Adrenocorticotropin-induced unresponsiveness in cultured adrenal tumor cells.

Our results demonstrate that adrenocorticotropin (ACTH)-induced refractoriness occurs in cultured adrenal tumor cells. Cells became 85% refractory to ACTH-induced cyclic AMP formation in 20 min and the effect persisted if the hormone remained in the incubation medium. Refractory cells gradually regained hormone-specific responsiveness within 24 h if cultures were incubated in fresh media containing serum. The observed effect is hormone specific since cyclic AMP could not induce unresponsiveness to ACTH. The addition of ACTH plus inhibitors of protein synthesis partially reversed hormone-specific refractoriness. However, preincubation with cycloheximide or diphtheria toxin led to superinduction of ACTH-induced cyclic AMP formation. These experiments suggest that unresponsiveness, following hormonal activation of adrenal cells, may be related to a decrease in hormone-specific binding sites or to synthesis of an adenylate cyclase inhibitor.

Clinical implications of large vegetations in infectious endocarditis.

Thirty-four patients with clinical infectious endocarditis were examined by M-mode and two-dimensional (2D) echocardiography. Vegetations were identified in 16 patients (47%) by M-mode and in 27 patients (87%) by 2D echocardiography. Vegetations identified by 2D echocardiography were categorized as small (less than 5 mm), medium (5 to 9 mm), or large (greater than or equal to 10 mm). Large vegetations were caused by a variety of organisms, had a higher incidence of surgery (44% v 0%), and had no increased incidence of stroke or death. The larger the vegetation, the more detectable it was by M-mode. Aortic valve vegetations were associated with a higher incidence of congestive heart failure (CHF) (67% v 14%) and stroke (44% v 9%). Four patients with large aortic valve vegetations had the highest complication rate; CHF developed in all four, two had valve replacement, one had a stroke, and two died.

Beevor's sign and facioscapulohumeral dystrophy.

We have frequently observed that Beevor's sign was present in patients with facioscapulohumeral dystrophy (FSHD) but absent in patients with other neuromuscular disorders. To determine the significance of this observation we prospectively evaluated 30 patients with FSHD and 40 patients with other neuromuscular disorders. Beevor's sign was present in 27 of 30 patients with FSHD but absent in all 40 control patients. We conclude that Beevor's sign is a common finding in patients with FSHD even before functional weakness of abdominal wall muscles is apparent. Testing for Beevor's sign is a simple screening test that may help in distinguishing FSHD from other forms of facioscapulohumeral syndrome.

CNS infection and bacteremia due to clostridium septicum.

Central nervous system infection with Clostridium septicum is rare. We report two fulminant cases of such infection with accompanying bacteremia. The presence of extensive brain necrosis was striking in our two cases. The association of C septicum bacteremia with hematologic disease, and with solid tumors, was present in our cases. We conclude that C septicum should be considered as a potential cause of life-threatening bacteremia and meningitis in the compromised host.

Colpocephaly in identical twins.

Colpocephaly is congenital disproportionately enlarged occipital horns of the lateral ventricles. It is easily recognized on computed tomography, magnetic resonance imaging or cerebral ultrasonography. The first report of colpocephaly in identical twins is presented. This is also the first reported instance of above normal intelligence occurring in conjunction with colpocephaly. The associated anomalies found as mirror images in these twins imply a genetic basis for their colpocephaly.

Nitrazepam-induced cricopharyngeal dysphagia, abnormal esophageal peristalsis and associated bronchospasm: probable cause of nitrazepam-related sudden death.

Nitrazepam was used in the treatment of resistant myoclonic epilepsy in 38 children. After the occurrence of nitrazepam-associated swallowing incoordination, high-peaked esophageal peristalsis and related bronchospasm in one patient, we initiated a prospective study of esophageal manometry using a station pull-through technique with a pediatric 4-channel continuous perfusing system. Three more patients were found to have delayed cricopharyngeal relaxation and high-peaked esophageal peristaltic waves. The initial patient developed severe respiratory distress and bronchospasm necessitating ventilatory support while on nitrazepam and improved dramatically with subsequent normal manometric study following nitrazepam discontinuation. Nitrazepam was reintroduced for its anticonvulsant and cognitive benefits and was tolerated at a reduced dosage. We postulate a central nervous system effect of nitrazepam promoting parasympathetic overactivity or vagotonia which can cause potentially fatal respiratory distress. Care must be exercised in nitrazepam use and esophageal manometry may be helpful in defining patients at greater risk for sudden death.

Effects of dietary ascorbic acid and vitamin E deficiency on rat adrenal cholesterol ester metabolism and corticosteroidgoenesis.

