The inhibitory effect of dopamine agonists on LH release in women. Our demonstration of an inhibitory effect of dopamine on LH release prompted us to examine whether a similar action exists for dopamine agonists, such as L-dopa and 2-bromo-alpha-ergocryptine (CB-154). Following the administration of L-dopa (0.5 g, orally) to 6 normal women in the early follicular phase, a significant fall in mean LH levels after 1 h which lasted for 5 h was observed (P less than 0.00005). This was followed by a significant rebound above basal levels between the 7th and 10th h (P less than 0.00005). The expected fall in mean PRL levels which lasted for 4 h (P less than 0.00001) was followed by a significant rebound above basal levels after the  6th h (P less than 0.00001)). There was no significant change in mean FSH levels. Following the administration of CB-154 (2.5 mg. orally) to 6 women with hyperprolactinemic amenorrhea, there was also a significant fall in LH levels (P less than 0.00001) and in FSH levels (P less than 0.00001) from 5 h until the study ended at 10 h. The anticipated PRL suppression was also observed and persisted for the duration of the 10 h study. The demonstration of an inhibitory effect of L-dopa and CB-154 on LH release adds further support to the role of dopaminergic control of pituitary LH secretion.


Lack of indomethacin effect on thyroid function in man. Administration of indomethacin 200 mg daily for 2 days to four euthyroid volunteers was without significant effect on serum triiodothyronine or thyroxine and caused no cinsistent alteration of serum TSH. There were minor and variable changes in the pattern of thyroidal iodine release (TIR) in these euthyroid subjects. In one subject both the TIR pattern and serum TSH concentration were altered in the same direction, suggesting that these minor changes were of central origin. Indomethacin also had no effect on the stimulated pattern of TIR in one euthyroid subject receiving daily exogenous TSH injections, or in a patient with untreated hyperthyroid Graves' disease. Prostaglandin A1 infusion in one subject did not alter serum TSH or thyroidal iodine release. It is concluded that prostaglandins probably have no obligatory physiological role in modulating TSH or thyroid hormone secretion in man.


Iodinating activity of thyroid tissue in toxic diffuse goiter. Thyroid tissue obtained from 12 patients with Graves' disease and treated with thionamide drugs for 3-7 mo before subtotal thyroidectomy, from 12 patients with Graves' disease, similarly treated, and given 50 mug of triiodothyronine (T3) for 10 days before surgery, and from 12 euthyroid patients with solitary cold nodules was investigated to compare in vitro iodination of thyroglobulin in toxic diffuse goiter and in normal thyroid tissue. The supernates of the homogenates (105,000g) were subjected to sucrose density gradient centrifugation (5--28%) to separate the thyroglobulin fraction. The precipitates were treated with 1% digitonin and centrifuged to collect the supernate (particulate fraction). When thyroglobulin and particulate fractions obtained from the same patient were incubated with 125I-, iodide, glucose, and glucose oxidase, the amount of iodine bound to thyroglobulin was several times greater in toxic diffuse goiter than in normal thyroid tissue; administration of T3 did not affect iodination in toxic diffuse goiter. When the thyroglobulin fraction from each patient was incubated with a standardized quantity of peroxidase instead of the individual particulate fraction, the amount of iodine bound to thyroglobulin was the same among the three groups of patients. Finally, when bovine serum albumin was substituted for thyroglobulin from each of the patients, iodination of bovine serum albumin was several times greater with the particulate fraction obtained from toxic diffuse goiter tissue than with that obtained from normal tissue. The guaiacol-oxidizing activity oty. These results suggest that in vitro iodination of thyroglobulin is increased in toxic diffuse goiter even when patients are made euthyroid by treatment with thionamide drugs as well as when they are given additional T3 for 10 days before operation. The increase in iodination of thyroglobulin appears to be due to an increase in peroxidase activity in the particulate fraction.


Treatment of mycotic intracranial aneurysms. Two patients with mycotic intracranial aneurysms were successfully treated with only antibiotic therapy. One patient, who had subacute bacterial endocarditis, rheumatic valvular disease, and an abscessed tooth, sustained a subarachnoid hemorrhage from a ruptured right middle cerebral artery trifurcation aneurysm. The other patient, who had Turner's syndrome and probable congenital aortic stenosis, developed multiple neurological findings during an ipisode of acute bacterial endocarditis precipitated by an infected ingrown toenail; a false aneurysm of the distal left middle cerebral artery and two lesions involving the left superior cerebellar artery were found. A study of the literature shows that only 45 patients with mycotic intracranial aneurysms have received adequate antibiotic therapy and angiographic documentation. Statistically, there does not appear to be a clear-cut advantage to antibiotic plus surgical therpy over antibiotic alone. In fact, in 21 patients who underwent serial angiography, lesions were smaller in six and not visualized in 11. In four patients the aneurysms increased in size; in two others fresh lesions formed. The author proposes the following diagnostic and therapeutic regimen: 1) earliest possible diagnosis of the underlying disorder; 2) appropriate antibiotic therapy; 3) early four-vessel cerebral angiography and follow-up studies every 2 to 3 weeks; study; 5) definitive operation upon completion of antibiotic therapy if the lesion is larger or the same size; and 6) postoperative angiography to evaluate the effectiveness of treatment and to search for interim lesions.


Selenosis, hepatic selenium accumulation, and plasma glutathione peroxidase activity in chicks as affected by a factor in linseed meal. Linseed meal has previously been reported to contain an organic factor that reduces toxicity of selenium in animals. The purpose of the studies reported here was to obtain information on the mechanism of action of the linseed meal factor in counteracting selenosis in chicks. Feeding a diet containing 20% linseed meal to chicks partially counteracted the growth depression caused by including high levels of selenium (10-40 ppm) in the diet. In contrast to the rat, chicks fed diets containing selenium did not accumulate significantly more of the element per unit of liver dry matter when the diet contained linseed meal, and at two selenium levels accumulated significantly less. Linseed meal did not interfere with the absorption of an oral dose of 75Se as measured by tissue retention 24 hours later. A methanol extract of linseed meal did not interfere with the normal increase in plasma glutathione peroxidase activity in chicks fed diets supplemented with low levels of selenium even though the extract counteracted the growth depression obtained by adding 20 ppm selenium. Linseed meal contains a factor that interacts with selenium in the tissues in some unknown way to reduce the toxic effects of the element, but does not prevent normal synthesis of glutathione peroxidase.


Alkaloids of Vinca rosea L. (Catharanthus roseus G. Don). 38. 4'-Dehydrated derivatives. A series of 4'-dehydrated derivatives of various dimeric Vinca alkaloids has been synthesized to further define the structure-activity relationships of Vinca alkaloids with onolytic potency. The concentrated sulfuric acid dehydration in most cases gave mixtures of the 3',4'-and two isomeric 4',20'-alkenes, which were isolated and characterized primarily by proton and 13C NMR. Compound tested for antitumor activity include the three dehydro isomers of 4'-deacetylvinblastine, 4-deacetylvincristine, and 4-deacetylvinblastine-23-amide and some4'-dehydrated derivatives epimeric at C-18'. Generally, the decrease in toxicity imparted by the new double bond was accompained by a decrease in potency. An exception was 3',4'-dehydro-4-deacetylvincristine, which showed a decrease in toxicity and increase in potency against at least one tumor in which vincristine itself has little effect.


Quantitative correlations between albumin binding constants and chromatographic Rm values of phenothiazine derivatives. The binding constants of 15 phenothiazine derivatives to bovine serum albumin were obtained by a circular dichroic probe technique; The lipophilicity of the drugs, measured by a reversed-phase thin-layer technique using oleyl alcohol and methanol-water mixtures as the solvents, is expressed as RMw. The binding constants were of the same order of magnitude as the literature values, and the RMw values correlated well with log P octanol values from the literature. Correlations of log K with RMw were found to be more satisfactory when corrections for the state of ionization of the phenothiazines were made, the nonprotonated species accounting for the bulk of the binding. A better correlation was obtained when contributions from both species were taken into account. Similar correlations were attempted between RMw values and enzyme inhibitory activities of these phenothiazines taken from the literature.


Anticoccidial derivatives of 6-azauracil. 1. Enhancement of activity by benzylation of nitrogen-1. Observations on the design of nucleotide analogues in chemotherapy. Benzylation of 6-azauracil at N-1 (which corresponds to the point of attachment of the ribose phosphate unit in pyrimidine nucleotides) has been found to augment its anticoccidial activity fourfold. The high potency of 1-benzyl-6-azauracil is ascribed to a combination of intrinsic activity, efficient oral absorption, and a moderate rate of excretion. Metabolism experiments using 1-benzyl-6-azauracil labeled with 14C in the heterocycle and (separately) in the side chain showed that, in the drug accounted for, no cleavage had occurred. Additional activity increases were achieved by introducing small, electron-withdrawing substituents in the meta and/or para position(s) of the benzyl group. One of the most active derivaties, 1-(3-cyanobenzyl)-6-azauracil, is about 16 times as potent as 6-azauracil.


Tumor formation in preneoplastic mammary nodule lines in mice treated with nafoxidine, testosterone, and 2-bromo-alpha-ergocryptine. The tumor potentials of five preneoplastic mammary nodule lines were examined in BALB/cCrgl mice treated with either nafoxidine, an estrogen antagonist; 2-bromo-alpha-ergocryptine, a prolactin suppressant; or testosterone. The inhibitory effect of any of the three agents was dependent on the individual nodule line and was not correlated with the effects of ovariectomy. Nafoxidine inhibited tumor formation only in nodule line D2; testosterone inhibited tumor formation in lines C3 and C4; and 2-bromo-alpha-ergocryptine failed to inhibit tumor formation in any of the nodule lines. These results provided information on the range of responses of mouse preneoplastic mammary tissues to a variety of antihormone treatments and suggested that responses to ovariectomy need not be correlated with responses to specific antihormone treatments.


