[The diagnostic value of bloodless methods and follow-up in young asymptomatic subjects with positive exercise test (author's transl)].

Fifty asymptomatic subjects, aged 22 to 40, with normal resting ECG and "ischemic" ST depressions during exercise were followed for 44 +/- 18 months. Coronary events occurred only in two cases. Unexpectedly in 12 subjects the response to maximal exercise became normal. In 25 subjects forced hyperventilation, exercise test after nitroglycerin (TNG), and after propranolol (P) were performed. Hyperventilation determined abnormalities of ventricular recovery in all cases. TNG did not improve the response to exercise, as it does in coronary patients, and even significantly decreased the "ischemic threshold"; after P the exercise test became normal in 20 subjects, while in 5 the electrocardiographic ST depressions were markedly reduced. The responses to pharmacological tests after the follow-up period were similar to the first observation. In 8 subjects, in which exercise ST depressions were particularly impressive, Tallium 201 myocardial scanning at rest and during exercise was performed. Myocardial perfusion imaging did not reveal any defect, thus confirming the non-ischemic nature of the ECG abnormalities. Our results confirm the low predictive accuracy (4%) of a positive stress test in a young asymptomatic population and suggest that, among non-invasive methods, exercise response after TNG is usefull in recognizing the "false positive" tests.


Autonomic neurons affected by lipid storage in the spinal cord in Fabry's disease: distribution of autonomic neurons in the sacral cord.

In five patients with Fabry's disease, the distribution of neurons in the spinal cord affected by lipid storage was investigated. Neurons ballooned by lipid storage were located mainly in the thoracolumbar and mid-sacral regions. In the former, they were located exclusively in the intermediolateral nucleus from the first thoracic (or eighth cervical) through the first or second lumbar segments. In the mid-sacral region they were located not only in the intermediolateral nucleus but also in the intermedioventral (Onuf's) nucleus and in the intermediate region of the ventral horn. The affected neurons in the sacral cord are also assumed to be autonomic neurons judging from the selective involvement of known autonomic neurons in the thoracolumbar segments. Based on the distribution of these neurons, it is concluded that autonomic neurons in the human sacral cord from a cell column which differs topographically from that in the thoracolumbar segments. The cell column begins rostrally at the ventral margin of the ventral horn in the second sacral segment as Onuf's nucleus and extends caudally in a dorsolateral direction along the intermediate region to the intermediolateral nucleus in the fourth sacral segment, which forms the caudal part of the cell column.


Role of the kidney and lung in the handling of prostaglandin E in hemorrhagic shock.

The polyuria and hyposthenuria noted particularly following blood transfusion after prolonged periods of hypotension (dog, monkey) seem best explained by a prostaglandin-antidiuretic hormone (PG-ADH) antagonism, operating primarily in the renal medulla. The kidney releases greatly enhanced amounts of PGE at this time, which probably act primarily in the renal medulla, then secondarily influence the systemic (arterial) levels by passing in greater amounts through the lungs. The lungs normally metabolize the major portion of PGs delivered to them. Our data suggest impairment of the lung's "up-take-metabolizing" mechanism, but also could be interpreted as involving enhanced release of PGE from the lung, so net pulmonary extraction, (V--A)/V, shifts from positive to zero or even negative values in the hypotensive shock phase. This ratio tends to improve after transfusion, but systemic PGE levels remain elevated. It is speculated that in hemorrhagic shock enhanced concentration of PGE and other vasodilator PGs, produced in increased amounts by the kidney (and possibly other organs and tissues), appear in greater amounts in the systemic plasma because of the lung's altered function. These exert a decompensatory action on the peripheral vasculature.


Automatable radiometric detection of growth of Mycobacterium tuberculosis in selective media.

The formulation of media for selective, automatable, radiometric detection of growth of Mycobacterium tuberculosis in vitro is described. Palmitic-1 acid labeled with carbon-14 and formic-14C acid were compared as substrate sources of [14C]O2 in media deficient in carbohydrate and containing appropriate antimicrobial agents that are not active against tubercle bacilli. A preliminary clinical laboratory study of a medium containing 4 microCi palmitic-1-14C acid per ml showed that this method might provide the basis for practical laboratory use.


[Semi-automatic determination of blood lactate during hypoglycemic treatment with biguanides].

Blood lactate levels were determined by Lactate Analyzer 640 Kontron in 67 adult insulin-independent diabetics during hypoglycemic treatment with usual therapeutical doses of phenformin. In 5 cases were found lactate values above 2 mmol/l and, in consideration of accompanying conditions prone to lactic acidosis, the drug was discontinued. However, the mean value of blood lactate in diabetics treated with phenformin was not significantly different from that found in a group of insulin-treated diabetics. The semiautomatic determination of blood lactate is proposed as a rapid screening of possible candidates for lactic acidosis during biguanide treatment.


[Blood lactate semiautomatic estimation during acidotic diabetic coma (author's transl)].

Blood lactate levels were determined by Lactate Analyzer 640 Kontron during the course of 7 cases of hyperglycemic hyperosmolar diabetic coma, with severe acidosis and more or less marked ketosis. In 5 cases lactate values were found in normal range; slight increases around 2 mmol/l were rapidly corrected following standard coma treatment. One of these cases presented with extreme acidosis and relatively mild hyperglycemia, with differential problems in regard to lactic acidosis. In 2 cases, the former with alcoholic cirrhosis, the latter with myocardial infarction, blood lactate was markedly increased; in the second case, full clinical recovery was accompanied by normalization of lactate levels. A previous biguanide treatment could be ruled out as a cause of lactic acidosis. Thus the association of lactic acidosis and diabetic ketoacidosis seems to be unusual in the absence of concurrent serious conditions. The semiautomatic determination of blood lactate, because of its remarkable prognostic importance, should be included among the routine procedures for the emergency treatment of diabetic coma.


Determination of total CO2 in plasma by automated flow-injection analysis.

We describe a procedure for measuring total CO2 in plasma, based on the principles of the flow-injection analysis technique, which makes use of unsegmented fast-flowing reagent streams, as developed by Růziĉka and co-workers. The further methodological design resembles the silicone-rubber membrane technique of Kenny and Cheng. CO2 in the sample is released by reaction with H2SO4. Appropriate amounts of CO2 permeate through the membrane that separates the acid reagent streams and a buffered cresol-red indicator system. The experimental set-up and functioning of this system are described.


[Personal experience in monitoring examination of intracranial pressure].

In our Department of Neurosurgery, during the last two years, we have measured the intracranial pressure (IPC) with an extradural transducer, in cases of head trauma, subarachnoid haemorrhages, pseudotumor cerebri, dilated ventricles and microcephalies. We remark the importance of the continuous measuring of the ICP and its value in relation with the use of hyperosmolar solutions in the diagnosis, treatment and outcome of this patients.


Calculation of the concentrations of free cations and cation-ligand complexes in solutions containing multiple divalent cations and ligands.

The method described permits the computation of the concentrations of free ions and ion-ligand complexes in a solution containing arbitrary numbers of divalent cations and ligands. It is required that the pH be known, along with appropriate sets of ligand-hydrogen and ligand-divalent cation concentration binding constants. It is assumed that these sets of constants are chosen to be consistent with the ionic strength of the complete solution which contains the divalent cations and ligands. The technique is an iterative one which provides upper and lower bounds for the values of the unknowns. The method does not require initial guesses at the values of the unknowns, and it gives correct answers even when the concentrations involved are many orders of magnitude apart. The present formulation of the problem is restricted to the case where only one cation can bind to a given ligand at any one time. The method is applicable to large molecules with multiple "sub-ligands" provided these sub-ligands are independent in their function as ion-binding sites. These sub-ligands need not all have the same properties. It is also shown that a simple modification of the method permits the determination of the subset of total ion concentrations that are required in order to produce a specified subset of free ion concentrations. The modifications required to include monovalent cation binding are presented in outline form.


Transepithelial current-voltage relationships of toad urinary bladder and colon. Estimates of ENaA and shunt resistance.

Studies were done to investigate the transepithelial current-voltage (IT-VT) relationships of urinary bladder and colon of the toad Bufo marinus. Like several other Na transporting epithelia, the IT-VT plots characteristically showed a break at voltage E1, averaging near 124 mV for urinary bladder and 110 mV for colon. With bladders treated with antidiuretic hormone, estimates of ENa and shunt resistance, Rs, were obtained according to a method outlined by Yonath and Civan, 1971 (J Membr. Biol. 5:336-385). Our results not only confirmed their observations, but were consistent with the notion that the values of E1 (IT-VT plots) were the same as those of ENa. In addition, the values of Rs were found to be the same as those estimated from the quotient E1/I1 obtained from the voltage and current coordinates at the break of the IT-VT plot of bladders studied in both stretched and unstretched states. Amiloride at concentrations up to 10(-5) M caused a small decrease of both E1 and  E1/I1 of urinary bladder. Similarly, amiloride caused small but significant changes of ENa and RNa of the colon. For both epithelia, the values of E1 and E1/I1 of the IT-VT plots were the same as those of ENa and Rs estimated by an independent method. In general, these findings are similar to those of several other epithelia where the ENa and Rs can be estimated directly from their IT-VT relationships.


Chromophore equilibria in bacteriorhodopsin.

An investigation of the dark equilibria between different chromophores of bacteriorhodopsin (BR) and studies of the kinetics of their interconversion and photochemical activity have led to the following conclusions. (a) A component of the 605-nm chromophore of BR decays in the millisecond range and is likely to be identical to the intermediate O of the photochemical cycle of BR and is assumed to be formed from the purple complex (PC) by the binding of one proton to BR. (b) An acidic form the PC, PCaL-, arises from the 605-nm chromophore by selective binding of anions L- (F- greater than Cl- greater than Br- greater than I- greater than Cl04-) to BR. (c) The isomeric equilibrium between 13-cis and all-trans retinal is approximately 0.15/0.85 in PCaCl-, 0.3/0.7 in the 605-nm chromophore as compared to 0.5/0.5 in the PC. (d) The 500-nm chromophore is formed from the PC by release of nearly one proton from BR. (e) The pH range in which the PC exists is reduced in a high-temperature structure of the purple membrane as compared to its low temperature structure. A model for the chromophore structure is proposed as a hypothesis, which allows a comprehensive interpretation of the results. In this model the absorption spectrum of the retinylidene lysine Schiff base is modulated by its protonation state and the interaction with an anionic group.


X-ray diffraction study of the kinetics of myelin lattice swelling. Effect of divalent cations.

