Long-term prognosis for patients with ulcerative proctosigmoiditis (ulcerative colitis confirmed to the rectum and sigmoid colon).

Despite its frequency, ulcerative proctosigmoiditis is poorly recognized and its prognosis is not well understood. This study reviews experience at the Cleveland Clinic from 1960 through 1972, with a 97% follow-up. A total of 359 patients with a diagnosis of ulcerative proctosigmoiditis were followed for a mean of 11 years (range 3.2--17.7 years). There were 219 men and 140 women. Mean age at diagnosis was 40.6 years. All had rectal bleeding, typical proctosigmoidoscopic findings of diffuse granularity, mucosal ulcerations and friability, and normal findings above the rectosigmoid on barium enema. The major complaint in all patients was rectal bleeding, and there were few other symptoms. Perianal disease was absent. On the whole, the patients were older than the usual patients with ulcerative colitis; 37 were older than age 61 at diagnosis. The disease remained localized and the prognosis accordingly was good for 90% of the patients. Extension to the proximal colon developed in 10% (36) of patients, and operation was required in 8% (29), two for toxic megacolon. Operation was carried out a mean of 5.6 years after diagnosis: 2.2% (8) of the patients died during the period of follow-up, six after operation. One patient had carcinoma of the sigmoid colon 12 years after diagnosis. Only one patient was subsequently found to have Crohn's disease. Thirty-nine patients died from causes unrelated to colitis. This study suggests that ulcerative proctosigmoiditis as defined by typical sigmoidoscopic appearance and a normal barium enema is relatively common, that proctosigmoidoscopic findings are identical with those of universal ulcerative colitis, but that the outlook is much better. Ulcerative proctosigmoiditis is rarely confused with Crohn's disease, and carcinoma is rare. Recurrences do occur, however, and proximal extension develops in 10% of patients, usually within 5 years after the diagnosis is first made.


Therapy of antibiotic-associated pseudomembranous colitis.

Seven patients treated with oral cholestyramine for antibiotic-associated pseudomembranous colitis are reported. Response was variable with only one patient having a totally satisfactory clinical outcome. Five of seven patients had continued systemic signs with fever and leukocytosis throughout the course of cholestyramine. Two observations were relatively consistent. First, six of the seven patient had a decrease in the number of daily stools during therapy. Second, all patients showed persistence of the cytopathic toxin in stools obtained after three to seven days of cholestyramine therapy. Six patients who were subsequently treated with oral vancomycin had a prompt clinical improvement and clearance of the cytopathic toxin in the stool.


A double-blind study of radiologic accuracy in diverticulitis, diverticulosis, and carcinoma of the sigmoid colon.

A review of the barium enema studies in 73 patients with diverticular disease of the colon and with and without associated neoplasm leads to the conclusion that the correct radiologic recognition of an associated neoplasm in a colon with diverticulitis or diverticulosis can be made only about half the time. The limitations of the radiographic method and radiologic findings in distinguishing diverticulitis from carcinoma should be more clearly recognized by the clinician.


Transition from diffuse esophageal spasm to achalasia.

A 19-year-old man first presented with clinical, radiological, and manometric features of diffuse spasm. Within a year his motility disorder progressed to "vigorous" and, finally, classic achalasia. After pneumatic dilatation and subsequent long myotomy, the features of classic achalasia disappeared and he again exhibited radiological and manometric evidence of "vigorous" achalasia. The evolution of this patient's disease provides evidence that diffuse spasm and achalasia are different stages of the same disease and lie at opposite ends of a spectrum of related esophageal motility disorders.


Fine-needle cholangiography (FNC) in the nonjaundiced patient.

Fine-needle cholangiography (FNC) in the jaundiced patient is well established, but its role in the diagnostic work-up of nonjaundiced patients has not been emphasized. We present 44 consecutive nonjaundiced patients with a serum bilirubin level of 2.4 mg% of less who underwent FNC. The indications were recurrent RUQ pain (77%), painless cholestasis (16%), and relapsing pancreatitis (7%). In all but two patients, one or more inconclusive techniques [oral cholecystography, ultrasonography, intravenous cholangiography, or endoscopic retrograde cholangiography (ERC)] had been employed prior to FNC. Biliary tract opacification was successful in 35 of 44 (80%). In nine of 35 (26%) choledocholithiasis and/or cholelithiasis was present. In four (11%) a significant extrahepatic biliary stricture was noted. More than five needle insertions were often required for successful entry. No complications occurred. Indications for FNC should be extended to include nonjaundiced patients with RUQ pain or painless cholestasis in whom oral cholecystography, ultrasonography, and intravenous cholangiography have been of no diagnostic help. The relative ease and low cost of FNC make it preferable to ERC in these patients.


Local duodenal metastasis from colonic carcinoma.

The clinical and radiologic appearance of an isolated metastasis to the duodenum may mimic a primary pancreatic or duodenal cancer. As lymphatics from the right colon drain to periduodenal lymph nodes, lymphatic spread from right colon cancer can cause enlargement of the duodenal loop, with ulceration or distortion of the mucosa on the medial aspect of the duodenum. We present three patients with ulcerating metastases in the duodenum from colon cancer whose cases exemplify the problems of diagnosis and management.


Keeping up-to-date: some current surgical and radiologic procedures.

Surgical advances often call for close radiologic scrutiny to assess their success or complications. At the same time, diagnostic radiology is also constantly developing new approaches. It is for this reason that we describe the radiographic analysis of several current surgical and radiological procedures which should be of interest to the practicing clinician. The current surgical procedures considered are gastric bypass for morbid obesity and continent ileostomy. The current new radiologic procedures include techniques for performing small bowel enema, per-oral ileal and colonic examinations with retrograde air insufflation, and improved evaluation of the postantrectomy stomach using double-contrast techniques.


Long-term prognosis of ulcerative colitis with onset in childhood or adolescence.

From 1955 through 1974, 336 patients with ulcerative colitis diagnosed before age 21 years were studied. In 93 patients (29%), a blood relative had ulcerative colitis, one case of Crohn's disease being found. The total colon was involved in 63% of patients; the entire colon or all but the rectal stump was removed in 35%. Eighteen patients died, nine of carcinoma of the colon. Sixty-five percent of patients had symptoms for longer than 6 months before the diagnosis of ulcerative colitis. If the diagnosis was delayed more than 24 months, there was a statistically significant correlation with increased rate of operations and complications and less good quality of life. When the 20-year study period was divided into two 10-year periods, the operative and complication rates were significantly different. Early diagnosis and treatment appear to improve the long-term prognosis of young patients with ulcerative colitis.


Management of toxic megacolon: the significance of early recognition in medical management.

Twenty-seven patients with acute toxic dilatation of the colon (TM) as a complication of inflammatory disease of the colon are reported. To emphasize the importance of early recognition and therapy, we separated the patients into two groups: 19 were receiving care by the authors (series A) before the development of TM, and eight were seen in consultation after its onset (series B), TM subsided with medical therapy in 13 episodes among 19 patients in series A and two of eight B. The others underwent surgical therapy. There were no deaths in either group. The differences in management and mortality from other reports suggest a program of surveillance and therapy for this life-threatening situation.


Esophageal roentgenographic "abnormalities" in patients without esophageal symptoms.

Esophageal roentgenographic studies were done on 100 persons with no esophageal symptoms to determine the range of normal anatomy and motor activity. Sixty-three persons had at least one "abnormality." Fifty-eight had an hiatal hernia, 42 had rings of one sort or another, and 21 had motor disorders. The high incidence of rings which can be demonstrated by maximal distention of the lower esophagus is of special interest in view of the recent additions to knowledge of the anatomy of this area. The range of what should be considered normal roentgenographically should be widened, and the physician should interpret with caution reports of esophageal abnormalities in asymptomatic persons.


Pneumatic dilation under general anesthesia after unsuccessful cardiomyotomy for achalasia.

A 12-year-old girl with achalasia was treated successfully under general anesthesia with pneumatic dilation after she had experienced two unsuccessful surgical procedures. The Mosher dilator was passed into the stomach by threading it over a guide wire. Our experience suggests that pneumatic dilation can be performed in children or adults after surgical failure and that general anesthesia may be employed.


Mechanical and neurogenic factors in postvagotomoy dysphagia.

Postvagotomy dysphagia (PVD) has been attributed to either periesophageal obstruction or failure of the lower esophageal sphincter (LES) to relax, presumably from interruption of preganglionic, contraction-inhibiting vagal fibers--a postvagotomy achalasia (PVA). This report describes a patient with periesophageal fibrosis which was successfully treated with dilation, and a second patient with an achalasia-like pattern on esophageal manometry after unilateral high, transthoracic vagotomy. The second patient is the first manometrically documented example of achalasia in a human subject related to proximal vagotomy. Most, if not all, PVD is due to esophageal obstruction and PVA is rare.


Ureteropelvic junction obstruction.

Physicians sometimes forget nongastrointestinal causes of abdominal pain. Yet, abdominal pain was the major complaint of three patients with ureteropelvic junction obstruction (UPJ). Definitive diagnosis can be made either by a "hydration" intravenous pyelogram or by an intravenous pyelogram during an attack.


Pelvic neoplasia in Peutz-Jeghers syndrome.

A cervical adenocarcinoma, a left ovarian granulosa cell tumor, and a right ovarian sex cord tumor with annular tubules developed in a woman with Peutz-Jeghers syndrome. This apparent first report of three different pelvic tumors occurring in a patient with Peutz-Jeghers polyposis suggests a possible link between pelvic tumors and the Peutz-Jeghers syndrome.


Effects of halogenated analogues of cortisol and progesterone upon hair growth in castrated mice.

Several synthetic analogues of cortisol and progesterone were compared to cortisol in their effect of inhibiting the hair growth waves in castrated male C3H/Ep mice. This inhibitory effect was enhanced by fluorination at C-9 alpha and by methylation at C-16 alpha; it decreased by hydroxylation at C-17 alpha and C-21, by removal of hydroxyl group at C-11 and by the addition to bromine to C-12 alpha; it was not modified by oxidation of the hydroxyl group at C-11 or by the delta 1-4 substitution. There was a correlation between the glucocorticoid and hair inhibiting potencies in the cortisol analogues, but some progesterone analogues with very low glucocorticoid activity have marked hair inhibitory effects. No relation was found with the mineralocorticoid effects.


Digital interface for bioelectrical data acquisition system.

The action potential digitalized and stored by means of a fast solid state electronic waveform recording system (Digitalizer) can be directly read out on a printer or in a computer for further processing. It has been designed a digital interface allowing the automatization of these bioelectrical data acquisition and printing process.