The effect of dietary ascorbic acid (AA) and deficiency of vitamin E, alone and in combination, upon adrenal steroidogenesis in rats have been tested in vivo. High concentrations of AA blocked the normal stress-induced increase in plasma and adrenal corticosteroid concentration. Adrenal cholesterol ester hydrolase activity was also markedly inhibited by the high AA diet, while acylcoenzyme A:cholesterol acyltransferase was significantly increased. Vitamin E deficiency caused generally opposite effect, while simultaneous excess AA and vitamin E deficiency caused these parameters to return toward control values. Thus the role of AA in blocking adrenal steroidogenic response to stress is confirmed. It's mode of action may be at least partly through control of cholesterol availability for steroidogenesis.

A variant of adrenomyeloneuropathy in a family with adrenoleukodystrophy and adrenomyeloneuropathy.

A 31-year-old man was seen with addisonian crisis, followed by the abrupt onset of spastic paraparesis and peripheral neuropathy. A workup revealed adrenal insufficiency, for which the patient was aggressively treated. The workup also revealed an increase in very-long-chain fatty acids consistent with the diagnosis of adrenomyeloneuropathy. Abnormal pituitary dysfunction improved with treatment of the Addison's disease. A review of the patient's pedigree revealed two family members in whom multiple sclerosis had been diagnosed but which, in retrospect, was thought to be adrenomyeloneuropathy. No other family member was found to have Addison's disease. A sibling died at age 8 of Schilder's disease, confirming the presence of adrenoleukodystrophy as well as adrenomyeloneuropathy within this family.

Churg-Strauss syndrome.

The neurologic manifestations of systemic necrotizing vasculitis are heterogeneous and often complex. Late onset asthma, systemic vasculitis manifest by mononeuritis multiplex, and peripheral eosinophilia-the triad of which is consistent with Churg-Strauss syndrome-developed in a 59-year-old woman. Electromyography and nerve conduction studies showed both myelinating and axonal neuropathy involving multiple nerves. Muscle and nerve biopsy showed neurogenic atrophy, demyelination, and axonal changes involving the sural nerve and inflammatory necrotizing small and medium vessel arterial changes. The patient was treated with high-dose prednisone and improved rapidly. Unusual in this case was the lack of multisystemic involvement. Churg-Strauss syndrome is a disease that is being recognized with increased clinical frequency and responds quickly to methylprednisolone treatment.

Clinical improvement of the myopathy in eosinophilia-myalgia syndrome with steroids and rehabilitative therapy.

The authors report a case of eosinophilia-myalgia syndrome with a progressive neuromyopathy. Progressive weakness, myalgia, and dermatitis developed in the patient described after chronic ingestion of high-dose L-tryptophan for insomnia. Laboratory, electrophysiologic, and muscle biopsy results support the diagnosis of an inflammatory myopathy consistent with that of eosinophilia-myalgia syndrome. The patient's weakness led to wheelchair dependency. A review of the literature regarding this disorder shows inconsistent results with steroid and other modes of therapy. After a course of high-dose steroids with long-term tapering and vigorous inpatient and outpatient rehabilitation, the patient was able to walk and function independently within 2 months.

An unusual presentation of salmonellal aortitis.

Our patient represents what we believe to be the first documented case of Salmonella choleraesuis aortitis presenting as a salmonellal empyema in an elderly diabetic man. Although S choleraesuis often causes septicemia, its absence should not lead one to forget the pathogenic nature of and high mortality associated with this organism. Aggressive efforts must be made to search for endovascular infection, because cures can be achieved only with surgical intervention and prolonged antibiotic therapy.

Escherichia coli enterotoxin-induced steroidogenesis in cultured adrenal tumor cells.

A heat-labile, Pronase-sensitive factor has been partially purified from cell-free culture filtrates of enterotoxigenic Escherichia coli. The partially purified factor contains both protein and carbohydrate moieties and appears to be E. coli enterotoxin (ECT). ECT binds to cultured adrenal tumor cells rapidly and irreversibly leads to adenosine 3', 5'-cyclic monophosphate formation and steroidogenesis after a 60-min lag phase. Further studies indicate that it interacts with the cholera toxin receptor site on adrenal cells rather than the adrenocorticotropin receptor to activate adenyl cyclase. Mixed gangliosides block stimulation of steroidogenesis in response to both E. coli and cholera enterotoxin. In contrast to adrenocorticotropin, ECT has no additive effect on cholera toxin-induced steroidogenesis. The protein moiety of ECT is similar to cholera enterotoxin because horse serum anticholeragenoid prevented stimulation of steroidogenesis by either enterotoxin. Cultured adrenal cells provide a quantitative assay system that has facilitated the purification and characterization of E. coli enterotoxin.

Interaction of cholera enterotoxin with cultured adrenal tumor cells.