The time-course of myelin lattice swelling and its reversal in dissected peripheral nerves was determined by small-angle x-ray diffraction using a position-sensitive proportional detector. The process of swelling can take place either in several hours or in less than 1 h depending on pretreatment of the nerves. The reversal of swelling was always completed within 1 h. The rapid structural transitions involved the disordering of membrane pairs as indicated by the transient appearance of a continuous intensity distribution similar to the membrane pair transform for myelin. The slow transitions involved the gradual replacement of the discrete reflections from the native structure by the reflections from the swollen lattice. Myelin membrane arrays reformed in normal Ringer's solution were much more stable to subsequent swelling than arrays reformed in Ca+2 and Mg+2-free Ringer's. These results suggest that these ions participate in stabilizing the interactions between the external surfaces of adjacent membrane pairs.


Nitroglycerin in acute myocardial infarction. X. Effect of small and large doses of nitroglycerin on sigma ST segment deviation -- experimental and clinical results.

The purpose of the present study was to investigate the effect of the dose of nitroglycerin (NTG) on myocardial ischemic injury. In 20 closed chest dogs the anterior descending branch of the left coronary artery was occluded by inflating a balloon in its lumen. Compared with the untreated control group the sigma ST elevation was significantly lower when NTG was applied at a rate of 0.02 mg/min, but significantly higher when NTG was administered at a rate of 0.10 mg/min. In 12 patients with acute myocardial infarction NTG was infused at a rate of 3 mg in the first hour (0.05 mg/min) and 6 mg in the second hour (0.1 mg/min). Sigma ST elevation and sigma ST depression decreased during the lower infusion rate (p less than 0.001). When the rate of NTG infusion was raised to 6 mg/hr, the improvement in ST segment deviation was partially reversed. This effect, particularly evident in patients not in heart failure, was associated with a significant rise in heart rate (p less than 0.05) and a fall in diastolic arterial pressure (p less than 0.025). Patients with left ventricular failure were less sensitive to higher doses of NTG than those without failure. Thus, the effect of NTG on myocardial ischemic injury depends on the NTG dose and on the functional state of the injured left ventricle.


Skin nodules in East Coast fever.

A skin eruption developed in five calves with advanced experimental East Coast fever (ECF) (Theileria parva infection). In three cases the eruption was due to intradermal nodules containing numerous theilerial schizonts, in one animal the nodules contained abscesses filled with Demodex mites, and in the fifth calf both types of nodules were present. No nodules were seen in 15 other experimental cases of ECF, which generally died or were killed in an earlier stage of the disease. It is postulated that demodicosis may become apparent in healthy carriers of the mite in the course of ECF, because of immuno-depression caused by the latter disease.


A simple technique to differentiate between animals infected with Yersinia enterocolitica IX and those infected with Brucella abortus.

While both Brucella abortus and Yersinia enterocolitica IX have O antigens in common, they differ significantly with respect to motility. Thus Br abortus is always non-motile while Y enterocolitica is motile when grown at room temperature. The presence of yersinia H agglutinins in serum can be shown to be evidence of previous exposure to Y enterocolitica. These agglutinins are not generated by brucella infection. A rapid H agglutination test will serve to provide this differentiation without interference from cross-reacting O antigens.


Artificial infection of the tick Rhipicephalus appendiculatus with Theileria parva.

Methods for infecting Rhipicephalus appendiculatus ticks with Theileria parva by injection and by artificial feeding were confirmed and compared. The injection method proved simpler and at best as effective and suggested improvements are described.


Divergent selection on locomotor activity in Drosophila melanogaster. I. Selection response.

Selection for high and low locomotor activity has been applied in two base populations of Drosophila melanogaster of distinct geographical origin. From each base population a high and a low line were selected, in which anesthesia was performed with ether. In addition, from one of the base populations a high line and a low line were selected under CO2 narcosis. Locomotor activity was measured in an apparatus consisting of rows of 20 tubes in a line. Heritabilities in the base populations determined in progeny tests were approximately 10%. Divergent directional selection was successful with realized heritabilities of similar value.


Divergent selection on locomotor activity in Drosophila melanogaster. II. Test for reproductive isolation between selected lines.

Tests for reproductive isolation between lines selected for locomotor activity were performed. Three sets of selection lines were used, each consisting of lines selected for low and high locomotor activity from the same base population. Females preferred high-activity males in almost every case. However, in one of the sets temporary sexual isolation was found between flies of the high and low lines. This was accompanied in the low-activity females with a higher fertility when they were mated with their own males. After further selection the partial isolation disappeared.


Divergent selection on locomotor activity in Drosophila melanogaster. III. Genetic analysis.

Divergent directional selection produced three pairs of lines each consisting of a line with high and a line with low locomotor activity. Reciprocal crosses between the high and low lines of one of these pairs showed that a considerable part of the activity differences was contributed by differences between the X chromosomes. This was confirmed by a substitution of the three large chromosomes, between the low and the high lines. The two large autosomal chromosomes had only minor effects. Interactions between chromosomes were sometimes significant. Low-activity alleles tended to be dominant over alleles for high activity.


Acute effects of alcohol on anterior pituitary secretion of the tropic hormones.

The plasma or serum concentrations of GH, TSH, LH, PRL, testosterone, cortisol, T4, and T3, and the values of the T3 uptake test were monitored in 12 healthy male volunteers for a period of 20 h after administration of one large dose of ethanol (1.5 g/kg BW). The effects of TRH and LRH on the secretion of TSH, PRL, and LH were studied in these subjects once during the period of acute alcohol intoxication (4 h after the start of drinking) and once during the hangover period (14 h after the start of drinking). Each subject served as his own control by drinking water only during another experimental session. Alcohol had no significant effect on basal concentrations of GH, TSH, LH, T4, T3, or testosterone. The concentration of cortisol in plasma was elevated during the whole 20-h period after ingestion of alcohol, as compared with the control values. Alcohol also did not significantly alter the effects of TRH and LRH on plasma TSH and LH levels at 4 and 14 h. During the hangover period, the PRL response to TRH was totally blocked, but during alcohol intoxication, there was a slight increase in the PRL response to TRH. The lack of response of PRL to TRH during the hangover suggests that withdrawal symptoms are associated with increased dopaminergic activity in the hypothalamus.


Cephalothoracic lipodystrophy with hypocomplementemic renal disease: discordance in identical twin sisters.

This report describes the occurrence of cephalothoracic lipodystrophy in one of 7-yr-old identical twin sisters. The affected twin had classical loss of sc fat from her face, upper arms, and trunk as well as associated hypocomplementemia, microscopic hematuria, and a borderline oral glucose tolerance test without hyperinsulinism. The unaffected twin had a normal urinalysis, serum complement, and oral glucose tolerance. Both twins, when challenged iv with LRH or TRH, showed appropriate FSH and LH or TSH and PRL responses, respectively. This report, in conjunction with another similar twin pair recently described in the German literature, makes a simple, single gene genetic etiology untenable and supports the view that cephalothoracic lipodystrophy in an acquired disease.


Impaired estrogen-induced luteinizing hormone release in young women with anovulatory dysfunctional uterine bleeding.

Spontaneous ovarian activity, as reflected by the urinary excretion of total estrogen and pregnanediol measured serially (thrice weekly) over a period of 3-4 months, was studied in nine young women (15-27 yr old) with a history of dysfunctional uterine bleeding of at least 2-yr duration. Results were compared to those obtained in sex regularly menstruating women, aged 23-45 yr. All control women had ovulatory cycles, but seven of the nine patients with DUB failed to ovulate during at least three consecutive cycles. The profiles of urinary total estrogen excretion in these seven subjects were consistent with regular follicular development, but the follicular phase was prolonged and the amount of estrogen excretion increased, as compared to controls. In four of these seven patients, the endometrium had previously shown cystic glandular hyperplasia. Although the release of LH and FSH after injection of 50 micrograms synthetic LRH was normal, the surge of LH induced in response to exogenous estrogen (200 micrograms ethinylestradiol/day for 3 days) was significantly (P less than 0.005) lower in the patients (16.2 +/- 3.7 mU/ml) than that of control women )35.0 +/- 5.5 mU/ml). It is concluded that the failure to ovulate in young women with anovulatory dysfunctional uterine bleeding is due to inadequate release of LH in response to estrogen. The results support the hypothesis that the basic defect in these women may be a decrease of hypothalamic sensitivity to positive feedback.


Influence of methyl-TRH-induced prolactin increase on serum testosterone levels in normal adult men.

Our previous studies suggest that increased serum PRL, secondary to haloperidol-induced dopamine blockade, augments serum testosterone (T) levels in normal men. To rule out a direct effect of haloperidol on the testis, serum samples from a methyl-TRH study in normal men, in whom serum PRL levels were increased by a stimulus other than dopamine blockade, were analyzed for T. Fourteen subjects received both a low dose (6.25-12.5 micrograms) and a high dose (100-500 micrograms) of methyl-TRH on separate days; blood sampling was done for 15 min before and for 4 h after drug infusion. Compared to a saline control group of 14 normal men, who showed a diurnal decline of serum T levels, the methyl-TRH treated subjects had statistically significant increases in serum T after both low and high doses. These data provide further support for the concept that PRL is a pituitary hormone capable of augmenting serum T levels in normal adult men.


Platelet adhesion and aggregation in diabetes mellitus.

Platelets from diabetic patients show both increased platelet adhesiveness and sensitivity to aggregating agents. Plasma levels of the platelet-active von Willebrand Factor and the closely related factor-VIII antigen are significantly elevated, while factor VIII procoagulant activity is not. This may reflect either intravascular coagulation or disproportionate production or degradation. Plasma factors that enhance ADP-induced platelet aggregation are found in 50% of unselected male diabetics. Activity is clearly demonstrated only when plasma is added immediately prior to adding subthreshold doses of ADP to platelet-rich plasma obtained from control subjects. Systematic investigations of the molecular nature of such factors and their interactions with platelets are in progress. In platelets obtained from diabetic subjects, we have previously found increased sensitivity to the aggregating effects of arachidonic acid, and increased synthesis of immunoreactive prostaglandin E-like material. More recent studies have shown that platelets obtained from diabetic subjects are less sensitive to the antiaggregatory effects of imidazole, a thromboxane synthetase inhibitor. These observations suggest that increased synthesis of the labile aggregating substance thromboxane A2 also occurs in platelets obtained from diabetics. Collectively, these platelet and plasma abnormalities may contribute to accelerated vascular disease of diabetes. Prospective studies using antiplatelet agents are presently underway or in the planning stages in diabetics to explore their potential beneficial effects.