Urate-oxidase in liver of oxonic acid treated mice.

Following a single intraperitoneal injection of oxonic acid, urate-oxidase inhibitor with optical and chromatographic properties of the injected drug was found in the supernatants of mouse liver homogenates. Maximal inhibitory activity of 40 000 g-20 minutes supernatants against Sigma urate-oxidase was found 30 minutes after injection, and it almost disappeared after six hours. In whole homogenates, urate-oxidase activity was found 50% inhibited at 30 minutes, and it returned to normal levels between 3 and 6 hours following injection. Urate-oxidase activity of resuspended nuclei-free 40 000 g particles from these homogenates showed a significative increase of activity over controls during the first three hours after injection, and it returned to a normal level between 3 and 6 hours after injection. There was, instead, no increase of activity in 40 000 g-20 minutes particles suspensions when these were separated from homogenates prepared from untreated mice and incubated with oxonic acid.


Digitalizer system and memory for electric transients.

It was designed a fast solid state electronic waveform recording system (Digitalizer), which can record, store and display action potentials or any type of event, either single pulse or repetitive, as a function of time. Above all, its capacity to record fast transients and to give the output in analog and digital form, makes this electronic device more convenient that conventional recorders or single trace oscilloscope systems.


Functional pharmacological and morphological characteristics of two regions of rat uterine horns.

A histological, physiological and pharmacological study of two regions of the isolated uterine muscle of the rat., i.e., the myometrial one (a zone close to the mesometrial insertion) and the linea uteri (the antimesometrial zone) was performed. From the histological point of view the linea uteri (LU) is characterized by the presence of small bundles of longitudinal smooth muscle fibers (20 to 50), closely packed and clearly surrounded by a connective tissue, whereas in the myometrial zone (M) the smooth muscle fibers are less closely packed and the connective tissue is surrounding a greater number of them. The spontaneous oxytocin or electrically-induced initial tension developed by the LU or the M, was similar. Also the stability with time did not differ between both regions. Atropine depressed consistently the isometric developed tension of M strips, either spontaneously active or driven by oxytocin or electrical stimulation, but had no action on the mechanical activity of preparations from the LU. A pretreatment with hemicholinium also inhibited the spontaneous as well the oxytocin-induced motility of M strips, without affecting those of LU. Pharmacologic evidences suggest that acetylcholine may play a "facilitating" role in M strips for the conduction of coordinate contractions. This does not appear to be the case in the LU, which has the required characteristics to be recognized as a conductive like tissue.


[Respirometry by bipolar electric transthoracic impendance].

In a population of ten young normal male subjects (average height of 174.2 cm +/- 3.8, average weight of 70.2 kg +/- 6.16), which was subjectively classified as mainly ectomorph (slightly biased towards the mesomorph type) a good correlation was found between the transthoracic impedance changes due to normal respiratory movements and tidal volume (average r of 0.963 +/- 0.034) and a mean coefficient b1 of 3.64 ohms/liter +/- 1.82. For equal volume, inspiratory and expiratory movements, on the average, produced impedance changes with no significant difference (p less than 0.55). Attempts to quantitatively correlate the coefficient b1 (ohms/liter) with the anthropometric parameters did not produce any consistent result.


Participation of the anterior hypothalamus in the regulation of arterial blood pressure.

Bilateral electrolyte lesions of the Anterior Hypothalamus (AH) were placed in rats to determine the extent to which this area participates in the regulation of Arterial Blood Pressure (ABP). Experiments were performed in two groups of rats; in one ABP was measured continuously for 44 hr subsequent to the lesion, and in a second group ABP was measured 24 hr after the placement of the lesion. The destruction of this area results in a rapid development of arterial hypertension, hypermotility and hyperexcitability. 24 hr later these effects are attenuated. We conclude that arterial hypertension is probably due to a disinhibition of sympathetic activity through central interruption of baroreceptors reflexes.


Temperature effects on the properties of the Hodgkin-Huxley propagated action potential model determined by computed solutions and phase-plane analysis.

The equation for membrane potential (V) of the squid giant axon or some muscle cells, which is the heart of the Hodgkin-Huxley model for the action potential, can be written in three ways: first, as a partial differential equation in time and space; second, as an ordinary differential equation in time, assuming uniform wave propagation for the action potential, and third, as an even simpler ordinary differential equation for the potential at a point, so-called "space clamp" conditions. Solutions were computed for the first two of these equations, at three different temperatures, and the results compared. Temperature dependence of the appropriate parameters was calculated from a simple exponential relationship. Significant changes in the quantitative predictions of the model were found as the temperature was changed from 6.3 C to 18.5 C. Phase-plane (V v V, I v V) analysis has been used to examine the nature of these differences.


The measurement of bile acid-dependent and independent fractions of rat bile.

Bile flow and bile acid secretory rate in rate in rats with interruption of the enterohepatic circulation had a biphasic decay with the second slower slope less marked for bile flow. A direct relationship between both parameters was observed in these animals. by knowing the choleretic efficiency of bile acids calculated from the regression line, the total bile acid output and the volume of bile collected, the fraction of bile produced by other way than bile water carried by bile acids was estimated. This fraction was found to be about 65 percent of the total bile formed.


Glucocorticoid action on rat spleen cells. I. Action of cortisone on antibody forming cells.

Corticosteroid action on rat spleen tissue was studied in order to determine the action of the hormone on cells involved in the early phase of the immune response. A significant reduction of plaque forming cells (PFC) was observed when the steroid was administered simultaneously with the antigen and even had some effect when injected up to three days immunization. Inasmuch as it can be assumed that at a period of 72 hr or less a great number if not all the cells are challenged by the antigen, results indicate a lympholytic action of the hormone on the already stimulated cells.


Effect of drugs on the force of spontaneous mechanical activity in rat portal vein.

A study was made on the force of spontaneous mechanical activity in the rat portal vein. Prostaglandin inhibitor, sodium meclofenamate, phosphodiesterase inhibitors, aminophylline and dipyridamole, adenosine and blockade of calcium entry by isoptin all reduced the force of spontaneous activity in a concentration-dependent manner, while imidazole enhanced it. Low concentration of aminophylline (10 microM), dipyridamole (6 microM) and meclofenamate (10 microM) depressed the spontaneous contraction of the vein by about 50% without modifying the response to noradrenaline. At higher concentration of these drugs, spontaneous mechanical contraction was reduced further and the response to noradrenaline antagonized. Low concentration of isoptin also reduced the mechanical activity without affecting maximum response to noradrenaline. A common mechanism of action for the drugs tested, namely the limiting of Ca2+ availability for muscular contraction, is discussed. Adenosine markedly reduced the spontaneous mechanical activity of the rat portal vein. Its relaxation effect could be due to the activation of a specific adenosine receptor.


Studies on the tissue specificity of a circulating renotropic factor.

In 1970, it was found that sera removed from rats 24 hr after unilateral nephrectomy stimulate the incorporation of 3H-Thymidine into the DNA of incubating rat renal cortex. The same sera did not influence isotope incorporation into the DNA of incubating liver, spleen, and lung tissue. Later, a substance was described in renal tissue that enhanced the action of the renotropic factor in sera. It was proposed that this tissue factor activated the circulating renotropic substance and that lack of this activator in other tissues was responsible for the specificity of the circulating renotropic substance to renal tissue. The present study suggests that this is the case as the addition of the renal tissue factor and sera from uninephrectomized rats can stimulate 3H-Thymidine incorporation into the DNA of rat liver slices.


Fluid pressure and fibrinolytic activity in implanted subcutaneous and intramuscular capsules.

Using the capsule implantation method, the relationship between the intracapsular fluid pressure (IFP) and fibrinolytic activity of the intracapsular fluid was examined in subcutaneous and intramuscular capsules. When IFP was positive, the sterility test was positive (indicating infection), the fibrinolytic activity was enhanced, and the response of IFP to volume change or hypertonic solutions was poor. On the other hand, when IFP was negative, the sterility test was negative, the fibrinolytic activity was weak, and the response of IFP to volume change or hypertonic solutions was good. Also, the more negative the IFP, the weaker was the fibrinolytic activity in the intracapsular fluid (r = 0.60, p less than 0.01). The ratio of the intracapsular fluid fibrinolytic activity to the plasma fibrinolytic activity showed a good correlation to the intracapsular fluid pressure (r = 0.68, p less than 0.01). When the fibrinolytic activity was activated by injection of streptokinase and human plasma, the IFP showed a tendency to increase. These results suggest that the fibrinolytic system plays some role in the maintenance of local fluid balance.


Influence of temperature on isometric contractions of rabbit atria during inotropic interventions.

Inotropic effects on strips of left atria promoted by 1-epinephrine, increase in frequency, post-extrasystolic potentiation, and by increase in extracellular calcium concentration were studied at 28 C and 36 C. The results show that at lower temperature the resulting changes in temporal parameters (activation time, deactivation time and duration above 10% of maximum force) are greater than those at the higher temperature. AT 36 C inotropic interventions have more prominent effects on the tension development and its first derivative, while changes in temporal parameters become less conspicuous. It is concluded that the inotropic interventions regulate the strength of contraction more effectively at 36 C and the temporal aspects of contraction more effectively at 28 C.


Phase plane determination of the mechanical properties of the myocardium.

A phase-plane diagram, obtained by plotting force versus the rate of force during isometric contractions, was used for determination of the mechanical properties of rabbit left atria. Considering the muscle as a two component mechanical analog we found: (a) the initial slope of the phase-plane diagram (m1) is proportional to the product KVmax, where K is the stiffness of the series elastic component, and (b) the final slope of the phase-plane diagram (m3) is equal to the product -Kb, where b is a constant with dimensions of velocity, and may be related to the absolute rate of energy liberation. It is shown that m1 increases with positive inotropic interventions (frequency increase, epinephrine, post-extrasystolic potentiation, elevation of calcium and increase in temperature) but does not change as a function of muscle length. The final slope M3 increases with frequency, temperature and epinephrine; decreases with calcium and stretch, and does not change with post-extrasystolic potentiation. The results also suggest that the change in m3 depends on the particular inotropic intervention. This supports the idea that separate mechanisms are responsible for the process of contraction and relaxation.


Sulfobromophthalein metabolism in isolated perfused rat liver. Factors determining the applicability of the model.