Suppression of mammary tumorigenesis in C3H/He mice by ovariectomy or treatment with 2-bromo-alpha-ergocryptine: a comparison. We compared the effects of chronic treatment with 2-Br-alpha-ergocryptine (CB-154) and of ovariectomy on the genesis of mammary hyperplastic nodules (HN) and mammary tumors in the C3H/He mouse. CB-154 is an established potent suppressor of pituitary prolactin. Eighty-five 21- to 25-day-old female mice were divided into three groups. Group I received daily sc injections of 0.1 mg CB-154. Group II was ovariectomized and group III served as controls. Mice were examined weekly for mammary tumors. Fifteen months from onset of treatment all surviving mice were killed. The mean number of HN per inguinal mammary gland, total number of mammary tumors, and number (percent) of mice with mammary tumors in each group were, respectively: controls--4.6 +/- 1.1, 41, 24/29 (83%); ovariectomized--1.2 +/- 0.6, 20, 14/28 (50%); and CB-154-treated--0.2 +/- 0.1, 16, 13/28 (46%). A significant (P less than 0.001) and equally comparable inhibition of mammary tumor incidence was observed in the ovariectomized and CB-154-treated mice. Thus early ovariectomy and CB-154 treatment (specific inhibition of prolactin secretion) appeared equally effective in the prophylaxis of mammary tumorigenesis in the C3H/He female mouse.


Description of a permeable eukaryotic cell system to study agents affecting DNA synthesis: demonstration that cytembena is a direct inhibitor of replicative DNA synthesis. Cells were made permeable to DNTP's by a 15-minute treatment with 0.01 M Tris/HCl (pH 7.8), 0.25 M sucrose, 1 mM EDTA, 30 mM 2-mercaptoethanol, and 4 mM MgCl2 at 4 degrees C. These cells used exogenously supplied dNTP's to carry out semiconservative, replicative DNA synthesis. This system could be used to identify inhibitors of DNA synthesis and to determine whether chemotherapeutic agents affect precursor synthesis or whether they have a direct effect on the DNA replication complex. Thus DNA synthesis in the permeable cells was not inhibited by hydroxyurea or by the nucleoside analogue arabinofuranosyl cytosine. In contrast, the active form of the nucleoside analogue, arabinofuranosyl cytosine triphosphate, and daunorubicin promptly inhibited DNA synthesis in the permeable cells. Cytembena, sodium cis-beta-4-methoxybenzoyl-beta-bromoacrylate, also inhibited DNA synthesis in the permeable cells; this demonstrated that this agent functioned as a direct inhibitor of the DNA replication complex.


Evaluation of possible sites of action of rubratoxin B-induced polyribosomal disaggregation in mouse liver. The disaggregation of liver polyribosomes (disruption of the site of protein synthesis) into single ribosomal units has been observed after treatment of mice with rubratoxin B, a toxic metabolite of Penicillium rubrum. Several mechanisms for the polysomal alteration were evaluated. A generalized decrease in mouse liver RNA following administration of rubratoxin B was noted. RNAase activity in the postmicrosomal fraction was increased after similar treatment; however, this increase was too small to account for the observed polysomal breakdown. Incubation of rubratoxin B with isolated polysome fractions indicated no direct interaction between the toxin and the polyribosomal complex, apparently eliminating such a complex as the cause of the in vivo disaggregation. Rubratoxin caused shifts in the ultraviolet absorption spectra of DNA and RNA in vitro, a preliminary indication of binding of the toxin to nucleic acid. Such preliminary observations lend support to the hypothesis that rubratoxin-induced polyribosomal disaggregation may result from an alteration in the critical informational macromolecules such as nucleic acids, or protein, or both in that both are involved in the control of cell growth. This alteration in the DNA-protein complex may then result in a malfunction of the DNA-dependent RNA polymerase activity and subsequent polysomal disaggregation.


Thyroid supplementation for hypothyroidism. An latrogenic cause of breast cancer? In four subpopulations grouped by varying durations of thyroid supplementation (none, one to five years, six to 15 years, and 15 years of more), breast cancer frequency correlated positively with attained age. The cancer experience of persons in the same age-group was relatively stable regardless of how long women took thyroid supplements. The present data support the provisional inference that breast cancer and duration of thyroid therapy are both age-dependent and question the belief that pretreatment with thyroid supplements increases the risk of breast cancer development. Relationship of these two variables can only be determined by prospective studies.


Myoglobinemia in inflammatory myopathies. Myoglobin was detected in the sera of patients with dermatomyositis, polymyositis, scleroderma, and systemic lupus erythematosus (LE) with active myopathy. Overall, myoglobinemia was detected in 74.1% of sera taken from patients with active myositis before therapy, with slightly greater frequency in the groups with dermatomyositis and polymositis. With steroid therapy, this frequency fell to 43.4% and to 9.5% in patients in clinical remission not requiring therapy. Serum enzyme (creatine phosphokinase, lactic dehydrogenase, and SGOT) activity was higher in samples containing myoglobin, but there was considerable overlap between those with and without myoglobinemia. Sequential serum determinations in six patients demonstrated rapid reduction in the levels of serum myoglobin with therapy, usually before enzyme values had returned to normal. In one patient followed up for 30 months, myoglobinemia correlated with clinically observed exacerbations of rash and weakness to a greater degree than did enzyme determinations.


Oral aminophylline therapy. Increased dosage requirements in children. While monitoring oral aminophylline (theophylline ethylenediamine) therapy, larger doses (milligrams per kilogram) were necessary for children than for adults to achieve similar therapeutic serum levels. The mean apparent theophylline clearance (ATC) determined in 59 children was significantly higher (P less than .001) than determined in 114 adults (84.8 versus 51.4 ml/hr/kg). Additionally, the younger children (1 to 9 years) eliminated theophylline more rapidly than the older children (0 to 18 years) (93.8 versus 77.3 ml/hr/kd). When initiating continuous oral aminophylline therapy, dosage guidelines, based on the mean ATC calculated for each group, were predicted, and trough theophylline serum levels of 10mug/ml were obtained. The guidelines for aminophylline were 28.0, 23.2, and 15.6 mg/kg/day administered in four divided doses for the younger children, older children, and adults, respectively. Monitoring of serum levels is suggested to further individualize the patient's aminophyline therapy.


Bronchopancreatic fistula following traumatic rupture of the diaphragm. A bronchopancreatic fistula developed in a 14-year-old boy two weeks following transabdominal splenectomy and repair of a ruptured diaphragm. This unusual entity should be suspected when a patient with pancreatitis or pancreatic trauma has pleural complications associated with profuse, frothy sputum. The diagnosis is established by the presence of high levels of amylase in the sputum or by the appearance in the sputum or the bronchi of dye or contrast material injected into the external fistula. The primary goal of treatment, in addition to the management of the thoracic complications, is subdiaphragmatic control of the pancreatic fistula. A brief summary of seven previously reported cases is presented.


Hypertension crisis. Recognition and management. Situations requiring immediate lowering of systemic blood pressure are infrequent. Certain clinical syndromes resulting from or complicated by severe hypertension demand vigorous, usually parenteral, antihypertensive therapy. Such syndromes include (1) diastolic hypertension accompanied by sudden disruption of cerebral function, (2) dissecting or leaking aortic aneurysm; (3) accelerated or malignant hypertension, (4) toxemia of pregnancy when either the fetus' or the mother's life is immediately threatened, (5) some instances of diastolic hypertension and acute left ventricular failure, (6) uncontrolled hypertension in the patient who requires emergency surgery, (7) refractory elevation of the diastolic pressure in the kidney transplant patient, and (8) refractory hypertension complicating myocardial infarction or angina. Drugs useful in acutely lowering blood pressure include diazoxide, sodium nitroprusside, methyldopa intravenously, reserpine intramuscularly, and trimethaphan camsylate intravenously. Use of furosemide reinforces the hypotensive effect of these agents. Theoretical advantages and disadvantages of these agents are not always encountered in clinical use.


Pseudo-Sjögren syndrome with hyperlipoproteinemia. Eight patients with parotid enlargement were seen because of varying musculoskeletal complaints. All were overweight and hypertensive; six had diabetes mellitus, four had palpable hepatomegaly, and six were 49 years or older. One patient had arthritis type IIB hyperlipoproteinemia. Four patients had varying degrees of fibrositis, and two of these also had osteoarthritis. Of the others, one each had gout, Reiter syndrome, and restless legs syndrome. All had hyperlipoproteinemia type IV or IIB, and none abused alcohol. None of these patients have true Sjögren syndrome.


Paraben allergy.

Paraben allergy. A hydrocortisone preparation containing methylparaben and propylparaben provoked bronchospasm and pruritus when given intravenously to an asthmatic patient, whereas another hydrocortisone preparation without paraben preservative did not. Direct and passive transfer (Prausnitz-Küstner) skin tests for immediate hypersensitivity to parabens were positive. Parabens, frequently employed as bacteriostatic agents, are capable of producing immunologically mediated, immmediate systemic hypersensitivity reactions.


Retrognathia and sleep apnea. A life-threatening condition masquerading as narcolepsy. The association of sleep apnea with daytime hypersomnolence without obesity, and its potentially lethal cardiopulmonary sequelae, make it crucial that this condition be distinguished from narcolepsy. A patient with retrognathia who had been diagnosed as a narcoleptic for 15 years had the primary complaint of excessive daytime sleepiness. Sleep laboratory evaluation showed severe hypoxemia and a mean of 366 upper airway obstructions per night. The patient was treated with a tracheotomy; this resulted in relief of the sleep-related upper airway obstructions, hypoxemia, and hypersomnolence.


Myocarditis associated with methyldopa therapy. Five patients with hypertension died as a result of myocarditis. Three were treated with methyldopa and hydrochlorothiazide, two with methyldopa alone. Their ages ranged from 30 to 71 years. In all instances death occurred suddenly, and myocarditis was not suspected clinically. The inflammatory changes in the hearts of these patients were most consistent with a hypersensitivity reaction. Additionally, there was hepatitis consistent with hypersensitivity in four of the cases.


Cooperative study of radiologic aspects of renovascular hypertension. Bilateral renovascular disease. Abnormal urographic features were present in 60.7% of 250 patients with bilateral diseases. The urogram was relatively insensitive in the minority of patients whose lesions were of approximately equivalent severity bilaterally. In bilateral renovascular disease, the urogram demonstrated some surgical prognostic value that was not evident in unilateral renovascular disease. Furthermore, in patients with bilateral disease, the urogram was helpful in deciding between unilateral or bilateral operation.


Eight-day survival without adrenal steroids. A patient with advanced breast cancer who had undergone a total bilateral adrenalectomy in the past refused adrenal steroid replacement therapy with the idea that this would be the easiest and quickest way to end her life. However, she continued to live for more than eight days. Survival under these circumstances is unusual, and the terminal course of her illness is described.


Edema associated with ibuprofen therapy. A 15-kg weight gain developed in a patient during the third week of ibuprofen therapy. The edema disappeared with discontinuation of the drug regimen and did not reappear during a subsequent six-month observation period. It should be recognized that ibuprofen may be associated with salt and water retention in the same fashion as previously described with phenylbutazone and indomethacin.


