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Purpose Depression is associated with recurrent cardiac events and death in patients with coronary heart disease and congestive heart failure. Furthermore, depression may be associated with reduced completion of outpatient cardiac rehabilitation (CR), an empirically supported treatment for patients with coronary heart disease and congestive heart failure that reduces recurrent coronary events and cardiac mortality. The goal of the current systematic review and meta-analysis was to explore the association between depression and outpatient CR completion. Method A systematic literature review cross-referenced 3 electronic databases (PsycINFO, MEDLINE, and Dissertation Abstracts International) from inception through February 15, 2015. Studies quantifying an association between depression and outpatient CR completion were identified for review. A random-effects model was used to pool quantitative data, moderators were tested, and publication bias was analyzed. Results Seventeen studies with 19 independent samples consisting of 30 586 cardiac patients were included in the meta-analysis. A moderate inverse relationship between depression and outpatient CR completion was observed (g = -0.44; 95% CI, -0.59 to -0.29), indicating that depressed CR patients were significantly less likely to complete their prescribed CR programs. No significant moderator variables were identified. A minor amount of publication bias was detected. Conclusion Depression is associated with reduced outpatient CR completion rates. Future research should focus on attendance interventions for depressed CR patients, as completion of outpatient CR reduces cardiac and all-cause mortality.

Objective To explore differences in blood cytokine profiles among distinct bronchopulmonary dysplasia (BPD) patterns. Study design We evaluated blood spots collected from 943 infants born at ≤1000 g and surviving to 28 days on postnatal days 1, 3, 7, 14, and 21 for 25 cytokines. Infants were assigned to the following lung disease patterns: (1) no lung disease (NLD); (2) respiratory distress syndrome without BPD; (3) classic BPD (persistent exposure to supplemental oxygen until 28 days of age); or (4) atypical BPD (period without supplemental oxygen before 28 days). Median cytokine levels for infants with BPD were compared with the IQR of results among infants with NLD. Results The distribution of enrolled infants by group was as follows: 69 (NLD), 73 (respiratory distress syndrome), 381 (classic BPD), and 160 (atypical BPD). The remaining 260 infants could not be classified because of missing data (104) or not fitting a predefined pattern (156). Median levels of 3 cytokines (elevated interleukin [IL]-8, matrix metalloproteinase-9; decreased granulocyte macrophage colony-stimulating factor) fell outside the IQR for at least 2 time points in both infants with atypical and classic BPD. Profiles of 7 cytokines (IL-6, IL-10, IL-18, macrophage inflammatory protein-1α, C-reactive protein, brain-derived neurotrophic factor, regulated on activation, normal T cell expressed and secreted) differed between infants with classic and atypical BPD. Conclusions Blood cytokine profiles may differ between infants developing classic and atypical BPD. These dissimilarities suggest the possibility that differing mechanisms could explain the varied patterns of pathophysiology of lung disease in extremely premature infants.

This report summarizes a meeting sponsored by the National Institute of Child Health and Development to review important scientific contributions over the past several years that addressed the causes and consequences of intrauterine growth restriction (IUGR). IUGR contributes significantly to perinatal morbidity and mortality. Considerable research has focused on various aspects of fetal growth, particularly with respect to the epidemiology of IUGR, the regulation of fetal growth by intrinsic growth factors and extrinsic nutrient supply, the role of the placenta in fetal growth, and diagnosis and treatment of IUGR. In addition to summarizing many of the advances in each of these important areas of research, a major purpose of the meeting was to consider future directions for research into the causes, consequences, diagnosis, and treatment of IUGR. At the onset of the meeting, Dr William Hay provided a broad overview of IUGR. Much of the impetus for studying IUGR began with the observation by pediatricians and neonatologists that when classified according to birth weight and gestational age, newborn infants were shown to be small, average, or large for gestational age (SGA, AGA, and LGA, respectively), and that specific morbidities and rates of death were unique to each of these birth weight-gestational age classifications.1 SGA infants, for example, were recognized as having more frequent problems with hypoglycemia, hypothermia, polycythemia, and neurodevelopmental handicaps, as well as a higher mortality rate.2 With the advent of improved fetal diagnosis, infants who were small at birth were increasingly recognized as representing a variety of fetal growth patterns. For example, infants who were considered constitutionally small simply grew parallel to, but less than, the 10th percentile for normal rates of fetal growth. Infants with genetic abnormalities or acquired diseases, particularly infections occurring in the first trimester, also grew slowly, and many of these infants …