Sulfobromophthalein (BSP) was used to test the applicability of the isolated perfused rat liver in the study of drug metabolism. Flow of perfusate through the liver averaged 35 ml per min and the bile flow rate was 0.75 microliters per min per g of liver. BSP was delivered into the system as a single dose of 4.7 to 9.5 mumoles. Samples of perfusate from the pre and posthepatic circuits and bile samples were obtained at different time intervals. The following parameters were elimination half life, mean hepatic clearance, mean intrinsic clearance, time course of hepatic and bile concentrations and percent dose excreted into bile. The results demonstrated that bile flow and BSP biliary excretion depended on hepatic blood flow. Time course of hepatic concentration decay and mean intrinsic clearance were a reflection of the inherent ability of the liver for BSP elimination into bile. The parameters tested and their correlations gave overall information on isolated liver function that may be applied to the study of other exogenous or endogenous compounds.


The handling of bilirubin and sulfobromophthalein by the isolated perfused rat liver.

The isolated perfused rat liver was used for the study of the characteristics of bilirubin transfer from perfusate to bile in comparison to those of sulfobromophthalein (BSP). The parameters estimated included mean extraction ratio, removal half life, hepatic clearance, intrinsic or metabolic clearance rate of biliary excretion, hepatic concentration and biliary concentration for both compounds. The results obtained favoured the conclusion that bilirubin was less efficiently handled than BSP by the isolated rat liver.


The effect of the anticonvulsants phenobarbital and diphenylhydantoin on intestinal absorption of calcium.

The effect of anticonvulsant drugs (phenobarbital and diphenylhydantoin) on the metabolic balance of calcium and on its intestinal absorption, as measured by an in situ intraluminal perfusion method, was studied in rats. The administration of these drugs produced: (a) an increase of the fecal excretion of calcium,. (b) a decrease of the intestinal absorption of calcium (45Ca). Both effects were more intense in rats treated with phenobarbital. There is evidence to suggest that the anticonvulsant drugs affect the intestinal mechanism of active transport of calcium.


Pitfalls in kinetic studies of multiexponential decay processes with special emphasis on desaturation curves of arterial Na.

The purpose of this study was to detect and solve apparently trivial methodological flaws in experiments of the decay type which can invalidate any fitting procedure or compartmental analysis. The problems dealt with consisted in maintaining the steady state conditions defining the "true" starting time of the efflux and its optimal duration, determining the number of exponential terms and finding how many data points are necessary to identify them. The solutions proposed include avoidance of tissue blotting prior to the efflux, running a separate non effluxed sample, stopping the washout when the log plot of remaining and effluent counts becomes parallel, use of the optimization if the correlation coefficient for curve fitting and adequate the frequency of counting to the decay rate. Errors resulting from the failure to comply with these requirements are illustrated with samples.


On the psychology of the aging woman. Depression in late mid-life: change or repetition? Another chance for working through.

A woman of 58 came for psychotherapy for the first time suffering from a depressive reaction precipitated by two mid-life events: the marriage of her daughter and the realization that her own cherished marital dream would never be fulfilled. She had postponed coming to terms with the disappointments of her marriage as long as she had had other objects. When these objects were lost, and the distance she had maintained to handle her feelings was threatened, she sought help. There was suggestive evidence that a collusive marital system had sustained an unsatisfactory relationship for 35 years. Her husband was described as an obsessive-compulsive character. His traits were both needed, feared, and resented by the patient, representing the rejected part of herself and aspects of her hated grandmother. Mrs. A. had character traits and a developmental history which supported a diagnosis of primitive hysterical personality. (This type has been described by Zetzel (1968) as "the so-called good hysteric.") The paucity of object relationships in her life, her poor work habits, her inability to tolerate affects were striking. The patient had identified with a pathological mother in a family dominated by rejecting and depreciating attitudes. The patient's use of the defense mechanisms of splitting, projection, and withdrawal as ways of dealing with ambivalence significantly interfered with her self-object differentiation and her capacity for intense emotional or physical intimacy. She could only love men whom she rescued or protected, a pattern consistent with the fact that she could not relate to equals or superiors. Yet she was unable to draw on a good identification with a nuturing mother, so as to really be able to give. There was too much hurt and uncontrolled anger when she was in the superior position with the kind of man who could not meet her dependency needs. Feeling unprotected, she had married a "strong" man, who she expected would meet her narcissistic and dependency demands. He was inhibited and controlled and could neither need nor be needed by her during his active work life. This led to immediate disappointment of her conflicting conscious and unconscious expectations. She wanted him to be strong and ideal, yet to need her and never oppose her. Hence, there was a failure to establish a mature or satisfying marital relationship. She turned to her children for comfort, particularly her daughter, becoming depressed when her daughter married. She found gratification by staying busy tutoring and teaching underprivileged children. In the course of treatment her depressive symptoms disappeared. She felt hopeful, capable of being believed in, and able to cope as a result of the therapist's functioning as her uncritical ally. After she resumed living with her husband she began to acknowledge an ambivalence toward her cherished, confidante daughter and in some ways reversed her previous splitting of husband and daughter. The mean husband became a kindly saint and the darling daughter became a critical, spiteful queen...


Strategies of dynamic psychotherapy with the wide range of older individuals.

Until recently contributions to geriatric psychotherapy tended to be limited to the consideration of the special problems of the most debilitated of the elderly, neglecting the vigorous majority of aging persons. The reluctance of psychoanalysts to treat individuals past 45 or 50 years of age by classical technique may have impeded the application of psychodynamic principles to the psychotherapy of older people. Gradually, a number of analysts and dynamic therapists reported favorable responses of the middle aged and elderly to such treatment and established some of its technical parameters. In this paper, distinguishing characteristics of the aging and of the debilitated aged are examined in order to clarify the techniques of geriatric psychotherapy. Six case vignettes illustrate the treatment aims of structural change, reinstatement of optimum functioning, and basic support in these two categories and in an intermediate group of those experiencing an emotional crisis. The application of psycho-therapeutic principles (promotion of insight, adaptive intervention, general supportive methods) is described. Psychological management is compared with psychotherapy in the debilitated aged. Treatment of emotional crises in older persons is illustrated. A sample of patients treated by means of psychotherapy--aging, in crisis, or debilitated--is examined with regard to diagnoses, precipitating stresses, the aims of therapy, and the involvement of their families in the treatment.


[Rabies vaccine inactivated with ethylenimine. Duration of the immunity in dogs].

The duration-of-immunity afforded by the ethylenimine inactivated rabies vaccine produced in BHK cells with the PV strain, was studied in dogs. One hundred per cent of the dogs became serologically positive 7 days after vaccination; the same percentage was still positive 3 years after vaccination with one dose of the vaccine. A good correlation was observed between the antibody profiles as determined by the titers obtained with the mouse neutralization and fluorescent field inhibition techniques. The correlation was not as good when the number of international units per ml was determined by both tests. The best correspondence between serological response and resistance to challenge was observed when the antibodies were determined by the number of international units per ml, using the neutralization test in mice. All the dogs challenged 12 and 25 months after vaccination resisted challenge; 89% (8/9) were protected 36 months after vaccination. Inactivated vaccines can be as effective to control rabies as those prepared with modified live virus; moreover, the inactivated vaccines are more stable and safer than the latter.


[Brucellosis in goats in San Luis Province].

A study on goat brucellosis has been done in the province of San Luis, a semidesertic area (annual precipitation ca. 500 ml) located in the center west of Argentina. Flocks were selected by an statistical method. Blood samples were obtained from young and adult females set apart for reproduction. Sera were submitted to a fast plate agglutination test with a standard antigen. Titres were expressed in International Units per ml, accorded to the recommendations of the Centro Panamericano de Zoonosis. Results (Table 1 and 2) of 10367 examined animals showed 13.25% of reacting sera. Out of this total, 8.22% yield a titre of 25 IU per ml, 2.86% 50 UI per ml, 1.13% 100 UI per ml and 1.04% 200 UI per ml.


Effect of in vivo administration of 5 alpha reductase inhibitors on epididymal function.

Progesterone, epitestosterone (4-androstene-17 alpha-ol-3-one, EpiT) and 4- androstene-3-one-17 beta-carboxylic acid (COOH), three known in vitro inhibitors of 5 alpha reductase, were injected daily for 30 days to male rats to study their effect on some parameters of epididymal function. Progesterone at the dose of 750 and 2000 micrograms/day decreased fertility by 59% and 50% respectively. EpiT at a dose of 1500 micrograms/day decreased fertility by 74%. These treatments did not change the sperm counts in the cauda epididymis. Treatment with COOH did not decrease fertility. Progesterone at 750 and 2000 micrograms/day and EpiT at 750 micrograms/day decreased the weight of the epididymis, prostate and seminal vesicles. None of the compounds tested produced variations in body weight or in the weight of liver and testis. The 5 alpha reductase activity of epididymis, testis and liver was diminished by progesterone treatment, while EpiT decreased only that of testis and liver.


Neonatal androgen effects on conditioned emotional response extinction of adult rats under various hormonal regimens.

Intact male rats and spayed female rats received 0.5 mg testosterone propionate in the first 24 hours after birth. They were divided into different groups, administered peanut oil, progesterone, oestradiol benzoate and testosterone propionate in adulthood. The animals were conditioned to fear with a shock paired sound. The experimental test consisted of investigating the conditioned emotional response (CER) extinction. It was verified that as to conditioned emotional response extinction, neonatally androgenized males were different from control males; neonatally androgenized females, testosterone propionate treated in adulthood were also different from control females. There was no significant difference between neonatally androgenized females oestradiol benzoate treated in adulthood and their control group. In comparing neonatally androgenized females having different hormonal treatment in adulthood, we verified that testosterone propionate treated females were significantly different from those treated with progesterone. On the other hand, neonatally androgenized females treated with oestradiol benzoate in adulthood were different from those that have had the same hormonal manipulation in neonatal period, but that were injected with progesterone in adulthood. It was concluded that conditioned emotional response extinction is facilitated by neonatal androgenization in non-oestrogenized male and female rats.


Transcriptional features of fractionated human breast tumor chromatin.

By means of controlled mechanical shearing it was possible to fractionate human breast tumor chromatin in "active" and "inactive" species, according to their in vitro template activity, using Escherichia coli RNA polymerase. The "active" molecules can be resolved in three well defined regions in an exponential sucrose gradient, showing approximately 300 times the efficiency for synthesizing ribonucleic acid, relative to the chromatin which migrated fastest. This technique could provide the initial tool to isolate eu-and heterochromatin from native human chromatin.


Modification by rumen of vitamin D-like activity of Solanum malacoxylon in rats.