In the adrenal tumor cell system ganglioside Gm1 inhibited cholera enterotoxin (CT)-induced steroidogenesis if it was preincubated with the toxin or added to adrenal cells 10 min before CT. In the preincubation studies a molar ratio of Gm1 to toxin of 3:1 was necessary for half-maximal inhibition of steroidogenesis. On the other hand, horse serum anticholeragenoid neutralized the steroidogenic response to cell-bound CT by 50% if it was added to adrenal monolayer cultures 15 min after the toxin. Specific antiserum was able to neutralized 20% of the toxin-induced activity even if it was added to adrenal cultures 2 h after CT. Phase contrast microscopy demonstrated that partial neutralization of the biochemical effect of CT by horse serum anticholeragenoid was accompanied by partial prevention of toxin-induced rounding of adrenal cells. Further studies showed that pretreatment of cultured adrenal cells with a maximal dose of CT increased cyclic adenosine 3'-5'-monophosphate formation in response to a maximal stimulating dose of adrenocorticotropin. This result suggested potentiation of hormonal activation of adenylate cyclase in intact adrenal tumor cells in response to CT.

Catabolite repression gene of Escherichia coli.

A catabolite repression gene (cat) which alters the sensitivity of Escherichia coli to catabolite repression has been mapped by transduction and shown to be located between the pyrC and purB genes. When the cat-1 mutation was studied in a number of genetic backgrounds, the results showed that this mutation affects the synthesis of more than one catabolic enzyme but does not completely eliminate catabolic repression under all conditions. It is suggested that this mutation may cause a block in the accumulation of the catabolite effector. Our experiments show that this effector is not glucose-6-phosphate.

Mode of action of Vibrio cholerae enterotoxin in cultured adrenal tumor cells.

The effects of Vibrio cholerae enterotoxin on steroidogenesis and on formation of adenosine 3':5'-cyclic phosphate (cyclic AMP) in two adrenal tumor cell lines were compared. Steroidogenesis was half-maximal at concentrations of 1 ng of cholera toxin/ml in the mutant OS-3 cells and 3 ng of cholera toxin/ml in the parent Y-1 cells. At the end of an 8-hr incubation, toxin-induced formation of cyclic AMP in the mutant cell line was reduced by 90%. A molar ratio of GM1 ganglioside (galactosyl-N-acetylgalactosaminyl [sialosyl] lactosyl ceramide; GGnSLC) to cholera toxin of 3:1 caused half-maximal inhibition of steroidogenesis in both cell lines. When equine antiserum to choleragenoid was added to adrenal cells 15 min after cholera toxin, there was marked inhibition of cyclic AMP formation and of steroidogenesis. Pretreatment of Y-1 cells with adrenocorticotropin rendered them unresponsive to hormonal induction of cyclic AMP formation, but these cells had an unimpaired response to cholera toxin. These studies, utilizing two adrenal cell lines, suggest important differences between the mode of action of cholera toxin and that of adrenocorticotropin in cultured adrenal tumor cells.

Factors influencing heat-labile Escherichia coli enterotoxin activity.

In this study, conditions for production, detection, and storage of heat-labile Escherichia coli enterotoxin (LT) in culture filtrates from E. coli H-10407 were defined by using the adrenal tumor cell assay system. An enriched medium containing 0.6% yeast extract, 2% Casamino Acids, and 0.25% glucose buffered at pH 8.5 produced the highest LT activity of the various test media. In E. coli strain H-10407, LT activity was markedly decreased if the initial pH of the culture media was reduced to pH 7.5 or less. In contrast to E. coli P-263, if strain H-10407 was grown in the presence of mitomycin C there was no increase in LT production. Crude-culture filtrates containing LT can be stored at 4 degrees C for several days without an appreciable loss of activity; however, for long-term storage lyophilization or freezing at -70 degrees C is recommended.

Oculofacial-skeletal myorhythmia in central nervous system Whipple's disease: additional case and review of the literature.

A case of oculofacial-skeletal myorhythmia associated with cerebral Whipple's disease is presented. This peculiar abnormal movement disorder consists of a convergent-divergent pendular nystagmus associated with a synchronous, rhythmic movement of the mouth, jaw, and extremities. The movements in previous cases have responded inconsistently to a variety of broad-spectrum antibiotic drugs, and antiepileptic, muscle relaxant, antispastic, and psychotropic drugs. The current patient's mental status improved after starting intravenous ceftriaxone but improvement of the abnormal movements occurred only after the addition of oral valproate. Current treatment consists of intravenous trimethoprim-sulfamethoxazole for 2 weeks followed by oral trimethoprim-sulfamethoxazole twice daily for 1 year. Presented here is an alternative treatment of intravenous ceftriazone followed by oral trimethoprim-sulfamethoxazole in combination with valproate for abnormal movements not responsive to antibiotic drugs alone.