Contents: N.A. Krasnegor, Introduction. Part I: N.A. Krasnegor, Definition of Compliance and Overview of Health Compliance Research. P. Karoly, Enlarging the Scope of the Compliance Construct: Toward Developmental and Motivational Relevance. J. Dunbar-Jacob, E.J. Dunning, K. Dwyer, Compliance Research in Pediatric and Adolescent Populations: Two Decades of Research. Part II: N.A. Krasnegor, Theories of Health Compliance Behavior. R.J. Ianotti, P.J. Bush, Toward a Developmental Theory of Compliance. B.J. Andersen, J.C. Coyne, Family Context and Compliance Behavior in Chronically Ill Children. H. Leventhal, Theories of Compliance, and Turning Necessities Into Preferences: Application to Adolescent Health Action. J. Brooks-Gunn, Why Do Adolescents Have Difficulty Adhering to Health Regimes? Part III: N.A. Krasnegor, Measurement. S.B. Johnson, Chronic Diseases of Childhood: Assessing Compliance With Complex Medical Regimens. P. Rudd, The Measurement of Compliance: Medication Taking. Part IV: N.A. Krasnegor, Prevention. E.R. Christophersen, Improving Compliance in Childhood Injury Control. L.H. Epstein, A. Valoski, J. McCurley, Compliance and Long-Term Follow-Up for Childhood Obesity: Retrospective Analysis. C.K. Ewart, Health Promotion and Disease Prevention: A Social Action Conception of Compliance Behavior. Part V: N.A. Krasnegor, Intervention. W.S. Agras, Adherence Intervention Research: The Need for a Multilevel Approach. T.L. Creer, Medication Compliance and Childhood Asthma. A.M. Delamater, Compliance Interventions for Children With Diabetes and Other Chronic Diseases. N.A. Krasnegor, Epilogue: Future Research Directions.

A neonatal bilirubin workshop took place at The Rockefeller University on June 20 through 22, 1993 to consider controversial issues in the field of neonatal jaundice and bilirubin neurotoxicity, particularly as they relate to management. The conference was sponsored by the National Institute of Child Health and Human Development (Pregnancy and Perinatology Branch, Center for Mothers and Children), The Rockefeller University, and the Consiglio Nazionale delle Richerche (Italy). tk;4Presentations and discussion emphasized diagnosis, biochemistry, and mechanisms of bilirubin toxicity, the definition and consequences of kernicterus, and the appropriateness and safety of the various therapies currently in use. Identification of future research needs was an important agenda item. The conferees agreed that conventional management of jaundice in the newborn with phototherapy and exchange transfusion, as well as with phenobarbital in certain situations, had significantly reduced the occurrence of "traditional" kernicterus. However, the conferees acknowledged that the classical definition of kernicterus was in need of re-examination in view of the potential of bilirubin as a CNS toxin. Early discharge of newborns from the hospital has significantly altered diagnostic and therapeutic management of neonatal jaundice, transforming it into an outpatient problem. This transformation raises new questions regarding the best time to ascertain the cause(s) of jaundice and to identify risk factors to insure optimal management of the infant. Review of the current state of knowledge of bilirubin metabolism focused on new methods for measurement of unconjugated and conjugated bilirubin, measurement of bilirubin synthesis rates, the molecular biology of bilirubin conjugation and the developmental role of the family of enzymes known as glucuronyl transferase(s), and the role of genetic and other host factors in determining the safety or toxicity of bilirubin in the newborn.

Background: Anxiety symptoms are associated with elevated coronary heart disease (CHD) risk, but it is not known whether such associations extend to anxiety disorders or if they are independent of depression. We sought to determine if generalized anxiety disorder is associated with elevated CHD risk, and whether this association is independent of or interacts with major depressive disorder. Methods: Generalized anxiety and major depressive disorders were assessed in a cross-sectional survey of a representative sample of U.S. adults aged 25–74 (N=3032). Coronary heart disease risk was determined by self-reported smoking status, body mass index, and recent medication use for hypertension, hypercholesterolemia, and diabetes. Results: Generalized anxiety disorder independently predicted increased CHD risk (F(1,3018)=5.14; b=0.39; 95% confidence interval (0.05–0.72)) and tended to denote the greatest risk in the absence of major depressive disorder. Limitations: The cross-sectional design cannot determine the causal direction of the association. Conclusions: Generalized anxiety disorder appears to be associated with elevated CHD risk in the general population. It may denote excess CHD risk relative to major depressive disorder, and clinicians should consider CHD risk when treating generalized anxiety disorder. D 2005 Elsevier B.V. All rights reserved.

The National Institute of Child Health and Human Development and the Agency for Health Care Policy and Research convened a workshop addressing the issues related to early discharge and hyperbilirubinemia on March 28, 1995. Recent reports have suggested that a high proportion of hospital readmissions in the neonatal period are related to hyperbilirubinemia.1-3 In addition, a growing number of anecdotal reports have raised concern about a resurgence of kernicterus and other hyperbilirubinemia-related morbidity, much of which may be preventable with improved neonatal discharge practices, monitoring technologies, and/or new pharmacologic therapies.4 Cost-containment strategies, such as managed care, have resulted in a continued trend toward shorter lengths of stay for all hospitalizations in all age groups. As a part of this trend, early discharge of neonates has also become common. The potential effects of these policies on subsequent outcomes for neonates and their mothers have generated concern. (In fact, Maryland has recently passed, and other states have introduced, legislation mandating at least 2 days postnatal hospital care.5) In addition to hyperbilirubinemia, other health issues related to early discharge that have been identified were discussed. These are reviewed in this issue of Pediatrics.6 They include potential adverse effects on newborn screening, poor preparation for breast-feeding, inadequate surveillance of mothers and neonates for health problems in the postpartum/neonatal period, reduced opportunities for parent training in "at-risk" populations, disruption of immunization practices, and shifting of economic burdens to families and nonhospital-based providers. The objectives of this workshop were: a) to review the present status of knowledge regarding hyperbilirubinemia requiring clinical intervention in the newborn and its prevention, and b) in the context of current practices, to begin outlining an agenda for research needs, practice guidance, and policy formulation related to morbidity and mortality associated with early discharge and neonatal jaundice.