The biological activity of aqueous extracts of Solanum malacoxylon (SM) and of extracts preincubated with ruminal fluid (SMRF) on calcium and phosphate metabolism in vitamin D depleted rats was compared. The responses in intestinal 32P and 45Ca absorption, measured in an isolated duodenal loop in situ after a single oral dose, were qualitatively similar to that of 1,25-OH2-vit.D3. However, the effects elicited by SMRF were significantly higher than those caused by SM. Both extracts were equally effective in promoting bone resorption when administered orally or subcutaneously. These results provide a basis to explain the greater effectiveness of SMRF to produce calcinosis in rats. The hypothesis is advanced that biologically active steroidal metabolites with predominant action on intestine, are formed during incubation with rumen.


Acute effects of three natural corticosteroids on the acid-base and electrolyte composition of urine in adrenalectomized rats.

In acute experiments, aldosterone (aldo), 18-hydroxycorticosterone (18 OH B) or corticosterone (B) were administered to adrenalectomized rats and parameters related to acid-base balance measured in urine samples collected for 3.5 hours after injection. Aldo reduced sodium excretion but did not affect pH nor the outputs of K, NH4+, CO3H-, phosphates nor titratable acidity. 18 OH B increased the excretion of titratable acidity and reduced drastically that of CO3H-. The lowest effective dose (3 micrograms) promoted Na excretion while the highest dose employed (6 micrograms) reduced pH and Na excretion. B increased the excretions of phosphates and ammonium, the former drastically. Potassium output either increased or did not change, and pH augmented marginally. It is postulated that a) 18 OH B is a naturally occurring steroid eliciting urine-acidification not necessarily accompanied by sodium retention; and b) at least B and 18 OH B in the rat, possess hormonal roles according to which the latter promotes the presence of protons, and the former, that of acute proton-acceptors in the lumen of tubuli.


Carbohydrate utilization by the avian oviduct during the laying cycle.

In the present work the carbohydrate utilization by the avian oviduct during the egg formation was studied. The pattern obtained for total hexose, fucose, hexosamines, sialic acid, fructose and sulphate demonstrated that in the domestic fowl's oviduct the isthmus and the shell gland secrete the precursors for the protein carbohydrate substance of the mammillae and shell matrix and may contribute during the shell formation with the substrates necessary for the metabolic energy of the organ. The infundibulum only participates as a donor for the metabolic energy.


Influence of the subfornical organ on water intake induced by septal lesion.

Rats bearing lesions in the septal area (SA), or in the subfornical organ (SFO) or simultaneously in both regions were submitted to various thirst-eliciting procedures. The rats with hyperdipsia induced by lesion of the SA drank more water than either normal rats or SFO-lesioned animals under the same thirst-eliciting or angiotensin-liberating stimuli (polyethyleneglycol, isoproterenol, water deprivation and ligation of the inferior vena cava). The overdrinking elicited by SA lesions was blocked after SFO lesions. Neither hypovolemia, nor hypotension or water deprivation could elicit increased water intake in SFO-lesioned animals even after destruction of the SA. Animals with SFO lesions did not show increase of the water intake after cellular dehydration. The results obtained suggest that the SFO acts as the main structure in the regulation of water intake elicited by angiotensin with two opposite effects: one direct, facilitating water intake and the other indirect inhibiting the SA. The SA has an inhibitory effect on the SFO and on water intake.


Dilution techniques for optimum recovery of cryopreserved bone marrow cells.

Bone marrow granulocyte progenitor cells (CFU-C) were assayed in methyl-cellulose prior to cryopreservation in Dimethylsulfoxide (DMSO) and after thawing and diluting the DMSO. The time of dilution from 10% to 1% DMSO and the temperature of the sample and diluting media were studied. Compared with samples diluted at 0 degrees-4 degrees C, samples which were diluted at 24 degrees C were more viable by Trypan Blue exclusion (p less than .01) and had greater CFU-C growth in vitro (p less than .01). There was no advantage to prolonging dilution time from 10 minutes at a constant rate to 40 minutes using stepwise technique. Recovery of CFU-C at 24 degrees C ranged from 40% to 114% with a mean +/- S.D. of 67% +/- 19.5%. There was evidence that clonogenic cells were selectively preserved under the conditions described.


Mobilization of murine hemopoietic stem cells (HSC) by Pyran Copolymer.

Pyran Copolymer, divinyl-ether maleic anhydride increases the concentration of circulating pluripotential stem cells in mice by a factor of 15 to 30. Maximal mobilization occurs five days after Pyran Copolymer injection with synchronous peaks of CFU-S and CFU-C. When Pyran fractions of defined molecular weight from 12,000 to 52,000 are injected into mice, mobilization of CFU-S and CFU-C parallels molecular weight. Hemopoietic stem cells are mobilized from bone marrow into peripheral blood and subsequently trapped in the spleen.


In vitro proliferation of hemopoietic stem cells in long-term marrow cultures: principles in mouse applied to man.

The continuous in vitro marrow culture system for proliferation of mouse pluripotent hemopoietic stem cells (CFUs) and granulocyte-macrophage progenitor cells (CFUc) as initially described by T. M. Dexter, depended upon a 25% concentration of special lots of horse serum and addition of fresh "recharging" marrow after 3-4 weeks. This system has been modified to permit longer hemopoiesis in non-recharged cultures over 25-30 weeks. Addition of 10(-7)M hydrocortisone sodium hemi-succinate during weekly feeding and switch from horse to 25% fetal calf serum with corticosteroid at week 4, maintains stability of the adherent marrow stromal cells, decreases lipogenesis (which is deleterious after 10 weeks) and increases proliferation of hemopoietic cells over longer duration. Stem cells removed from 8 week old primary NIH/Swiss marrow cultures reconstituted hemopoiesis in lethally irradiated mice. While 16 week old cultures produced total numbers of CFUc equivalent to 8 week cultures, these cells could not prevent marrow death following similar total body irradiation. Thus, stem cells moved progressively from a pluripotent to a committed CFUc compartment between weeks 8-16. Human femur marrow required thyroxine in addition to hydrocortisone for sustained CFUc maintenance over a shorter 8 week period. Improved technology for mouse long-term marrow cultures should further aid in developing a usable human "Dexter-system".


Lack of genetic damage in mammalian cells after cryopreservation at -196 degrees C.

Mammalian tissue culture cells when cryopreserved according to standard procedures do not show gross chromosomal changes as evidenced by the formation of micronuclei. Cryoprotective agents used in this study included dimethyl sulfoxide (DMSO), glycerol and polyvinylpyrollidone (PVP) in combination with serum and using freezing and thawing rates normally employed in cryopreservation studies. In preliminary experiments, point mutations as evidenced by oubain resistance were not observed. These results are discussed in relation to previous studies indicating genetic stability after freezing and thawing.


The use of stem cell assays to monitor the proliferative potential of bone marrow cells.

A number of assays exist for hematopoietic stem cells in both humans and mice, but the appropriate stem cell assay for the repopulating potential of human marrow is not clear. Two murine models suggest that these assays may not always predict marrow proliferative potential. In vivo diffusion chamber culture growth of CD1 marrow depleted of pluripotent stem cells (CFU-S) by exposure to mouse-brain antisera plus complement was equivalent to or greater than that of normal serum treated control marrow. Furthermore, CF1 mice repeatedly injected with endotoxin had markedly stimulated granulopoiesis with increases in the number of marrow CFU-S and the % in S phase but no changes in the number or proliferative status of marrow CFU-C. However, inbred BDF1 mice chronically injected with endotoxin although also showing striking increases in granulopoiesis had no significant alteration in their marrow CFU-S or CFU-C number or cell cycle status relative to saline injected controls. Both models present examples where conventional stem cell assays do not provide insight into marrow cell production and suggest that in vitro clonal assays of human marrow cells may not always predict for the potential of marrow to repopulate a human transplant recipient.


Beyond kinetics: the study of DNA damage and repair in bone marrow cells.

The response of the bone marrow to cytotoxic agents is a prime determinant of differential toxicity in cancer chemotherapy. Previous attempts to characterize drug effects on the bone marrow have largely been concerned with the proliferative status of the marrow cells. The DNA alkaline elution technique has recently proven to be a simple, sensitive technique for the study of drug-induced DNA damage and repair. The potential for applying this technique to mechanisms of bone marrow toxicity is discussed.


Dose limiting extramedullary toxicity of high dose chemotherapy.

Autologous marrow support may allow higher doses of myelosuppressive chemotherapy administration with the hope of improving tumor responses. The approach will be limited by the extramedullary toxicities of the drugs employed. This paper reviews some of these toxicities for selected drugs, and gives examples of techniques which could be used to reduce their incidence.


Collection and cryopreservation of mononuclear blood leukocytes and of CFU-C in man.

For bone marrow reconstitution after hemopoietic failure as a consequence of the action of a variety of etiological factors, hemopoietic stem cells are needed. These have been derived in the past mainly from bone marrow. This report describes studies and their results that indicate that granulocytic progenitor cells, measured in cell culture systems as "colony forming units in culture - CFU-C", can be collected in large quantities from the peripheral blood of human blood donors by continuous flow leukapheresis. They can be stored at ultra-low temperatures. Their recovery rate after thawing and washing is better than 85%. In a canine model, evidence was obtained that the presence of CFU-C in a suspension of mononuclear blood leukocytes is also indicative for the presence of pluripotent hemopoietic stem-cells. Therefore it is suggested that stem cells can also be collected from human blood as an alternative source for bone marrow reconstitution.


Erythroid progenitor cell numbers in human marrow - implications for regulation.

Marrow specimens were obtained from 34 different individuals (mainly stage I or II Hodgkins or Lymphomas) and evaluated for their content of erythropoietic and granulopoietic progenitor cells using conventional colony assay procedures and a standardized set of re-agents. Frequency distributions showed that the data for all types of progenitors appeared to be log normally distributed. Estimates of compartment size (i.e. no. of progenitors per 2 X 10(5) buffy coat cells) were 107 CFU-E, 70 BFU-E (37 classified as mature, 12 classified as primitive) and 64 CFU-C. The ratio's of CFU-E: mature BFU-E: primitive BFU-E numbers in vivo correspond well to those predicted by their proliferative capacity in vitro. Interestingly the spread of values obtained for each erythropoietic compartment was not the same but decreased with progressive differentiation, suggesting that stringent regulation of red cell output may not occur until the latter stages of erythroid cell maturation. The ratio of total BFU-E: CFU-C numbers was 1.25 +/- 0.15 suggesting that on average the probability of stem cell commitment to either the erythropoietic or granulopoietic pathway may be roughly equal.


Use of videotape feedback with severely disturbed adolescents.