Circulating autoantibody against human myoglobin in polymyositis. A passive hemagglutination method for circulating autoantibody to purified human skeletal muscle myoglobin has been developed. This antibody was detected in the sera of 22 of 31 patients with polymyositis. The incidence and the antibody titers were significantly higher than in other myopathies such as myasthenia gravis (P less than .02), Duchenne-type muscular dystrophy (P less than .001), and other conditions (P less than .001). This new antibody test is useful in diagnosing polymyositis.


Prognosis of surgically treated intracranial arterial aneurysm patients. From 1969 to 1973, we undertook a direct surgical therapeutic approach with 62 patients who had intracranial aneurysms. The surgical mortality for patients in the first three clinical grades was 5%. Sixty-eight percent of the entire group of patients had improved conditions at follow-up. When these results are compared to the expected outcome of the natural course of the disease under conservative management, the superiority of the direct approach is seen. With the aid of modern instrumentation, anesthesia, steroid therapy, and magnification, neurosurgical centers handling a reasonable volume of these cases should achieve comparable results.


Infantile agammaglobulinemia and immediate hypersensitivity to penicillin G. A case of X-linked infantile agammaglobulinemia with preserved synthesis of IgE and resultant normal serum levels of IgE is described. The patient had manifestations of atopy and an anaphylactic reaction following the administration of penicillin G. Because he had multiple respiratory tract infections with Gram-positive organisms and did not respond adequately to prophylactic gamma-globulin administration, penicillin therapy was deemed desirable. Therefore, after successful desensitization, therapy with prophylactic ampicillin was started with a resultant decrease in both number and severity of infections.


Septicemia in a Community Hospital 1970 through 1973. Septicemia developed in 34 patients per 10,000 admissions to a community hospital during 1970 through 1973. Two thirds of the 207 patients had community-acquired septicemia, and one third had nosocomial septicemia. Septicemia-related mortality was 20.3%. Mortality and incidence of septicemia was substantially higher in patients with ultimately fatal and rapidly fatal underlying diseases. Septicemia was associated with shock in 9.7% of the patients. Foley catheterization and prophylactic antibiotic therapy could not be implicated as major risk factors for the development of septicemia. This study shows an incidence of Gram-negative bacteremia, septic shock, and mortality substantially less than that described in published data from noncommunity hospitals.


Leukocytosis and artifactual hypoglycemia. Two patients are described with asymptomatic low blood glucose and excessive in vitro consumption of glucose by leukocytes before separation of the serum for assay. This may be a more common problem than is appreciated and need not be associated with leukemia or extreme leukocytosis. The circumstances that allow this avoidable type of artifactual hypoglycemia may also produce factitious euglycemia during evaluation of suspected diabetes mellitus.


Health status of the New York City prison population. During a two-week period in June 1975, all 1,420 prisoners admitted to New York City Correctional Facilities were studied to determine the prevalence of current and past health conditions. Information was obtained from a standard admission health examination. Almost three-quarters of the male and female prisoners were 30 years or less. Of the study population, 57 per cent were black, 24 per cent were Hispanic and 17 per cent were white. Forty-one per cent reported a history of illicit drug use. More than one-quarter of the prisoners reported a present illness and three-fifths received at least one diagnosis. Commonly diagnosed conditions included drug abuse, psychiatric disorder, trauma, and alcohol abuse. Seven per cent of male prisoners had a previous psychiatric hospitalization. On examination, new trauma was noted in 10 per cent of the male population. In addition to these findings, a history of seizure disorder was reported in 4 per cent of the male population. Health services within prisons must be able to manage the most pressing problems in this population-substance abuse and psychiatric disorder and provide care for the range of conditions that is similar to that found in the general population for this age group.


Hypersensitivity to foods: the adaptation phenomenon. The ability of certain patients with an allergic diathesis to adapt to the ingestion of specific foods to which they are allergic accounts for the present confusion relative to the role food hypersensitivity plays in clinical medicine. An understanding of the concept of adaptation in ingestant allergy, with its stimulatory and withdrawal periods, aids both patient and physician in appreciating the problems involved in the recognition of food hypersensitivity. Specific adaptation undergoes a chronological development from the nonadapted stage through full adaptation to eventual maladaptation. Recognition of the stage of development present offers further diagnostic help in evaluation of the allergic patient. Reintroduction of a specific food into the diet after establishment of an induced nonadapted phase provides an accurate means of determining hypersensitivity to individual ingestants.


Food hypersensitivity allergy or malabsorption. The terms milk allergy, milk sensitivity, and milk intolerance are used in the medical literature with different meanings. Milk allergy and lactase deficiency to which they are usually referring can be specifically differentiated and diagnosed. A modification of the Rinkel oral test meal can be used to separate these two entities for medical diagnostic accuracy and understanding.


Bromocriptine treatment of acromegaly.

Bromocriptine treatment of acromegaly. Bromocriptine at a dose of 7.5-30 mg/day was given to 12 acromegalics for 6 mo. Mean serum growth hormone (GH) levels during a glucose tolerance test (GTT) were significantly lowered by the drug. In four patients the serum GH response during a GTT was suppressed to normal (i.e. less than or equal to 5 mlU/liter). If bromocriptine had not brought the serum GH response to a GTT to normal at a dose of 20 mg/day, this effect was not achieved by raising the dose to 30 mg/day. Bromocriptine was effective for the duration of treatment. On discontinuing therapy there was an increase in serum GH levels. No obvious clinical changes in the acromegalic features were noted. One patient with impaired glucose tolerance and one with established diabetes had normal glucose tolerance while on bromocriptine and another two patients with impaired glucose tolerance showed no obvious changes while on the drug. Side effects were minor. X-rays of the pituitary fossa before starting and at the end of treatment showed no significant change. We conclude that although bromocriptine is the most promising form of medical treatment for acromegaly to date, it is fully effective only in a minority of patients.


[Isocount scanning in brain tumors-a quantitative investigation of the tracer activity (author's transl)]. In the previous reports, the theoretical background [corrected] and technical details of the Isocount scanning were described. Based on clinical experiences of various brain diseases, the newly developed scanning method was confirmed to be more useful than the conventional scintiscanning. Besides the new scanning method, a new display system was also developed for the sake of more precise analysis of the Isocount scanned data. This display method is called MULTILEVEL ANALYSIS or MULTILEVEL SLICING. In the present investigation, this method was applied to fortysix cases of brain tumors, including forty cases of supratentorial tumors and six cases of infratentorial tumors, positive rates being 95% and 67% respectively. Furthermore, as a measure of the quantitative investigation of the radioactive tracer uptake of the target area, the maximum uptake rate of the target area (RTmax.=Tmax./NTmean), and the deviation index (DI=DT/DNT) were introduced; Tmax., NTmean, DT and DNT are respectively defined as a maximum uptake of the target area, a mean uptake of the non-target area, a deviation rate of the target area and a deviation rate of the non-target area. They can be obtained from analysing the television figures of MULTILEVEL ANALYSIS. By this method, thirty-four cases of supratentorial tumors were studied. In cases of glioma (12 scans), meningioma (9 scans), and metastatic tumor (7 scans), the mean values of RTmax. were 1.26, 1.37, and 1.24 and the mean values of DI were 0.81, 0.68 and 0.60 respectively. In gliomas, the RTmax. and the DI were correlated with the degree of malignancy of the tumors. This quantitative analysis could be considered to be useful to foresee the nature of the brain tumor from the scintiscanning findings.


Cerebrospinal fluid imaging using serial metrizamide CT cisternography. Twenty-five patients studied by serial metrizamide (Amipaque) CT cisternography were used to analyze CSF kinetics. Delayed CSF flow patterns were noted in 7 patients, while intermediate patterns occurred in 4. The abnormal cisternogram was characterized primarily by ventricular reflux and stasis and secondarily by diminution of the parasagittal blush and a periventricular rim of decreased absorption. The intermediate group had minimal ventricular stasis after 24 hours and a normal parasagittal blush. After clinical and biochemical evaluation of the patient with dementia, CT scanning is usually indicated. If a profile suggestive of communicating hydrocephalus emerges, CSF kinetics can be monitored dynamically by CT scanning with metrizamide enhancement.


A new miniaturized system for monitoring the epidural pressure in children and adults. A new miniaturized epidural pressure transducing system for monitoring intracranial pressure (ICP) has been developed. The system is of the as yet smallest known dimensions. The transducer is implanted automatically coplanar to the dura via a burr hole of 4 mm diameter in the conscious patient without special surgical equipment. Application is possible in adults, children and infants. We have achieved a maximal resolution of 10(-3) mm of Hg. At a full scale range of 100 mm of Hg the zero-point drift is less than 1 mm of Hg/24 h.


Smooth muscle involvement in congenital myotonic dystrophy. Dysfunction of smooth muscles is not unusual in adults suffering from myotonic dystrophy but has not yet been reported in patients with the congenital form of the disease. Of two brothers, the younger one presented with the typical features of congenital myotonic dystrophy at birth. He developed severe constipation due to megacolon during his second year of life. In the older brother disturbances of gastrointestinal motility, causing repeated bouts of subileus during the newborn period, sprue-like symptoms during early childhood, and megacolon with constipation and incontinence later on, remained the only manifestation of myotonic dystrophy until the age of eight years when the diagnosis could be finally established by electromyography.


Infantile spinal muscular atrophy (morbus Werdnig-Hoffmann) causing neonatal asphyxia. A case of infantile spinal muscular atrophy (Werdnig-Hoffmann's disease) with complete proximal pareses obvious at birth giving rise to neonatal asphyxia is reported. Reduction of fetal movements was noted from the 32nd week of pregnancy. The infant was extremely floppy at birth and spontaneous movements were restricted to hands, feet and face. Fibrillations of the tongue, diaphragmatic hemiparesis and dysphagia were observed. Unassisted ventilation was not compatible with survival and the infant succumbed to the disease in the neonatal period. Muscle biopsy and autopsy confirmed the clinical diagnosis. Infantile spinal muscular atrophy causing neonatal asphyxia seems to be unusual and not earlier described. Constant muscular hypotonus in an asphyctic newborn should raise suspicion of a neuromuscular disorder.


Joubert syndrome: episodic hyperpnea, abnormal eye movements, retardation and ataxia, associated with dysplasia of the cerebellar vermis. A unique syndrome consisting of episodic hyperpnea, abnormal eye movements, ataxia and mental retardation, associated with agenesis of the cerebellar vermis, has been delineated in four siblings by Joubert et al. (1969). We describe three other children with this clinically recognizable condition which we suggest to call Joubert syndrome. There is good evidence that it is inherited as autosomal recessive. Two of out patients were brothers, the third child's parents were related. Recognition of this syndrome is important in view of prognosis and for genetic counseling.