(1995). Measuring the Experience, Expression, and Control of Anger. Issues in Comprehensive Pediatric Nursing: Vol. 18, No. 3, pp. 207-232.

It is now generally accepted that the developing fetus may be adversely affected by exposure to drugs and environmental chemicals. The stage of development of the intrauterine host is a major determinant of the resultant drug or chemical action. With rare exception, all foreign compounds are transmitted across the placenta, and depending upon their solubility and chemical structure, achieve varying concentrations in the fetus. Historically, the concept that external agents could adversely effect the fetus was first expounded by Gregg1 in Australia nearly 50 years ago when he demonstrated that rubella infection in the mother could lead to congenital cataracts in the newborn infant. During the several decades following Gregg’s report, most concern regarding drug effects on the fetus had to do with the perinatal period, particularly with the effect of narcotics and analgesics on the ability of the newborn infant to sustain respiration following delivery.

The distribution of digoxin in the myocardium, skeletal muscle, erythrocytes, and plasma (or serum) was studied in 19 infants. There was a linear relationship between myocardium and serum concentrations and no saturation was observed over the serum concentration range of 0.5-8.6 ng/ml. Myocardium uptake of digoxin was nearly twice as great in infants as in adults at any given serum concentration. Erythrocyte: plasma concentration ratios of digoxin were one-third smaller during digitalization than during maintenance digoxin therapy. The latter ratios were also three times greater in infants than found previously in adults. Their findings are consistent with a greater apparent volume of distribution of digoxin in infants and may partly explain the unusually large therapeutic doses needed in infants.

Epidemiologic studies have provided much of the knowledge concerning adverse side effects of exposure to drugs and other xenobiotics transmitted via breast milk. Adverse effects can be immediate and usually recognizable or long-term and difficult to define. Acute effects may be due to individual idiosyncrasy, allergic reaction, or manifestation of acute toxicity. We need further human clinical investigations to determine actual dosing to nursing infants and to ascertain the existence of subtle and presently unrecognized long-term effects.

Summary: Phenobartital (PB) (40 mg/kg/day) was administered to pregnant rats at 12 to 20, 14 to 20, and 17 to 20 days of gestation and female offspring were tested for the onset of puberty, estrous cycle pattern, and fertility. Another group of rats received PB (20 mg/kg/day) during the neonatal period (1 to 8 days). PB administration during both the pre- and postnatal periods resulted in a significant delay in the onset of puberty (control: 34.6 ± 1.2 days, PB: 37.5 ±1.2 days), disorders of estrous cycle (control: normal cycles 91%, PB: normal cycles 40%), and infertility (control: 100% fertile PB: 50% fertile). Associated with these effects, we observed high levels of estrogen in plasma (control: 58.5 ± 12.2 pg/ml, PB: 155.2 ± 25.1 pg/ml) and increased estrogen receptors in the uterus (control: 0.136 ± 0.026 pmole/mg protein, PB: 0.242 ± 0.031 pmole/mg protein. This study shows that PB administration only during the period of neuroendocrine differentiation (17 to 20 days of pregnancy and 1 to 8 postnatal days) is capable of producing all of the adverse effects of PB, indicating that its action is upon neuroendocrine development. Speculation: Since phenobarbital (PB) administration during 17 to 20 days of pregnancy is capable of producing reproductive disorders in the offspring, the results suggest that PB interferes with neuroendocrine differentiation. The mechanism of action of PB, however, has not been delineated. Neuroendocrine differentiation is mediated by gonadotropin, present during the neonatal period. PB may act at this site by interfering with gonadotrophin release or action. Support for this hypothesis is derived from the observation that PB can inhibit gonadotrophin secretion in the adult rat.

A P P R O X I M A T E L Y 27 years ago, diethylstilbestrol came into widespread use in support of high-risk pregnancy. 316 Only 2 years ago, the relationship between adenocarcinoma of the vagina in young women and their exposure to stilbestrol while-still in utero came to light, 146 and in many ways even this discovery was "fortuitous." Adenocarcinoma of the vagina in adolescent females had been an extremely rare disease. If maternal stilbestrol therapy had been the cause of an increase in the incidence of some relatively more common and slightly less dramatic adolescent disease, say diabetes, it probably would still be undetected today. And so the age of long-range complications of fetal drug therapy has been ushered in. The implications of this are enormous. We are caught between therapeutic nihilism and the eternal truth of the drug l abe l "When this preparation is used in women of childbearing age, the potential benefits should be weighed against the possible hazards to the fetus." Where is there a scale so fine?.Not only are the benefits often unproved but the hazards, for the most part, are not known. It is the purpose of this monograph to condense a major portion of the literature concerning drugs administered during pregnancy as they pertain to the unintended pat ient the fetus. In so doing, it is hoped that the practicing physician will be made more aware of the effects that drugs have on fetal outcome and therefore will be better able to prevent unnecessary fetal exposure as well as being better