A year of group therapy using videotape feedback with seriously disturbed adolescents offers evidence that such feedback facilitates the correction of these youngsters' distorted body images, low self-esteem, lack of capacity for self-observation, and poor peer relationships. The conscious use of videotape also played an integral part in the group process. It seemed to serve as a third therapist, with considerable amounts of resistance and transference focused on the equipment as it went through the process of being monster, toy and useful tool. An additional benefit was provided to the cotherapists in terms of supervision, and in teaching other staff the techniques of group therapy.


Leukocyte donor and recipient reactions with filtration leukapheresis: their character, frequency, and management.

Neutrophil collection by filtration leukapheresis can be recommended chiefly on the basis of simplicity, low cost and efficiency. The disadvantages of the FL technique include a slightly increased incidence of adverse donor reactions, an increased risk of donor bleeding complications due to the large doses of heparin employed and a marked increase in the incidence recipient reactions, chiefly in the form of fever and chills. Because of these disadvantages, alternative methods of neutrophil collection should be considered when possible. The recently described technique of gravity leukapheresis is one such alternative which does not require investment in expensive new equipment and could be undertaken in any center familiar with plasmapheresis procedures (5).


Phenobarbital in the acute management of febrile convulsions.

Blood levels of phenobarbital were determined after a single oral or intramuscular (IM) dose in children in the hospital after febrile convulsions. At a dose of 15 mg/kg, both the oral and IM routes gave therapeutic blood levels within 90 minutes. Absorption from the IM route before 90 minutes was inconsistent and would be unlikely to arrest an established convulsion within a critical time period. For use as a drug to prevent convulsions, oral phenobarbital at 15 mg/kg deserves further study.


Ethical issues in pediatric surgery: a national survey of pediatricians and pediatric surgeons.

The findings reported in this article are based on a nationwide survey of the attitudes and practices of pediatric surgeons and pediatricians with respect to some of the difficult ethical choices confronting them in medical practice. Four hundred fifty-seven physicians completed a questionnaire in the spring of 1975 in which they reacted to a wide range of issues that have been of increasing concern to the public, as well as to the medical profession. The survey attempts to identify some areas of physician consensus as well as some of the factors, personal and professional, influencing physicians' attitudes. The survey and its statistical analysis are intended to provide current sociological data and are not intended by the authors as an endorsement of any particular point of view or course of action.


Outpatient pediatric surgery in a developing country.

A total of 5,522 outpatient surgical procedures were performed at the Children's Hospital in Kingston, Jamaica, West Indies, between 1968 and 1973. This included 2,662 general surgical procedures. There were no deaths or major complications. Parents participated actively in the preoperative and postoperative care. Outpatient surgery can be a safe, inexpensive, and effective means of health care delivery. It is of special value in developing countries with limited facilities for inpatient care.


Child psychiatry and pediatrics: the state of the relationship.

A great deal of attention has been focused on the notion that child psychiatry and pediatrics should develop strong ties. Yet, a review of the literature suggests that, in spite of exhortations to the contrary, little true collaboration has developed between the two disciplines. This study surveys the major pediatric teaching and training centers throughout the country in an attempt to assess the current state of the relationship between child psychiatry and pediatrics. Of the 82 centers surveyed, 68% responded. Although enthusiasm and desire for closer collaboration were expressed repeatedly, actual successful efforts remain minimal. Psychiatric consultations on pediatric inpatient units continue to be the predominant child psychiatry service provided. A method for achieving closer relationships between the two disciplines is proposed.


Temperament as a factor in early school adjustment.

Infant temperament profiles of "difficult," "intermediate," and "easy" in a randomly selected group of 51 children were shown to correlate with impulsivity and school adjustment at ages 5 1/2 to 7 years. However, the nonlinear relationship makes this a finding of uncertain significance. On the other hand, contemporaneous temperament determinations using the Behavioral Style Questionnaire completed by the children's mothers showed a significant correlation between the adaptability subscale and teacher judgments of school adjustment. This latter finding adds support to the view that temperament is a significant factor in school adjustment and that it can be measured by a clinical instrument appropriate for pediatric use.


[125I]hGH metabolism in acromegaly: effects of chronic treatment with 2-Br-alpha-ergocryptine.

To assess the effects of 2-Br-alpha-ergocryptine (CB-154 Sandoz) on hGH metabolism, six acromegalic women were studied before and after 2 months of treatment with 10 mg bromocriptine/day. GH kinetics were evaluated by noncompartmental analysis of the plasma disappearance curve of immunoprecipitable [125I]human GH after pulse administration of the labeled hormone. MCR was increased in all acromegalics after treatment; the difference between the means [153 +/- 11 vs. 200 +/- 16 ml/min . m2 (mean +/- SE)] was highly significant. Secretion rate (SR), measured as the product of MCR by integrated 12-h concentration, was decreased in four patients after treatment, while it was slightly increased in the other two. No change was found after treatment, either initial distribution volume [2.0 +/-0.1 before (B) vs. 2.1 +/- 0.1 liters/m2 after (A)] or total distribution volume [5.0 +/- 0.3 (B) vs. 5.4 +/- 0.4 liters/m2 (A)]. Diffusion of GH from the intravascular pool, measured as reentry rate, was unchanged with treatment [66 +/- 4 (B) vs. 76 +/- 11 ml/min . m2 (A)]. In conclusion, our study shows that in acromegaly, by increasing the MCR of the hormone, and 2) by reducing the SR. The mechanisms by which bromocriptine increased MCR of the GH are also suggested on the basis of kinetic results; like dopamine, bromocriptine could induce a redistribution of blood flows to different organs, thus resulting in a net increase of blood flow to the liver and kidneys which are the major catabolic sites of GH.


Radioimmunoassay of human thyroglobulin: effect of antithyroglobulin autoantibodies.

This study was designed to investigate quantitatively the interference of thyroglobulin autoantibodies in the RIA of human thyroglobulin (hTG). Anti-hTG autoantibodies were combined with purified hTG to produce samples with known antibody titers and hTG concentrations. These samples were analyzed in the RIA. By using anti-human globulin serum it was first shown that immune complexes formed between labeled hTG and human anti-hTG. It was then shown that the most important factor in determining the direction of the interference was the specificity of the precipitating (second) antiserum with respect to these immune complexes. When the precipitating antiserum was specific, i.e. did not recognize human antibodies, the immune complexes remained in the supernatant and the measured hTG concentration was falsely elevated. When the precipitating antiserum cross-reacted with human antibodies, the direction of the interference depended on the sample volume. At small volumes there was false depression while at large volumes there was false elevation of apparent hTG levels, depending on the capacity of the precipitating antiserum to combine with human antibodies. Anti-hTG titers far below those detected by the tanned-red cell hemagglutination test had very large effects, to the point where measurements of hTG could not be made, when a cross-reactive precipitating antiserum was used. Therefore, the procedure which investigators have used until now, to exclude samples with anti-hTG hemagglutination titers above an arbitrary limit, is not adequate. It is necessary, until methods are developed which avoid the problem of autoantibody interference, to characterize each assay to determine the limits of anti-hTG that can be tolerated. The factors which influence anti-hTG interference in the hTG RIA are 1) the specificity of the precipitating antiserum, 2) the sample volume, 3) the maximum tracer binding, and 4) the anti-hTG titer.


SC 25152: A potent mineralocorticoid antagonist with reduced affinity for the 5 alpha-dihydrotestosterone receptor of human and rat prostate.

It has previously been shown that spironolactone possesses antiandrogenic activity in the rat and interacts with rat prostate 5 alpha-dihydrotestosterone cytoplasmic receptors to block the nuclear uptake of this hormone. Current evidence suggests that this androgen receptor interaction may be an important mechanism through which spironolactone causes endocrine side effects in rat and man. We have analyzed the interactions of several spirolactone analogs with the androgen receptor of human and rat prostate and the mineralocorticoid receptor of human and rat kidney. One analog, SC 25152, was found to have considerably reduced affinity for the prostate 5 alpha-dihydrotestosterone receptor [Ka = 24 +/- 1% and 19 +/- 6% (mean +/- SE) in the human and rat, respectively, of the Ka for spironolactone] while maintaining similar affinity for the mineralocorticoid receptors of human and rat kidney [Ka = 113 +/- 37% and 86 +/- 7% (mean +/- SE), respectively, of the Ka for spironolactone]. These findings would predict this analog to have reduced antiandrogenicity at equivalent therapeutic doses.


Calcitonin secretion in normal human subjects.

A sensitive RIA for human calcitonin has been developed which can detect 1-2 pg hormone. This procedure permits the measurement of the low concentrations of calcitonin in the unextracted plasma of normal human subjects. In 55 normal adults, mean plasma calcitonin was 24 pg/ml with an SD of +/- 18 pg/ml, an SE of +/- 2 pg/ml, and a range of less than 10 - 75 pg/ml. There were no discernible age or sex differences in basal hormone concentration. Infusions of calcium, pentagastrin, and glucagon stimulated plasma calcitonin, whereas food and oral calcium did not. The stimulatory effect of pentagastrin was greater in males than in females. These data demonstrate that the low concentration of calcitonin in humans can be stimulated by several secretagogues and suggest that females may have decreased calcitonin reserve.


Serum 3,5,3'-triiodothyronine, thyroxine, and thyrotropin in hypothyroid infants with congenital goiter and the response to iodine.

Iodine deficiency in adults caused preferred synthesis of T3; this observation has not been reported in iodine-deficient hypothyroid newborns. Serum total T4, total T3, and TSH have been determined in nine full term newborns with congenital hypothyroid goiter before and after cutaneous application of iodine. The mothers of these infants had untreated euthyroid goiter and lived during pregnancy in the area of Göttingen, West Germany, known as an iodine-deficient region. Mean total T4 in the newborns was 6.3 +/- 1.6 (mean +/- SD) micrograms/dl compared to 16.6 +/- 3.4 micrograms/dl in normal newborns at 3-4 days of age. Mean T3 in the goitrous newborns was 2.74 +/- 0.66 ng/ml compared to 1.58 +/-0.41 ng/ml in the control group of the same age. Serum TSH remained elevated during the first week of life, with a concentration of 40.9 +/- 28.7 microU/ml (control group, 4.16 +/- 1.43 microU/ml). The cutaneous application of iodine resulted in rapid disappearance of goiter and normalization of T4 and TSH within 5 days. After 30 days of iodine treatment, T3 decreased slowly but remained elevated (2.0 +/- 0.42 ng/ml vs. 1.67 +/- 0.36 ng/ml in the control group). The present findings confirm preferential T3 secretion in newborns with hypothyroid goiter. The goiter is thought to be caused by intrauterine iodine deficiency, because hypothyroid values of T4 and TSH normalized during iodine treatment. General iodine prophylaxis of the population is recommended.