Non-ketotic hyperglycinemia in two sibs with mild psycho-neurological symptoms. Non-ketotic hyperglycinemia (NKH) has been diagnosed in two sibs. At the age 2:5 years and 1:3 years respectively only moderate psycho-motor retardation and muscular hypotonia were seen in the elderly child while no psycho-neurological symptoms were seen in the younger sib. Neither of the children had convulsions. This observation is in contrast to earlier published cases of this disorder. A summary of earlier published cases of non-ketotic hyperglycinemia is presented.


Congenital spongy degeneration of the brain (van Bogaert - Bertrand) associated with micrencephaly and ponto - cerebellar atrophy (contributions to the pathology of glial dystrophy of intrauterin origin). The present paper reports on two twin brothers who presented clinically at birth a syndrome characterized by progressive development of muscular hypertonia, opisthotonus, micrencephaly, amaurosis and short, localized clonic seizures. Both children died soon after one year of age. The anatomic examination performed in one case revealed a spongy degeneration of the brain of van Bogaert-Bertrand type. Associated to the cerebral degenerative syndrome was a severe malformative syndrome characterized by micrencephaly, internal hydrocephalus and pontocerebellar atrophy. The ultrastructure of the cerebellar cortex showed degenerative phenomena in the Purkinje and glial cells, demonstrating the evolutive character of the ponto-cerebellar lesions. The degenerative process consisted of the accumulation of lamellar bodies within the mitochondria and free in the cellular cytoplasm with tendency to form inclusions of the multilamellar or finger-print type. Association of the degenerative with the malformative process is not considered to be accidental but based upon the same fundamental pathologic process: glial dystrophy. It may be assumed that the pathologic defect, which as a rule produces syndromes that appear after birth (spongy degeneration of the brain, ponto-cerebellar atrophy), may in some instances act at an early date in intrauterine life, the glial dystrophy that appears so early producing both the degenerative and the malformative process.


Infantile Gaucher's disease: neuropathology, acid hydrolase activities and negative staining observations. A case of infantile Gaucher's disease with widespread cerebral degenerative changes is presented. Neuropathological features included perivascular Gaucher cell infiltrates accompanied by periadventitial fibrogliosis, focal neuronophagia, Purkinje cell vacuolation and diffuse astrocytosis of cerebellar white matter, brain stem and spinal paracentral grey matter. Gaucher cell tubules were isolated from formalin fixed material. Negative staining confirmed the appearance of a coiled helical structure, 200--400 A in diameter composed of microfibrils. A relative deficiency of acid beta-glucosidase was found in spleen homogenate accompanied by a considerable increase in acid phosphohydrolase, N-acetylglucosaminidase, beta-glucuronidase and beta-galactosidase.


Central necrosis following contusion to the sheep's spinal cord. This paper presents the results of a study on the pathological changes associated with post traumatic central spinal cord necrosis.


Temperature and hydration: factor affecting increased recoil of excised rabbit lung. We have examined two factors which strongly affect the rate and amount by which excised rabbit lungs become stiffer during mechanical hyperventilation, Pressure-volume (PV) curves were compared before and after 3 hr ventilation (tidal volume 50% TLC, frequency 8/min, end-expiratory pressure of zero) in the temperature range 4 degrees C to 37 degrees C. Lungs were separated into three groups according to method of suspension: (A) floated on saline, (B) floated on mineral oil, and (C) suspended from the trachea. Lung wet/dry weight ratios (W/D) were obtained from groups A and C. In all lungs marked stiffening occurred below 22 degrees C, but the effect diminished sharply between 22 and 28 degrees C. Lungs not in contact with saline (Groups B and C) revealed little change in recoil above 28 degrees C, whereas those in Group A once again tended to become stiff near 37 degrees C. Lung water content in Group A at 37 degrees C was found to be more than double that in Group C. We conclude that two factors can contribute to the stiffening induced by ventilation: (a) temperature maintained below 27-28 degrees C, or (b) excess lung water in combination with temperature above 28 degrees C.


Atopic dermatitis: the concept of flare factors. A flare factor is a biologic or environmental factor which induces exacerbation of atopic dermatis. Serosis, sweating, scratchy clothes, allergy, infection, scratching, allergic contact dermatitis, anxiety, and coexisting disease are potential flare factors. Different patients have different flare factors, and individual patients may have different flare factors at each patient visit maximizes chances of eliminating or reducing dermatitis.


[Disorders of microcirculation in diffuse toxic goiter and their correction in the early postoperative period]. A study was made of microcirculation in 45 patients suffering from diffuse toxic goiter at the early postoperative period with the aid of microphotography of the bulbar conjunctiva vessels, and investigation of the rate of the isotope elimination from the intradermal depot and the capillary permeability by V. P. Kaznacheev's method. The data obtained permitted to draw a conclusion that on admission to the clinic patients with toxic goiter were suffering from arteriolar spasm, had poor vascular pattern in the bulbar conjunctiva, the sledge phenomenon in small venules, an acceleration of the isotope elimination from the intradermal depot and an increase of the capillary permeability. Preoperative preparation improved the microcirculation indices, without completely normalizing them, however. Microcirculatory disturbances reached their maximum the first two days after the operation and declined by the 3rd-5th day. Recommendations on correction of the microcirculatory disturbances are given.


Classification and management of mycotic aneurysms. After a review of 14 patients with extracranial mycotic aneurysms, a classification of mycotic aneurysms has been proposed based upon the pre-existing pathologic condition of the artery and on the pathogenesis. Ten aneurysms resulted from an infection due to intravascular sources and four, due to extravascular sources. Ten patients in this series were treated surgically, and of these, eight were cured. All four patients who did not undergo a surgical procedure died. Early diagnosis, appropriate antibiotic therapy and prompt surgical intervention are recommended in the management of these aneurysms. Excision or exclusion of aneurysms is preferred. If necessary, the circulation to the distal part of the extremity can be restored by vascular reconstruction using an autogenous bypass graft, preferably through a noninfected field.


Changes in pulmonary lipoprotein lipase activity in dogs following experimental bone fracture. A new concept on the pathogenesis of post-traumatic impairment of lung surfactant synthesis and accumulation of fat in lung vessels? Five hours after a limited, nonhypotensive trauma without gross interference with coagulopathy, lungs of dogs were found to be completely deficient of heparin-releasable, metabolically active lipoprotein lipase. This indicates that the pathway of circulating lipoprotein triglyceride hydrolysis as a source of palmitate for pulmonary dipalmitoyllecithin synthesis is blocked post-traumatically. The possible significance of this finding on post-traumatic impairment of pulmonary surfactant synthesis and accumulation of fatty material in the pulmonary capillary bed is discussed.


Metabolic disposition of cytembena in rats and dogs. 1. The metabolic disposition of cytembena (sodium cis-3-p-methoxybenzoyl-3-bromoacrylate)labelled at both carbonyl carbon atoms was studied in rats and dogs. 2. Rats excreted over 70% and dogs excreted over 50% of the radioactive dose in 24 h. Most of the radioactivity was found in urine. Kidney retained the highest level of radioactivity after 24 h. Renal cortex was responsible for the observed high retention. Both species exhibited similar tissue distribution and urinary metabolic patterns. 3. Cytembena was metabolized by demethylation catalysed by microsomes and by debromination and double bond saturation catalysed by the 100,000 g supernatant fraction in the presence of glutathione and NADPH. Tentative structures of the metabolites identified by mass spectrometry and the probable metabolic pathway of cytembena are presented,


[Persistent ache caused by a residual meniscus (author's transl)]. The residual meniscus as a cause of persistent ache of the knee is a rare condition. Permanent trouble demands an active instrumental diagnostic approach. A reliable diagnostic measure is repeated arthrography. Operative removal of the residual menicsus is the treatment of choice.


[The problem of post-operative complications after colonic surgery because of malignant tumors (author's transl)]. Post-operative complications after colonic surgery because of malignant tumours were analysed in 412 patients from 1961 to 1974 at the Surgical-Clinic of Innsbruck University. 42% of the patients had postoperative complications. 60% of these complications were directly due to surgery, 40% indirectly. Attention should be paid to the fact that colonic surgery in particular has a high rate of complications, i.e. 76% of these cases seen in relation to 38% of routinely operated patients. With reference to all patients 18 different complications were observed. Causes of these complications and prophylactic treatment, likely to decrease the rate of lethality and complications are discussed.


[Complications of lumbar sympathectomy. Retrospective study of 791 patients]. The purpose of this paper is to define the nature and the frequency of post-lumbar sympathectomy complications and to reappreciate their importance in the evaluation of operative indication. The non specific miscellaneous complications are no more frequent than after any other lombotomy. The specific complications occur in less than 10%; they are almost always transient. Prolonged paralytic ileus is related to post-operative hematoma in retroperitoneal space. Ejaculation disturbances are produced either by bilateral resection of one of the two first lumbar ganglian or by section of the intermesenteric plexus, the presacral nerves or the hypogastric nerves during associated dissection of the aortic bifurcaiton. Late neuralgia is probably induced by retroperitoneal hematoma; its size increases gradually during the postoperative period by transference of tissue fluids. In conclusion, the morbidity and the morbidity rates of lumbar sympathectomy are remarkably low; these are not arguments against the lumbar sympathectomy.


Plasma exchange for cold agglutinin hemolytic anemia. Two patients with advanced lymphoma, chronic cold agglutinin disease refractory to conventional therapy and severe, progressive anemia were treated with exchange plasma transfusion. Both experienced significant reduction in titers. The first patient, in whom the procedure was done manually, died with widespread lymphoma without achieving apparent clinical benefit. The second patient was exchanged using the Aminco Celltrifuge, with improvement in in vitro compatibility tests and transfusion tolerance. The technical details of continuous-flow centrifugation exchange plasma transfusion are described.