Platelets: cell proliferation and atherosclerosis.

Intimal smooth muscle proliferation is the hallmark of the lesions of atherosclerosis. Endothelial injury is postulated to precede this intimal smooth muscle proliferative response, which is mediated by a potent mitogenic factor derived from adherence, aggregation, and release by platelets at sites of endothelial injury. Smooth muscle proliferation is accompanied by varying amounts of connective tissue formation and intracellular and extracellular lipid deposition, dependent upon the risk factors encountered in each patient. The platelet-derived mitogen (PF) is a stable, cationic, relatively low molecular weight (10,000-30,000) protein that has been partially purified by ion exchange chromotography and gel filtration. Less than 100 ng of PF/ml culture medium can stimulate sparse 3T3 cells or smooth muscle cells, but not endothelial cells, to undergo multiple cell divisions in the presence of 5% cell-free, plasma-derived serum. The latter contains no mitogenic activity. The interaction of the platelet mitogen and plasma-derived components, including lipoproteins, plays a critical role in smooth muscle proliferation in vitro and in vivo in the induction of the lesions of atherosclerosis.


Nonenzymatic glycosylation of human hemoglobin at multiple sites.

The most abundant minor hemoglobin component of human hemolysate is Hb A1c, which has glucose bound to the N-terminus of the beta chain by a ketoamine linkage. Hb A1c is formed slowly and continuously throughout the 120 day lifespan of the red cell. It can be synthesized in vitro by incubating purified hemoglobin with 14C-glucose. Other minor components, Hb A1a1 and Hb A1a2 are adducts of sugar phosphates at the N-terminus of the beta chain. Hb A1b contains an unidentified nonphosphorylated sugar at the beta N-terminus. In addition, a significant portion of the major hemoglobin component (Hb Ao) is also glycosylated by a glucose ketoamine linkage at other sites on the molecule, including the N-terminus of the alpha chain and the epsilon-amino group of several lysine residues on both the alpha and the beta chains. The results indicate that the interaction of glucose and hemoglobin is rather nonspecific and suggests that other proteins are modified in a similar fashion.


Role of nonenzymatic glycosylation in the development of the sequelae of diabetes mellitus.

The increased level of the glycosylated hemoglobin (hemoglobin A1c) in the diabetic patient has proved to be an interesting clue to understanding the biochemical basis of the sequelae of diabetes. This minor hemoglobin, which arises as nonenzymatic postsynthetic addition of glucose to hemoglobin A, acts as an indicator molecule for the glucose environment over a 3-5-wk period prior to measurement. Reasoning that a similar glycosylation reaction could be occurring with other body proteins, we have studied the ocular lens. The lens, like the erythrocyte, is not dependent on insulin for glucose concentration in the extracellular milieu that would be elevated in the diabetic state. These studies have revealed that a high glucose in vivo or an increased glucose or glucose-6-phosphate concentration in vitro leads to the glycosylation of epsilon-amino groups of lysine residues in bovine and rat lens crystallins. This glycosylation imparts an increased susceptibility of the crystallins to sulfhydryl oxidation. Disulfide crosslinks result in the formation of high molecular weight aggregates and an opalescence of the crystallin solutions.


CP-45,634: a novel aldose reductase inhibitor that inhibits polyol pathway activity in diabetic and galactosemic rats.

In some tissues containing aldose reductase, increased flux through the polyol pathway has been implicated as being causative in diabetic complications (e.g., cataracts, peripheral neuropathy). We have found CP-45,634 (d-6-fluoro-spiro[chroman-4,4'-imidazolidine]-2',5'-dione) to be a highly potent, structurally novel, uncompetitive inhibitor of calf lens aldose reductase (IC50 approximately 5 X 10(-7)M). In a system in which sorbitol accumulation in isolated rat sciatic nerves was monitored in the presence of high (50 mM) glucose concentrations, CP-45,634 produced inhibition of polyol accumulation at levels as low as 1 X 10(-6)M. To determine if in vitro activity would translate to in vivo models, sorbitol accumulation in rat sciatic nerves was measured 27 hr after induction of diabetes with streptozotocin. Orally administered CP-45,634 was effective at dose levels as low as 0.25 mg/kg, t.i.d., and at 0.75 mg/kg produced an 85% inhibition of sorbitol accumulation. Two weeks after induction of diabetes by streptozotocin, sorbitol levels in rat lens and the sciatic nerve rose to 21,203 nmole/gm and 1,161 nmole/gm, respectively. Subsequent oral administration of CP-45,634 (2.5 mg/kg, b.i.d.) for 1 wk reduced these levels by 92% in nerves and 90% in lenses. In galactosemic rats, CP-45,634 inhibited the rise in lens galactitol and effectively delayed cataract formation at oral doses as low as 5 mg/kg/day. These high levels of in vivo activity suggest that CP-45,634 has potential for assessing the role of the polyol pathway in diabetic complications.


Aldose reductase inhibition: studies with alrestatin.

Studies with the aldose reductase inhibitor alrestatin in animal models have suggested that the sorbitol pathway may be of etiologic significance in the pathogenesis of peripheral neuropathy in diabetes. In normal subjects and in highly selected diabetic patients with severe peripheral neuropathy, alrestatin given either intravenously (50 mg/kg body weight) or orally (1 gm q.i.d.) produced no acute toxicity. The serum half-life of alrestatin was approximately 1 hr, and 99% was recovered in the urine within 24 hr. Two diabetic patients receiving alrestatin intravenously reported subjective improvements in clinical symptoms 2 days following the start of infusions. These improvements lasted approximately 3 wk after infusions were discontinued. However, there were no significant objective changes in peripheral nerve condition velocities, or on neurologic examination. In a 30-day oral trial with alrestatin in 4 diabetics, there were no subjective improvements in clinical symptoms nor were there objective improvements on neurologic examination or in peripheral nerve conduction velocities. In this study, peak serum levels of alrestatin were approximately 3 times lower than those obtained on intravenous administration, and it is possible that a high peak serum level is critical to the attainment of adequate tissue drug concentrations. Furthermore, the patients were suffering from severe clinical peripheral neuropathy, which could represent a stage of permanent irreversible nerve damage. Studies with alrestatin in newly diagnosed diabetics with peripheral nerve conduction velocity deficits but without clinical neuropathy might provide a better test of the sorbitol pathway hypothesis.


[Immune response to tetanus toxoid in mice receiving protein deficient diet immediately after weaning].

The humoral immune response to tetanus toxoid is evaluated by passive haemagglutination test in mice receiving low diet immediately after weaning during 15 and 30 days. The results show that the more deficient mice give the best antitoxin titers but after the challenge the antibody immune response become proportional to the protein restriction. In other respects and antitoxin titers are higher in 30 days restricted mice than in 15 days deficient ones. The effect of Bordetella pertussis adjuvant on the immune response of protein deficient mice seems nul. These results are discussed.


[Role of Mycobacterium tuberculosis in bovine tuberculosis].

The authors report the results of a survey on the possible role of human Mycobacterium in the ganglio-pulmonary tuberculosis of bovines. 232 bovines seized in the abattoirs of Algiers over a period of 8 months were concerned by this work. The results obtained showed that microscopic examination was negative in 50% of cases. This result was expected as ganglionary lesions are paucibacillary. Cultures were also negative in 50% of cases, 25% of them were contaminated. 50% rate of positive cultures was obtained when Loewenstein-Jensen medium with 1% pyruvate was used. Morphological and biochemical identification showed that out of 113 strains, 7 were Mycobacterium tuberculosis (6.2%). In seems therefore that Mycobacterium tuberculosis, human pathogen, is also pathogenic for bovines. Its frequent occurrence could be explained by the high prevalence of human tuberculosis in Algeria.


[Critical analysis of practical sensitivity tests in the evaluation of the primary resistance rate of tuberculosis bacilli to antibiotics].

Tuberculosis bacilli strains isolated from patients with pulmonary tuberculosis were tested to antituberculosis drugs in our laboratory since 1967 with the same method and by the same staff. However, there was a great fluctuation in the primary resistance rates calculated from one year to another and from one area to another. The analysis of strain sample showed that the main reasons were : the unprecision of patients questionnary, the preselection of strains sent to the laboratory and the unrespect of sanitary sectorisation.


[Comparison of reversed phase passive hemagglutination test and the electro-immunodiffusion technic for the detection of HBs antigen].

In this study, were compared two methods used in case-finding of the australian antigen (Ag. HBs) : the electro-immunodiffusion technique (E.I.D.) and the passive reverse hemagglutination tests. All the tests were carried out on couple of sera obtained from mothers and her newborns, giving on the whole 717 sera. The results we obtained led us to maintain the E.I.D. for the biological diagnosis of B virus hepatitis. The passive reverse hemagglutination test has been kept back for the titration of the Ag. HBs in the sera found positive by E.I.D. With regard to the vertical transmission (mother-newborn) of Ag. HBs, we could not draw any good conclusion.


[Model experimental study of protein-calorie malnutrition in mice].

With a view to form an experimental model of protein-malnutrition, mice are fed with two different commercial diets, the "nutrixan" and the "provende" which are included in different concentrations to a rice starch. Only the "provende" gives an workable model with three different growths which differ from the normal by a decrease which is proportional to the protein-deficiency. The incidence of the age and weight of the animals and the period of life of the beginning of the malnutrition are studied.


Experience with PGF2 alpha in mid-trimester pregnancy termination in Ibadan.

Twenty-five cases of mid-trimester pregnancy termination using intra-amniotic PGF2 alpha are described. The dose of PGF2 alpha used ranged between 40 and 80 mgs. Eighty-eight percent of all patients received 66mg or less of PGF2 alpha. Complete abortion without surgical intervention occurred in 13 (52%) of the women. The mean instillation abortion interval was 22 h. Surgical intervention was required in twelve patients. Side effects, mainly gastrointestinal symptoms, occurred in 72% of our patients. No epileptic seizure or cervical laceration was reported. It is suggested that the use of prostaglandin for pregnancy termination should be restricted to large medical centres with adequate facilities for coping with complications. Introduction of mid-trimester abortion with prostaglandin offers a back up method for failed contraception and obviates the need for surgical dilation of the cervix with its attendant risks.


The risks of umbilical vessel catheterization in a neonatal intensive care unit.