Opiates, prolactin, and the dopamine receptor.

The administration of a dopamine antagonist, chlorpromazine, and two opiates, morphine and methadone, resulted in a significant rise in serum PRL within 90-150 min. Prior administration of dopamine receptor agonists (apomorphine, levodopa, aand bromocriptine) blocked this effect. In contrast, cyproheptadine, a serotonin antagonist, did not. We suggest that the opiates induce hyperprolactinemia in man via dopamine receptor blockade.


Lack of arginine vasopressin response to central dopamine blockade in normal adults.

Haloperidol, a central nervous system dopamine blocker, was given im to seven normal volunteers at a dose level (1.0 mg) known to have central nervous system effects. Plasma PRL levels rose sharply in response to haloperidol, but plasma arginine vasopressin levels did not change significantly. These data do not support the hypothesis of a prominent dopamine neurotransmitter regulation of arginine vasopressin secretion.


Conjugated glucocorticoids in amniotic fluid and fetal lung maturation.

While recent studies suggest that cortisol plays a role in lung maturation, conflicting reports have recently appeared relating cortisol in amniotic fluid to indices of lung maturation. the variation in the levels and differences in correlation appear to be due to differences in methodology, principally with respect to cross-reactivity in the radioimmunoassays with the conjugates of cortisol and corticosterone. We have found that the glucocorticoid conjugates correlate better with lung maturation (rs = 0.79) than does cortisol itself (rs = 0.58). This is probably because the conjugates are derived exclusively from the fetal compartment whereas cortisol is also produced by the chorionic membrane. In anencephaly, conjugate levels were very low while cortisol levels were relatively normal. Conjugate levels (mainly sulfates) appear promising as an adjunct to tests of fetal maturation.


Melatonin concentration in human blood and cerebrospinal fluid: relationship to stress.

In 35 daytime paired blood and cerebrospinal fluid (CSF) samples from 15 patients, melatonin levels in CSF were undetectable or detectable but not higher than blood levels. During pneumoencephalography in 6 patients, no significant elevation of blood melatonin levels was observed, whereas cortisol concentration increased.


Damped oscillations in serum thyroid hormone levels of normal newborn infants.

Exposure to the extrauterine environment is associated with marked stimulation of the hypothalamic-pituitary-thyroid system after which, pituitary-thyroid equilibrium must be reestablished. This marked endogenous perturbation offers the opportunity to study the manner in which the pituitary-thyroid axis is reequilibrated. T4, T3 and TSH concentrations have been measured by RIA in sera from 440 healthy newborn infants, whose ages ranged from birth to 236 h. Results were analyzed by nonlinear curve-fitting procedures to assess the changes in mean hormone concentrations with age (t). Equations have been derived by Danziger and Elmergreen to allow assessment of oscillatory behavior during hormone equilibration. Applying these equations to the present data, we observed the presence of an oscillatory cosine term in the equation for each hormone. This indicates significant oscillations in serum T4, T3, and TSH concentrations during the first 5 days of life. The period of the oscillations approximates 16 h. The oscillations in T4, lag 1/2 to 3/4 cycle behind TSH; T3 lags behind T4. Thus, disturbances in hypothalamic-pituitary-thyroid equilibrium seem to be followed by periodic oscillations in hormone concentrations; these oscillations decrease in amplitude as the negative feedback system establishes new equilibrium conditions.


Changes in NSILA-S in response to somatotropin administration and hypophysectomy.

The effects on the serum levels of NSILA-S of the administration of human GH (hGH) or of hypophysectomy have been studied. hGH given im (5 mg daily for 3 days) raised the NSILA-S levels of three GH-deficient subjects into the normal range. Significant elevations of NSILA-S were also seen in three normal subjects given im GH. In the same groups of three normal and three GH-deficient subjects, 5 mg hGH administered iv induced an elevation of NSILA-S within 15-60 min. Hypophysectomy in three acromegalics and one subject with a chromophobe adenoma was followed by significant falls of serum NSILA-S. These studies provide further evidence of the dependence of NSILA-S levels on GH.


Assessment of acute and chronic changes in parathyroid hormone secretion by a radioimmunoassay with predominant specificity for the carboxy-terminal region of the molecule.

A sensitive RIA for parathyroid hormone (PTH) with specificity for the carboxy-terminal region of the hormone was developed and applied to clinical studies. The assay was useful in identifying patients with chronic hyperparathyroid states, such as primary and secondary hyperparathyroidism. In addition, the assay could detect acute changes in PTH seen during calcium, pentagastrin, and EDTA infusions and after parathyroidectomy. These studies demonstrated that an immunoassay with predominant specificity for the carboxy-terminal fragment of PTH can be used to evaluate acute as well as chronic changes in hormone secretion.


Hydroxyproline peptides and bone mass in postmenopausal and osteoporotic women.

Total and nondialyzable hydroxyproline excretion was measured in 59 postmenopausal women and 68 women with spinal osteoporosis. Hydroxyproline excretion was similar in both groups of women and the hypothesis that hydroxyproline excretion is normally distributed could not be rejected for either group. No relationship was found between hydroxyproline excretion (total and percentage of nondialyzable) and body weight, height, body surface area, or total body calcium or bone mineral content of the radius, or these latter values normalized for age, sex, and body size. There was no difference in hydroxyproline excretion in osteoporotic women who took supplemental calcium as compared to those that did not. These data fail to provide any evidence that bone turnover in osteoporotic women differs from that in younger postmenopausal women, or that osteoporosis arises from a subpopulation of women with rapid bone loss.


Adenylate cyclase of human parathyroid gland.

Experiments were performed on a particulate fraction from human parathyroid glands. A high activity of adenylate cyclase was detected which was linear with time and protein concentration. The enzyme had an optimum pH in the range of 7-8 and a Km for ATP of 0.44 X 10(-3) M. Ca++ had a profound inhibitory effect; a concentration of 0.5 mM Ca++ reduced enzyme activity by 60%. Maximal enzyme activity was obtained with 5 mM Mg++; higher concentrations of this cation also inhibited enzyme activity. The effect of Mn++ was similar to that of Mg++. Enzyme activity was stimulated by NaF, catecholamines, glucagon, and calcitonin. The effect of catecholamines seems to be mediated through beta-adrenergic receptors.


Properties of human chorionic gonadotropin produced in vitro by ovarian carcinoma cells.

The present study was designed to compare the immunological, physical, and biological properties of native hCG with an hCG molecule secreted ectopically in vitro by an ovarian adenocarcinoma cell line maintained in long term tissue culture. The hCG produced by the cell line was concentrated by ultrafiltration of the tissue culture medium. The inhibition curves generated by serial dilutions of the culture medium concentrates were parallel to those obtained with purified urinary hCG in the beta-hCG RIA and the rat Leydig cell radioreceptor assay (RRA). The ectopic hCG also reacted with an antibody generated against the carboxyl-terminal peptide (109-145) of beta-hCG. The immunoreactive material cochromatographed with urinary hCG on a Sephadex G-100 column, as determined by the beta-hCG RIA and RRA. Neither free alpha nor free beta subunits were found in the tissue culture medium. The tissue culture gonadotropin was adsorbed onto a Concanavalin A-Sepharose column and could be eluted with alpha-D-methylglucoside. The biological activity of the ectopic hCG was 9289 IU/mg, as determined by the ventral prostate weight (VPW) method in hypophysectomized immature male rats. The biological to immunological ratios by the ventral prostate weight method and RRA were 1.79 and 2.17, respectively. The in vivo disappearance rate of ectopic hCG after injection into immature female rats was significantly faster than that of placental or urinary hCG, but was considerably slower than the disappearance rate of human LH. These studies demonstrate that the immunoreactive and biologically active portions of the hCG produced by the ovarian adenocarcinoma cell line and native hCG are similar or identical. The faster disappearance rate of the ectopic hCG in the rat model may be due to incomplete sialylation of the oligosaccharide moiety of the hCG molecule.


Metabolic clearance and production rates of 3,3',5-triiodothyronine in hyperthyroid, euthyroid, and hypothyroid subjects.

To further elucidate the peripheral metabolism of rT3 and to determine if rT3 production rates vary directly with thyroid function, we measured the disappearance of [125I]rT3 in thyrotoxic and hypothyroid subjects as well as in athyreotic patients maintained eumetabolic on exogenous T4. Kinetic parameters were determined by noncompartmental analysis, and serum concentrations of rT3 and T4 were determined by specific RIAs. In six hyperthyroid, seven euthyroid, and six hypothyroid subjects, the MCRs were 190.7 +/- 15.7, 111.7 +/- 13.2, and 71.8 +/- 7.0 liters/day kg, respectively (mean +/- SE). Production rates (PR) for these same groups were 271.3 +/- 40.5, 51.7 +/- 9.1, and 4.3 +/- 0.6 micrograms/day/70 kg. The observed differences in MCR and PR among the three study groups were highly significant (P less than 0.002). These data indicate that in comparison to euthyroid subjects, rT3 PR and MCR are increased in thyrotoxic and decreased in hypothyroid individuals.


Measurement of the corticosteroid-binding globulin, progesterone, and progesterone "receptor" content in human endometrium.

The corticosteroid-binding globulin (CBG) content has been determined in cytosols prepared from human endometrium taken at different phases of the menstrual cycle, at 8-10 weeks gestation, and during treatment with an oral contraceptive. The data were compared to the progesterone "receptor" and the progesterone concentration in the same tissue extracts. The plasma contamination was estimated by the serum albumin content. It was observed that CBG is a constant contaminant of the endometrial cytosols. All of the CBG content can be considered to be of plasma origin. The cytoplasmic progesterone "receptor" content is between 21-33% of the CBG concentration during the menstrual cycle and is only 1% during pregnancy. The cytosol progesterone concentration is much higher in endometrium than would be expected from the plasma contamination and the level of the progesterone "receptor".


Fetal hypothyroidism and maternal thyroid status in severe endemic goiter.