Comparative rapidity of response of height, limb muscle and limb fat to treatment with human growth hormone in patients with and without growth hormone deficiency. The widths of muscle and fat in the upper arm and calf have been measured radiologically before treatment and at intervals of 1, 3. 6 and 12 months during administration of human growth hormone in 41 pre-pubertal patients with "isolated" growth hormone deficiency and in 22 patients with multiple deficiencies following gross CNS lesions. Height was also measured. The curves of response of muscle and fat on the one hand and height on the other were strikingly dissimilar. A very rapid increase of muscle took place in the first month; but after 6 months the increments had fallen to normal values for size and bone age. Decrements in fat followed the same pattern. Height, however, showed a smaller increment in the first month than in the period 1 to 3 months in the "isolated" deficiency cases, and much slower fall back towards normal. The first-year height increment was not at all correlated with the first-month height increment in the "isolated" deficiency cases, though it had a correlation coefficient of 0.46 with the first-month muscle increment. Nine cases of short stature not due to GH deficiency were similarly studied. There was considerable overlap between deficient and non-deficient in all responses in the first 3 months, though children in the top half of the responder's distribution could be distinguished. A  1-month radiological test of responses to hGH in doubtful cases is proposed, using in all only 40 IU of hormone. It is emphasised that a small response of muscle and fat may occur in cases who do nevertheless respond in height to hGH administration; a large response in muscle and fat, however, is indivative that treatment will be effective, though it does not well predict the precise amount of height that may be gained.


Biologically active luteinizing hormone (LH) in plasma: II. Comparison with immunologically active LH levels throughout the human menstrual cycle. The levels of biologically active luteinizing hormone were determined by an in vitro bioassay method in plasma samples collected daily over a complete menstrual cycle from 12 menstruating women. These cycles were normal according to a number of criteria, including daily plasma levels of oestradiol, 17-hydroxyprogesterone and progesterone. Immunoreactive LH was estimated in the same 12 cycles by a radio-immunoassay (RIA) procedure (HCG-RIA) using an HCG antiserum and iodinated HCG. The 2nd IRP of HMG was selected as standard although significant deviations from parallelism were found with 7 out of the 12 plasma pools studied. The use of the 1st IRP of human pituitary gonadotrophins (FSH and LH (ICSH)) for bioassay (herafter HPG-1st IRP) as standard in this system resulted invariably in invalid assays, due to lack of parallelism. Immunoreactive LH was also measured in 8 of the 12 cycles by a RIA procedure (HLA-RIA) using a human LH antiserum and iodinated human LH of pituitary origin. Results are expressed in terms of the HPG-1st IRP. The plasma levels of biologically and immunologically active LH were qualitatively similar throughout the menstrual cycle. However, the LH levels measured by the bioassay invariably exceeded those estimated by the RIA procedures. The biological to immunological (B/I) ratio over the entire menstrual cycle (312 comparisons) was 5.5 with 95% confidence limits at 5.2 and 5.8 when the HCG-RIA system was employed. Using the HLH-RIA system (208 comparisons), the corresponding ratio was 6.4 (6.0:6.9). When regression lines were calculated using the bioassay results as the independent variable and the RIA results as the dependent variable, the 95% confidence limits of the regression lines did not include the origin. Furthermore,, in keeping with the high B/I ratios, the slopes of the two regression lines and their conficence limits differed markedly from unity. It is concluded that although qualitatively similar profiles were observed between the biological and immunological activities throughtout the menstrual cycle, two aspects require further attention. Firstly, the elevated B/I ratios together with the behaviour of the dose-effect lines obtained with different standards in the various RIA systems suggest that presently available reference standard preparations of pituitary and/or urinary origin are not suitable for the assay of LH in human plasms. Secondly, from the regression analyses of the biological and immunological activities it is infered that the RIA methods detect immunological activity which is not associated with biological activity. If so, the validity of these RIA procedures for specifically measuring low levels of biologically active LH in plasma may be in question.


Evolution of the menstrual pattern of gonadotrophin and sex steroid concentrations in serum. Consecutive daily serum samples were obtained over 25-30 days from 2 pre-pubertal girls (Stage I), 2 girls with breast development alone (Stage II); one girl with both breast development and pubic hair (Stage III), and 2 girls who were six months and three years post-menarche, respectively (Stage IV). All serum samples were assayed for LH, FSH, progesterone and 17-hydroxyprogesterone. Sera from 6 girls were assayed for testosterone, and sera from 3 were assayed for oestradiol. The patterns of gonadotrophins and sex steroid concentrations in both Stage I and Stage II girls were characterized by day to day stability. LH and FSH concentration was increased in Stage II subjects, while steroid concentration were similar to those in Stage I. The Stage III subject showed marked, apparently random, fluctuations in the concentrations of LH, FSH, oestradiol and 17-hydroxyrogesterone. In Stage IV, as early as six months post-menarche, there was a definte peak in the serum concentration of gonadotrophins, 17-hydroxyprogesterone and oestradiol. However, luteal phase length and maximal progesterone levels of these post-menarchial girls were less than those observed for normal adult females. These data are consistent with evolution of the adult menstrual pattern of hormone secretion through a series of developmental stages.


Effects of chronic renal disease on thyroid hormone metabolism. Serum concentrations of total and free thyroxine and triiodothyronine together with urine losses of unconjugated thyroid hormones have been measured in normal subjects and in patients with renal disease. Serum total hormone values in the hypothyroid range were common the renal group and correlated inversely with the degree of renal impairment but not with renal loss of hormone which in the case of thyroxine exceeded the average normal daily loss ten-fold. The euthyroid state of patients with renal disease was best reflected by serum free thyroxine concentration which in every case was within the normal range. Poor correlation was apparent between the respective urine concentrations of albumin and thyroxine, and the reasons for this are discussed.


Protein concentration of the rat thyroid colloid during thyroxine treatment. Sprague-Dawley rats were given daily doses of 20 mug thyroxine for varying periods between 1 and 21 days. Samples of colloid were obtained by micropuncture in vivo of follicles in the thyroid isthmus. The protein content of the samples was determined by gel electrophoresis and the volume by a technique based on radioactivity measurement. The relative volume of the follicle lumina was determined by light microscopy. Treatment with thyroxine resulted in an increase in the protein concentration of the colloid. This increase was statistically significant after 2 days and the concentration remained elevated throughout the experimental period. The size of the follicle lumina also increased, most rapidly during the first week. It is suggested that the increase in protein concentration of the colloid during thyroxine treatment is due to inhibition of endocytosis of colloid in combination with the discharge into the follicle lumen of highly concentrated protein.


Comparison of thyroid antigens by the experimental production of precipitating antibodies to human thyroid fractions and the identification of an antibody which competes with long-acting thyroid stimulator (LATS) for thyroid binding. Antibodies were raised to various sub-cellular fractions of human thyroids, (of Graves' disease, Hashimoto's thyroiditis, and non-toxic goitre). With one exception it was found that antibodies to the Graves' thyroid fractions crooss-reacted with both the non-toxic goitre and Hashimoto's thyroiditis fractions. This exception was in the antiserum to the Graves' 105 000 x g pellet (Gr4) which contained an anr the Hashimoto's (/) thyroid preparations. The antibody-antigen between A-1 and Gr4 could be blocked by the addition of LATS (or TSH) to the antigen, thus suggesting that A- 1 might be a LATS-like immunoglobulin. These results suggest that the TSH receptor can be produced in vivo. Production of such an antibody to the TSH receptor would permit the development for the first time fo a good animal model of Graves' disease.


Decreased bone sensitivity of thyroidectomized rats to the calcaemic effect of 1,25-dihydroxycholecalciferol. The calcaemic response of thyroidectomized parathyroid transplanted rats to a single dose of biosynthetic 1,25-dihydroxycholecalciferol (50 ng) injected into a jugular vein, was evaluated. The animals were fed a vitamin D-free, low calcium diet. Compared to sham-operated and to thyroid-intact parathyroid transplanted rats thyroidectomized animals had a significantly reduced calcaemic response to 1,25-dihydroxycholecalciferol. Daily supplementation with d,1-thyroxine (100 mug/rat) during the experimental period restored a normal response. The increase in serum calcium concentration after 1,25-dihydroxycholecalciferol injection was a similar in thyroidectomized bilaterally nephrectomized animals, and in thyroidectomized kidney-intact rats. The results suggest that in thyroxine depleted rats, the sensitivity of bone to the calcaemic effect of 1,25-dihydroxycholecalciferol is decreased.


Effect of hydrocortisone on ammonia intoxication in the adrenalectomized rat. Adrenalectomy induces a hypersensitivity in the rat to ammonia intoxication. Daily injection of hydrocortisone hydrochloride to adrenalectomized rats restored normal sensitivity to ammonia intoxication, with concomitant restoration of liver urea-synthesizing capacity to the normal value. When injected with a large dose of ammonium acetate, hydrocortisone-treated adrenalectomized rats were able to reduce the plasma ammonia concentration much more rapidly than the adrenalectomized control rats. However, neither the increase in liver urea synthesis nor the more rapid decrease in the plasma ammonia concentration were sufficient to explain the protective aciton of hydrocortisone against ammonia intoxication.


Endocrine and reproductive repercussions of immunization against progesterone and oestradiol in female rats. Mature female rats were immunized with BSA-conjugates of oestradiol-17beta-6-carboxymethyloxime or progesterone-11-hymisuccinate. Sera tested two months later at 1/2000 dilution bound 63.3% +/- 3.1 SEM and 21.2% +/- 2.3 of the homologous tritiated hormone (10 pg),--oestradiol-17beta(Oe2) and progesterone (P), respectively. Rats immunized against Oe2 had a significantly longer oestrous cycle (8.2 days vs. 4.5 days in BSA-immunized rats), with a prolonged leukocytic phase. The cycle of rats immunized against P was also prolonged (10.5 days), but in this group the cornified smear phase was abnormally extended. The luteinizing hormone (LH) normally observed on the afternoon of pro-oestrus failed to occur in the rats immunized against Oe2 and in 70% of rats immunized against P. The latter animals, however, showed sporadic LH discharges during periods of persistent cornification. Immunization against P resulted in elevated total (free plus bound) plasma P levels; immunization against Oe2 prevented the pro-oestrous rise in plasma P. Mating of rats immunized against Oe2 resulated in normal pregnanices, while none of the rats immunized against P delivered.


Exogenous hormone uptake and retention in the rat uterus at the time of ovo-implantation. The uterine uptake of tritiated hormones, oestradiol and progesterone, was studied at the time of ovum implantation in the rat. Macromolecular dyes such as trypan blue were used to distinguish implanted sites from the unimplanted ones. A differential uptake was found between the implanted and unimplanted sites in normal 6th day pregnant females. Oestradiol was retained more at the unimplanted sites, whereas its half-life was approximately the same at the two levels. On the other hand progesterone was found in greater amounts in the implanted sites due to a difference in half-life for each site (30 min for unimplanted sites, 40 min for implanted ones during the first 30 min following injection). When endogenous oestradiol retention was suppressed by ovariectomy, higher uptake of [3H] oestradiol in unimplanted sites was not found. These results suggest a heterogeneity in the binding sites of oestradiol in the pregnant uterus.