It would be reasonable to assume that all o r most of the important aspects of the absorption, distribution, metabolism, and excretion of a long established and widely used group of drugs such as the salicylates (particularly aspirin and salicylic acid) have been fully elucidated many years ago. Surprisingly, this i s not the case. Detailed studies of the pharmacokinetics of salicylate absorption and elimination have been carried out only recently [1-3]. These studies have revealed that man eliminates salicylate relatively more slowly as the amount of the drug in the body i s increased. This effect is due to a limited biotransformation capacity which i s apparent also in the elimination of certain other drugs [4]. It has potentially important implications with respect to the causation and treatment of salicylate poisoning, particularly in in-fants and children. It is appropriate therefore to summarize the available knowledge of salicylate elimination in man and to present some results of recent st...

IN the last twenty years, the staphylococcus has replaced the streptococcus as the chief cause of infection in maternity units. Sporadic and epidemic staphylococcal infection among newborn infants now ranks as one of the most serious hazards in the modern nursery (as summarized by Williams et al.1). Previous reports2 3 4 indicate that hexachlorophene-containing compounds applied to newborn infants reduce staphylococcal infections in nurseries and incidentally decrease nasal carriage of staphylococci. The opening of the new Palo Alto—Stanford Hospital Center in the summer of 1959 afforded an opportunity to institute a program centered around the prevention of staphylococcal colonization of the . . .

Advanced salicylate intoxication in young children may produce severe acidosis due not only to the production and accumulation of organic acids in tissues, but also to the diminished content of buffer cation which is secondary to the loss of buffer cation during the excretion of organic acids. The excretion of an intensely acid urine all but prevents the excretion of free salicylate and thereby perpetuates the toxic effects of this ion. Despite severe deficit of buffer cation, the kidney responds to administration of a carbonic anhydrase inhibitor with excretion of alkaline urine. The magnitude of the loss of buffer cation is unpredictable both before and after enzyme inhibition. However, the systemic acidosis may be controlled by infusion of solutions of sodium bicarbonate, but frequent determinations of pH and content of carbon dioxide in the serum are mandatory. While the alterations in acid-base disturbance may be controlled during administration of acetazolamide, the occurrence of neurologic complications late in the course must be accepted as a serious additional hazard which may preclude the successful therapeutic value of this agent.

Neonatal deaths from tracheal obstruction caused by congenital goiters have been reported from such widely scattered locales as Buffalo, New York, New York City, Philadelphia, Washington, D.C., Seattle, Tokyo, Japan, and Glasgow, Scotland. The mothers of these infants had asthma and were receiving conventional doses of iodides, either as potassium iodide or as mixtures of bronchodilators and iodides. Because of these deaths, the Committee on Drugs of the American Academy of Pediatrics has reviewed the use of iodides in the therapy of asthma and other chronic pulmonary diseases. Five current textbooks advocate the use of iodides in chronic asthma.1-5 "Iodide compounds have a stimulating effect on bronchial secretions and represent expectorants of major importance in treating asthma and particularly status asthmaticus."2 The AMA Drug Evaluations6 recommends the use of iodides only for short-term medication. Current Pediatric Therapy7 emphasizes careful patient selection because only an occasional patient may benefit. Dosage recommendations usually are 300 mg of potassium iodide every two hours in adults1 and 60 mg per year of age four times daily in children.4 These dosage recommendations are many times greater than the 65 mg of organic iodine (T4 and T3) which the average human thyroid gland delivers to the circulation per day, or the estimated daily adult iodide requirement of 200 mg of iodide.8 As a matter of fact, these recommended dosages for iodides represent 10 to 30 times the total body content of iodide! Many preparations–some of which are available on an over-the-counter (nonprescription) basis–contain iodides, including antiasthmatic preparations, expectorants, and preparations whose trade names may not suggest the presence of iodides.

Phenobarbital administration to pregnant rats from day 12 to day 19 of gestation suppressed body weight gain and produced significant effects on reproductive function in their offspring. These effects included delays in the onset of puberty, disorders in the estrous cycle, and infertility. Moreover, the animals exposed to phenobarbital in utero showed altered concentrations of sex steroids, gonadotrophic hormones, and estrogen receptors. These findings suggest that phenobarbital treatment during prenatal development can produce permanent alterations in sexual maturation.

Since their introduction into clinical use, corticosteroids have been employed as therapeutic agents in virtually every known disease state, ranging from minor dermatologic disorders to major and serious diseases. These agents have undoubtedly altered the clinical picture and prognosis of certain diseases. However, the use of corticosteroids is always potentially associated with a variety of untoward effects, some of which may be life threatening, i.e., decreased resistance to infection, growth retardation, neurological reactions, hypertension, peptic ulcerations, and many others.1 The time honored principle—first do no harm—should always be the guideline of therapy, especially when a definite indication for a particular therapeutic agent has not been established. In recent years corticosteroids have been employed in the treatment of bronchiolitis on the hypothesis that their anti-inflammatory action would decrease swelling, inflammation, and the consequent respiratory obstruction. The opinions of different investigators on the efficacy of corticosteroids in this disorder have varied greatly; some have regarded their use as ineffective and others as lifesaving. It is the purpose of this report to review the findings from various studies and to outline the current status the use of corticosteroids in this common disorder of infants and children. Bronchiolitis is a common, acute respiratory syndrome characterized by infection of the bronchioles and respiratory distress of varying degrees due to obstructive emphysema. It is common in the first year of life and is rare in the child over 2 years of age. It frequently occurs in outbreaks. The great majority of cases are due to viruses, especially the respiratory syncitial, influenza B, and parainfluenza viruses, but it may be due to bacteria and other respiratory pathogens.