The relationship between maternal thyroid function and newborn thyroid function was studied in a region of very severe endemic goiter (Ubangi, Republic of Zaïre). T4, T3, and TSH concentrations were measured in the sera of 56 mothers (at the time of delivery) and 60 newborns (in the cord). The results obtained in these groups (untreated) were compared with those obtained in two control groups, comprising 53 mothers whose iodine deficiency had been corrected by the injection of iodized oil and 68 neonates born to such mothers. The results show that the mean (+/- SEM) T4 serum concentration (micrograms per dl) was 11.5 +/- 0.7 in the untreated mothers compared with 15.7 +/- 0.7 in the treated mothers (P less than 0.001), and 9.4 +/- 0.8 in the untreated newborns compared with 12.4 +/- 0.5 in the newborns of treated mothers (P less than 0.01). The values observed for the mean T3 serum concentrations (nanograms per dl) in the same groups were 171 +/- 10 and 154 +/- 9 (mothers; P greater than 0.05) and 68 +/- 6 and 55 +/- 6 (newborns; P greater than 0.05); the mean TSH serum concentrations (microunits per ml) were 8.7 (7.6 - 9.9) and 5.4 (4.9 - 5.9; mothers; P less than 0.001) and 19.6 (16.6 - 23.2) and 6.4 (5.8 - 7.0; newborns; P less than 0.001). The proportion of untreated newborns, i.e. 40%, with individual TSH values deviating by more than 2 SDS above the mean of the treated newborns is much greater than the corresponding proportion, i.e. 15%, of untreated mothers in relation to the treated ones. In 6 out of 34 untreated newborns, definite biochemical signs of congenital hypothyroidism were observed. Correlation coefficients were calculated between the untreated subjects. A positive correlation coefficient of 0.80 (P less than 0.001) was observed between the serum T4 concentrations of the mothers and those of the newborns, and one of 0.61 (P less than 0.001) was observed between their respective serum TSH values. Significant inverse correlations were observed between maternal serum T4 and cord serum TSH (-0.79; P less than 0.001) and between cord T4 concentrations and maternal TSH concentrations (-0.57; P less than 0.01). No definite trend is observed between the variations of serum T3 on one hand, and those of serum T4 or serum TSH on the other hand. Out of 51 mothers in whom serum T4 was determined, 11 showed values below 8 micrograms /dl; the newborns of those mothers showed very low serum T4 values (5.5 +/- 1.6 micrograms/100 ml) and extremely high serum TSH levels [144 (98-210) microU/ml]. It is concluded that, contrary to the situation observed in physiological conditions, maternal thyroid function in regions of severe endemic goiter is a good indicator of newborn thyroid function. The reasons for this probably lie in the influence of environmental factors acting simultaneously on the mother and the fetus.


A direct microassay for aldosterone in plasma extracts.

We previously described an RIA for aldosterone based on highly specific antibodies elicited with aldosterone-3,20 dioxime bovine gamma-globulin (Poulsen, K. J. Sancho, and E. Haber, Clin Immunol Immunopathol 2: 373, 1974). We now report the development of higher affinity antibodies of similar specificity that allow the direct measurement of normal aldosterone concentrations in extracts of 100 microliters plasma. The detection limit at +/- 2 SD of mean zero value was 0.2-0.3 pg. The assay was validated by 1) zero values in adrenalectomized plasma, 2) parallel displacement plots of aldosterone standards and plasma extracts, 3) 97.7 +/- 2.5% recovery of added tracer, 4) a correlation coefficient of 0.992 and a slope of 1.08 in a plot of added vs. recovered unlabeled aldosterone, 5) 10.2% interassay variation and 5.6% intraassay variation, and 6)failure of high concentrations of a variety of steroids added to plasma to perturb the measured aldosterone concentration. The simplicity of the assay results in a high degree of productivity, in that 195 plasma samples may be processed in duplicate, in addition to standard curves, in a single working day.


Approach to the mechanism of androgen overproduction in a case of Krukenbery tumor responsible for virilization during pregnancy.

Virilization may occur during pregnancy as the result of an ovarian Krukenberg tumor. mechanism of the androgen overproduction in this exceptional condition is still poorly understood. A new case is reported in which only in the postpartum clinical, endocrine, and endoscopic studies led to the diagnosis of an ovarian Krukenberg tumor secondary to a gastric carcinoma. In the mother, basal hormonal studies were done 1 and 4 weeks after delivery, then after gastric and ovarian surgery. Three months after delivery, ovarian steroid response to hCG (priming dose, 5000 IU; then 1500 IU every other day for 12 days) and a study of progesterone (P) metabolism at a steady state after a constant infusion of [3H]P and cold P (92 micrograms/min leads to blood production rate (BPR) of 152 mg/day designed to reproduce the BPR of P usually seen in pregnancy) were successively performed. Hormones were measured by specific RIAs after chromatographical purification. Basal hormonal levels were normal in the child. In the mother, on the 5th day postpartum, mean hormone levels (in nanograms per dl) were: testosterone (T), 4181; androstenedione (delta 4), 8876; 17 alpha-hydroxyprogesterone (17-OHP), 9746; P 1075; estrone (E1), 195; and estradiol (E2), 151. One month later, levels were normal for the follicular phase; T, 40; delta 4, 146; P, 52; E2, 9; and E2, 4.5. At both times, dehydroepiandrosterone was normal (703-750). Hormone levels increased progressively during hCG stimulation but their time course was different between hormones. At the end of the test, T. 144; delta 4, 746;' 17-OHP, 789; P, 723; E1, 37; and E2, 20. The MCR of P was decreased, 1450 liters/day (normal, 2020). Conversion ratios between products and precursor during constant infusion were normal. From these data, obtained in four different conditions (postpartum period, hCG stimulation, progesterone infusion, and after oophorectomy), the following can be concluded: adrenal production of dehydroepiandrosterone was normal; the ovarian overproduction of androgens likely resulted from the excessive reductive metabolism of both placental and ovarian P along the delta 4 steroid biosynthetic pathway by an hypertrophic stromal compartment; and HCG stimulation seems to be the necessary stimulus for this condition. The enhancement by T on its own peripheral production is also discussed.


Prolactin stimulation of alpha-lactalbumin in normal primate mammary gland.

An in vitro system has been developed to examine the effects of PRL on the normal primate mammary gland. alpha-Lactalbumin a milk protein, was found in breast tissue samples from 17 of 19 primates representing several Macaca and Papio species; concentrations ranged from 10-768 ng/mg protein. That none of the animals was pregnant or lactating and half were nulliparous indicates that milk protein production takes place under normal circumstances, even in breast tissue of nonlactating animals. Studies of the effect of PRL on alpha-lactalbumin production in these tissues in organ culture revealed that PRL maintained existing or stimulated new production of alpha-lactalbumin for periods of up to 9 days. Measurement of alpha-lactalbumin in medium bathing mammary tissue from three animals revealed that mean alpha-lactalbumin production during days 7-9 when PRL was added (100 and 1000 ng/ml) was 11 and 59 times greater, respectively, than control. Simultaneous measurement of tissue concentrations of alpha-lactalbumin revealed that those tissues maintained with PRL (1000 ng/ml) had a mean concentration of alpha-lactalbumin that was 61 times that of controls without PRL. PRL consistently maintained or increased alpha-lactalbumin production in tissues from all 22 primates tested. Even in those premenarchal animals in whose mammary tissue alpha-lactalbumin was undetectable initially, PRL stimulated alpha-lactalbumin production in a dose-related fashion. In contrast, when PRL was absent from medium, alpha-lactalbumin concentrations decreased at 9 days to less than 20% of the initial 3-day value in all cases. These studies provide evidence that mammary tissue from normal nonlactating, nonpregnant primates produces milk proteins and that when tissues are exposed to PRL in culture, production of alpha-lactalbumin is stimulated.


Growth failure with normal serum RIA-GH and low somatomedin activity: somatomedin restoration and growth acceleration after exogenous GH.

Two three-year-old boys with dwarfism (height ages 1-4/2 and 1-11/12 years) and delayed bone ages (1-4/12 and 1-9/12 years) had normal growth hormone (GH) responses after stimulation and low levels of somatomedin. Unlike patients with Laron syndrome, the two patients generated normal levels of somatomedin after administration of exogenous hGH. Treatment with hGH (2 IU every other day) brought about a significant increase in the growth rate of both patients. The growth rate of the first patient increased from 2 cm/year before treatment to 12 cm/year on therapy. The growth rate of the second patient was 4.5 cm/year before treatment, and 8.3 cm/year while on treatment. The two cases represent a new syndrome of dwarfism which may be caused by secretion of a biologically inactive but immunoreactive GH.


3,3',5'-triiodothyronine, thyroxine, triiodothyronine, and thyrotropin levels in maternal and cord blood sera from endemic goiter regions of Brazil.

T4, T3, rT3, and TSH were measured in cord blood of infants born in mild to severe endemic goiter areas and nonendemic urban areas in South and North America. A significantly high rT3 concentration was found in newborns living in the urban area of South America as compared to a Canadian newborn population. There were no differences among the various thyroid parameters in the groups of newborns studied. Blood from goitrous mothers showed significantly higher concentrations of T3 and TSH than nongoitrous mothers. However, these changes did not affect the concentrations of thyroid hormones, rT3, or TSH in the fetal circulation.


Conversion of androgen to estrogen by the human fetal ovary.

The conversion of radiolabeled androgen to estrone and 17 beta-estradiol was assessed in tissues of human embryos that varied from phenotypically indifferent stages (1-3 cm crownrump length) to midgestation (15. 1-20 cm crownrump length). Significant rates of estrogen synthesis were demonstrated only in ovaries, liver, and brain. Estrogen synthesis was undetectable in gonads from 1-3 cm fetuses, but by the 3.1-5-cm stage it had reached an average rate of 1.9 pmol . h-1 . mg protein -1 in ovaries and remained at this level of activity through the latest stages examined. Estrogen formation was undetectable in testes at all stages examined, but the time of appearance of the capacity to form estrogens in the fetal ovary is similar to the onset of the capacity of the fetal testis to synthesize testosterone. The capacity of the fetal ovary to form estrogen develops before histological differentiation of the tissue.


Hemoglobin A1c levels in a diabetes detection program.

Hemoglobin A1c concentration (HbA1c) was compared to the plasma glucose responses at 1 and 2 h of an oral glucose tolerance test (OGTT) in 63 subjects preselected because of postprandial hyperglycemia. HbA1c concentrations were correlated with 1- and 2-hour plasma glucose responses during the OGTT (r = 0.776 and 0.8602, respectively). The OGTT responses were diabetic-like in 21, indeterminate in 15, and normal in 27 subjects. HbA1c values were within normal limits in all subjects who had a normal or indeterminate OGTT response and in 10 out of 21 with a diabetic OGTT. The 2-h OGTT response among the 10 diabetic responders with normal HbA1c was 200 +/- 31 mg/100 ml (mean +/- SD), while that of the 11 diabetic responders with elevated HbA1c was 352 +/- 122 mg/100 ml. All subjects with an elevated HbA1c had a 2-h plasma glucose above 228 mg/100 ml, whereas only 7% of subjects with a normal HbA1c had a 2-h glucose above this value. It is concluded that only about half of the patients currently diagnosed as having mild or chemical diabetes by OGTT have elevated HbA1c and that an elevated HbA1c is usually associated with 2-h OGTT levels above 228 mg/100 mg.