Peripheral and central androgenic stimulation of sexual behaviour of castrated male rats. The effects of androgens on the maintenance and restoration of sexual behaviour (mounts, intromissions and ejaculations) of castrated male rats were studied. In the maintenance study the rats were treated during 5 weeks, starting one day following castration. Testosterone propionate maintained sexual behaviour at an almost normal level. The androgenoestrogen intermediate 19-hydroxytestosterone propionate was unable to prevent the decline in the number of ejaculations over the weeks although this hormone maintained the post-ejaculatory refractory period in those rats that ejaculated and also maintained normal sexual latencies. In the restoration study administration of testosterone propionate during 7 weeks to long-term castrated rats restored sexual behaviour to normal. 19-Hydroxytestosterone propionate treated rats displayed mounts but no other signs of sexual behaviour. The 5alpha-reduced androgen dihydrotestosterone propionate did not restore sexual behaviour. Testosterone propionate and dihydrotestosterone propionate stimulated peripheral target organs; 19-hydroxytestosterone propionate was ineffective in this respect. It has been suggested that testosterone might stimulate sexual behaviour in rats in two ways, i.e., via its aromatization to oestradiol in the brain, andy by stimulating growth of peripheral tissues via its 5alpha-reduction to dihydrotestosterone. In support for this view we have found that the combination of 19-hydroxytestosterone propionate and dihydrotestosterone propionate was effective in restoring the full pattern of sexual behaviour in castrated male rats.


Comparison of effects of C19 (androstene or androstane) steroids on serum gonadotrophin concentrations and on accessory reproductive organ weights in gonadectomized, adult male rats. The effects of subcutaneous administration of graded doses of C19 (androstene or androstane) steroids on serum levels of LH and FSH and on weights of accessory reproductive organs in gonadectomized, adult male rats were investigated. The C19 steroids were administered during 7 days in doses of 100, 50, 25, 12.5 or 6.25 mug per 100 g body weight per day. With the amounts of steroids used, 5alpha-dihydrotestosterone and 5alpha-androstane-3alpha, 17beta-diol had a high potency in preventing the rise of serum gonadotrophin concentrations and in curbing the decrease weights of ventral prostates and seminal vesicles following orchidectomy. 5alpha-Androstane-3beta, 17beta-diol showed no such effects. Positive feedback effects on serum gonadotrophins in castrates were observed following injection of certain doses of some steroids. Effects of steroids on accessory reprosuctive organs did not always correlate with those on gonadotrophic function of the hypothalamic-pituitary unit.


Gonadotrophin suppression by steroids in normal, adult male rats. Effect of subcutaneous administration of various doses of different steroids on serum levels of LH and FSH in normal, adult male rats were investigated. Each steroid was injected daily during 7 days in doses of 50, 25, 12.5 or 6.25 mug per 100 g body weight. Ring A 5alpha-reduced testosterone metabolites exerted high activity in the suppressing serum LH and FSH levels. 5alpha-Androstane-3beta, 17 beta-diol had in the doses tested, however, no such effects on serum gonadotrophins, Serum LH concentrations in normal rats appeared more sensitive to steroid treatment than serum FSH concentrations.


Human testosterone-oestradiol binding globulin in health and disease. Levels of testosterone-oestradiol binding globulin (TeBG) were measured by a precipitation technique in terms of dihydrotestosterone-5alpha (DHT) binding capacity in children, adult males and females, pregnant and hirsute women and women with various trophoblastic disorders. It was found that TeBG levels in children of either sex (1.92 +/- 0.16 mug DHT bound/100 ml serum) approached the normal female range (2.31 +/- 0.11) and were distinctly higher than those of the adult male (1.04 +/- 0.09). In both pregnancy and trophoblastic disease (hydatidiform mole and choriocarcinoma but not metastatic choriocarcinoma) TeBG levels were elevated (17.5 +/- 0.70 and 14.9 +/- 1.49, respectively). In hirsutism TeBG was depressed (1.17 +/- 0.09) and comparable with the levels in normal male subjects. A number of other parameters, HCG, oestradiol-17 beta, testosterone and progesterone were measured and found to be similar to those previously reported in the literature. It appears that TeBG titre might provide an additional index in following the prognosis of trophoblastic disorders, besides HCG measurement.


Esterase XXV. On the induction of Es-9 esterase of mouse kidney by testosterone. The Es-9 esterase is expressed in the cortical zone of the NMRI mouse kidney only in the presence of testosterone. In disc electrophoresis, three esterase bands, absent in the control, emerge under the influence of exogenous testosterone, accompanied by the appearance of active sites, as shown by marking with [3H] diisopropyl fluorophosphate ([3H]DFP). It is suggested that the testosterone dependent appearance of Es-9 activity is due to true enzyme induction which requires the presence of an intact testosterone receptor.


Lymphocytic thyroiditis. I. correlation between morphological, immunological and clinical findings. Biopsies from the thyroid glands in 32 selected patients with goitre and lymphocytic thyroiditis have been investigated with quantitation of the morphological changes. This permitted a comparison with immunological and clinical findings. The three main elements in the destruction of glandular tissue--lymphocytes, plasma cells and fibrosis varied relatively independently of each other as an expression of the great variation in the appearance of the tissue lesion. Thyroglobulin antibodies showed a correlation to the number of plasma cells, whereas the microsomal thyroid antibodies showed a correlation to the number of lymphocytes. The morphologic changes were independent of the duration of the disease. The degree of fibrosis increased parallel with age and there was a tendency towards glandular fibrosis in myxoedematous patients.


Morphological aspects of type II alveolar pneumocytes following treatment with puromycin in vivo. Ultrastructural modifications of type II pneumocytes (PNM-II) in mice were analysed 125 and 155 minutes after puromycin treatment (12 mg/100 gm at 0, 30, 60 and 90 minutes). A quantitative evaluation of the cell compartments was carried out and the inhibition of protein synthesis in PNM-II was monitored by light microscopic radioautography, following 3H-leucine injection. In electron micrographs, following a 125-minute puromycin treatment, the number and size of lamellar bodies, the precursors of lung surfactant material appeared markedly reduced. The multivesicular bodies (MVB), which are normally very frequent in PNM-II, had almost completely disappeared, as had composite bodies. Golgi saccules were dilated, while the area occupied by Golgi vesicles was enlarged. Observations following the 155-minute puromycin treatment showed a strong enhancement of these modifications. Smooth and coated vesicles of the Golgi area, as well as peroxisomes, did not appear modified by puromycin. Elongated zones of autophagy were more prevalent after 125-minute treatment than after the 155-minute one. Small bodies were frequently observed in the cytoplasm, near the Golgi zone. They were bounded by a smooth membrane and contained tiny vesicles and/or electron-dense lamellae similar to those present within the lamellar bodies. Parallel membranes formed folds, some of them in continuity with lamellar bodies, thus encircling portions of cytoplasm. These structures, which were few in number in controls, were very frequently observed in treated cells, mainly after the 125-minute treatment. These extensive alterations of PNM-II morphology appeared to be related to a disturbed production of pulmonary surfactant.


Problems in diagnosis and treatment of lupus psychosis. Report of a patient with systemic lupus erythematosus, Hashimoto's thyroiditis, and Sjögren's syndrome. A 34-year-old woman with an organic psychosis was presumed to be suffering from corticosteroid psychosis because of prednisone treatment for urticaria. Lupus was found to be the cause of both urticaria and psychosis. The lupus psychosis was reversed when sufficiently high doses of steroids were given, in combination with immunosuppressant agents.


Cholecystectomy without drainage, nasogastric suction, and intravenous fluids. A comparative study was made between 60 patients in whom drainage of subhepatic space was performed after uncomplicated cholecystectomy and 60 patients in whom no drainage was performed. In addition, 30 patients were treated without drainage, nasogastric suction, or intravenous fluids. After operation the patients were evaluated as to postoperative pyrexia, wound infection, lung atelectasis, thrombophlebitis, and postoperative stay in hospital. Fever and wound infection occurred in fewer patients without drainage than those with drainage, but omission of nasogastric suction and intravenous fluids did not influence the incidence of wound infection. Postoperative stay in hospital was shorter in the patients without drainage and shortest in those treated without drainage, nasogastric suction, and intravenous fluids. Nasogastric suction and intravenous fluids are not needed postoperatively, as the degree of the paralytic ileus is very slight and they may be harmful, causing lung atelectasis and thrombophlebitis. Uncomplicated cholecystectomy may be performed safely without drainage, postoperative nasogastric suction, and intravenous fluids.


Radioimmunoassay of pulmonary surface-active material in the tracheal fluid of the fetal lamb. We measured pulmonary surfactant antigen by radioimmunoassay and phospholipid by lipid phosphorus assay in fluid collected during 12-hour periods from the trachea of lambs in utero between 102 and 147 days of gestation. Both phospholipid and antigen were detectable at 114 days and were present at low concentrations until 137 days. The concentrations then increased rapidly and reached 5- to 10-fold higher concentrations before parturition. The ratio of lipid phosphorus to antigen increased approximately 5-fold as the lungs passed from canalicular to alveolar architecture and approximated the adult ratio only during the alveolar stage of development.


Intensive physical therapy after meniscectomy. Fifty six meniscectomy patients were divided into 2 groups. One group (27 patients) was given the standard postoperative physiotherapy and the remainder (29 patients) received intensive physiotherapy. Clinical examination of the knee joint was performed preoperatively and 1, 2 and 4 weeks postoperatively. The patients' age was 36.26 +/- 12.34 and 34.00 +/- 9.21 years in the two groups respectively. The medial meniscus was removed from 47 patients, the lateral meniscus from 8 patients and bilateral meniscectomy was performed on one patient; no tear was seen in the excised meniscus in 8 cases. The clinical findings for the patient groups did not differ significantly either before or after the operation. The flexion strength of the knee of patients given intensive physiotherapy increased less in these 4 weeks than the flexion strength of the routine therapy group. The range of knee movement of the patients given intensive therapy was still below the preoperative value 4 weeks after the operation. Knee punctures were made more frequently on patients given intensive physiotherapy. Their walking capacity 2 weeks postoperatively was inferior to that of patients given routine physiotherapy, but this difference had disappeared at the 4-week examination. The isometric quadriceps strength and isotonic strength correlated well. The thigh girth gave no evidence of quadriceps atrophy. It can be concluded that intensified physiotherapy in meniscectomy patients does not shorten the rehabilitation period.