The frequent use of marijuana by American youth has compelled the Committee on Drugs to explore the present methods of and recommendations for controlling marijuana. On October 15, 1970, the Executive Board of the American Academy of Pediatrics endorsed in principle a statement on marijuana which was prepared by the Massachusetts Chapter of the Academy and published in the Academy's Newsletter.1 This statement called for considering possession of marijuana as a misdemeanor rather than a felony, but it was against legalizing use of marijuana at the present time. On October 27, 1970, President Nixon signed into law the Comprehensive Drug Abuse, Prevention and Control Act of 1970 (P.L. 91-513). This law became effective May 1, 1971; it is the Federal Government's attempt to control drug abuse by scientific and medical measures (under control of the Department of Health, Education, and Welfare) and by law enforcement activities (Department of Justice). The new Federal law has stopped short of legalizing marijuana, but it does allow a judge the discrelion to withhold criminal charges for the first offense of possession. The Massachusetts Chapter notes2 that marijuana is not a narcotic and does not produce addiction. Short-term physical effects are innocuous. However, impaired performance on simple intellectual and psychomotor tests is seen after individuals have smoked marijuana for the first time; but, such effects are not seen in regular users. There is no evidence to substantiate the common misconceptions that use of marijuana leads to crime or addiction to opiates. But, so little scientific information is available on the long-term use of marijuana that it should be considered a potentially harmful drug.

When broad-spectrum antibiotics were first introduced two decades ago for the treatment of acne, justification for such therapy seemed reasonably straightforward, e.g., the suppression of the suppurative inflammatory lesions commonly encountered in acne. As time went on, however, certain observations raised questions concerning the rationale for this form of treatment. First, it became apparent with cumulative clinical experience that the disease could ordinarily be controlled by doses of antibiotics lower than those required to treat bacterial infections. Second, bacteriologic studies disclosed that the only bacteria regularly recoverable from acne lesions were the anaerobic diphtheroid Corynebacterium acnes and aerobic coagulase-negative cocci, predominantly staphylococcus type II; both of these bacteria are known to be normal resident skin organisms.1 Thus, as no reports of controlled studies were then available for assessing the true efficacy of antibiotics used in the treatment of acne, the uneasy suspicion arose that such therapy might be inducing a primarily placebo response. In 1965, Freinkel and her collaborators2 demonstrated that the oral administration of tetracycline, even in doses as small as 250 mg daily, resulted in a significant reduction of the free fatty acid concentration of the lipid (sebum) secreted to the skin surface by the sebaceous glands. This effect could be observed in normal subjects as well as in patients with acne and was entirely reversible on discontinuance of drug. The inflammatory lesions of acne are known to result from disorganization of the follicular epithelium, with consequent liberation of the intrafollicular contents, containing sebum, into the dermis.3

One of the most important concepts in pediatric pharmacology is that exposure to drugs or chemicals may have latent, unforeseen effects on the child later in life. Some of the most dramatic occurrences, other than teratogenesis, are those in which hormonal exposure during the fetal or newborn period alters adult sexual development. However, none of these episodes is more impressive and ominous than that reported by Herbst et al.1 Herbst, an obstetrician at the Massachusetts General Hospital, was intrigued by the presentation of seven patients with adenocarcinoma of the vagina, an extremely rare tumor not previously seen at the hospital. The patients ranged in age from 14 to 22 years and sought medical advice because of vaginal bleeding. Several had benign adenosis, suggesting that the malignant change seen in all was based on a fundamental alteration in the biology of the vaginal epithelium. Six of the patients were treated with radical surgery, and one was treated with wide, local excision. One of the patients died after surgery. In what could serve as a model of a scientifically conducted, epidemiologic study, each of the seven patients, plus an additional patient from another hospital, was matched with four controls born in the same hospital within four days. Thus, the "control" group was chosen in a manner to eliminate many biases of artificially contrived control populations. A wide variety of possible influences in both mothers and offspring were considered, e.g., maternal age, smoking habits, exposure to X-rays, breast-feeding, birth weight, age at menarche, medications during pregnancy, and so forth.