Effect of propranolol on extrathyroidal metabolism of thyroxine and 3,3',5-triiodothyronine evaluated by noncompartmental kinetics.

Kinetic studies of T4 and T3 using a noncompartmental approach were performed in seven patients with pretreatment severe hypothyroidism maintained on L-T4 replacement. Each subject received a combined tracer dose of labeled T4 and T3 as an iv bolus before and during peroral treatment with propranolol. Serum T4 was unchanged, while a significant decrease of 13% was found in serum T3. The disposal rates (DR) of T4 and T3 decreased significantly, and the ratio between the DR off T3 and the DR of T4, the conversion rate, was significantly reduced during propranolol treatment. The decrease in the DR of T4 suggests a reduction in the bioavailability of L-T4 during propranolol, possibly due to a decrease in intestinal absorption. The decrease in the conversion rate indicates a reduced extrathyroidal conversion of T4 to T3 during propranolol treatment.


Steroid production by definitive and fetal zones of the human fetal adrenal gland.

This study was performed to assess the relative contributions of the fetal and definitive zones of the human fetal adrenal gland to "corticoid" (cortisol and perhaps other corticosteroids) and dehydroepiandrosterone sulfate (DHAS) production, and the possible regulatory role of ACTH and the fetal pituitary in the secretion of of these steroids. Corticoid and radioimmunoassayable DHAS or total aromatizable androgen secretion by the isolated definitive and fetal zones of the human fetal adrenal gland between 10-20 weeks gestation has been studied in a superfusion system. Different functional capacities of the two zones were seen; corticoids were found to be secreted primarily by the definitive zone, while DHAS was found to be the main secretory product of the fetal zone. Addition of ACTH (250 ng/ml) or fetal pituitary homogenate produced a 2- to 5-fold stimulation of corticoid production by the definitive zone at all gestational ages studied. DHAS secretion by the fetal zone was also stimulated by ACTH. These results indicate that the definitive and fetal zones of the human fetal adrenal gland at midgestation have the capacity to respond to ACTH with increased corticoid or DHAS secretion, respectively.


Iodide organification defect in iodine deficiency endemic goiter.

In 17 goitrous persons in an iodine-deficient area, in 23 nongoitrous inhabitants of the same village, in 10 goitrous persons in Athens, and 8 normal controls the perchlorate discharge test was performed, either in the simple standard form or after pretreatment with either 0.5 or 2.0 mg potassium iodide or 2.5 mg carbimazole. With the simple test or with 0.5 mg potassium iodide, there was no significant discharge in any group studied. With 2.5 mg carbimazole, there was a profound discharge of the trapped iodide in both groups in the iodine-deficient area. With 2.0 mg potassium iodide, however, there was a clear discharge in the two goitrous groups (i.e. the one in the endemic area and the second in Athens), a less pronounced discharge in the controls studied in Athens, and no discharge at all in the nongoitrous inhabitants of the iodine-deficient endemic area. These findings provide evidence for an abnormality present in the patients with endemic goiter, most probably faulty iodine utilization due to impaired organic binding. The nongoitrous persons in the endemic areas, on the other hand, seem to be even more efficient in handling the trapped iodide than the controls studied in Athens. These findings may provide an explanation for previous observations that in endemic areas only part of the population develop a goiter, whereas the others adapt successfully to iodine deficiency without significantly enlarging their glands.


Calcium-regulating hormones during the menstrual cycle.

Calcium metabolism during the menstrual cycle was studied in seven women from whom fasting blood samples were drawn daily or every other day throughout ovulatory cycles. Total calcium (Ca), ionic calcium (Ca++), magnesium (Mg), phosphorus (P), and immunoreactive parathyroid hormone (PTH) and calcitonin (CT) were measured. LH levels were used to date each cycle and progesterone levels were used to confirm ovulation. Plasma estradiol was measured in two of the subjects. In six subjects with cycle lengths of 27-31 days, PTH levels rose progressively through the follicular phase to a peak at or slightly before the LH surge, then fell progressively through the luteal phase; peak PTH levels were 30-35% above early follicular and late luteal values. CT levels were also highest at midcycle, but the CT pattern was somewhat more variable than that of PTH. Ca++ tended to fall until 3-4 days before ovulation and then to increase, while Ca, Mg, and P exhibited no particular pattern. One subject experienced a prolonged (44 day) ovulatory cycle characterized by three distinct PTH peaks, each of which coincided with elevations in plasma estradiol level. These results represent the first report of menstrual cyclicity in calcium-regulating hormones. The timing suggest an estrogen effect and it is hypothesized that estrogen inhibits PTH-induced bone resorption, lowering serum Ca++, which in turn provokes a compensatory PTH output. With the decline of the preovulatory estrogen peak, Ca++ levels rise and PTH secretion falls. Alternatively, it is possible that the primary action may be an estrogen-induced rise in CT release, causing hypocalcemia and consequent PTH output. Cyclic changes in PRL release or vitamin D metabolism might also be involved.


Calcium and salmon calcitonin in treatment of osteoporosis.

Calcitonin has been considered of therapeutic value in osteoporosis because of its effects in tissue culture. In the whole animal, however, the predominant result seems to be hypocalcemia, which might be expected to have the opposite effect of stimulating parathyroid hormone secretion and therefore resorption of bone. Indeed, in a short term study of 3- and 4-month duration in osteoporotic women, this was found to be so. A combination of calcium and calcitonin was therefore considered a more promising therapeutic alternative for this disease. Calcium was given to 26 patients, alone or with vitamin D, for a period of 15 months, and the effects on serum and urine calcium and phosphorus and on bone resorption and formation were evaluated. Calcium and vitamin D decreased serum parathyroid hormone levels, reduced bone resorption, and increased urinary calcium. The addition of calcitonin to the calcium and vitamin D did not seem to change these effects. Neither form of treatment resulted in change of bone mass. Calcium, with or without vitamin D supplements, may prevent the development of osteoporosis, but it seems unlikely that calcitonin has any additional desirable effect in the disease.


Carbidopa inhibits the growth hormone- and prolactin-suppressive effect of L-dopa in acromegalic patients.

The plasma GH, PRL, TSH, and dopamine (DA) responses to an infusion of L-dopa were examined in six acromegalic patients before and after pretreatment with carbidopa, a drug which inhibits the peripheral conversion of L-dopa to DA. Carbidopa neither modified baseline DA nor induced changes in baseline GH, PRL, or TSH levels. The drug instead markedly reduced the L-dopa-induced DA rise, an effect which was concomitant to a striking reduction of the suppressive effect of L-dopa on plasma GH and a partial inhibition of the suppressive effect of L-dopa on plasma PRL. TSH levels did not change either after L-dopa alone or L-dopa plus carbidopa. These data demonstrate that in "responder" acromegalics, L-dopa inhibits GH secretion through its peripheral conversion to DA and not via activation of central DA neurotransmission. For the effect of L-dopa on PRL secretion, in addition to a peripheral dopaminergic component, a central component cannot be disregarded.


Clinical, endocrinological, and enzymatic characterization of two patients with 5 alpha-reductase deficiency: evidence that a single enzyme is responsible for the 5 alpha-reduction of cortisol and testosterone.

Two siblings with 46,XY male pseudohermapthroditism were demonstrated to have the phenotype characteristic of 5 alpha-reductase deficiency, namely normal testes and male Wolffian duct derivatives (epididymis, vas deferens, and seminal vesicle) terminating in a blind-ending vagina. Clitoromegaly was present at birth and increased further at the time of expected puberty. The diagnosis of 5 alpha-reductase deficiency was confirmed by demonstration of male levels of testosterone and testosterone precursors before and after hCG administration, elevated plasma testosterone to dihydrotestosterone and urinary etiocholanolone to androsterone ratios, and by in vitro studies indicating 5 alpha-reductase enzyme deficiency in the epididymis of one patient. Studies of control and mutant epididymal microsomes indicated that a single enzyme is responsible in the normal person for the 5 alpha-reduction of testosterone and cortisol (and probably other delta 4-3-ketosteroids as well) and that 5 alpha-reductase activity is undetectable for all substrates examined in the mutant. This finding explains why the formation of 5 alpha-reduced glucocorticoids is also defective in the disorder.


Extraction of human chorionic thyrotropin (hCT) from term placentas: failure to recover thyrotropic activity.

We extracted human placentas by three methods to obtain chorionic TSH (hCT). The extracts were assayed by a sensitive homologous RIA for bovine TSH with an antibody which had veen used previously for assay of hCT. Based on the RIA for hCT, the yield of hCT was only 0.68 +/- 0.15 (SE) mU/100 g placenta by the Bates method, 2.01 +/- 0.35 mU/100 g by the Reisfeld method, and 4 mU/100 g by a Concanavalin A-Sepharose technique. Thyrotropic activity was detected by bioassay only in one Reisfeld extract; this biological activity could be attributed to hCG in this fraction. In TSH bioassays of other extracts, the responses were less than the sensitivity of the assay; some extracts were lethal to the bioassay mice. The low yield of hCT, about one-tenth to one-hundredth of that reported previously, casts doubt on the validity of the previous observations.


Collaborative study of the effects of human growth hormone in growth hormone deficiency. V. Treatment with growth hormone administered once a week.

Twenty-two GH-deficient patients received 6 IU GH weekly for 6 months. They increased their growth rate from 1.0 +/- 0.2 to 2.9 +/- 0.3 (SE) cm/6 months (P less than 0.01). However, their rate of growth was significantly less (P less than 0.05) than the rate [4.1 +/- 0.5 (SE) cm/6 months] observed earlier when they had received 2 IU GH three times a week. Seven patients received weekly GH for 18 months and they also grew significantly less (P less than 0.01) than when they had received GH divided over the week. These results suggest that once a week GH does not provide the most effective therapy for GH deficiency.


Effect of pyridoxine on pituitary release of growth hormone and prolactin in childhood and adolescence.

The dopamine agonist, pyridoxine, was administered to 10 children being evaluated for short stature. Serum GH and PRL responses were contrasted to those after insulin-induced hypoglycemia (ITT) and L-dopa administration. Levels of GH did not change after pyridoxine, but PRL fell (P less than 0.05) to 42% of the zero time concentration. Significant increments of GH occurred during ITT and after L-dopa, while PRL was suppressed to a greater extent by L-dopa. We conclude that pyridoxine is not useful in assessment of hypothalamic-pituitary function.