Five hundred and fourteen high-risk neonates who had indwelling umbilical catheters at the neonatal intensive care unit of the University of Benin Teaching Hospital were studied. of these 514 neonates, 122 (23.8%) had their catheters in-situ for longer than 24 h. Of the 122, fifty-four (44%) had positive bacterial cultures from their catheter tips. Seven (5.7%) and four (3.2%) of the 122 neonates studied developed septicaemia and necrotizing enterocolitis respectively. Catheterization for periods in excess of 48 h significantly increased the risk of bacterial colonization. Malposition of umbilical catheter tips include: insertion into the right portal vein (thirty-six cases); superior mesenteric vein (three cases) and the left atrium (four cases). The complications related specifically to the malposition were: air collection in the hepatic venous system (two cases); cardiac arrest (one case); necrotising enterocolitis (one case) and a case of blanching of the abdominal wall. Because of these complications, the indications for catheterization should be restricted to carefully selected patients and strict aseptic technique be adhered to during the procedure.


Depression in Africans revisited: a critical review of the literature.

The much-discussed problem of diagnosing depression in Africans is re-examined in this article. First, the incidence of depression as reported by various authors is discussed. Then, the universal difficulty associated with diagnosis of depression is considered. Factors related to diagnosis of depression in Africans are reviewed next. Finally, suggestions are offered as to how diagnosis of depression in Africans can be facilitated.


Chemotaxis by lipids isolated from Bacteroides fragilis.

Living, heat or formalin killed Bacteroides fragilis and a crude preparation of their cell walls were examined by the Boyden technique for chemotactic activity upon guinea pig peritoneal exudate cells. Their relative chemotactic activity ranged from 3.0 to 5.2 compared to an average value of 6.4 for the positive control, an endotoxic culture filtrate of Escherichia coli. A culture filtrate of B. fragilis and an index of 3.7. Miocrogram quantities of cytoplasmic preparations obtained by ammonium sulphate precipitation had chemotactic indices ranging from 2.8 to 6.4, the highest value being displayed by the precipitate formed between 50 and 75% saturation with ammonium sulphate. This fraction retained leucotactic activity after exposure to strong acid and heat. The leucotactic potency of these fractions did not correlate directly with their protein content. Further precipitation of the most active fraction with 80% ethanol revealed that there was little chemotactic activity attributable to polysaccharides. Gas liquid chromatography of a chloroform-methanol extract of the cells which had a chemotactic index of 6.1 revealed the presence of more than thirty fatty acids ranging in carbon length from C8 to C25. These results suggest a role of lipids as initiators of the leucotactic response associated with infections caused by B. fragilis.


Serum immunoconglutinin levels in healthy subjects, malaria nephrosis and other conditions.

Serum immunoconglutinin (I-K) levels were estimated and compared in 189 normal school children, ninety blood donors, eight-seven nephrotic children, twenty-eight nephrotic adults, twenty-five falciparum malaria children and 126 miscellaneous patients. Low levels (1/32 or less) were recorded in 75.1% of normal school children and 68.9% of blood donors. Similarly 95.4% of nephrotic children and 71.4% of nephrotic adults had low titres. The trend was the same in other disease groups in which 88.0% of falciparum malaria children and 65.1% miscellaneous patients had low titres. The relevance of the I-K levels obtained in the study groups is discussed.


Roentgenological measurement of skull size in Nigerian children.

The maximal internal length L, height H, and width W, were measured on normal A.P. and lateral skull radiographs on 352 Nigerian children whose age range was from birth to 12 years. The distance between the necks of the mandibles M, was also measured. Based on the above measurements the Cronqvist cranial indices (Formula: see text) and a simple summation index, L + W + H were determined. Normal mean values and standard deviation for Nigerian children were then calculated. The mean Cronqvist index (Formula: see text) was found to be 57.3, at birth, 53.3 at 5 years and 50.3 at 10 years. The simple summation index was 340 mm at birth and 495 mm at 10 years. There is a striking similarity in head size and growth pattern to those of North American children. There was little to choose between the various indices in the first year of life. The simple summation index seemed most sensitive after 2 years.


Haemoglobin DIbadan in a haemoglobin S endemic population.

Haemoglobin DIbadan (beta 87 threonine leads to lysine) was originally found in Ibadan, an area with a high incidence of sickle cell haemoglobin (HbS). Since haemoglobin D and S are indistinguishable by most common conventional methods, the geographical coincidence of the two haemoglobin poses a serious screening problem which was investigated in the propositus who is heterozygous for S and D, his wife who is heterozygous for A and S, and their six children. The combined techniques of haemoglobin solubility, sickling rate, shaking test and routine electrophoresis have yielded an unequivocal diagnosis of the haemoglobin types of the family both for identification and quantitative estimation of the percentage of haemoglobins in the heterozygotes. HbD was found to be slightly less soluble than HbA but otherwise normal blood from S+D individuals was found to contain 57-60% HbD suggesting an increased systhesis of HbD relative to S, whereas A+D heterozygote has 41% HbD suggesting a diminished synthesis of HbD relative to HbA. The physicochemical characteristic of HbD and the haematological data in simple heterozygotes are normal.


Biochemically unmonitored treatment of diabetic ketoacidosis for the first eight hours using the low dose intra-muscular insulin regimen: preliminary report.

The clinical efficacy of frequent low dose intra-muscular insulin in treating diabetic ketoacidosis was tested in eight patients who presented over a period of nine months. Blood sugar, urea and electrolytes were estimated only at presentation and eight hours after commencing insulin therapy instead of the initial one to two hourly estimations usually advocated. All the patients responded satisfactorily by eight hours despite the infrequent monitoring of blood sugars, urea and electrolytes. No hypoglycaemic episodes or clinical evidence of hypokalaemia were encountered. It is suggested that where facilities and staffing are inadequate, as in some developing countries, the first eight hours of treatment of diabetic ketoacidosis can be safely carried out using the frequent intramuscular low dose insulin regimen without much emphasis laid on monitoring the blood sugar, urea and electrolytes, provided there are no contraindicating cardio-pulmonary or renal diseases.


Pyocine typing of Pseudomonas aeruginosa strains isolated in Ahmadu Bello University Teaching Hospital, Zaria.

Pseudomonas aeruginosa strains isolated from clinical and environmental sources in Ahmadu Bello University Teaching Hospital, Zaria, were pyocine typed using the indicator strains and the standardized method of Gillies & Govan. Out of 302 clinical isolates 9.6% were untypable and 3.6% were unclassifiable. Among typable isolates fourteen pyocine types were identified, types 1, 3, 11, 5, and 10 being the commonest. Among ninety-six environmental isolates types 1, 3 and 10 were most common, 18.7% were untypable and 3.1% were unclassifiable. Sink traps were environmental sites most frequently contaminated with Ps. aeruginosa. Out of ten pyocine types identified in environmental strains, eight were the same as those isolated from patients. Seven subtypes were found among the most commonly encountered pyocine type 1 isolates. The procedure is a simple and reliable method to study the epidemiology of infections due to Ps. aeruginosa.


Ventilatory function in normal Nigerian school children.

Lung function studies were performed on 522 school children in Ibadan to determine normal values among Nigerian School children. From four schools 257 boys and 265 girls aged 7 - 18 with different socio-economic background were selected. The forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) wee estimated using the wedge bellows vitalograph. It was observed from the results that the mean FVC and FEV1, values were lower than the predicted mean values matched for age, sex, height and weight. It was further observed that the values obtained were lower than those of the caucasian children. However, it was observed that the FVC values correlate significantly with age, weight and height (P less than 0.01).


Studies on transmission of Tataguine virus by Culex (pipens) fatigans mosquitoes.

Culex (pipens) fatigans mosquitoes were infected with Tataguine virus by pledget method. Virus was recovered from 40% of mosquitoes that fed on the infective blood meal after 21 days of incubation. Low titres of infective virus were found in the mosquitoes. Tataguine virus was not successfully transmitted to suckling hamsters exposed to the bites of infected mosquitoes.


Interaction of the aflatoxins with classical antibiotics which inhibit Bacillus brevis (2611).

Synergism, antagonism and addictive action are three modes of interaction among antibiotics and non-antibiotic compounds. The present paper reports the type of interaction between each of the four main members of the aflatoxin family (BB, G and G) and each of five commonly used classical antibiotics. The test aflatoxins were freshly prepared and confirmed crystalline pure by the use of ultraviolet (u.v.), infrared (i.r.) and nuclear magnetic resonane (n.m.r.) spectroscopy. Interaction between penicillin and aflatoxin B (AFB) gave an antagonistic profile. The interaction of AFB with tetracycline was synergistic. Novobiocin interaction with aflatoxin G also reflected synergism. All other characteristics of interaction between antibiotics and the aflatoxins showed additive profiles.


Criminal justice and psychiatry: a study of the pattern of criminality in Ibadan division.

Two thousand, one hundred and fifty-eight offenders committed for trial at the Ibadan Magistrate courts between 1974 and 1975 were reviewed. A preponderance of males (95.9%) and young adults (81% less than 40 years) was found in the population of the offenders. A decline in criminal offences was found with increase in age. Stealing was found to be the commonest crime and it was about half (49%) of the total offences. There were significant increases in fraud and assault between 1974 and 1975. Within the 2 years, only cases of homicide (twenty-three out of seventy-one cases) were referred for psychiatric assessment. Attempted suicide and drug abuse were not referred. It was concluded that psychiatric cases can commit any form of crime and that where the sanity of a criminal, whatever the type, is doubted, he should be referred for psychiatric evaluation.


Plasma and erythrocyte cations and permeability of the erythrocyte membrane to cations in essential hypertension.

Untreated African patients with essential hypertension were found to have high plasma sodium and low plasma potassium. The red cel contents of these cations determined from the same sample of blood were found to be high for sodium and normal for potassium. The passive permeability of the erythrocytes for potassium was lower in hypertensives than in controls. The ouabain-sensitive active sodium efflux was lower in hypertensives than in controls. The relationships between the erythrocyte cation content and the total body content of the cations, and between the membrane function in red cells and other cells of the body are discussed.


Personality characteristics and mental health of university students.

The selective review of the enormous literature on student personality development and mental health shows that three sets of variables have been found to influence the personality of the university student. These variables include pre-university factors, contemporary experience in the university and the status of the student as an adolescent or young adult. As very little information is presently available on the psychology of the African university student, there is urgent need for systematic research in this area.


A double-blind comparative study of cimetidine and placebo in adult Nigerian duodenal ulcer patients with special reference to gastroduodenal mucosal morphology and intestinal bacterial activity.

