this syndrome. The patient presented with fever, arthralgias, and malaise. Skin lesions included a diffuse violet macular rash with erythema and multiple bullous lesions on her neck and abdomen. The skin biopsy was consistent with SJS. Multiple mucocutaneous ulcers were found in her mouth, but no evidence of lower gastrointestinal tract involvement was documented. She remained relatively free of pulmonary complaints except for the presenting bronchitis. CONCLUSIONS: Cephalexin should be added to the list of agents to consider as iatrogenic causes of SJS.

Review of drug-induced acute interstitial nephritis.

Drug-induced acute interstitial nephritis (AIN) is a rare, potentially correctable cause of acute renal failure. Early recognition and appropriate therapy are essential to its management. Several drugs have been associated with the development of AIN, including antibiotics and nonsteroidal antiinflammatory, agents, all with characteristic mechanisms of toxicity.

Populations at risk for penicillin-induced seizures.

OBJECTIVE: This article reviews principles associated with penicillin's epileptogenic activity in an effort to alert clinicians of patients at high risk for penicillin-induced seizures. The case presentation exemplifies the most prevalent factor predisposing patients to penicillin-induced seizures--renal impairment. DATA SOURCES: References are identified from pertinent articles and books. DATA SYNTHESIS: The epileptogenic properties of penicillin are explained on the basis of the beta-lactam ring's binding to gamma aminobutyric acid receptors. Several patient populations are at risk for potentially fatal neurotoxic symptoms. Most of these patients demonstrate impaired renal function, either as the primary condition or secondary to an infectious process. The other at-risk populations include infants and the elderly, patients with meningitis, patients undergoing intraventricular antibiotic therapy, and patients with a history of seizures. Treatment remains controversial; however, benzodiazepines theoretically produce a favorable response. CONCLUSIONS: Pharmacokinetic parameters explain patient populations most at risk; a guideline equation has been recommended to allow clinicians to make appropriate dose adjustments based on creatinine clearance. Physicians and pharmacists must recognize the populations most at risk for high-dose, penicillin-induced neurotoxicities; monitor these patients at least during the first 72 hours, and reduce or discontinue therapy when appropriate.

Calcium-channel blockers for treatment of diabetic nephropathy.

The use of calcium-channel blockers (CCBs) to reduce proteinuria associated with nephropathy in patients with diabetes mellitus is discussed. Metabolically induced damage to the nephrons in diabetic nephropathy decreases the filtration rate and increases the glomerular plasma flow rate and transcapillary hydraulic pressure. Microalbuminuria, which is predictive of nephropathy in patients with insulin-dependent diabetes mellitus, is associated with the development of clinical proteinuria and increased mortality. Micro-albuminuria should be evaluated periodically in diabetic patients, and antihypertensive therapy should be initiated when proteinuria is present or blood pressure control is needed. CCBs lower blood pressure because they prevent the action of angiotensin II by blocking the entry of calcium into renal vascular smooth muscle. Some CCBs, such as diltiazem and nicardipine, decrease glomerular pressure by increasing efferent arteriolar dilation. Others, such as nifedipine, may dilate both the afferent and efferent arterioles, thus causing increased excretion of protein. Studies in patients with diabetic nephropathy have shown that individual CCBs vary in their effects on proteinuria; this variation is attributable to their different sites of action and different effects on intrarenal activity. The choice of a CCB or an angiotensin-converting-enzyme inhibitor should be based on concomitant disease states and adverse-effect profiles. For control of hypertension in patients with diabetic nephropathy, diltiazem should be considered initially. Nicardipine is effective for short-term use but has not been tested in long-term studies; it should be considered a reasonable alternative.

Use of angiotensin-converting-enzyme inhibitors in the management of renal disease.

The role of angiotensin-converting-enzyme inhibitors (ACEIs) in the treatment of progressive renal disease is described. Researchers have evaluated the use of ACEIs in patients with two types of progressive kidney disease: diabetic nephropathy and renal insufficiency associated with connective-tissue disease. When introduced early in the course of diabetic nephropathy, ACEIs appear to produce greater reductions in urinary protein concentrations than do other antihypertensive agents, even when systemic blood pressure does not decrease. They also slow the rate of decline of renal plasma flow and glomerular filtration rate. Results are less impressive when ACEIs are initiated at a later stage of disease. Captopril has been shown to be associated with a decline in serum creatinine level in patients with systemic scleroderma, and with reductions in blood pressure and increases in the glomerular filtration rate in patients with systemic lupus erythematosus. Because these patients were receiving other agents that might have influenced study outcome, specific conclusions about the efficacy of ACEIs in connective-tissue disease cannot yet be drawn. They may, however, be recommended as adjunctive agents in treatment of this condition. The relative safety of the ACEIs, combined with their ability to arrest or slow the progression of renal failure, makes them primary options in the management of selected renal diseases.

Suspected ciprofloxacin-induced interstitial nephritis.

Interstitial nephritis is a rare but serious adverse effect of many drugs and usually is diagnosed by clinical signs and symptoms of hematuria, proteinuria, eosinophilia, fever, azotemia, and rash. Ciprofloxacin is one drug that has been reported to cause interstitial nephritis. Renal toxicities have been reported in less than one percent of the patients receiving ciprofloxacin therapy. Limited documentation of this adverse effect exists in the literature. This article describes a patient with suspected ciprofloxacin-induced interstitial nephritis.