Antihistamines were introduced in France by Halpern in 1942 and in the United States at the end of World War II; they had been investigated extensively during the war for therapy of motion sickness. By the late 1940s, a mass of information on the structure activity relationship had accumulated and most major drug manufacturens had introduced antihistamines into the market for oral, parenteral, and topical administration. Topical use was efficacious in acute dermatitis because the local anesthetic activity of the drugs diminished pruritus. The first reports of sensitization to the topical antihistamines, which began to appear in 1947, incriminated tnipelennamine (Pyribenzamine), diphenhydramine (Benadryl), antazoline (Antistine), and pheniramine (Trimeton).1-4 In the ensuing 25 years, though thousands of instances of antihistamine contact dermatitis have occurred, many topical antihistamines remain on the market. The Committee is concerned about the use of topical antihistamines which are sold over the counter for use in such conditions as chickenpox and poison ivy. Table I lists most of the preparations currently available for topical use. CLASSES OF ANTIHISTAMINES The antihistamines are classified according to their chemical structure into five primary groups as shown in Table II. Each drug carries its own index of sensitization and other adverse effects when employed topically. The ethylenediamine derivatives include the following: antazoline phosphate (Antistine), promethazine hydrochloride (Phenergan*), and tripelennamine (Pyribenzamine). They are particularly active in inducing contact dermatitis and were responsible for the cases first reported.5,6 Ethylenediamine, because of its dibasic structure, is widely used in various organic syntheses for the preparation of dyes, inhibitors, rubber accelerators, fungicides, synthetic waxes, resins, insecticides, and asphalt-wetting agents.

The first annual W. E. Upjohn Lecture concerned itself with the interrelationship between administration of drugs to the pregnant woman and fetal outcome. The epidemiology of drug intake (both prescribed and self-administered drugs) during pregnancy is reviewed, using data derived from several surveys conducted both in the United States and in Scotland. The complexities of establishing a causal relationship between drug intake during pregnancy and effects upon the fetus are considered. Special emphasis is given to the adverse effects of aspirin and cigarette smoking. The shortage of data is critical and the need for further research is stressed.

Protein deficiency in post-suckling rats produced changes in the activity of hepatic drug-metabolizing enzymes. Significant decreases occurred in the N-demethylation of aminopyrine, in the azo-reduction of neoprontosil and in sulfokinase activity (using p-nitrophenylsulfate as S04 donor). An increase was recorded for the glucuronidation of p-nitrophenol and no changes were noted in the hydroxylations of hexobarbital and aniline. Refeeding the animals for 3 weeks returned all activities to control values. An exception was the azo-reductase activity indicating either a slower recovery or a permanent change.

Pathology, microbiology, and selected serum chemistries were evaluated in 144 male Fischer rats from 4 to 33 mo of age. The rats were reared and maintained under barrier conditions, which successfully excluded the introduction of major infectious disease agents throughout the entire study, including Mycoplasma pulmonis. A wide variety of pathology was found and tabulated, and many lesions were found to increase in severity and incidence with age. There was a high correlation of renal disease severity with increasing age. Serum total protein and albumin decreased with age, while alpha-1 globulin and cholesterol increased.

The report on aspirin hepatitis by Zucker and colleagues in this issue of theJournal(page 1433) is the latest in a series of recent publications concerned with this phenomenon.1-5These reports follow at least two earlier communications on the same subject about 20 years ago.6,7Elevated activity of serum glutamic oxaloacetic and pyruvic transaminases (SGOT and SGPT) and other evidence of hepatotoxicity have been observed in patients receiving relatively high doses of aspirin or other salicylates such as choline salicylate or sodium salicylate. Most, but not all, of the reported cases involved children with rheumatic fever or rheumatoid arthritis rather than adults. One of the two patients reported by Zucker et al, as well as the three patients described by Seaman et al,5had systemic lupus erythematosus. Evidence of liver injury usually appeared at plasma salicylate concentrations above 25 mg/100 ml and disappeared promptly when salicylate

The disposition of methicillin in normal subjects and in subjects with cystic fibrosis (CF) was studied after administration of single intravenous doses of 15 mg/kg. The area under the serum concentration vs. time curve for CF patients was, on the average, only 75% of that found for normal subjects. The low concentrations in serum were caused by more rapid urinary excretion of the antibiotic, with rates of renal clearance averaging 425 ml/min per 1.73 m2 in the patients with CF and 362 ml/min per 1.73 m2 in the normal subjects. No differences were found in volumes of distribution and metabolic clearance rates of methicillin or in rates of creatinine clearance between the two groups of subjects. These data support previous findings with dicloxacillin which show that patients with CF exhibit unusually rapid, active tubular secretion of certain penicillins that may necessitate use of larger doses of these drugs in treatment of infections.

The disposition of theophylline was examined in seven children with asthma on two occasions before and on one occasion after chronic phenobarbital dosing (2 mg/kg/day). There was little intrapatient variability in apparent theophylline clearance between the two baseline assessments (0.081 versus 0.073 L/hr/kg). After 19 days of phenobarbital therapy, there was a significant increase in apparent theophylline clearance (0.104 versus 0.077 L/hr/kg), accompanied by a 30% decrease in the mean steady-state serum theophylline concentration (12.0 versus 8.4 micrograms/ml). The inducing effect of phenobarbital on theophylline metabolism may require theophylline dosage adjustment in patients with asthma who receive both drugs concurrently to maintain a given average steady-state theophylline concentration.