Twenty-seven adult Nigerian patients with endoscopically proven active duodenal ulcers have received in a double-blind trial either the histamine H2 - receptor antagonist cimetidine 1g daily or placebo tablets of identical appearance for 4 weeks. Fifty-six per cent of the cimetidine patients and 18% of those receiving placebo had endoscopically completely healed ulcers and total pain relief at the completion of trial. This response amounted to clinical cure. An additional 19% of patients in the cimetidine group experienced clinical improvement either in endoscopic or symptomatic reassessment but not in both, thus leading to a disparity between clinical cure rate (56%), healing rate (69%), and pain relief (64%). Though therefore significantly better than placebo, this less favourable response to cimetidine in this study may be due to the short trial period, the disparity between healing and pain relief rates or to co-existing and persistent antroduodenitis in ulcer patients as shown on gastroduodenal mucosal biopsies taken at the time of the clinical investigation. There were no untoward clinical laboratory side effects with the exception of the one cimetidine patient who experienced diarrhoea and a small number who showed slight, asymptomatic rise in plasma creatinine level. Of particular interest to the reported occurrence of diarrhoea with cimetidine therapy is the finding in the bacteriological studies of intestinal aspirates and biochemistry estimations for indicanuria in the consenting patients which showed that orally administered cimetidine 1g daily for 4 weeks neither produced demonstratable alterations in the bacterial content of the small bowel not pathological indicanuria, thereby excluding bacterial overgrowth syndrome as a therapeutic hazard in the clinical application of cimetidine.


Neurological diseases in Addis Ababa, Ethiopia.

The pattern of neurological disease seen in Ethiopian patients hospitalized in general medical wards in two hospitals in Addis Ababa is analyzed and discussed. Cerebrovascular disease, most commonly cerebral thrombosis, accounted for 45% of the neurological diseases seen. The second commonest disorder was bacterial meningitis (12%). Hepatic encephalopathy and intracranial haemorrhage, the latter commonly due to hypertension, were found to be the commonest causes of admission in coma.


Case report: a fatal case of amniotic fluid embolism.

A primigravida was induced for PET, the liquor was meconium stained; she was put on oxytocin in-fussion and developed hypertonic uterine action. She then had an amniotic fluid embolism which presented clinically as profound shock, dyspnoea, tachycardia, cyanosis, hypotension and pyrexia. The patient was delivered by vacuum extraction. The picture was further complicated by pulmonary oedema intravascular microcoagulation and anuria. She deteriorated rapidly and died despite treatment with double strength plasma (in the absence of fibrinogen), massive hydrocortiosone therapy, blood transfusion amd sub-total hysterectomy. Post mortem findings in the lungs confirmed amniotic fluid embolism.


[Posttraumatic and postoperative catabolism: protein metabolism].

Patients with catabolism during the postoperative phase, after trauma or in a toxifectious state present with serious disorders of their protein metabolism. These alterations are caused mostly by endocrine factors and are characterized by destruction of proteins, gluconeogenesis, ketogenesis and increased renal nitrogen excretion. The nitrogen losses are most important in patients with multiple trauma, in sepsis and in burned patients. In view of the intricate etiology, the treatment of these disorders is difficult.


[The importance of amino acids].

Complete AS mixtures which permit prolonged parenteral feeding are known. It is possible to achieve normal growth even in nursing infants with such solutions (reference should be made to the contributions of Professor Riccour and Professor Schärli). On the other hand the composition of an AS solution of maximum biological value, e.g. for the growing body, is not yet known. Improvements in this respect can be envisaged although they are relevant only to certain patients. Changes in the method administration of AS may affect the biological value. Continuous administration throughout the 24 hours by-passing the portal vein, as is usual today, must considerably impair the capacity of the liver to regulate the pattern of plasma amino acids. Possibly, an approximation to physiological proportions is possible and useful through intermittent administration. Further progress in this aspect of parenteral feeding can undoubtedly be expected.


Principles of intravenous nutrition.

In my view intravenous feeding represents a substantial advance in the management of critically ill patients. It is no longer tenable that patients should die as a result of complications of malnutrition simply because they cannot or are unable to take adequate oral nutrition. Intravenous feeding is a challenge both in concept and application. With it, however, the outcome for many patients, who formerly would have died, has considerably improved.


[Metabolic problems and indications for exclusive and prolonged parenteral feeding in children].

In the light of 350 cases of E.P.N., prevention of complications rests upon: 1. supply of hydroelectrolytics and proteinoenergetics at reduced dosage, initially, and then adapted to the anabolic stimulation, taking into consideration the correlations which exist between calories, nitrogen, calcium, phosphorus, zinc and vitamins, particularly those of the B-complex; 2. the necessity to achieve a progressive withdrawal through the supply of enteral elementary substances which will permit a modulated new induction of the digestive enzymatic secretory activities. The indications for such a highly technical program may emanate in the course of serious malabsorption with severe denutrition within the framework of inflammatory and vascular enteropathies and in the presence of certain metabolic disturbances, either congenital or acquired.


[Parenteral feeding in pediatric surgery].

Complete, parenteral feeding by continuous drip infusion into large veins over long periods has a solid, therapeutic place in children's surgery. It embraces complete filling of the need for water, salts, glucose, amino acids, triglycerides, essential fatty acids, vitamins and trace elements. Bearing in mind certain basic principles, it can achieve a positive nitrogen balance and so anabolism even in the newborn and nursing infant, in spite of the high demand for calories and nitrogen.


[Nutritional requirements and parenteral feeding].

1. The nutritional needs of man are governed by the law of the minimum (structural and protective substances) and the isodynamic rule (exchangeability of various energy carriers) There is a tendency to abandon the traditional concept of requirement as an absolute value (g or mg/day) and replace it by 3 graded parameters (minimal - lowest acceptable - desirable supply). Today nutrient density is of utmost importance in the planning and evaluation of food formulas, i.e. the content per 1000 kcal or per MJ = mega-Joule. 2. The metabolism of nutrients proceeds (simplified) in 3 phases: a) digestion (comminution); b) coordination and conversion in intermediary metabolism; c) direct use in synthetic or oxidation processes. This creates problems of balance, of co-ordination and regulation. In the phases b and c the same conformities apply for oral and parenteral feeding. 3. Particular features of parenteral feeding: Exclusion of intestinal flora, limited capacity of uptake by the circulation and, especially, the lowered capacity of biochemical regulatory mechanisms (homeostasis) in patients requiring parenteral feeding necessitate optimal coordination of supply and effective needs. Attempts to comply are made by continuous infusions, diversification of the substrate supply and optimisation of the different components. In principle, priority is given to those nutritional factors which promote anabolism (tissue formation) and counteract catabolism (tissue breakdown). 4. Example: protein needs. --Recapitulation of quantitative and qualitative requirements regarding protein and amino acid supply. --Discussion of the different recommendations and guidelines. --Discussion of the criteria for evaluation and the composition of an optimal amino acid mixture (nitrogen balance and growth as criteria). 5. Conclusions for parenteral feeding. The supply of amino acids should be on the generous side because there is an increased requirement in the "acute phase" and in convalescence. The amino acid composition should correspond to the pattern of a high quality food protein. The E/T ratio (essential AS versus total AS supply) is an indicator. The value proposed as a guideline is E/T approximately 3. However, an exaggerated amino acid cosmetic is not recommended. 6. Diagnostic problems. In the interest of optimal results of treatment, foremost attention should be given to the detection of latent deficiency states and the improvement of nutrition at large. The list of indicators given in the figures should be consulted whenever there is evidence of undersupply. The so-called "hospital malnutrition", as described in recent studies, should obviously not occur.


[Technical aspects of parenteral feeding].

The following approaches to the caval vein are applicable: Vena saphena, respectively femoralis, vena basilica, subclavia respectively anonyma and vena jugularis. Based on collective studies from literature and own experience the puncture of the internal jugular vein is recommended. The approach via the veins of lower extremities is to be used no more on adults. Numerous complications, however, are independent of the approach. They may be caused by the catheter model applied or by poor application technique. A model of our own was developed presenting siliconized polyethylene and a removable needle as main features. The material of the catheter proved to be neutral towards tissue experimentally and clinically. As compared to PVC the rate of inflammation and thrombosis was significantly decreased. Finally the removable split needle prevents catheter embolization with its grave consequence.


Testicular lipids and serum FSH of mice in experimental Schistosomiasis mansoni.

Morphological and histopathological changes in the testis have been reported to result from bilharzial infestation. There should be certain changes in the biochemical composition of the cells which might lead to these changes in the structure. This study was undertaken to compare the lipid composition of the testis and the serum level of FSH of normal and infected white Swiss albino mice at 8, 10 and 12 weeks after infection. The results indicate that infection produced a marked and persistent decrease in serum FSH indicating hypofunction of the anterior pituitary gland. There was also marked alterations in the lipid composition of the testis. These include an elevation in the levels of triglycerides. NEFA, cholesterol and cholesterol esters and a lowering in the level of phospholipids. The changes observed could be due to various forms of endocrine disturbances associated with schistosomiasis.


The influence of temperature, darkness, and starvation on growth and survival of Helisoma duryi, Biomphalaria alexandrina and Bulinus truncatus.

The influence of 10 degrees, 18 degrees, 26 degrees, 28 degrees and 33 degrees C, different periods of complete darkness and starvation on growth and survival of H. duryi, B. alexandrina and B. truncatus were studied. The optimum temperature for the growth and survival was about 26 degrees C. Survivorship and growth rates decreased proportionately according to starvation period. However, darkness had no significant effect on the growth of B. truncatus and H. duryi. Under the chosen experimental conditions H. duryi revealed higher tolerance limits and survival rates than B. alexandrina and B. truncatus. The potential of H. duryi as biological control agent of Schistosome vector snails is discussed.


Micropreparation techniques in quantitative histochemistry - density gradient centrifugation, manual microdissection and laser microbeam preparation of tissue.