Mechanisms underlying the suppression of erythropoiesis by hyperoxia. The possible mechanisms underlying the suppression of erythropoiesis in hyperoxic animals were studied. Male Long-Evans rats were injected with cobaltous chloride hexahydrate, a known erythropoietic stimulant. One group was exposed to a hyperoxic environment for ten hours. Both serum levels of erythropoietin (Ep) and renal levels of erythrogenin were significantly lower (p less than 0.005) in the hyperoxic animals compared to those left at room air. In addition, inhibitors to Ep or erythrogenin could not be detected in either the serum or renal tissue of the hyperoxic rats. These results indicate that the primary factor responsible for the erythropoietic suppression observed in a hyperoxic environment is a decreased production of erythrogenin which results in turn, in a lowered level of circulating Ep.


Sudden infant death due to congenital adrenal hypoplasia. Adrenocortical hypoplasia was found to be the cause of sudden death in a 9-month-old infant. Most sudden infant deaths in the first year of life are related to the sudden infant death syndrome, in which no specific pathologic changes are found at autopsy. Although specific causes for sudden death in infancy are well documented, adrenocortical hypoplasia is not a well-recognized cause of sudden infant death.


Granulomatous pulmonary angiitis in sarcoidosis. The occurrence and morphologic aspects of granulomatous pulmonary angiitis were evaluated in open lung biopsy specimens from 128 patients with sarcoidosis. All of the specimens showed parenchymal granulomas characteristic of sarcoidosis, and in 88(69%), granulomatous angiitis was seen. In the speclimens that exhibited granulomatous angiitis, venous involvement was mos common, seen in 92% of the cases. In 61% of these biopsy specimens, only venous involvement was seen; in 31%, both venous and arterial involvement was present. Only 8% of the positive specimens showed arterial lesions exclusively. The extent of angiitis was quantitated. Focal segmental elastic tissue destruction, partial or complete, was a common finding. No instances of aneurysm formation, endothelial erosion, or thrombosis were observed. Occlusive narrowing of small vessels was frequent. Bronchial blood vessels were not involved.


Changes with age in muscular pulmonary arteries. The mean wall thickness, in relation to the external diameter, of 100 muscular arteries distended by barium gelatin at 100cm H2O pressure was calculated in "normal" lungs from patients who ranged in age from 3 to 79 years. For normal vessels less than 2 mm in diameter the mean was 2.4% of the external diameter. The mean for vessels in the five persons under 40 years was 1.8% but it was 2.8% for the five older individuals. Although this difference may reflect some increased muscularity with age, some of the increment may be related to a reduced distensibility of vessels caused by the accumulation of interstitial fluid, as manifested by increased weight in the older lungs. Intimal fibrosis was found to increase with age but occurred in less than 50% of the vessels measured.


Muscular pulmonary arteries in chronic obstructive lung disease. The small muscular pulmonary arteries are thought to be normal in obstructive pulmonary disease despite prolonged hypoxic stimulation to medial thickening. Because measurements on nondistended vessels have considerable variability, we reinvestigated the problem by studying the percentage of wall thickness of distended arteries in lungs taken post mortem from 5 asymptomatic emphysematous patients and 11 symptomatic patients with obstructive pulmonary disease. Vessels in the former patients had normal medial thicknesses. In contrast, we found an elevated mean percentage of wall thickness for vessels between 0.3 and 2.0 mm in diameter of 4.46% +/-1.44% (mean +/-SD) for patients with obstructive airways disease. Obstructive pulmonary disease, therefore, produced medial hypertrophy in small muscular arteries similar to that seen in other conditions associated with chronic hypoxia.


Reactive eosinophilic pleuritis: a lesion to be distinguished from pulmonary eosinophilic granuloma. Pleural nodules or sheets of histiocytes, admixed with eosinophils, giant cells, and other inflammatory cells are observed frequently in patients with spontaneous pneumothorax. This reaction, designated reactive eosinophillic pleuritis (REP), can closely resemble eosinophilic granuloma. Reactive eosinophilic pleuritis was found in pleural tissue of 22 of 57 patients with spontaneous pneumothorax in whom tissue was available for study. None of these patients had clinical or radiographic evidence of interstitial lung disease. Follow-up of 20 patients with REP ranged from six months to five years. None developed evidence of eosinophilic granuloma. Electron microscopy of one case did not show the Langerhans granules characteristic of the histiocytoses, including eosinophilic granuloma. Reactive eosinophilic pleuritit appears to be a nonspecific reaction to pleural injury, and is not a prodromal feature of pulmonary eosinophilic granuloma.


[Antitumor effect of Corynebacterium parvum]. The protective effect produced by pre-treatment with C. parvum is studied in two syngeneic tumours: mammary carcinoma in C3H mice and lymphosarcoma in XVII mice. The best anti-tumour effect is obtained when both C. parvum and tumour cells are injected by the same route, which, however varies for the two tumours. The study of the recovery of C. parvum protective effect after its suppression by a sub-letal dose of x-irradiation shows that, in the C3H mice, it is parallel to the restoration of the antibody response. On the contrary, in XVII mice, the recovery of the protection is obtained in mice still immunologically suppressed.


Gestational development of brain.

Gestational development of brain. Eighty normal human brains varying from 22 weeks' gestation to 1 month postnatal life were graded according to convolutional development and compared with the microscopical development of kidneys and the gestational age as given by the mother. Excellent correlation was obtained between the gross appearance of the brain and the microscopical appearance of the kidney. The history of the mother mostly, but not always agreed with the anatomical appearance, which was considered a reliable guide to the gestational age of the infant.


Epithelial cysts of the neuraxis: presentation of three cases and a review of the origins and classification. Benign, epithelial-lined cysts of the neuraxis may be asymptomatic or may behave as space-occupying lesions. Presentation of three such cysts, including an intramedullary epidermoid cyst, a lumbosacral subcutaneous enteric cyst that has an epithelium resembling ependyma, and a hypophyseal duct cyst, illustrates typical problems encountered. Review of their histogenesis and possible embryogenesis indicates that intracranial ependymal cysts and cysts of the sella turcica are not normally associated with other anomalies and frequently occur after middle age, whereas dermal and enteric cysts occur within the first two decades and are commonly associated with vertebral anomalies and other dysraphic syndromes. Enteric cysts may have a variable histologic appearance, including one resembling ependymal cysts. Recognition of the latter is important because of a possible associated dysraphic syndrome and the presence of an extraneuraxial component with the former but not the latter.


Aspirin- and bile- induced acute erosive gastritis: its prevention by metiamide therapy. Aspirin or bile administered by esophageal intubation to rats produced acute gastric erosions. These injuries could have been prevented by the prior administration by esophageal intubation of metiamide, a histamine H2 receptor antagonist that is known to inhibit gastric acid secretion.


Gallbladder bile composition in different ethnic groups. A total of 194 gallbladder biles from various ethnic groups were analyzed for their composition. The solubility of cholesterol in bile was determined mainly by its relative amounts of phospholipid and bile salt present. Bile from patients with gallstones was usually supersaturated with cholesterol above the boundary of the metastable state. Biles from normal white subjects of Finland, New Zealand, and the United States were already in the metastable state of supersaturation with cholesterol. The Masai of East Africa and black subjects of the Unites States had a bile level below the limit of maximum cholesterol solubility. This study indicates that the difference in the prevalence of cholesterol cholelithiasis in various ethnic groups was related to the difference in their bile compontified factors.


Large spindle cell variant of peripheral bronchial carcinoid tumor. I report a case of peripheral bronchial carcinoid tumor composed of bundles of large spindle cells, very much resembling cells of smooth muscle or neural tumors. Despite the unusual appearance, argyrophil staining and electron microscopic examination demonstrated small secretory granules of the type found in other peripheral carcinoid tumors. The histologic heterogeneity of peripheral bronchial carcinoid tumors is emphasized.


Striated muscle ultrastructure in intermittent claudication. Twenty-four biopsy specimens from the lower leg muscles of 21 patients with intermittent claudication were studied by electron microscopy. Sixteen of the specimens contained hypertrophic, atrophic, autolytic, or phagocytic fibers, or other forms of macroscopic fiber degeneration. Of the pathological changes in the cell organelles, the most common was simple myofibrillar degeneration, followed by slightly pathological mitochondria and excessive accumulations of glycogen and lipofuscin. Different types of basement membrane alterations and central nuclei were present in 16 of the biopsy specimens. Most of the pathological changes were the same as those previously reported by others to occur in specific diseases of muscle. There was some positive correlation of the degree of pathological changes to the estimated clinical severity of claudication.


Scanning electron microscopical study of human mitral valve chordae tendineae. Scanning electron microscopy was used to examine the surface and internal structure of adult human mitral valve chordae tendineae. The endocardial cell surface of the tissue was found to be relatively smooth and even. Just beneath the endocardial surface, widely spaced collagen fibers were found. These were observed to be aligned at an angle to the chordal long axis and to wrap themselves around the central collagen core. The chordal core consisted of relatively straight collagen fibers that were arranged with their axis parallel to the long axis of the chordae. At the microstructural level, these collagen fibers were observed to consist of a network of collagen fibrils. This architectural arrangement is an advantageous feature for a tissue that is under constant dynamic stress. The scanning observations were confirmed by transmission electron microscopy.


Gaucher disease in mice induced by conduritol-B-epoxide: morphologic features. Morphologic changes were studied in mice in which Gaucher disease was induced by the administration of conduritol-B-epoxide. Sixteen newborn Swiss mice received a daily subcutaneous dosage of 100 mg/kg of body weight of conduritol-B-epoxide from one day after birth to 28 days. Light microscopically, no Gaucher cells were noted in the viscera, bone marrow, and the CNS during this study. Ultrastructurally, the spleen and liver showed irregular granules and fibrils in histiocytes and Kupffer cells during the second to fourth week. In the CNS, the neurons showed fibrils and tubular structures within the cisternae of the endoplasmic reticulum at three to four weeks. During the fourth week, they frequently contained well-organized inclusion bodies that were membrane-bound and contained tubular structures that varied from 250 to 500 A in diameter. These inclusion bodies were similar to Gaucher bodies seen in human cases.


Congenital hepatic fibrosis: asymptomatic adults without renal anomaly. Two cases with the pathologic changes of congenital hepatic fibrosis are described in asymptomatic adults without renal anomaly, Foci of necrosis adjacent to abnormal portal areas suggest that the lesion may not be congenital. It is also suggested that this variant of the disorder may be more common than generally recognized.


