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ImportanceNeurodevelopmental disabilities are commonly associated with congenital heart disease (CHD), but medical and sociodemographic factors explain only one-third of the variance in outcomes.ObjectiveTo examine whether potentially damaging de novo variants (dDNVs) in genes not previously linked to neurodevelopmental disability are associated with neurologic outcomes in CHD and, post hoc, whether some dDNVs or rare putative loss-of-function variants (pLOFs) in specific gene categories are associated with outcomes.Design, Setting, and ParticipantsThis cross-sectional study was conducted from September 2017 to June 2020 in 8 US centers. Inclusion criteria were CHD, age 8 years or older, and available exome sequencing data. Individuals with pathogenic gene variants in known CHD- or neurodevelopment-related genes were excluded. Cases and controls were frequency-matched for CHD class, age group, and sex.ExposuresHeterozygous for (cases) or lacking (controls) dDNVs in genes not previously associated with neurodevelopmental disability. Participants were separately stratified as heterozygous or not heterozygous for dDNVs and/or pLOFs in 4 gene categories: chromatin modifying, constrained, high level of brain expression, and neurodevelopmental risk.Main Outcomes and MeasuresMain outcomes were neurodevelopmental assessments of academic achievement, intelligence, fine motor skills, executive function, attention, memory, social cognition, language, adaptive functioning, and anxiety and depression, as well as 7 structural, diffusion, and functional brain magnetic resonance imaging metrics.ResultsThe study cohort included 221 participants in the post hoc analysis and 219 in the case-control analysis (109 cases [49.8%] and 110 controls [50.2%]). Of those 219 participants (median age, 15.0 years [IQR, 10.0-21.2 years]), 120 (54.8%) were male. Cases and controls had similar primary outcomes (reading composite, spelling, and math computation on the Wide Range Achievement Test, Fourth Edition) and secondary outcomes. dDNVs and/or pLOFs in chromatin-modifying genes were associated with lower mean (SD) verbal comprehension index scores (91.4 [20.4] vs 103.4 [17.8]; P = .01), Social Responsiveness Scale, Second Edition, scores (57.3 [17.2] vs 49.4 [11.2]; P = .03), and Wechsler Adult Intelligence Scale, Fourth Edition, working memory scores (73.8 [16.4] vs 97.2 [15.7]; P = .03), as well as higher likelihood of autism spectrum disorder (28.6% vs 5.2%; P = .01). dDNVs and/or pLOFs in constrained genes were associated with lower mean (SD) scores on the Wide Range Assessment of Memory and Learning, Second Edition (immediate story memory: 9.7 [3.7] vs 10.7 [3.0]; P = .03; immediate picture memory: 7.8 [3.1] vs 9.0 [2.9]; P = .008). Adults with dDNVs and/or pLOFs in genes with a high level of brain expression had greater Conners adult attention-deficit hyperactivity disorder rating scale scores (mean [SD], 55.5 [15.4] vs 46.6 [12.3]; P = .007).Conclusions and RelevanceThe study findings suggest neurodevelopmental outcomes are not associated with dDNVs as a group but may be worse in individuals with dDNVs and/or pLOFs in some gene sets, such as chromatin-modifying genes. Future studies should confirm the importance of specific gene variants to brain function and structure.

Widespread availability of the fungal endecapeptide cyclosporine in 1983 ushered in an era of improved success and broader application of organ transplantation. In 1985, a review1of the clinical results with immunosuppression using cyclosporine identified nephrotoxic reactions as the most serious adverse effect of cyclosporine2; a 50% incidence of hypertension was also recognized and thought to be more frequent than with previous immunosuppressive regimens. The cause was unknown, and further investigation was encouraged. Other autoimmune diseases, such as psoriasis, primary biliary cirrhosis, rheumatoid arthritis, and type I diabetes mellitus, have been treated successfully with cyclosporine but with similar complications.3 The purpose of this report is to alert the practicing physician regarding these issues and to provide guidance in treating patients. In addition to incidence, the characteristics of cyclosporine-associated hypertension (CAH) will be reviewed along with data supporting various speculated mechanisms. Drug management of CAH and further directions

TRADITIONALLY, nephrologists have focused on a defect in the salt-excreting capacity of the kidney as pivotal to edema formation in heart failure. 1 Furthermore, based on the concept of "effective central blood volume," they have argued that the renal response is appropriate to the afferent stimuli impacting the kidney, ie, "relative hypoperfusion of the kidneys." Thus, it seems logical that the first order for therapeutic management of congestive heart failure (CHF) would involve elimination of the excess salt and water contained principally in the extracellular volume (ECV). To accomplish this, pharmacologically active diuretic compounds have been employed with both substantial success and recognized imperfections. One might inquire as to the logic of causing a diureticinduced volume depletion that will cause a fall in cardiac output through a reduction in left ventricular end-diastolic pressure. It would be more logical to either add an ionotropic agent that would improve cardiac performance through

Functional renal failure accompanying advanced cirrhosis of the liver carries a grave prognosis. Seven patients with the hepatorenal syndrome and five patients with decompensated cirrhosis of the liver without renal failure were studied by the xenon Xe 133 washout technique. Mean renal blood flow and its cortical component were decreased in both groups compared to normal transplant donors, but to a significantly greater degree in hepatorenal syndrome. In hepatorenal patients, intra-arterial infusion of subpressor doses of dopamine hydrochloride improved the angiographic appearance of the renal cortical vasculature and the cortical blood flow rate. Urine flow rate and glomerular filtration rate did not consistently improve with 12- to 24-hour intravenous infusions, although two patients survived, temporally related to the study. These patients had shown signs of liver function recovery.