Each quantitative histochemical problem needs its specific method for tissue preparation. In this connection two of the most important preparation methods, density gradient centrifugation and microdissection of freeze-dried tissue slices, are described. Density gradient centrifugation is a very effective procedure for preparative separation of cell particles such as cell nuclei. The details of the preparation of glial and neuronal cell nuclei are described. The in vitro phosphorylation of histone in the chromatin in relation to age is given as a practical example of the quantitative histochemical application to a preparation of cell nuclei. Other techniques of tissue preparation are the manual tissue microdissection according to Lowry and the Laser microbeam preparation. Advantages and disadvantages of both methods are compared. It is shown, that the introduction of Laser microbeam dissection technique, as alternative to manual microdissection, add new dimensions to Lowry's ultramicrochemical methods. One has greater freedom in the choice of the sample size and the number of samples dissected from the same slice. Furthermore, the need for a well-trained person for the preparation is eliminated. The preparation is also considerably less time consuming and easier to perform than the manual free hand preparation. Two quantitative histochemical methods used for the investigation of microdissected tissue samples are described: the gas-chromatography-massfragmentography (GC/MS)-method for determination of transmitters and its metabolites as well as the enzymatic cycling technique of Lowry. The GC/MS-method is explained with an example of noradrenaline and dopamine determination. The enzymatic cycling technique is demonstrated in combination with the Oil-Well-Technique for determination of the NADP-cycle.


Life-threatening enterocolitis after gold salt therapy.

Two patients developed life-threatening enterocolitis after receiving gold salt therapy. This disorder is attended by a mortality rate of 50% but the intestinal lesion appears to be reversible. The mechanism of the drug toxicity is not known. The course may be fulminant and recovery may occur only after many weeks. Total bowel rest, nasogastric suction, total parenteral nutrition with supplemental colloid and careful monitoring of fluid and electrolyte balance may improve survival.


[Effect of mannitol on oxygen consumption of the renal cortex of rats].

We have determined the oxygen consumption (QO2) in renal cortical tissue from controls and from rats which received in vivo and infusion of mannitol (600 mM) in order to study the metabolic changes which occurred in the tissue. QO2 was significantly higher (+20%, p less than 0.01) in slices from animals which received the infusion than in those from non-infused animals, when incubated in mannitol containing solutions; these slices had tubules with their lumens open. When the slices were incubated in solutions without mannitol or obtained from animals not infused with mannitol, the QO2 was lower and the tubules appeared histologically with the lumen closed. A short (2 min) exposure to 2 mM ethacrinic acid inhibited QO2 only in slices from mannitol infused animals incubated in mannitol containing solutions. Similar exposures to 1 mM ouabain inhibited QO2 both in slices from infused and from non-infused animals and independently of the composition of the incubation media. We suggest that the higher QO2 found in those slices which had their tubular lumens open, as well as the specific inhibitory effect of ethacrinic acid on the excess QO2 of such slices, might relate to transport processes, linked to tissue metabolism, and only present in tubules which have their lumens open. Such active transport process may correspond, for example, to the coupled transcellular Na+ and Cl- transport. The effects of mannitol on the tissue water content is discussed.


Relationship between changes in lactase activity and monosaccharide uptake in the small intestine of the rat during development.

The relationship between changes in intestinal lactase activity and monosaccharide uptake was studied in rats of different ages using the technique of intestinal everted sacs. In the postweaning period there is a sharp decrease in the rate of glucose and galactose uptake by the small intestinal mucosa. This change occurs simultaneously with a decrease in lactase activity in the tissue. The kinetic analysis showed a lower Vmax for monosaccharide uptake in the 50-days-old rats as compared with the fifteen-days-old animals, with no change in the apparent Kt. The addition of Tris+ (40 mM) to the incubation media was found to produce a decrease in Vmax for monosaccharide uptake only in the suckling rats but not in the 50-days-old animals; the K1 remained unchanged. Tris+, at the concentration used had previously been shown to completely inhibit lactase activity in homogenates of small intestinal mucosa. These observations lead us to postulate the lactase in the suckling rat might possess a translocating role for sugar, in addition to its hydrolytic function. The decrease in sugar uptake after weaning could be explained by the disappearance of this role.


Carcinoma in a Zenker's diverticulum.

Zenker's diverticulum is a common developmental anomaly seen usually in the elderly. Carcinoma in this pharyngoesophageal outpouching has been reported in only 23 instances. A 55-year-old woman is presented whose only symptoms were dysphagia and periodic regurgitation of bloodstained material. Barium swallow and esophagoscopy confirmed the presence of a neoplasm, and biopsy revealed an epidermoid carcinoma. Wide field resection was followed by a full course of irradiation and secondary pharyngoesophageal reconstruction. The patient was free of disease at three-year follow-up.


Learned and emotional behavior in chronically malnourished rats.

Weanling male and female Wistar rats, whose mothers received low protein diet (6.8%) during pregnancy and lactation, were fed on the same diet of their mothers and trained in an active avoidance situation at the ages of 60, 90 or 120 days. Control animals fed on a 20% protein diet of the same age groups were submitted to similar training. The consolidation and performance of the conditioned avoidance response and other behavioral reactions were studied. The malnourished animals showed delay of consolidation and lower frequency of conditioned avoidance responses, escape responses and holdings as well as higher frequency of anticipatory reactions, vocalization, riddance attempts and touching of surroundings. The results show that chronic malnutrition impairs the active avoidance response. They also show that chronic malnutrition affects the emotional behavior more markedly than early malnutrition. Chronic malnutrition also enhances the exploratory activity, in contrast to early malnutrition, and this is attributed to an alimentary drive-dependent mechanism.


[Solid-phase radioimmunoassay for the study of the humoral response to Trypanosoma cruzi].

A solid-phase micro-radioimmunoassay (RIE-S) test was adapted fore the study of the humoral immune response induced by Trypanosoma cruzi infection. The solid phase, consisting of disposable polypropylene tubes, was sensitized by absorption of T. cruzi antigen. The procedure was performed by sequential adding to the solid-phase, the human serum under study and 131I anti-human immunoglobulin. Then, the specific label binding was estimated. Several factors which influence the test were studied. The RIE-S results correlated well with those obtained by complement-fixation, passive hemagglutination and immunofluorescence tests. Since it is a relatively simple and sensitive procedure, it seems available for screening studies, Besides, it also allows to know the class and molecular specificity of the antibody detected.


[Microbial etiology of subclinical bovine mastitis in the Santa Fe dairy basin].

A study of 320 samples of mammary quarters from cows in 40 dairy farms around Santa Fe city during 1977-1978 was made. The samples were selected based on clinical examination and California Mastitis Test (GMT). High percentage of subclinical mastitis was found. The etiological agents most frequently isolated were Staphylococcus aureus (54,1%), Streptococcus agalactiae (23.4%) and Pseudomonas aeruginosa (13,2%). A winter increment of S. aureus (48,1%) and P. aeruginosa (3,7% and 22,5%) was observed. But S. agalactiae did not experiment considerable variation (26,8% and 20% throughout the year. The sensitivity to antibiotics of some strains decreased in winter specially in S. aureus and P. aeruginosa (61,5% and 38,9%), and some biochemical properties related with their virulence increased. Penicillin in milk was not detected, but the levels of contamination by non specific inhibitory substances were very high (40%). Besides it was found a great contamination with aerobic sporeforming bacteria in these samples, being Bacillus coagulans (59,1%), B. polymyxa (26,1%) and B. sphaericus (9,5%) the most frequent.


[Comparative study of microbial methods for the detection of genetic toxicity].

It is important to have a rapid and accurate method to detect the toxic action of drugs and chemical compounds used by man. A comparative study with two microbial systems was carried out: one using Salmonella typhimurium and the other using Bacillus subtilis. The 1-8-dihydroxyantraquinone was the tested drug and the N-methyl-N'-nitro-N-nitrosoguanidine and the 2-aminofluorene were used as control substances. These compounds were used as such or after previous transformation by a microsomal system. The results obtained showed that both systems: the S. typhimurium and the B. subtilis work in a similar way, but the latter allows a more direct action of drug on the genetic material. The effect of the solvents: ethanol and dimethylsulfoxide was analysed, because they affected the transformation and reversion processes that were carried out.


[Determination of aflatoxins and toxicogenic fungi in mixed feed for poultry].

The presence of aflatoxins was determined in 155 samples of chicken feeds, as well as their fungal contamination. Aflatoxins were detected in 3 of the analized samples; one of them contained 1620 micrograms/kg, a highly dangerous amount for chickens. The amount found in the remaining 2 samples was 30 micrograms/kg. A study of toxigenic fungus showed a prevalence of 69.3% of Aspergillus flovus: 72.4% of this percentage corresponded to aflatoxins producing strains. The prevalence of Aspergillus ocraceus was 18.6%; ten per cent of it corresponded to ochratoxin A producing strains. Chicken feeds are an adequate substratum for the formation of aflatoxins; this was demonstrated by raising the humidity contents of initially negative samples, which contained toxigenic Aspergillus flavus spores. The danger of storing chicken feeds under certain humidity and temperature conditions was demonstrated.


[Evaluation of the myeloculture by puncture of the ilium crest for isolation of Brucella from patients with brucellosis].

Hemocultures and myelocultures of samples obtained from the ilium crest were made simultaneously of 61 patients with serologic diagnosis of brucellosis. Five strains were isolated by both methods and 18, by myeloculture only. All samples from which Brucella were isolated by hemoculture were also positive by myeloculture. The advantages of making myelocultures of patients previously treated with antibiotics are emphasized.


Development of anti-hLH antibodies after therapy with posterior pituitary extract.

This report describes the appearance of high affinity antibodies to human LH in a girl who had been treated for diabetes insipidus with injections of pitressin tannate, plus occasional nasal insufflations of posterior pituitary powder. Immunological studies indicated that the antibody was a 7S IgG directed against the beta subunit of LH, which is not species-specific. The demonstration of immunoassayable LH in a commercially available pitressin preparation strongly suggests that this patient was immunized by bovine or porcine LH. Although studies of her urinary LH excretion and serum LH (by an interstitial cell bioassay system) suggest that at least some of her endogenous LH is not bound by the antibody, the possibility remains that this type of immunization may have important implications for the development and maintenance of normal adult pituitary-ovarian relationships.


Progesterone effects on gonadotropin release in women pretreated with estradiol.