Basophilic cells in allergic nasal secretions. Evidences on the important role of tissue mast cells in inducing allergy have accumulated. There cells are known to be present in nasal secretion but have not been well studied. In the present study basophilic cells containing granules which stained metachromatically appeared in the nasal secretion in various kinds of inhalant allergy. An increase in their number was observed after nasal provocation and during the pollinosis season and showed a decrease after a course of immunotherapy or during the off-season of pollinosis. They were well correlated in degree with nasal symptoms, nasal eosinophilia, and nasal provocative reactions. These results suggest that the appearance of the basophilic cell in nasal secretion is related to their specifity in nasal allergy. The possibility of onset of nasal allergy due to the release of chemical mediators from basophilic cells in nasal secretion was discussed.


[Critical reflections to the problem of timing in the synchronization therapy of human malignant tumors. Mitotic-index determination, cytophotometric and radioautographic studies (author's transl)]. Formerly (1969) we have been able to demonstrate that during a lengthy inhibition of the DNA synthesis with 5-fluoro-uracil (FU), cells assemble just before, at the outset of, and within the S-phase. By taking off the inhibition, these cells start off together for the rest of the life cycle and pass the S, G2 and M phase like a wave. By the experimental condition given, the time required for passing the S phase was rather constant for all tissues. It generally took about 8 h. The sensitivity of cells to radiation depends on the current phase of their life cycle. Normally they are highly radiosensitive during the transition from G1 to S phase and within the G2 phase. Therefore we tried to improve the effectiveness of radiotherapy by radiating the synchronized cell population in the G2 phase. In clinical treatment we give an infusion with 1 g FU in 1000 ml 5.4% Glucose for 12 h. 8--9 h after the end of the infusion radiation will be applied (Betatron, individual doses: 500 rad). This treatment will be repeated until a total dose of 5000--6000 rad. Until now nearly 300 cases of patients treated in this way have been published. The 5 year-results show only in about 60% of the patients a fast reduction of the tumor. The long term results are unsatisfactory. Beside many other points the most important reason for these clinical results might be the individual length of the S phase of the tumors which prevents that radiation can be given exactly in G2 phase in each case. With mitotic-index determination, with cytophotometric investigations and the double labelling technique (3H- and 14C-Thymidine) we therefore tried to find an answer to the following questions: 1. How long is the DNA synthesis time in the individual case of human ENT tumors? 2. Does the application of FU influence the length of the S phase? 3. Will the synchronization-degree become higher by using other methods of cell cycle inhibition? With the above mentioned experimental methods we found that the length of the S phase in human tumor spreads from about 8--16 h in the individual case. The application of FU has no influence on DNA synthesis time. By using FU the degree of synchronization is about 2.5 in according to former experimental work and that of other authors. These results will be discussed in detail as well as the conclusion we draw from our experiments: to give radiation not in G2 but in G1/S of the cell cycle. Long-term observation of the patients and further animal experiments shall demonstrate whether this technique of synchronization therapy will improve the clinical results.


[Ultrastructural morphometric analysis of the spiral ganglion in guinea pigs (author's transl)]. This is the first morphometric analysis of the cochlear spiral ganglion. Therefore the ganglion was subdivided in precisely defined compartments. We found that the normal, untreated spiral ganglion in guinea pigs contains 58% ganglion cells of the granular type, 26% satellite cells and Schwann cells, 8.6% extracellular space, 6.4% myelinated nerve fibers and 1% ganglion cells of the filamentous type. The granular ganglion cell consists in 83% out of cytoplasm and in 17% out of nuclei. The cytoplasm is containing 13% ribosomes, 12% mitochondria, 10% RER, 2.1% Golgi apparatus, 1.3% lysosomes. Based on these quantitative datas we expect to detect alterations of the normal structure earlier and more precisely under pathophysiological conditions as before.


[Light- and electronmicroscopic investigations on ultrastructure and enzyme distribution in the external sulcus of the cochlea (author's transl)]. The ultrastructure of the external sulcus of the cochlea of young healthy guinea pigs and hamsters was investigated as well as the distribution of lactate dehydrogenase (LDH) in this region. The demonstration of LDH activity was carried out as follows. The unfixed and undecalcified cochlea was cut in 80 micron thick frozen sections, which were incubated immediately in the reaction mixture for LDH and subsequently fixed with paraformaldehyde. For electron microscopy the usual procedure was applied. The epithelial cells of the external sulcus show deep reaching extensions into the vessel-rich connective tissue of the basal part of the spiral ligament. These roots are bound together into root bundles surrounded by the basement membrane and fibrills. The root cells differ in their ultrastructure. The light cells, which have been described previously, contain a number of stretched mitochondria and only few other cell organels. Beside these, dark cells can be found (Fig. 2). Their cytoplasm shows high contrast and contains many mitochondria, ribosomes, rough endoplasmatic reticulum and Golgi apparatus. In the dark cells big vasuoles can be seen. All these structures indicate a high rate of synthesis in the dark cells. The root cells are linked together by membranous foldings, which diverge in some parts, forming intercellular spaces in which small cell protrusions are found. Other intercellular gaps can also be detected building a system of small channels. It is possible that these structures serve for extracellular transport. The LDH activity, which is demonstrated by formazan deposits can be exclusively found in the root cells. This could be demonstrated in light microscopic semithin sections (Fig. 3) and with electron microscopy (Fig 4). The possible role of LDH in the root cells is discussed.


[The neuro-otological findings of the multiple sclerosis (author's transl)]. The present paper is based on an exact analysis of the neurootological findings in 30 cases of multiple sclerosis (MS). Ms-diagnosis was verified using Schumacher's criteria and cerebro-spinal fluid findings. Central vestibular disorders were found in most of the cases. From our observation it may be assumed that the brainstem is an early site of involvement causing imbalance which can only be verified by an accurate neuro-otological evaluation. The most important pathological findings are the following: central spontaneous nystagmus, gaze-deviation nystagmus, positional nystagmus, disinhibition of induced (caloric and galvanic) nystagmus, delay of the reversal phenomenon of galvanic nystagmus,dysrhythmia as well as distorted optokinetic nystagmus. An extensive neuro-otological investigation is of clinical importance with respect to detecting cases of MS at an early stage of this disease.


[Experience with the inlaytechnic of tympanoplasties type I. (author's transl)]. After more than ten years of experience with the inlaytechnic of tympanoplasties type I at the ENT-department of the University of Freiburg, and evaluating tha datas of 451 consecutive ears operated between 1970 and 1974, this technic proved to be good. The quote of recidive-surgery was about 19.9%. Hearing improved markedly in 80.4% of the patients. Complications like the appearence of Cholesteatoma, lateral migration of the transplant or flatening of the anterior tympanomeatal angle have not been noticed.


[Fast isoamylases in saliva from mucoviscidosis patients (author's transl)]. Human parotid saliva is characterized by a basic pattern of 6 isoamylases; during ageing, it contains additional isoamylases which migrate faster towards the anode. An increasing number of 'fast isoamylases' are also found in saliva from mucoviscidosis patients. Their possible symptomatological significance for the pathogenesis of mucoviscidosis which is as yet not solved is being discussed.


[Drug influence of benzopyrones on experimental ascites (author's transl)]. The effect of the treatment with benzopyrones has been examined in dogs with experimental ascites (provoked by constriction of the vena cava inf.). Five weeks after cava-constriction nine of the twelve treated and only two of the untreated animals were free of ascites.


Structure-anorectic activity relationships in substituted phenethylamines. A series of phenylisopropylamine derivatives are compared with the correspondent beta-methoxy- and beta-hydroxy-phenethylamine compounds. Unlike amphetamine, the beta-methoxy phenethylamine has no anorectic activity. This property appears only with the introduction of a CF3 group on the benzene nucleus. The racemic N-alkyl derivatives are more active than the racemic or even the levorotatory N-benzyl compound. The beta-hydroxy-phenethylamines are devoid of anorectic activity.


Distribution and fate of alpha-naphthl-isothiocyanate (ANIT) in the organs and body fluids of the rat. alpha-Naphthyl-isothiocyanate (ANIT) is a well known toxic substance which induces characteristic hepatic lesions. Its distribution in some organs and body fluids was investigated by using spectrophotometry, gas-chromatography and thin-layer chromatography. The results indicate that ANIT concentrates in the liver, kidneys and blood but not in the brain, urine and bile. Another five ANIT-like substances have also been examined, but no trace of them has been found in these organs and body fluids. The authors suppose that ANIT is metabolized to an unknown metabolite which is responsible for the toxic action of ANIT. None of the ANIT-like substances examined by us can be indentified with this metabolite.


[Teratogenic effect of N-phthaloyl-L-aspartic acid on the mouse (author's transl)]. The optical isomers of N-phthaloyl-aspartic acid, structurally related to thalidomide, were administered i.p. to pregnant mice on day 9 of gestation; the injected solutions contained Tween 20 as solubilizer. N-Phthaloyl-L-aspartic acid exerts an embryotoxic and teratogenic effect as is evident by the high incidence of resorption and malformations. On the other hand the D-isomer is devoid of any embryotoxic and teratogenic activity under the same conditions of experiment.


[Subchronic toxicologic studies using cyclamate-Na in dogs]. 2 male and 2 female beagle dogs were fed cyclamate-Na in daily doses of 0 (control), 150, 500, 1500 mg/kg of body weight with the diet. Liquid feces occurred only after feeding 1500 mg/kg/day during the first few days of the experiment. Haematological, clotting and clinical chemistry parameters were unchanged in the groups up to the level of 1500 mg/kg/day. No effects were noted in carbohydrate and fat metabolism, nor in ECG or blood pressure. Gross pathology and histopathology did not reveal any change in any dose group. Daily fed doses of cyclamate-Na up to 1500 mg/kg body weight were well tolerated for three month in the dog.


E1On the effect of 6-methyluracil on mice damaged by 2,4,6-triethylene-imino-1,3,5-triazine or by X-irradiation (author's transl). Survival time of mice after i.v. injections of 2,4.6-triethylene-imino-1,3,5-trazine (TEM) or total body-X-irradiation (TBI) was increased by 6-methyluraclil (6-MU) when given in food (200 ppm). Under the same conditions, 6-MU decreased the involution of spleen and thymus (as measured by DNA-content and DNase II activity) under the infuence of TEM and enhanced the regeneration of the spleen after TBI. Elevation of DNase I- and protein content of the kidneys and a (short-dated) increase of incorporation of 14C-phenylalamine into microsomes of liver of 14C-orotic acid into RNA of liver and kidney suggest that the influence of 6-MU is mediated at least partly by a specfically anabolic effect.