The renal response to a single intravenous dose of ethacrynic acid was evaluated in ten patients with cardiac decompensation. Following infusion of the drug, a prompt increase in urine flow occurred lasting for approximately two hours. During this diuresis, renal function studies disclosed a fall in tubular reabsorption of water, sodium and chloride, and an increase in osmolar clearance. These findings are compatible with a blockade of coupled sodium chloride reabsorption in either the ascending loop of Henle or early distal tubule or both, but do not exclude a redistribution of intrarenal blood flow as contributing significantly to ethacrynic acid's mode of action. Distal tubular exchange between sodium and potassium-hydrogen does not seem to be affected by this diuretic.

Ethylene glycol, a major ingredient in radiator antifreeze, is an aliphatic alcohol with prominent toxic effects on central nervous, cardiac, pulmonary, and renal systems. Toxicity results mainly from calcium oxalate and other metabolites rather than ethylene glycol per se. Symptoms resembling those of alcohol intoxication may occur soon after ingestion, and poisonings have resulted when ethylene glycol has been substituted for alcohol. 1 Suicide attempts also account for a substantial number of cases of ethylene glycol poisoning. Death is the usual outcome, 2 but the survival rate has improved with vigorous treatment of metabolic acidosis with hemodialysis 3 and competitive inhibition with alcohol administered parenterally. 4 The present case is unique; despite 50 days of oliguria, during which time the patient had hemodialysis repeatedly, renal function recovered sufficiently so that her only treatment at time of discharge was a modified protein diet. Patient Summary The patient, a 65-year-old woman, was

Introduction There can be no doubt that viruses are a cause of cancer in certain animals. 1-31 While the total process of oncogenesis may be a complex of many known factors such as chronic inflammation, hormonal influences, radiant energy, chemicals, x-irradiation, and the proper genetic constitution, 32-34 the known virus-induced malignancies are the sole naturally occurring neoplasms of known and specific cause. 6 Facts relating viruses to tumor formation have accumulated rapidly during the last 25 years, largely through improved tissue culture techniques, 14,35,36 electron microscopy, 31,37-41 immunofluorescent microscopy, and ferritin antibody procedures in electron microscopy. 42 Improved immunologic methods, the great advances in genetics and protein chemistry, and the demonstration of infectious nucleic acids 43-51 are all responsible for provoking intense interest in the potential relationship between viruses and cancer in man. The purpose of this review is to trace the development of viral oncology which has led to

The syndrome of inappropriate antidiuretic hormone (SIADH) secretion is being recognized with increasing frequency particularly in association with tumors which secrete antidiuretic hormone (ADH), notably, bronchogenic carcinoma. In many of the tumor-related cases, increased amounts of polypeptide with ADH properties have been measured in the serum, urine, or tumor extracts by bioassay or immunoassay. In other instances, the presence of increased antidiuretic hormonal activity has been shown by careful metabolic balance studies. This syndrome also has been demonstrated in a variety of nonneoplastic states, but microscopic changes in the hypothalamic-neurohypophyseal tract have been described only once. 1 Furthermore, tumor-related cases with involvement in this area of the brain have rarely been reported, and such cases show destruction limited to the posterior lobe of the pituitary gland, indicating that this structure, per se, is not necessary for ADH formation. 2,3 This communication describes a unique instance of adenocarcinoma of the lung

Renal tubular acidosis is a relatively rare but well documented disorder of renal acidification in which both the rate and concentration of acid excretion are subnormal during metabolic acidosis. The report of Morris and Fudenberg 1 has called attention to the association of hyperglobulinemic states which defects in urine acidification. In this regard, we have recently studied a patient with inability to acidify the urine, adult Fanconi syndrome, γ-globulinuria, and a primary myopathy. To the best of our knowledge, this combination has not been previously described. Patient Summary A 57-year-old Negro man was admitted to Multnomah Hospital Sept 1, 1966, with a four year history of progressive weakness of his legs. The patient stated that he had difficulty stepping up onto a curb or arising from a kneeling position and, in addition, had shortened his stride because of a subjective impression that he could not adequately support his weight. Two

To the Editor.— This LETTER is in response to an article by Dillon and Postlewait on the use of cephaloridine in patients with impaired renal function ( 218 :250, 1971). The authors conclude that although 81 of 362 patients had renal impairment during courses of therapy with cephaloridine, the drug was not to be implicated as a causative factor in the renal injury. They state, without presenting any data, that elevation of blood urea nitrogen level was secondary to inadequate hydration, obstructive uropathy, or increased sources of nitrogenous products in the majority of these patients. We would choose to look at their data in a slightly different fashion. It is well known that hypotension and various toxic chemicals may be additive in the syndrome of acute tubular necrosis. Hollenberg et al 1 have shown that many nephrotoxic substances act by causing preferential cortical ischemia. Certainly hypotension with resultant catecholamine release also