This study was designed to investigate whether the amounts of progesterone (P) normally present at midcycle, when administered to normal women pretreated with estradiol benzoate (E2B), alter the release of LH and FSH. Twelve subjects (four groups of three) were studied during two menstrual cycles. On day 1 of both the initial (E2 control) and a subsequent (study) cycle, each subject received E2B im (2.5 micrograms/kg/12 h) for a total of seven injections. Twelve hours after the final injection, gonadotropin-releasing hormone (GnRH) was given. In the study cycle, P in oil was added to each of the last three injections of E2B in doses of 1.25 (group I), 2.5 (group II), or 5.0 (group III) mg/12 h, and in one group (IV) in graded doses of 1.25 2.5, and 5.0 mg/12 h. Estradiol levels were similar in both cycles, with a mean (+/- SE) of 271 +/- 3 pg/ml. During the interval of P administration, mean P levels rose gradually from 0.3 +/- 0.02 to 1.3 +/-0.12 ng/ml (mean +/- SE of all groups). In the study cycle, an FSH rise occurred in 8 of 12 subjects, while an LH surge greater than that in the E2 control cycle occurred in all but one subject. Peak levels of these surges usually occurred within 24 h of the initial P injection, which is similar to the relationship between the initial rise of P and the occurrence of peak gonadotropin levels at midcycle in normal women. The mean delta max of FSH and LH in subjects exhibiting gonadotropin rises approximated the magnitude of the gonadotropin increases observed normally at midcycle. In response to GnRH during the study cycle, the magnitude of the FSH rise was augmented in 6 of 12 subjects and of LH in 9 of 12, when compared to the E2 control cycles. These data suggest that P, in the presence of late follicular phase levels of E2, 1) augments the release of LH, 2) may induce the release of FSH, and 3) further modulates pituitary responsiveness to GnRH. The data are consistent with the hypothesis that the rising concentrations of E2 to which the hypothalamic-pituitary system is exposed for an appropriate duration serve to initiate the surge of LH at midcycle. This increased LH in turn, stimulates the production of P, which not only further augments the LH surge but, when coupled with E2, also can effect the midcycle FSH surge.


Abnormal gonadotropin secretory responses to LRH in transsexual women after diethylstilbestrol priming.

To determine whether female transsexuals have abnormal hypothalamic-pituitary feedback control, pituitary LH and FSH secretory responses to synthetic LRH (100 micrograms iv) were measured in nine female transsexuals with normal menstrual cycles before and after a 7-day course of treatment with diethylstilbestrol (DES; 2 mg/day). Control groups included five heterosexual women and seven heterosexual men. Pituitary responses to LHR in heterosexual women studied in the early follicular phase increased markedly after DES administration and were clearly different from responses in men, which were all inhibited by DES. Responses to LRH in nine transsexual women studied in the early follicular phase differed strikingly from normal women in that gonadotropin responses were not enhanced by DES. The finding that the responses of female transsexuals to DES and LRH were intermediate between the female and the male patterns suggests that a biological abnormality accompanies the psychological abnormality in such patients.


Progestin binding in testes from three siblings with the syndrome of male pseudohermaphroditism with testicular feminization.

We have found a specific binding protein for synthetic progestins 6,7-[3H]methyltrienolone (R1881) and 17,21-dimethyl-19-norpregna-4,9-diene-3,20-dione (R5020) and in the testis cytosol from three "sisters" with the complete form of the testicular feminization syndrome. The binding component sediments in the 8S region of sucrose gradients. It is saturable. The apparent affinity constant (Ka) for R5020 was determined in two cases and found to be 1.8 and 0.6 X 10(8) M-1. The number of binding sites calculated from Scatchard plots is relatively high: 572 and 826 fmol/mg protein. Competition studies indicate that this putative receptor is specific for natural and synthetic progestins but not for 5 alpha-dihydrotestosterone and cortisol. Similar progestin binding could not be found in normal human and rat testes.


TRH test as an index of suppression compared with the thyroid radioiodine uptake in euthyroid goitrous patients treated with thyroxine.

To determine an index of adequate suppression of pituitary TSH secretion in euthyroid goitrous patients treated with sodium levothyroxine (T4), TSH responses to 500 micrograms TRH given iv were compared with thyroid 24-h radioiodine uptakes during therapy with T4 in 12 euthyroid goitrous patients. The patients received sequentially 100, 150, 200, 250, and 300 micrograms T4 with the doses increased at 4-6 week intervals. The mean dose of T4 that reduced the peak TSH response to TSH to the lower limit of normal (TSH = 5 microU/ml) was 130 micrograms; the mean T4 dose that suppressed the TSH response to one-half the lower limit of normal (TSH = 2.5 microU/ml) was 165 micrograms. The mean T4 dose that nearly obliterated the TSH response was 200 micrograms; this degree of suppression occurred with doses of 100-300 micrograms T4 in individual patients. Suppression of thyroid uptake correlated closely with suppression of the TSH response to TRH. The goiter diminished in size significantly in 6 of the 12 patients during the 6 months of observation adn did not enlarge in any patient. The data indicate that suppression of the TSH response to TRH is a convenient technique to assess the adequacy of suppressive therapy of goiter.


17 beta-Estradiol biosynthesis in cultured granulosa and thecal cells of human ovarian follicles: stimulation by follicle-stimulating hormone.

Cellular sites and gonadotropic control of human follicular estrogen secretion have been assessed by culturing the theca and granulosa components separately under different hormonal conditions. Granulosa cells from human follicles were grown in chemically defined media containing gonadotropins and/or testosterone (T) for 24 h. The production of 17 beta-estradiol (E2) by cells cultivated in T-free media with or without FSH was very low during the culture period. There was a highly significant increase (P less than 0.001) in E2 production when T alone was added and a more marked increase was consistently noted in the presence of FSH and T. In all cases, hCG failed to exert any significant effect on E2 production by granulosa cells in the presence or absence of T. No treatments examined altered the E2 production of thecal cells during a 24-h culture period and the amounts of E2 released into media were negligible when compared with levels produced by granulosa cells from the same follicles. It is concluded that granulosa cells but not thecal cells are the prime site of follicular estrogen production and that FSH regulates estrogen secretion by nonluteinized granulosa cells of the human follicle.


Depressed plasma testosterone and fractional binding of testosterone in obese males.

Plasma testosterone (T), fractional binding of T to T-binding globulin (TeBG), LH, and FSH were evaluated in 22 obese men. Only 1 of 12 men weighing from 176-200% of ideal body weight (group I) had a low T concentration, while 9 of 10 men greater than 200% of ideal weight (group II) had plasma T concentrations 2 SD below the normal mean. The fractional binding of T to TeBG was equally and significantly decreased in both groups. As a result, the mean and individually calculated free T concentrations (free T index) were normal in group I. In contrast, the mean free T index in group II was significantly less than normal males and group I. Individually, 1 of 7 group II men had a free T index 2 SD below the normal mean. LH and FSH were normal in both groups. These studies indicate that in most obese males a low or low normal T is offset by decreased binding to TeBG, resulting in a normal free T index. However, some morbidly obese males are unable to alter their hypothalamic-hypophyseal-gonadal axis to maintain a normal free T index.


Effect of thyroid hormones on the prolactin response to thyrotropin-releasing hormone in normal persons and euthyroid goitrous patients.

In nine euthyroid goitrous patients, increasing doses of T4 caused a significant decrease in the PRL response to TRH; the PRL response fell significantly at a dose of T4 of 100 micrograms/day for 1 month (P less than 0.02) and fell further with increasing doses so that at 300 micrograms T4/day, the PRL response was 40% of that in the untreated state. T4 treatment also blunted the PRL response to chlorpromazine (P less than 0.05) in a separate group of euthyroid goitrous patients. In contrast, there was only a small drop of the PRL response to TRH in normal subjects treated with T4 (n = 9) and none at all with T3 (n = 7). These data, together with previously published reports, suggest that thyroid hormone may affect PRL secretion in the presence of thyroid disease (hyperthyroidism, hypothyroidism, or euthyroid goiter), but that physiological amounts of thyroid hormone have little or no modulating effect on PRL secretion in normal persons.


Primary amenorrhea in a black female with duplication and inversion of the secondary constriction regions of chromosome 9.

A 36-yr-old black female presented with primary amenorrhea. The chromosomal constitution based on QFQ (Q bands by fluorescence using quinacrine) RFA (R bands by fluorescence using acridine orange), GTG (G band by Giemsa using trypsin), and CBG (C band by Giemsa using barium hydroxide) techniques was 46, XX, duplicated (9; q12), inverted (9; p12q12.1) in lymphocytes and skin fibroblasts. Both sex chromosomes were normal. Buccal smear revealed 22% Barr bodies. Duplication and inversion of secondary constriction regions of chromosome 9 may possibly be associated with abnormal clinical features.


Pituitary function after removal of pituitary microadenomas in Cushing's disease.

Pituitary function has been studied sequentially after transsphenoidal removal of pituitary microadenomas in two men with Cushing's disease. Patient 1 gradually regained normal glucocorticoid levels with normal diurnal variation, metyrapone responsiveness, and low dose dexamethasone suppressibility (17-hydroxycorticosteroid, 6.5-0.9 mg/24 h). GH levels rose from 1 to 35 ng/ml during insulin hypoglycemia and from 2.3 to 27 ng/ml during arginine infusion. PRL secretion rose normally in response to thorazine, and gonadotropin and TSH levels remained normal. Patient 2 regained significant metyrapone responsiveness by 9 months postoperatively (11-deoxycortisol rose to 11.7 micrograms/dl), had a normal spontaneous nocturnal rise in PRL secretion, and normal levels of testosterone and thyroid hormones. The return to normal of cortisol-ACTH dynamics and GH responsiveness in Patient 1 and the normal nocturnal surge in PRL secretion in Patient 2 imply that in these patients the etiology of Cushing's disease was not related to hypothalamic dysfunction.


Effects of prolactin and prolactin plus luteinizing hormone on plasma testosterone levels in normal adult men.

In an earlier study, normal adult men were shown to have increased plasma testosterone (T) levels over a several-hour period after haloperidol-induced increases in plasma PRL levels. The present study was designed both to replicate our first study and to examine the potential synergism of PRL and LH in influencing T levels on a short term basis in normal men. Eight volunteers received on 4 separate days an in injection of saline or 0.5 mg haloperidol at 1000 h and an iv injection of saline or 88 IU human LH (hLH) at 1100 h in a double blind randomized block design arranged to augment plasma levels of PRL, LH, and PRL and LH together on the different test days as well as to afford a saline control day. Only five of the eight subjects had prompt PRL responses to haloperidol equivalent to those of our earlier study. As the purpose of this study was to examine the effect of increased PRL on plasma T levels, these five subjects were used for the determination of changes in plasma T. After haloperidol administration, their PRL levels rose an average of 19 ng/ml, to the high-normal range, and after the hLH infusions, their LH levels rose an average of 71 ng/ml. On the saline control day, mean T levels showed the normal diurnal decline. After 0.5 mg haloperidol, T levels were maintained for several hours, and after 88 IU hLH, T levels were increased for several hours. Increased PRL levels concomitant with hLH administration did not produce a T response greater than that caused by hLH alone. The results of this study replicate the effect of drug-induced PRL augmentation on plasma T levels found in our earlier study, but they fail to demonstrate a synergistic effect of acutely increased PRL on LH-stimulated T secretion. PRL thus seems to be another pituitary hormone capable of increasing plasma T in adult men, but it clearly is a weaker stimulus than LH.