SummaryWhen succinate is administered to the heart-lung preparation of the dog at sufficiently high rates (0.2 g or more of un-hydrated succinate anion per kg heart-lung system per minute) the phosphocreatine concentration in the myocardium declines markedly and the heart goes into failure. The concentration of ATP declines to a lesser extent or remains unchanged. Heart failure in the heart-lung preparation caused by pentobarbital and chlorobutanol is intensified by succinate. These findings are discussed in the light of existing information on the coupling of succinate oxidation with phosphorylation and on the metabolism of cardiac tissue poisoned with anesthetics.

A metabolic case study of a four year old girl with renal tubular acidosis is presented. Renal function was normal except for inability to maintain a hydrogen gradient across the tubular epithelium. There was minimal limitation in total transfer of hydrogen ions into the urine, as expressed by titratable acidity, ammonia and reabsorbed bicarbonate. Histologic examination of a renal biopsy specimen disclosed dilatation of the tubules with some alteration in cellular surface. Enzyme assays for carbonic anhydrase and glutaminase activities were normal. Histochemical assay showed deficient staining for TPN diaphorase, but this was not corroborated by direct biochemical assay. No adequate explanation for the disorder was obtained, but it is suggested that a quantitative defect in energy production might have limited the renal secretion of free hydrogen ions.

The epidemic of HIV infection and disease in women, adolescents and children represents a complexly intertwined biological and social challenge to health care workers and researchers alike. When considering various issues in confronting this epidemic, women must be viewed as individuals important in their own right, as the primary caretaker of their family members (both infected and uninfected), and as the sexual partners of men who may or may not be infected. Of the myriad of compelling biological questions facing AIDS researchers today, two of the most interesting involve the timing and determinants of vertical transmission and the natural history of HIV infection and disease in women. Scientifically, confronting this epidemic involves research into pathogenesis, epidemiology, natural history, treatment, and prevention of HIV infection. Primary emphasis in the research arena in HIV/AIDS in the United States is focused on therapeutic and prophylactic research. Other research issues are very important, including studies of early diagnostic techniques, behavioral research concerning reproductive choices, the role of breastfeeding in HIV transmission, HIV-specific adolescent issues, and surrogate markers of disease progression.

Research on the fetus and newborn is of the greatest importance in contributing to the health and welfare of the entire population. Such research, motivated by humane concern, should be continued and fostered, subject to adequate and clearly defined safeguards.* The American Academy of Pediatrics recognizes that through research involving previable fetuses, new knowledge may be gained which would ultimately benefit viable infants. The American Academy of Pediatrics also recognizes that some of these areas of research, while not jeopardizing the health and welfare of the fetus, are not of direct benefit to that particular fetus. In such cases express consent should be obtained from the parent. "The whole previable fetus has offered an important opportunity that cannot be obtained in any other way for making observations of great value on the transfer of substances across the human placenta, the reaction of the immature fetus to drugs, and on the endocrinological development of the fetus and the development of the placenta."1 Research activities involving the fetus in utero or pregnant women may be undertaken1 for the purpose of benefiting that particular fetus or to respond to the health needs of the mother,2 as part of the procedure to terminate the pregnancy, and for the purpose of evaluating or improving methods of prenatal diagnosis, methods of prevention of premature birth, or methods of intervention to offset the effects of genetic abnormality or congenital injury or to ascertain the safety and efficacy to the fetus of drugs which might be needed by pregnant women.2

The halogenated hydroxyquinolines can cause serious, permanent neuropathy. Optic atrophy, causing permanent blindness, is the most commonly reported neuropathy in children. In young children, the onset of neuropathy is insidious and hard to diagnose. We, therefore, recommend that these drugs not be used in children, with two possible exceptions: the treatment of the asymptomatic cyst passer of E. histolytica in a person not living in an endemic area and the treatment of acrodermatitis enteropathica. If used, parents should be informed of the possible toxicity. Parents, child, and physician should diligently search for the first indication of neuropathy. These drugs are contraindicated in the treatment of nonspecific, chronic diarrhea, and "traveler's diarrhea."

The Committee on Drugs unites with the Joint Committee on Physical Fitness, Recreation, and Sports Medicine in condemning the use of drugs to improve athletic performance, However, the Committee on Drugs would like to clearly distinguish between the promiscuous use of drugs and their pharmacologic use to control a specific disease state enabling the adolescent to participate in sports, for example, the use of insulin for diabetes, anticonvulsants for epilepsy, digitalis for heart disease, or bronchodilators for asthma. Children and adolescents with handicaps should be given the same advantages as other children, including participation in athletic activities. Athletes with medical conditions controlled by drugs should not be placed in the same category as youths taking drugs for other purposes, and there should be minimal, if any, restrictions imposed on them. One recent example of the type of restrictions which should not be imposed is the athlete with exercise-induced bronchoconstriction who was disqualified in the 1972 Olympics in Munich because he used a bronchodilator prescribed by his physician. Exercise-induced bronchospasm is a common handicap of allergic youth, and may occur in between 60% and 80% of individuals with allergic respiratory distress.1 Such bronchoconstriction can be modified by the administration of theopylline, theophylline epherdrine combinations,3 or cromolyn sodium,4, 5 The Committee on Children with Handicaps also recommends that children with asthma participate in sports and physical education and that every effort be made to minimize restrictions.6 At the annual meeting of the American Academy of Allergy in Washington, D.C., February 14, 1973, the following resolution was approved unanimously: "Participants in competitive athletics with asthma and other allergic conditions should not be disqualified because of the use, with medical supervision, of therapeutic doses of ephednine before and during athletic competition."7