Responses to TRH and T3 suppression tests in euthyroid subjects with a family history of Graves' disease.

The relationship of Graves' disease and heredity was studied in 97 clinically and biochemically euthyroid relatives (resin T3 uptake and serum T3, T4, and TSH within normal ranges) who had more than two thyrotoxic relatives within the second degree relationship. TRH tests were preformed in all 97 cases. In 56 of the 97, T3 suppression tests were performed shortly after the TRH test. Results revealed that 29 of the 97 (29.9%) showed an abnormal response to TRH. fourteen of these (14.4%) revealed no response or a hyporesponse, and 15 (15.5%) revealed a hyperresponse to TRH. Four of 56 (7.1%) were T3 nonsuppressible. Seven individuals who showed no response or a hyporesponse to TRH consisted of 2 nonsuppressible and 5 suppressible subjects. In 14 non- or hyporesponsive cases, serum T3 (1.51 +/- 0.05 ng/ml; mean +/- SE) and T4 (9.91 +/- 0.31 micrograms/dl) were significantly higher compared with those of normal responders (1.30 +/- 0.04 ng/ml, 8.57 +/- 0.21 micrograms/dl; P less than 0.001) or hyperresponders (1.16 +/- 0.06 ng/ml, 7.77 +/- 0.63 micrograms/dl; P less than 0.01). There was no correlation between TRH responsiveness and T3 suppressibility. A relatively high occurrence of thyroglobulin and microsomal antibodies was observed, further suggesting a hereditary predisposition. The findings indicate that even in euthyroid relatives with a family history of Graves' disease who have no clinical or biochemical abnormalities of thyroid dysfunction, many have abnormalities in TRH responsiveness, T3 suppressibility, and thyroidal antibodies.


Dopamine affects basal and augmented pituitary hormone secretion.

Although the role of the neurotransmitter, dopamine (DA), in the regulation of PRL has been well documented, controversy exists regarding its participation in the regulation of the other pituitary hormones. Consequently, we infused DA into six healthy male subjects (ages 19-32) and studied its effects on both basal pituitary hormone levels and augmented hormonal release induced by insulin hypoglycemia (ITT), TRH, and gonadotropin-releasing hormone (GnRH). DA alone produced a modest though significant increase in GH concentration from 2.2 +/- 0.5 to 11.9 +/- 3.7 ng/ml (P less than 0.05) by 60 min, but the peak incremental GH response to ITT was significantly inhibited by DA (43.5 +/- 5.0 vs. 16.3 +/- 3.3 ng/ml; P less than 0.01). PRL concentrations fell during the DA infusion (20.4 +/- 3.0 to 10.6 +/- 1.5 ng/ml; P less than 0.02) at 235 min, and the PRL responses to both ITT and TRH were completely abolished. Although the basal LH and FSH concentrations were unaffected by DA, the incremental LH response to GnRH was inhibited (45.5 +/- 10.6 to 24.4 +/- 5.4 mIU/ml; P less than 0.05), while the FSH response was unchanged. DA significantly reduced the basal TSH concentration from 3.9 +/- 0.2 to 2.5 +/- 0.2 micro U/ml (P less than 0.01) at 230 min and blunted the peak incremental TSH response to TRH (6.0 +/- 1.5 vs. 2.9 +/- 0.9 microU/ml; P less than 0.01). DA had no effect on basal cortisol levels, the cortisol response to ITT, basal plasma glucose, or the degree of hypoglycemia after ITT. Our data provide new evidence that DA has an inhibitory as well as a stimulatory role in the regulation of GH secretion in normal humans. It inhibits centrally as well as peripherally mediated PRL secretion and blunts the LH response to GnRH. In addition, DA lowers both basal and TRH-mediated TSH release, confirming the reports of other investigators.


Inhibition of gonadotropin and prolactin release by dopamine: effect of endogenous estradiol levels.

The influence of endogenous estradiol (E2) levels on gonadotropin and PRL sensitivity to dopamine (DA) infusion (4 micrograms/kg/min) was assessed at different stages of the follicular phase of the menstrual cycle. Basal LH and FSH levels were comparable in day 2 and day 12 subjects, and despite a 4-fold increase in E2 concentration, the inhibition of LH by DA was small and quantitatively similar and there was no discernible effect on FSH in either group. In marked contrast, day 14 subjects with an elevated basal LH level exhibited a dramatic increase in the sensitivity of LH and FSH to DA inhibition. Further, a remarkable rebound release for LH but not FSH occurred on the termination of DA infusion. There was a significant correlation between basal LH and response to DA (r = 0.979). This unique increase in response to DA at a time when hypothalamic LRF secretion is assumed to be elevated suggests that DA may exert its effect by inhibiting LRF release. The inhibition of PRL release by DA is correlated with endogenous E2 levels (r equal 0.685) as well as basal PRL levels (r = 0.878). Rebound release of PRL occurs in all three groups of women on termination of the DA infusion, but the magnitude was greatest in Day 14 subjects with the highest endogenous E2 levels. These data suggest that while E2 seems to augment the sensitivity of PRL inhibition by DA, its does not seem to directly influence gonadotropin sensitivity to DA inhibition. The selective hypersensitivity of both LH and FSH to DA observed on the day before midcycle LH peak is consistent with a reduction in LRF neuronal inhibition by tuberoinfundibular DA neurons at this time.


Transient TRH deficiency after prolonged thyroid hormone therapy.

A patient who had been treated with large doses of thyroid hormone for several years developed features of secondary hypothyroidism after thyroid hormone withdrawal. These findings were low serum T4 (3.8 micrograms/dl), T3 (23 ng/dl), and a failure of serum TSH to rise after TRH injection. Serum PRL values rose normally after TRH administration, and evaluation of other pituitary hormones was normal. When retested 3 months later, at which time the serum T4 was 5.5 micrograms/dl, the patient was somewhat less hypothyroid and there was an exaggerated TSH response to exogenous TRH, indicating recovery of pituitary TSH reserve. Indirect assessment of endogenous TRH reserve capacity was consistent with impairment of endogenous TRH activity. Repeat studies performed 7 months later indicated some improvements in this indirect assessment of endogenous TRH reserve capacity but a continued exaggerated TSH response to exogenous TRH administration. Further testing at 28 months revealed a serum T4 value of 7.8 micrograms/dl and a serum T3 value of 141 ng/dl. At this time, the TSH response to TRH was normal and the patient was considered fully recovered. A causal relationship between high doses of thyroid hormone and the presumptive impairment of endogenous TRH reserve is suggested.


Clinical and endocrinological analyses of patients with galactorrhea and menstrual disorders due to sulpiride or metoclopramide.

The clinical courses of galactorrhea and menstrual disorders were studied in 18 women with galactorrhea induced by sulpiride (SLP) or metoclopramide (MCP) given for the treatment of gastrointestinal diseases. The response of PRL and TSH to 500 micrograms iv TRH and the response of LH and FSH to 100  micrograms LRH were assessed by retrospective analysis during treatment in nine patients (six, SLP; three, MCP) and shortly after the end of treatment in nine patients (seven, SLP; two, MCP). The average time from the initiation of treatment to the onset of galactorrhea was 27.2 +/- 4.7 (mean +/- SE) days in the 13 SLP-treated patients and 23.2 +/- 5.8 days in the 5 MCP-treated patients. Five of the SLP-treated patients experienced amenorrhea, four had oligomenorrhea, and one had dysfunctional bleeding. In the MCP-treated patients, oligomenorrhea and dysfunctional bleeding occurred in one each. The average length of time from the end of treatment to disappearance of galactorrhea was 50.0 +/- 7.3 days in the SLP-treated patients and 56.6 +/- 12.1 days in the MCP-treated patients. Cyclic uterine bleeding returned within 2 months after treatment was stopped. Elevated PRL levels with good response to TRH were observed in four of six patients during SLP treatment, and in two of three patients during MCP treatment. Basal PRL levels and response to TRH were normal in almost all patients after the drugs were withdrawn. Normal HL and FSH levels with exaggerated responses of LH to LRH were observed in most patients during treatment, whereas the response of LH to LRH was normal in about half of the patients after treatment. Our findings suggest that hyperprolactinemia in patients treated with SLP or MCP may be in part the cause of both galactorrhea and menstrual abnormalities, and that these symptoms can be reversed by stopping treatment, provided the patients have not taken the drugs for longer than a year.


Reduced thyroid function after thyrotropin stimulation.

The course of serum T4 and T3 return to baseline after TSH stimulation was studied in two groups at six normal subjects over 28 days after im bovine TSH (b TSH; 0.15 U/kg). In the first group of six subjects, serum bTSH rose from undetectable levels to a mean peak of 5.6 +/- 0.5 ng/ml (mean +/- SE) at 2 h, and fell below detectable levels by 24 h with a t1/2 of 7 +/- 1 h. T4 rose to a peak 59 +/- 10% above basal levels within 24 h, returned to basal levels on day 7, then dropped below basal levels on days 9-24, with a nadir of -16 +/- 4% on day 14. Free T4 paralleled T4 levels. T3 rose to a peak 104 +/- 28% above basal at 24 h, then fell faster than T4, reaching basal levels by day 4. During the period of low T4, T3 was at or below basal levels. Human TSH (h TSH) concentration dropped when T4 and T3 rose, but did not rise above basal levels when T4 and T3 fell below basal levels. Neither a T3 elevation nor an increased percentage of free T4 was present during the time of reduced T4 levels. The same pattern of thyroidal response was seen in the second group of six subjects. In this second group, hTSH response to repeated TRH challenge was studied. During the period of reduced T4 and T3, hTSH response to TRH was diminished. On day 28, T4, T3, hTSH, and hTSH response to TRH returned to basal levels. We conclude that the brief elevation of T4 and T3 after bTSH stimulation exerts a suppressive effect on the pituitary which extends beyond the period of elevated thyroid hormone levels, and that delay in pituitary recovery is the mechanism of the decreased thyroid function after acute bTSH stimulation.