Published reports and unpublished communications to the Committee on Drugs of the American Academy of Pediatrics indicate that substances potentially hazardous to the premature and full-term newborn infant continue to be used in the laundering of clothing, diapers, and bedding for hospital nurseries. In 1962 the Subcommittee on Accidental Poisoning called attention to occurrences of methemoglobinemia in premature and full-term newborn infants whose diapers were autoclaved after a final laundry rinse with the bacteriostatic agent, 3-4-4' trichlorocarbanilide (TCC).1 Subsequent reports in the pediatric literature confirmed and added to these "epidemics" of neonatal methemoglobinemia2-4 and suggested that aniline–a wellknown cause of methemoglobinemia5–resulting from the break-down of TCC during autoclaving, was absorbed from diapers and other nursery clothing through the skin of the infants. Although direct proof of the etiologic role of TCC is lacking, the association is of sufficient concern that the forthcoming Academy manual, Standards and Recommendations for Hospital Care of Newborn Infants, Second Edition, makes reference to the hazards of using TCC. Although a limited and informal survey of hospital nurseries in the United States and Canada indicates that most hospital laundry procedures have abandoned TCC in treating clothing and bed linens of newborn infants, sporadic instances of neonatal methemoglobinemia associated with exposure to this substance still come to the attention of local, state, and national health agencies, manufacturers, and the Committee on Drugs. In 1967, deaths and severe illness occurred in epidemic form in the newborn nursery of a small Midwestern maternity hospital.6 Investigation revealed that the sodium salt of pentachlorophenol (PCP)— which was present in the antimicrobial neutralizer product used in the final rinse of the laundry process for diapers, infant undershirts, and crib linens for the nursery–intoxicated babies by percutaneous absorption.7

Drug-protein interaction is of major importance in modulating drug distribution and action in the intact organism. Drug binding to serum proteins in the gravid female is of special interest because of physiological changes during pregnancy which may influence drug activity in the primary host and in the developing fetus. A detailed investigation of salicylate binding to serum albumin during pregnancy was undertaken since aspirin is universally ingested by the pregnant woman and has been implicated as having adverse effects upon the fetus. Serum was obtained from 51 patients taken at their routine examinations during pregnancy and categorized into trimesters. Equilibrium dialysis was performed at 4°C utilizing varying concentrations of sodium salicylate C14 with 1 ml of serum. The apparent association constant (k′) of the albumin-salicylate interaction was determined from the construction of Scatchard plots from the data. The mean k′ values for 1st, 2nd and 3rd trimesters are 3.2, 2.8 and 2.6 × 105M−1 respectively with one mole of salicylate bound at the primary site. These results indicate that there is a decrease in the binding affinity of salicylate for serum albumin as pregnancy progresses. The increased concentrations of free unbound salicylate present during pregnancy would be readily available to diffuse across the placenta and effect the fetus as well as act upon host receptors. The change in binding affinity may result from competitive or allosteric binding by endogenous compounds.

Differences in mean birth weight and low birth weight (< 2.5 Kg.) are analyzed among Asians, Blacks, Hispanics, and Whites who were enrolled in the Northern California Kaiser-Permanente Birth Defects Study, a prospective study of 29,415 pregnancy outcomes. Large differences in birth weight among babies of different ethnic groups persist after controlling for the joint effects of maternal smoking and alcohol use during pregnancy, sex of child, parity, length of prenatal care, and maternal weight-for-height percentile. Compared to Whites, the relative mean differences in birth weight are estimated as -246 grams for Blacks, -210 grams for Asians, -105 grams for Hispanics, and -140 grams for Others. The low birth weight rates and crude odds ratios are 7.70%. (2.17) for Blacks, 5.57% (1.57) for Asians 5.52% (1.55) for Others, 4.007. (1.13) for Hispanics, and 3.55% (1.00) for Whites. After controlling for the effects of 21 factors, the odds ratios for a low birth weight infant are 2.41 for Blacks, 1.37 for Asians, 1.93 for Others, and 1.25 for Hispanics. It is concluded that factors currently used to control for ethnic differences in birth weight are insufficient to explain the observed differences.

The search for factors that can predict a large for gestational age (LGA) infant has, thus far, uncovered only maternal diabetes, large maternal size and seme uncommon genetic and metabolic syndromes. This study examined the relationship between mother's birth weight and the probability of producing a LGA (>90 percentile for age and sex) infant using prospectively collected data from the Collaborative Perinatal Project (Buffalo center). Among 1337 white women without preexisting diabetes delivering liveborn singleton infants, the percentage of LGA births was 2.4% for mothers weighing 4-5.9 lbs at birth, 7.3% for mothers weighing 6-7.9 lbs at birth, and 13.6% for mothers weighing 8 or more pounds at birth. (There were too few women weighing